User login
Saxophone Penis: A Forgotten Manifestation of Hidradenitis Suppurativa
To the Editor:
Hidradenitis suppurativa (HS) is a multifactorial chronic inflammatory skin disease affecting 1% to 4% of Europeans. It is characterized by recurrent inflamed nodules, abscesses, and sinus tracts in intertriginous regions.1 The genital area is affected in 11% of cases2 and usually is connected to severe forms of HS in both men and women.3 The prevalence of HS-associated genital lymphedema remains unknown.
Saxophone penis is a specific penile malformation characterized by a saxophone shape due to inflammation of the major penile lymphatic vessels that cause fibrosis of the surrounding connective tissue. Poor blood flow further causes contracture and distortion of the penile axis.4 Saxophone penis also has been associated with primary lymphedema, lymphogranuloma venereum, filariasis,5 and administration of paraffin injections.6 We describe 3 men with HS who presented with saxophone penis.
A 33-year-old man with Hurley stage III HS presented with a medical history of groin lesions and progressive penoscrotal edema of 13 years’ duration. He had a body mass index (BMI) of 37, no family history of HS or comorbidities, and a 15-year history of smoking 20 cigarettes per day. After repeated surgical drainage of the HS lesions as well as antibiotic treatment with clindamycin 600 mg/d and rifampicin 600 mg/d, the patient was kept on a maintenance therapy with adalimumab 40 mg/wk. Due to lack of response, treatment was discontinued at week 16. Clindamycin and rifampicin 300 mg were immediately reintroduced with no benefit on the genital lesions. The patient underwent genital reconstruction, including penile degloving, scrotoplasty, infrapubic fat pad removal, and perineoplasty (Figure 1). The patient currently is not undergoing any therapies.
A 55-year-old man presented with Hurley stage II HS of 33 years’ duration. He had a BMI of 52; a history of hypertension, hyperuricemia, severe hip and knee osteoarthritis, and orchiopexy in childhood; a smoking history of 40 cigarettes per day; and an alcohol consumption history of 200 mL per day since 18 years of age. He had radical excision of axillary lesions 8 years prior. One year later, he was treated with concomitant clindamycin and rifampicin 300 mg twice daily for 3 months with no desirable effects. Adalimumab 40 mg/wk was initiated. After 12 weeks of treatment, he experienced 80% improvement in all areas except the genital region. He continued adalimumab for 3 years with good clinical response in all HS-affected sites except the genital region.
A 66-year-old man presented with Hurley stage III HS of 37 years’ duration. He had a smoking history of 10 cigarettes per day for 30 years, a BMI of 24.6, and a medical history of long-standing hypertension and hypothyroidism. A 3-month course of clindamycin and rifampicin 600 mg/d was ineffective; adalimumab 40 mg/wk was initiated. All affected areas improved, except for the saxophone penis. He continues his fifth year of therapy with adalimumab (Figure 2).
Hidradenitis suppurativa is associated with chronic pain, purulent malodor, and scarring with structural deformity. Repetitive inflammation causes fibrosis, scar formation, and soft-tissue destruction of lymphatic vessels, leading to lymphedema; primary lymphedema of the genitals in men has been reported to result in a saxophone penis.4
The only approved biologic treatments for moderate to severe HS are the tumor necrosis factor α inhibitor adalimumab and anti-IL-17 secukinumab.1 All 3 of our patients with HS were treated with adalimumab with reasonable success; however, the penile condition remained refractory, which we speculate may be due to adalimumab’s ability to control only active inflammatory lesions but not scars or fibrotic tissue.7 Higher adalimumab dosages were unlikely to be beneficial for their penile condition; some improvements have been reported following fluoroquinolone therapy. To our knowledge, there is no effective medical treatment for saxophone penis. However, surgery showed good results in one of our patients. Among our 3 adalimumab-treated patients, only 1 patient had corrective surgery that resulted in improvement in the penile deformity, further confirming adalimumab’s limited role in genital lymphedema.7 Extensive resection of the lymphedematous tissue, scrotoplasty, and Charles procedure are treatment options.8
Genital lymphedema has been associated with lymphangiectasia, lymphangioma circumscriptum, infections, and neoplasms such as lymphangiosarcoma and squamous cell carcinoma.9 Our patients reported discomfort, hygiene issues, and swelling. One patient reported micturition, and 2 patients reported sexual dysfunction.
Saxophone penis remains a disabling sequela of HS. Early diagnosis and treatment of HS may help prevent development of this condition.
- Lee EY, Alhusayen R, Lansang P, et al. What is hidradenitis suppurativa? Can Fam Physician. 2017;63:114-120.
- Fertitta L, Hotz C, Wolkenstein P, et al. Efficacy and satisfaction of surgical treatment for hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2020;34:839-845.
- Micieli R, Alavi A. Lymphedema in patients with hidradenitis suppurativa: a systematic review of published literature. Int J Dermatol. 2018;57:1471-1480.
- Maatouk I, Moutran R. Saxophone penis. JAMA Dermatol. 2013;149:802.
- Koley S, Mandal RK. Saxophone penis after unilateral inguinal bubo of lymphogranuloma venereum. Indian J Sex Transm Dis AIDS. 2013;34:149-151.
- D’Antuono A, Lambertini M, Gaspari V, et al. Visual dermatology: self-induced chronic saxophone penis due to paraffin injections. J Cutan Med Surg. 2019;23:330.
- Musumeci ML, Scilletta A, Sorci F, et al. Genital lymphedema associated with hidradenitis suppurativa unresponsive to adalimumab treatment. JAAD Case Rep. 2019;5:326-328.
- Jain V, Singh S, Garge S, et al. Saxophone penis due to primary lymphoedema. J Indian Assoc Pediatr Surg. 2009;14:230-231.
- Moosbrugger EA, Mutasim DF. Hidradenitis suppurativa complicated by severe lymphedema and lymphangiectasias. J Am Acad Dermatol. 2011;64:1223-1224.
To the Editor:
Hidradenitis suppurativa (HS) is a multifactorial chronic inflammatory skin disease affecting 1% to 4% of Europeans. It is characterized by recurrent inflamed nodules, abscesses, and sinus tracts in intertriginous regions.1 The genital area is affected in 11% of cases2 and usually is connected to severe forms of HS in both men and women.3 The prevalence of HS-associated genital lymphedema remains unknown.
Saxophone penis is a specific penile malformation characterized by a saxophone shape due to inflammation of the major penile lymphatic vessels that cause fibrosis of the surrounding connective tissue. Poor blood flow further causes contracture and distortion of the penile axis.4 Saxophone penis also has been associated with primary lymphedema, lymphogranuloma venereum, filariasis,5 and administration of paraffin injections.6 We describe 3 men with HS who presented with saxophone penis.
A 33-year-old man with Hurley stage III HS presented with a medical history of groin lesions and progressive penoscrotal edema of 13 years’ duration. He had a body mass index (BMI) of 37, no family history of HS or comorbidities, and a 15-year history of smoking 20 cigarettes per day. After repeated surgical drainage of the HS lesions as well as antibiotic treatment with clindamycin 600 mg/d and rifampicin 600 mg/d, the patient was kept on a maintenance therapy with adalimumab 40 mg/wk. Due to lack of response, treatment was discontinued at week 16. Clindamycin and rifampicin 300 mg were immediately reintroduced with no benefit on the genital lesions. The patient underwent genital reconstruction, including penile degloving, scrotoplasty, infrapubic fat pad removal, and perineoplasty (Figure 1). The patient currently is not undergoing any therapies.
A 55-year-old man presented with Hurley stage II HS of 33 years’ duration. He had a BMI of 52; a history of hypertension, hyperuricemia, severe hip and knee osteoarthritis, and orchiopexy in childhood; a smoking history of 40 cigarettes per day; and an alcohol consumption history of 200 mL per day since 18 years of age. He had radical excision of axillary lesions 8 years prior. One year later, he was treated with concomitant clindamycin and rifampicin 300 mg twice daily for 3 months with no desirable effects. Adalimumab 40 mg/wk was initiated. After 12 weeks of treatment, he experienced 80% improvement in all areas except the genital region. He continued adalimumab for 3 years with good clinical response in all HS-affected sites except the genital region.
A 66-year-old man presented with Hurley stage III HS of 37 years’ duration. He had a smoking history of 10 cigarettes per day for 30 years, a BMI of 24.6, and a medical history of long-standing hypertension and hypothyroidism. A 3-month course of clindamycin and rifampicin 600 mg/d was ineffective; adalimumab 40 mg/wk was initiated. All affected areas improved, except for the saxophone penis. He continues his fifth year of therapy with adalimumab (Figure 2).
Hidradenitis suppurativa is associated with chronic pain, purulent malodor, and scarring with structural deformity. Repetitive inflammation causes fibrosis, scar formation, and soft-tissue destruction of lymphatic vessels, leading to lymphedema; primary lymphedema of the genitals in men has been reported to result in a saxophone penis.4
The only approved biologic treatments for moderate to severe HS are the tumor necrosis factor α inhibitor adalimumab and anti-IL-17 secukinumab.1 All 3 of our patients with HS were treated with adalimumab with reasonable success; however, the penile condition remained refractory, which we speculate may be due to adalimumab’s ability to control only active inflammatory lesions but not scars or fibrotic tissue.7 Higher adalimumab dosages were unlikely to be beneficial for their penile condition; some improvements have been reported following fluoroquinolone therapy. To our knowledge, there is no effective medical treatment for saxophone penis. However, surgery showed good results in one of our patients. Among our 3 adalimumab-treated patients, only 1 patient had corrective surgery that resulted in improvement in the penile deformity, further confirming adalimumab’s limited role in genital lymphedema.7 Extensive resection of the lymphedematous tissue, scrotoplasty, and Charles procedure are treatment options.8
Genital lymphedema has been associated with lymphangiectasia, lymphangioma circumscriptum, infections, and neoplasms such as lymphangiosarcoma and squamous cell carcinoma.9 Our patients reported discomfort, hygiene issues, and swelling. One patient reported micturition, and 2 patients reported sexual dysfunction.
Saxophone penis remains a disabling sequela of HS. Early diagnosis and treatment of HS may help prevent development of this condition.
To the Editor:
Hidradenitis suppurativa (HS) is a multifactorial chronic inflammatory skin disease affecting 1% to 4% of Europeans. It is characterized by recurrent inflamed nodules, abscesses, and sinus tracts in intertriginous regions.1 The genital area is affected in 11% of cases2 and usually is connected to severe forms of HS in both men and women.3 The prevalence of HS-associated genital lymphedema remains unknown.
Saxophone penis is a specific penile malformation characterized by a saxophone shape due to inflammation of the major penile lymphatic vessels that cause fibrosis of the surrounding connective tissue. Poor blood flow further causes contracture and distortion of the penile axis.4 Saxophone penis also has been associated with primary lymphedema, lymphogranuloma venereum, filariasis,5 and administration of paraffin injections.6 We describe 3 men with HS who presented with saxophone penis.
A 33-year-old man with Hurley stage III HS presented with a medical history of groin lesions and progressive penoscrotal edema of 13 years’ duration. He had a body mass index (BMI) of 37, no family history of HS or comorbidities, and a 15-year history of smoking 20 cigarettes per day. After repeated surgical drainage of the HS lesions as well as antibiotic treatment with clindamycin 600 mg/d and rifampicin 600 mg/d, the patient was kept on a maintenance therapy with adalimumab 40 mg/wk. Due to lack of response, treatment was discontinued at week 16. Clindamycin and rifampicin 300 mg were immediately reintroduced with no benefit on the genital lesions. The patient underwent genital reconstruction, including penile degloving, scrotoplasty, infrapubic fat pad removal, and perineoplasty (Figure 1). The patient currently is not undergoing any therapies.
A 55-year-old man presented with Hurley stage II HS of 33 years’ duration. He had a BMI of 52; a history of hypertension, hyperuricemia, severe hip and knee osteoarthritis, and orchiopexy in childhood; a smoking history of 40 cigarettes per day; and an alcohol consumption history of 200 mL per day since 18 years of age. He had radical excision of axillary lesions 8 years prior. One year later, he was treated with concomitant clindamycin and rifampicin 300 mg twice daily for 3 months with no desirable effects. Adalimumab 40 mg/wk was initiated. After 12 weeks of treatment, he experienced 80% improvement in all areas except the genital region. He continued adalimumab for 3 years with good clinical response in all HS-affected sites except the genital region.
A 66-year-old man presented with Hurley stage III HS of 37 years’ duration. He had a smoking history of 10 cigarettes per day for 30 years, a BMI of 24.6, and a medical history of long-standing hypertension and hypothyroidism. A 3-month course of clindamycin and rifampicin 600 mg/d was ineffective; adalimumab 40 mg/wk was initiated. All affected areas improved, except for the saxophone penis. He continues his fifth year of therapy with adalimumab (Figure 2).
Hidradenitis suppurativa is associated with chronic pain, purulent malodor, and scarring with structural deformity. Repetitive inflammation causes fibrosis, scar formation, and soft-tissue destruction of lymphatic vessels, leading to lymphedema; primary lymphedema of the genitals in men has been reported to result in a saxophone penis.4
The only approved biologic treatments for moderate to severe HS are the tumor necrosis factor α inhibitor adalimumab and anti-IL-17 secukinumab.1 All 3 of our patients with HS were treated with adalimumab with reasonable success; however, the penile condition remained refractory, which we speculate may be due to adalimumab’s ability to control only active inflammatory lesions but not scars or fibrotic tissue.7 Higher adalimumab dosages were unlikely to be beneficial for their penile condition; some improvements have been reported following fluoroquinolone therapy. To our knowledge, there is no effective medical treatment for saxophone penis. However, surgery showed good results in one of our patients. Among our 3 adalimumab-treated patients, only 1 patient had corrective surgery that resulted in improvement in the penile deformity, further confirming adalimumab’s limited role in genital lymphedema.7 Extensive resection of the lymphedematous tissue, scrotoplasty, and Charles procedure are treatment options.8
Genital lymphedema has been associated with lymphangiectasia, lymphangioma circumscriptum, infections, and neoplasms such as lymphangiosarcoma and squamous cell carcinoma.9 Our patients reported discomfort, hygiene issues, and swelling. One patient reported micturition, and 2 patients reported sexual dysfunction.
Saxophone penis remains a disabling sequela of HS. Early diagnosis and treatment of HS may help prevent development of this condition.
- Lee EY, Alhusayen R, Lansang P, et al. What is hidradenitis suppurativa? Can Fam Physician. 2017;63:114-120.
- Fertitta L, Hotz C, Wolkenstein P, et al. Efficacy and satisfaction of surgical treatment for hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2020;34:839-845.
- Micieli R, Alavi A. Lymphedema in patients with hidradenitis suppurativa: a systematic review of published literature. Int J Dermatol. 2018;57:1471-1480.
- Maatouk I, Moutran R. Saxophone penis. JAMA Dermatol. 2013;149:802.
- Koley S, Mandal RK. Saxophone penis after unilateral inguinal bubo of lymphogranuloma venereum. Indian J Sex Transm Dis AIDS. 2013;34:149-151.
- D’Antuono A, Lambertini M, Gaspari V, et al. Visual dermatology: self-induced chronic saxophone penis due to paraffin injections. J Cutan Med Surg. 2019;23:330.
- Musumeci ML, Scilletta A, Sorci F, et al. Genital lymphedema associated with hidradenitis suppurativa unresponsive to adalimumab treatment. JAAD Case Rep. 2019;5:326-328.
- Jain V, Singh S, Garge S, et al. Saxophone penis due to primary lymphoedema. J Indian Assoc Pediatr Surg. 2009;14:230-231.
- Moosbrugger EA, Mutasim DF. Hidradenitis suppurativa complicated by severe lymphedema and lymphangiectasias. J Am Acad Dermatol. 2011;64:1223-1224.
- Lee EY, Alhusayen R, Lansang P, et al. What is hidradenitis suppurativa? Can Fam Physician. 2017;63:114-120.
- Fertitta L, Hotz C, Wolkenstein P, et al. Efficacy and satisfaction of surgical treatment for hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2020;34:839-845.
- Micieli R, Alavi A. Lymphedema in patients with hidradenitis suppurativa: a systematic review of published literature. Int J Dermatol. 2018;57:1471-1480.
- Maatouk I, Moutran R. Saxophone penis. JAMA Dermatol. 2013;149:802.
- Koley S, Mandal RK. Saxophone penis after unilateral inguinal bubo of lymphogranuloma venereum. Indian J Sex Transm Dis AIDS. 2013;34:149-151.
- D’Antuono A, Lambertini M, Gaspari V, et al. Visual dermatology: self-induced chronic saxophone penis due to paraffin injections. J Cutan Med Surg. 2019;23:330.
- Musumeci ML, Scilletta A, Sorci F, et al. Genital lymphedema associated with hidradenitis suppurativa unresponsive to adalimumab treatment. JAAD Case Rep. 2019;5:326-328.
- Jain V, Singh S, Garge S, et al. Saxophone penis due to primary lymphoedema. J Indian Assoc Pediatr Surg. 2009;14:230-231.
- Moosbrugger EA, Mutasim DF. Hidradenitis suppurativa complicated by severe lymphedema and lymphangiectasias. J Am Acad Dermatol. 2011;64:1223-1224.
Practice Points
- Hidradenitis suppurativa (HS) is a multifactorial chronic inflammatory skin disease.
- Saxophone penis is a specific penile malformation characterized by a saxophone shape due to inflammation.
- Repetitive inflammation within the context of HS may cause structural deformity of the penis, resulting in a saxophone penis.
- Early diagnosis and treatment of HS may help prevent development of this condition.
Anti-Smith and Anti–Double-Stranded DNA Antibodies in a Patient With Henoch-Schönlein Purpura Following COVID-19 Vaccination
To the Editor:
Henoch-Schönlein purpura (HSP)(also known as IgA vasculitis) is a small vessel vasculitis characterized by deposition of IgA in small vessels, resulting in the development of purpura on the legs. Based on the European Alliance of Associations for Rheumatology criteria,1 the patient also must have at least 1 of the following: arthritis, arthralgia, abdominal pain, leukocytoclastic vasculitis with IgA deposition, or kidney involvement. The disease can be triggered by infection—with more than 75% of patients reporting an antecedent upper respiratory tract infection2—as well as medications, circulating immune complexes, certain foods, vaccines, and rarely cancer.3,4 The disease more commonly occurs in children but also can affect adults.
Several cases of HSP have been reported following COVID-19 vaccination.5 We report a case of HSP developing days after the messenger RNA Pfizer-BioNTech COVID-19 vaccine booster that was associated with anti-Smith and anti–double-stranded DNA (dsDNA) antibodies as well as antineutrophil cytoplasmic antibodies (ANCAs).
A 24-year-old man presented to dermatology with a rash of 3 weeks’ duration that first appeared 1 week after receiving his second booster of the messenger RNA Pfizer-BioNTech COVID-19 vaccine. Physical examination revealed petechiae with nonblanching erythematous macules and papules covering the legs below the knees (Figure 1) as well as the back of the right arm. A few days later, he developed arthralgia in the knees, hands, and feet. The patient denied any recent infections as well as respiratory and urinary tract symptoms. Approximately 10 days after the rash appeared, he developed epigastric abdominal pain that gradually worsened and sought care from his primary care physician, who ordered computed tomography and referred him for endoscopy. Computed tomography with and without contrast was suspicious for colitis. Colonoscopy and endoscopy were unremarkable. Laboratory tests were notable for elevated white blood cell count (17.08×103/µL [reference range, 3.66–10.60×103/µL]), serum IgA (437 mg/dL [reference range, 70–400 mg/dL]), C-reactive protein (1.5 mg/dL [reference range, <0.5 mg/dL]), anti-Smith antibody (28.1 CU [reference range, <20 CU), positive antinuclear antibody with titer (1:160 [reference range, <1:80]), anti-dsDNA (40.4 IU/mL [reference range, <27 IU/mL]), and cytoplasmic ANCA (c-ANCA) titer (1:320 [reference range, <1:20]). Blood urea nitrogen, creatinine, and estimated glomerular filtration rate were all within reference range. Urinalysis with microscopic examination was notable for 2 to 5 red blood cells per high-power field (reference range, 0) and proteinuria of 1+ (reference range, negative for protein).
The patient’s rash progressively worsened over the next few weeks, spreading proximally on the legs to the buttocks and the back of both elbows. A repeat complete blood cell count showed resolution of the leukocytosis. Two biopsies were taken from a lesion on the left proximal thigh: 1 for hematoxylin and eosin stain for histopathologic examination and 1 for direct immunofluorescence examination.
The patient was preliminarily diagnosed with HSP, and dermatology prescribed oral tofacitinib 5 mg twice daily for 5 days, which was supposed to be increased to 10 mg twice daily on the sixth day of treatment; however, the patient discontinued the medication after 4 days based on his primary care physician’s recommendation due to clotting concerns. The rash and arthralgia temporarily improved for 1 week, then relapsed.
Histopathology revealed neutrophils surrounding and infiltrating small dermal blood vessel walls as well as associated neutrophilic debris and erythrocytes, consistent with leukocytoclastic vasculitis (Figure 2). Direct immunofluorescence was negative for IgA antibodies. His primary care physician, in consultation with his dermatologist, then started the patient on oral prednisone 70 mg once daily for 7 days with a plan to taper. Three days after prednisone was started, the arthralgia and abdominal pain resolved, and the rash became lighter in color. After 1 week, the rash resolved completely.
Due to the unusual antibodies, the patient was referred to a rheumatologist, who repeated the blood tests approximately 1 week after the patient started prednisone. The tests were negative for anti-Smith, anti-dsDNA, and c-ANCA but showed an elevated atypical perinuclear ANCA (p-ANCA) titer of 1:80 (reference range [negative], <1:20). A repeat urinalysis was unremarkable. The patient slowly tapered the prednisone over the course of 3 months and was subsequently lost to follow-up. The rash and other symptoms had not recurred as of the patient’s last physician contact. The most recent laboratory results showed a white blood cell count of 14.0×103/µL (reference range, 3.4–10.8×103/µL), likely due to the prednisone; blood urea nitrogen, creatinine, and estimated glomerular filtration rate were within reference range. The urinalysis was notable for occult blood and was negative for protein. C-reactive protein was 1 mg/dL (reference range, 0–10 mg/dL); p-ANCA, c-ANCA, and atypical p-ANCA, as well as antinuclear antibody, were negative. As of his last follow-up, the patient felt well.
The major differential diagnoses for our patient included HSP, ANCA vasculitis, and systemic lupus erythematosus. Although ANCA vasculitis has been reported after SARS-CoV-2 infection,6 the lack of pulmonary symptoms made this diagnosis unlikely.7 Although our patient initially had elevated anti-Smith and anti-dsDNA antibodies as well as mild renal involvement, he fulfilled at most only 2 of the 11 criteria necessary for diagnosing lupus: malar rash, discoid rash (includes alopecia), photosensitivity, ocular ulcers, nonerosive arthritis, serositis, renal disorder (protein >500 mg/24 h, red blood cells, casts), neurologic disorder (seizures, psychosis), hematologic disorders (hemolytic anemia, leukopenia), ANA, and immunologic disorder (anti-Smith). Four of the 11 criteria are necessary for the diagnosis of lupus.8
Torraca et al7 reported a case of HSP with positive c-ANCA (1:640) in a patient lacking pulmonary symptoms who was diagnosed with HSP. Cytoplasmic ANCA is not a typical finding in HSP. However, the additional findings of anti-Smith, anti-dsDNA, and mildly elevated atypical p-ANCA antibodies in our patient were unexpected and could be explained by the proposed pathogenesis of HSP—an overzealous immune response resulting in aberrant antibody complex deposition with ensuing complement activation.5,9 Production of these additional antibodies could be part of the overzealous response to COVID-19 vaccination.
Of all the COVID-19 vaccines, messenger RNA–based vaccines have been associated with the majority of cutaneous reactions, including local injection-site reactions (most common), delayed local reactions, urticaria, angioedema, morbilliform eruption, herpes zoster eruption, bullous eruptions, dermal filler reactions, chilblains, and pityriasis rosea. Less common reactions have included acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, erythema multiforme, Sweet Syndrome, lichen planus, papulovesicular eruptions, pityriasis rosea–like eruptions, generalized annular lesions, facial pustular neutrophilic eruptions, and flares of underlying autoimmune skin conditions.10 Multiple cases of HSP have been reported following COVID-19 vaccination from all the major vaccine companies.5
In our patient, laboratory tests were repeated by a rheumatologist and were negative for anti-Smith and anti-dsDNA antibodies as well as c-ANCA, most likely because he started taking prednisone approximately 1 week prior, which may have resulted in decreased antibodies. Also, the patient’s symptoms resolved after 1 week of steroid therapy. Therefore, the diagnosis is most consistent with HSP associated with COVID-19 vaccination. The clinical presentation, microscopic hematuria and proteinuria, and histopathology were consistent with the European Alliance of Associations for Rheumatology criteria for HSP.1
Although direct immunofluorescence typically is positive for IgA deposition on biopsies, it can be negative for IgA, especially in lesions that are biopsied more than 7 days after their appearance, as shown in our case; a negative IgA on immunofluorescence does not rule out HSP.4 Elevated serum IgA is seen in more than 50% of cases of HSP.11 Although the disease typically is self-limited, glucocorticoids are used if the disease course is prolonged or if there is evidence of kidney involvement.9 The unique combination of anti-Smith and anti-dsDNA antibodies as well as ANCAs associated with HSP with negative IgA on direct immunofluorescence has been reported with lupus.12 Clinicians should be aware of COVID-19 vaccine–associated HSP that is negative for IgA deposition and positive for anti-Smith and anti-dsDNA antibodies as well as ANCAs.
Acknowledgment—We thank our patient for granting permission to publish this information.
- Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936-941. doi:10.1136/ard.2005.046300
- Rai A, Nast C, Adler S. Henoch–Schönlein purpura nephritis. J Am Soc Nephrol. 1999;10:2637-2644.
- Casini F, Magenes VC, De Sanctis M, et al. Henoch-Schönlein purpura following COVID-19 vaccine in a child: a case report. Ital J Pediatr. 2022;48:158. doi:10.1186/s13052-022-01351-1
- Poudel P, Adams SH, Mirchia K, et al. IgA negative immunofluorescence in diagnoses of adult-onset Henoch-Schönlein purpura. Proc (Bayl Univ Med Cent). 2020;33:436-437. doi:10.1080/08998280.2020.1770526
- Maronese CA, Zelin E, Avallone G, et al. Cutaneous vasculitis and vasculopathy in the era of COVID-19 pandemic. Front Med (Lausanne). 2022;9:996288. doi:10.3389/fmed.2022.996288
- Bryant MC, Spencer LT, Yalcindag A. A case of ANCA-associated vasculitis in a 16-year-old female following SARS-COV-2 infection and a systematic review of the literature. Pediatr Rheumatol Online J. 2022;20:65. doi:10.1186/s12969-022-00727-1
- Torraca PFS, Castro BC, Hans Filho G. Henoch-Schönlein purpura with c-ANCA antibody in adult. An Bras Dermatol. 2016;91:667-669. doi:10.1590/abd1806-4841.20164181
- Agabegi SS, Agabegi ED. Step-Up to Medicine. 4th ed. Wolters Kluwer; 2015.
- Ball-Burack MR, Kosowsky JM. A Case of leukocytoclastic vasculitis following SARS-CoV-2 vaccination. J Emerg Med. 2022;63:E62-E65. doi:10.1016/j.jemermed.2021.10.005
- Tan SW, Tam YC, Pang SM. Cutaneous reactions to COVID-19 vaccines: a review. JAAD Int. 2022;7:178-186. doi:10.1016/j.jdin.2022.01.011
- Calviño MC, Llorca J, García-Porrúa C, et al. Henoch-Schönlein purpura in children from northwestern Spain: a 20-year epidemiologic and clinical study. Medicine (Baltimore). 2001;80:279-290.
- Hu P, Huang BY, Zhang DD, et al. Henoch-Schönlein purpura in a pediatric patient with lupus. Arch Med Sci. 2017;13:689-690. doi:10.5114/aoms.2017.67288
To the Editor:
Henoch-Schönlein purpura (HSP)(also known as IgA vasculitis) is a small vessel vasculitis characterized by deposition of IgA in small vessels, resulting in the development of purpura on the legs. Based on the European Alliance of Associations for Rheumatology criteria,1 the patient also must have at least 1 of the following: arthritis, arthralgia, abdominal pain, leukocytoclastic vasculitis with IgA deposition, or kidney involvement. The disease can be triggered by infection—with more than 75% of patients reporting an antecedent upper respiratory tract infection2—as well as medications, circulating immune complexes, certain foods, vaccines, and rarely cancer.3,4 The disease more commonly occurs in children but also can affect adults.
Several cases of HSP have been reported following COVID-19 vaccination.5 We report a case of HSP developing days after the messenger RNA Pfizer-BioNTech COVID-19 vaccine booster that was associated with anti-Smith and anti–double-stranded DNA (dsDNA) antibodies as well as antineutrophil cytoplasmic antibodies (ANCAs).
A 24-year-old man presented to dermatology with a rash of 3 weeks’ duration that first appeared 1 week after receiving his second booster of the messenger RNA Pfizer-BioNTech COVID-19 vaccine. Physical examination revealed petechiae with nonblanching erythematous macules and papules covering the legs below the knees (Figure 1) as well as the back of the right arm. A few days later, he developed arthralgia in the knees, hands, and feet. The patient denied any recent infections as well as respiratory and urinary tract symptoms. Approximately 10 days after the rash appeared, he developed epigastric abdominal pain that gradually worsened and sought care from his primary care physician, who ordered computed tomography and referred him for endoscopy. Computed tomography with and without contrast was suspicious for colitis. Colonoscopy and endoscopy were unremarkable. Laboratory tests were notable for elevated white blood cell count (17.08×103/µL [reference range, 3.66–10.60×103/µL]), serum IgA (437 mg/dL [reference range, 70–400 mg/dL]), C-reactive protein (1.5 mg/dL [reference range, <0.5 mg/dL]), anti-Smith antibody (28.1 CU [reference range, <20 CU), positive antinuclear antibody with titer (1:160 [reference range, <1:80]), anti-dsDNA (40.4 IU/mL [reference range, <27 IU/mL]), and cytoplasmic ANCA (c-ANCA) titer (1:320 [reference range, <1:20]). Blood urea nitrogen, creatinine, and estimated glomerular filtration rate were all within reference range. Urinalysis with microscopic examination was notable for 2 to 5 red blood cells per high-power field (reference range, 0) and proteinuria of 1+ (reference range, negative for protein).
The patient’s rash progressively worsened over the next few weeks, spreading proximally on the legs to the buttocks and the back of both elbows. A repeat complete blood cell count showed resolution of the leukocytosis. Two biopsies were taken from a lesion on the left proximal thigh: 1 for hematoxylin and eosin stain for histopathologic examination and 1 for direct immunofluorescence examination.
The patient was preliminarily diagnosed with HSP, and dermatology prescribed oral tofacitinib 5 mg twice daily for 5 days, which was supposed to be increased to 10 mg twice daily on the sixth day of treatment; however, the patient discontinued the medication after 4 days based on his primary care physician’s recommendation due to clotting concerns. The rash and arthralgia temporarily improved for 1 week, then relapsed.
Histopathology revealed neutrophils surrounding and infiltrating small dermal blood vessel walls as well as associated neutrophilic debris and erythrocytes, consistent with leukocytoclastic vasculitis (Figure 2). Direct immunofluorescence was negative for IgA antibodies. His primary care physician, in consultation with his dermatologist, then started the patient on oral prednisone 70 mg once daily for 7 days with a plan to taper. Three days after prednisone was started, the arthralgia and abdominal pain resolved, and the rash became lighter in color. After 1 week, the rash resolved completely.
Due to the unusual antibodies, the patient was referred to a rheumatologist, who repeated the blood tests approximately 1 week after the patient started prednisone. The tests were negative for anti-Smith, anti-dsDNA, and c-ANCA but showed an elevated atypical perinuclear ANCA (p-ANCA) titer of 1:80 (reference range [negative], <1:20). A repeat urinalysis was unremarkable. The patient slowly tapered the prednisone over the course of 3 months and was subsequently lost to follow-up. The rash and other symptoms had not recurred as of the patient’s last physician contact. The most recent laboratory results showed a white blood cell count of 14.0×103/µL (reference range, 3.4–10.8×103/µL), likely due to the prednisone; blood urea nitrogen, creatinine, and estimated glomerular filtration rate were within reference range. The urinalysis was notable for occult blood and was negative for protein. C-reactive protein was 1 mg/dL (reference range, 0–10 mg/dL); p-ANCA, c-ANCA, and atypical p-ANCA, as well as antinuclear antibody, were negative. As of his last follow-up, the patient felt well.
The major differential diagnoses for our patient included HSP, ANCA vasculitis, and systemic lupus erythematosus. Although ANCA vasculitis has been reported after SARS-CoV-2 infection,6 the lack of pulmonary symptoms made this diagnosis unlikely.7 Although our patient initially had elevated anti-Smith and anti-dsDNA antibodies as well as mild renal involvement, he fulfilled at most only 2 of the 11 criteria necessary for diagnosing lupus: malar rash, discoid rash (includes alopecia), photosensitivity, ocular ulcers, nonerosive arthritis, serositis, renal disorder (protein >500 mg/24 h, red blood cells, casts), neurologic disorder (seizures, psychosis), hematologic disorders (hemolytic anemia, leukopenia), ANA, and immunologic disorder (anti-Smith). Four of the 11 criteria are necessary for the diagnosis of lupus.8
Torraca et al7 reported a case of HSP with positive c-ANCA (1:640) in a patient lacking pulmonary symptoms who was diagnosed with HSP. Cytoplasmic ANCA is not a typical finding in HSP. However, the additional findings of anti-Smith, anti-dsDNA, and mildly elevated atypical p-ANCA antibodies in our patient were unexpected and could be explained by the proposed pathogenesis of HSP—an overzealous immune response resulting in aberrant antibody complex deposition with ensuing complement activation.5,9 Production of these additional antibodies could be part of the overzealous response to COVID-19 vaccination.
Of all the COVID-19 vaccines, messenger RNA–based vaccines have been associated with the majority of cutaneous reactions, including local injection-site reactions (most common), delayed local reactions, urticaria, angioedema, morbilliform eruption, herpes zoster eruption, bullous eruptions, dermal filler reactions, chilblains, and pityriasis rosea. Less common reactions have included acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, erythema multiforme, Sweet Syndrome, lichen planus, papulovesicular eruptions, pityriasis rosea–like eruptions, generalized annular lesions, facial pustular neutrophilic eruptions, and flares of underlying autoimmune skin conditions.10 Multiple cases of HSP have been reported following COVID-19 vaccination from all the major vaccine companies.5
In our patient, laboratory tests were repeated by a rheumatologist and were negative for anti-Smith and anti-dsDNA antibodies as well as c-ANCA, most likely because he started taking prednisone approximately 1 week prior, which may have resulted in decreased antibodies. Also, the patient’s symptoms resolved after 1 week of steroid therapy. Therefore, the diagnosis is most consistent with HSP associated with COVID-19 vaccination. The clinical presentation, microscopic hematuria and proteinuria, and histopathology were consistent with the European Alliance of Associations for Rheumatology criteria for HSP.1
Although direct immunofluorescence typically is positive for IgA deposition on biopsies, it can be negative for IgA, especially in lesions that are biopsied more than 7 days after their appearance, as shown in our case; a negative IgA on immunofluorescence does not rule out HSP.4 Elevated serum IgA is seen in more than 50% of cases of HSP.11 Although the disease typically is self-limited, glucocorticoids are used if the disease course is prolonged or if there is evidence of kidney involvement.9 The unique combination of anti-Smith and anti-dsDNA antibodies as well as ANCAs associated with HSP with negative IgA on direct immunofluorescence has been reported with lupus.12 Clinicians should be aware of COVID-19 vaccine–associated HSP that is negative for IgA deposition and positive for anti-Smith and anti-dsDNA antibodies as well as ANCAs.
Acknowledgment—We thank our patient for granting permission to publish this information.
To the Editor:
Henoch-Schönlein purpura (HSP)(also known as IgA vasculitis) is a small vessel vasculitis characterized by deposition of IgA in small vessels, resulting in the development of purpura on the legs. Based on the European Alliance of Associations for Rheumatology criteria,1 the patient also must have at least 1 of the following: arthritis, arthralgia, abdominal pain, leukocytoclastic vasculitis with IgA deposition, or kidney involvement. The disease can be triggered by infection—with more than 75% of patients reporting an antecedent upper respiratory tract infection2—as well as medications, circulating immune complexes, certain foods, vaccines, and rarely cancer.3,4 The disease more commonly occurs in children but also can affect adults.
Several cases of HSP have been reported following COVID-19 vaccination.5 We report a case of HSP developing days after the messenger RNA Pfizer-BioNTech COVID-19 vaccine booster that was associated with anti-Smith and anti–double-stranded DNA (dsDNA) antibodies as well as antineutrophil cytoplasmic antibodies (ANCAs).
A 24-year-old man presented to dermatology with a rash of 3 weeks’ duration that first appeared 1 week after receiving his second booster of the messenger RNA Pfizer-BioNTech COVID-19 vaccine. Physical examination revealed petechiae with nonblanching erythematous macules and papules covering the legs below the knees (Figure 1) as well as the back of the right arm. A few days later, he developed arthralgia in the knees, hands, and feet. The patient denied any recent infections as well as respiratory and urinary tract symptoms. Approximately 10 days after the rash appeared, he developed epigastric abdominal pain that gradually worsened and sought care from his primary care physician, who ordered computed tomography and referred him for endoscopy. Computed tomography with and without contrast was suspicious for colitis. Colonoscopy and endoscopy were unremarkable. Laboratory tests were notable for elevated white blood cell count (17.08×103/µL [reference range, 3.66–10.60×103/µL]), serum IgA (437 mg/dL [reference range, 70–400 mg/dL]), C-reactive protein (1.5 mg/dL [reference range, <0.5 mg/dL]), anti-Smith antibody (28.1 CU [reference range, <20 CU), positive antinuclear antibody with titer (1:160 [reference range, <1:80]), anti-dsDNA (40.4 IU/mL [reference range, <27 IU/mL]), and cytoplasmic ANCA (c-ANCA) titer (1:320 [reference range, <1:20]). Blood urea nitrogen, creatinine, and estimated glomerular filtration rate were all within reference range. Urinalysis with microscopic examination was notable for 2 to 5 red blood cells per high-power field (reference range, 0) and proteinuria of 1+ (reference range, negative for protein).
The patient’s rash progressively worsened over the next few weeks, spreading proximally on the legs to the buttocks and the back of both elbows. A repeat complete blood cell count showed resolution of the leukocytosis. Two biopsies were taken from a lesion on the left proximal thigh: 1 for hematoxylin and eosin stain for histopathologic examination and 1 for direct immunofluorescence examination.
The patient was preliminarily diagnosed with HSP, and dermatology prescribed oral tofacitinib 5 mg twice daily for 5 days, which was supposed to be increased to 10 mg twice daily on the sixth day of treatment; however, the patient discontinued the medication after 4 days based on his primary care physician’s recommendation due to clotting concerns. The rash and arthralgia temporarily improved for 1 week, then relapsed.
Histopathology revealed neutrophils surrounding and infiltrating small dermal blood vessel walls as well as associated neutrophilic debris and erythrocytes, consistent with leukocytoclastic vasculitis (Figure 2). Direct immunofluorescence was negative for IgA antibodies. His primary care physician, in consultation with his dermatologist, then started the patient on oral prednisone 70 mg once daily for 7 days with a plan to taper. Three days after prednisone was started, the arthralgia and abdominal pain resolved, and the rash became lighter in color. After 1 week, the rash resolved completely.
Due to the unusual antibodies, the patient was referred to a rheumatologist, who repeated the blood tests approximately 1 week after the patient started prednisone. The tests were negative for anti-Smith, anti-dsDNA, and c-ANCA but showed an elevated atypical perinuclear ANCA (p-ANCA) titer of 1:80 (reference range [negative], <1:20). A repeat urinalysis was unremarkable. The patient slowly tapered the prednisone over the course of 3 months and was subsequently lost to follow-up. The rash and other symptoms had not recurred as of the patient’s last physician contact. The most recent laboratory results showed a white blood cell count of 14.0×103/µL (reference range, 3.4–10.8×103/µL), likely due to the prednisone; blood urea nitrogen, creatinine, and estimated glomerular filtration rate were within reference range. The urinalysis was notable for occult blood and was negative for protein. C-reactive protein was 1 mg/dL (reference range, 0–10 mg/dL); p-ANCA, c-ANCA, and atypical p-ANCA, as well as antinuclear antibody, were negative. As of his last follow-up, the patient felt well.
The major differential diagnoses for our patient included HSP, ANCA vasculitis, and systemic lupus erythematosus. Although ANCA vasculitis has been reported after SARS-CoV-2 infection,6 the lack of pulmonary symptoms made this diagnosis unlikely.7 Although our patient initially had elevated anti-Smith and anti-dsDNA antibodies as well as mild renal involvement, he fulfilled at most only 2 of the 11 criteria necessary for diagnosing lupus: malar rash, discoid rash (includes alopecia), photosensitivity, ocular ulcers, nonerosive arthritis, serositis, renal disorder (protein >500 mg/24 h, red blood cells, casts), neurologic disorder (seizures, psychosis), hematologic disorders (hemolytic anemia, leukopenia), ANA, and immunologic disorder (anti-Smith). Four of the 11 criteria are necessary for the diagnosis of lupus.8
Torraca et al7 reported a case of HSP with positive c-ANCA (1:640) in a patient lacking pulmonary symptoms who was diagnosed with HSP. Cytoplasmic ANCA is not a typical finding in HSP. However, the additional findings of anti-Smith, anti-dsDNA, and mildly elevated atypical p-ANCA antibodies in our patient were unexpected and could be explained by the proposed pathogenesis of HSP—an overzealous immune response resulting in aberrant antibody complex deposition with ensuing complement activation.5,9 Production of these additional antibodies could be part of the overzealous response to COVID-19 vaccination.
Of all the COVID-19 vaccines, messenger RNA–based vaccines have been associated with the majority of cutaneous reactions, including local injection-site reactions (most common), delayed local reactions, urticaria, angioedema, morbilliform eruption, herpes zoster eruption, bullous eruptions, dermal filler reactions, chilblains, and pityriasis rosea. Less common reactions have included acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, erythema multiforme, Sweet Syndrome, lichen planus, papulovesicular eruptions, pityriasis rosea–like eruptions, generalized annular lesions, facial pustular neutrophilic eruptions, and flares of underlying autoimmune skin conditions.10 Multiple cases of HSP have been reported following COVID-19 vaccination from all the major vaccine companies.5
In our patient, laboratory tests were repeated by a rheumatologist and were negative for anti-Smith and anti-dsDNA antibodies as well as c-ANCA, most likely because he started taking prednisone approximately 1 week prior, which may have resulted in decreased antibodies. Also, the patient’s symptoms resolved after 1 week of steroid therapy. Therefore, the diagnosis is most consistent with HSP associated with COVID-19 vaccination. The clinical presentation, microscopic hematuria and proteinuria, and histopathology were consistent with the European Alliance of Associations for Rheumatology criteria for HSP.1
Although direct immunofluorescence typically is positive for IgA deposition on biopsies, it can be negative for IgA, especially in lesions that are biopsied more than 7 days after their appearance, as shown in our case; a negative IgA on immunofluorescence does not rule out HSP.4 Elevated serum IgA is seen in more than 50% of cases of HSP.11 Although the disease typically is self-limited, glucocorticoids are used if the disease course is prolonged or if there is evidence of kidney involvement.9 The unique combination of anti-Smith and anti-dsDNA antibodies as well as ANCAs associated with HSP with negative IgA on direct immunofluorescence has been reported with lupus.12 Clinicians should be aware of COVID-19 vaccine–associated HSP that is negative for IgA deposition and positive for anti-Smith and anti-dsDNA antibodies as well as ANCAs.
Acknowledgment—We thank our patient for granting permission to publish this information.
- Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936-941. doi:10.1136/ard.2005.046300
- Rai A, Nast C, Adler S. Henoch–Schönlein purpura nephritis. J Am Soc Nephrol. 1999;10:2637-2644.
- Casini F, Magenes VC, De Sanctis M, et al. Henoch-Schönlein purpura following COVID-19 vaccine in a child: a case report. Ital J Pediatr. 2022;48:158. doi:10.1186/s13052-022-01351-1
- Poudel P, Adams SH, Mirchia K, et al. IgA negative immunofluorescence in diagnoses of adult-onset Henoch-Schönlein purpura. Proc (Bayl Univ Med Cent). 2020;33:436-437. doi:10.1080/08998280.2020.1770526
- Maronese CA, Zelin E, Avallone G, et al. Cutaneous vasculitis and vasculopathy in the era of COVID-19 pandemic. Front Med (Lausanne). 2022;9:996288. doi:10.3389/fmed.2022.996288
- Bryant MC, Spencer LT, Yalcindag A. A case of ANCA-associated vasculitis in a 16-year-old female following SARS-COV-2 infection and a systematic review of the literature. Pediatr Rheumatol Online J. 2022;20:65. doi:10.1186/s12969-022-00727-1
- Torraca PFS, Castro BC, Hans Filho G. Henoch-Schönlein purpura with c-ANCA antibody in adult. An Bras Dermatol. 2016;91:667-669. doi:10.1590/abd1806-4841.20164181
- Agabegi SS, Agabegi ED. Step-Up to Medicine. 4th ed. Wolters Kluwer; 2015.
- Ball-Burack MR, Kosowsky JM. A Case of leukocytoclastic vasculitis following SARS-CoV-2 vaccination. J Emerg Med. 2022;63:E62-E65. doi:10.1016/j.jemermed.2021.10.005
- Tan SW, Tam YC, Pang SM. Cutaneous reactions to COVID-19 vaccines: a review. JAAD Int. 2022;7:178-186. doi:10.1016/j.jdin.2022.01.011
- Calviño MC, Llorca J, García-Porrúa C, et al. Henoch-Schönlein purpura in children from northwestern Spain: a 20-year epidemiologic and clinical study. Medicine (Baltimore). 2001;80:279-290.
- Hu P, Huang BY, Zhang DD, et al. Henoch-Schönlein purpura in a pediatric patient with lupus. Arch Med Sci. 2017;13:689-690. doi:10.5114/aoms.2017.67288
- Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936-941. doi:10.1136/ard.2005.046300
- Rai A, Nast C, Adler S. Henoch–Schönlein purpura nephritis. J Am Soc Nephrol. 1999;10:2637-2644.
- Casini F, Magenes VC, De Sanctis M, et al. Henoch-Schönlein purpura following COVID-19 vaccine in a child: a case report. Ital J Pediatr. 2022;48:158. doi:10.1186/s13052-022-01351-1
- Poudel P, Adams SH, Mirchia K, et al. IgA negative immunofluorescence in diagnoses of adult-onset Henoch-Schönlein purpura. Proc (Bayl Univ Med Cent). 2020;33:436-437. doi:10.1080/08998280.2020.1770526
- Maronese CA, Zelin E, Avallone G, et al. Cutaneous vasculitis and vasculopathy in the era of COVID-19 pandemic. Front Med (Lausanne). 2022;9:996288. doi:10.3389/fmed.2022.996288
- Bryant MC, Spencer LT, Yalcindag A. A case of ANCA-associated vasculitis in a 16-year-old female following SARS-COV-2 infection and a systematic review of the literature. Pediatr Rheumatol Online J. 2022;20:65. doi:10.1186/s12969-022-00727-1
- Torraca PFS, Castro BC, Hans Filho G. Henoch-Schönlein purpura with c-ANCA antibody in adult. An Bras Dermatol. 2016;91:667-669. doi:10.1590/abd1806-4841.20164181
- Agabegi SS, Agabegi ED. Step-Up to Medicine. 4th ed. Wolters Kluwer; 2015.
- Ball-Burack MR, Kosowsky JM. A Case of leukocytoclastic vasculitis following SARS-CoV-2 vaccination. J Emerg Med. 2022;63:E62-E65. doi:10.1016/j.jemermed.2021.10.005
- Tan SW, Tam YC, Pang SM. Cutaneous reactions to COVID-19 vaccines: a review. JAAD Int. 2022;7:178-186. doi:10.1016/j.jdin.2022.01.011
- Calviño MC, Llorca J, García-Porrúa C, et al. Henoch-Schönlein purpura in children from northwestern Spain: a 20-year epidemiologic and clinical study. Medicine (Baltimore). 2001;80:279-290.
- Hu P, Huang BY, Zhang DD, et al. Henoch-Schönlein purpura in a pediatric patient with lupus. Arch Med Sci. 2017;13:689-690. doi:10.5114/aoms.2017.67288
Practice Points
- Dermatologists should be vigilant for Henoch-Schönlein purpura (HSP) despite negative direct immunofluorescence of IgA deposition and unusual antibodies.
- Messenger RNA–based COVID-19 vaccines are associated with various cutaneous reactions, including HSP.
- Anti-Smith and anti–double-stranded DNA antibodies typically are not associated with HSP but may be seen in patients with coexisting systemic lupus erythematosus.
Painful Anal Lesions in a Patient With HIV
The Diagnosis: Condyloma Latum
Laboratory test results were notable for a rapid plasma reagin titer of 1:512, a positive Treponema pallidum particle agglutination test, negative rectal nucleic acid amplification tests for gonorrhea and chlamydia, and a negative herpes simplex virus polymerase chain reaction. A VDRL test of cerebrospinal fluid from a lumbar puncture was negative. Histopathology of the punch biopsy sample revealed marked verrucous epidermal hyperplasia without keratinocytic atypia and with mixed inflammation (Figure 1), while immunohistochemical staining showed numerus T pallidum organisms (Figure 2). A diagnosis of condyloma latum was made based on the laboratory, lumbar puncture, and punch biopsy results. Due to a penicillin allergy, the patient was treated with oral doxycycline for 14 days. On follow-up at day 12 of therapy, he reported cessation of rectal pain, and resolution of anal lesions was noted on physical examination.
Condylomata lata are highly infectious cutaneous lesions that can manifest during secondary syphilis.1 They typically are described as white or gray, raised, flatappearing plaques and occur in moist areas or skin folds including the anus, scrotum, and vulva. However, these lesions also have been reported in the axillae, umbilicus, nasolabial folds, and other anatomic areas.1,2 The lesions can be painful and often manifest in multiples, especially in patients living with HIV.3
Condylomata lata can have a verrucous appearance and may mimic other anogenital lesions, such as condylomata acuminata, genital herpes, and malignant tumors, leading to an initial misdiagnosis.1,2 Condylomata lata should always be included in the differential when evaluating anogenital lesions. Other conditions in the differential diagnosis include psoriasis, typically manifesting as erythematous plaques with silver scale, and molluscum contagiosum, appearing as small umbilicated papules on physical examination.
Condylomata lata have been reported to occur in 6% to 23% of patients with secondary syphilis.1 Although secondary syphilis more typically manifests with a diffuse maculopapular rash, condylomata lata may be the sole dermatologic manifestation.4
Histopathology of condylomata lata consists of epithelial hyperplasia as well as lymphocytic and plasma cell infiltrates. It is diagnosed by serologic testing as well as immunohistochemical staining or dark-field microscopy.
First-line treatment of secondary syphilis is a single dose of benzathine penicillin G administered intramuscularly.5 However, a 14-day course of oral doxycycline can be used in patients with a penicillin allergy. When compliance and follow-up cannot be guaranteed, penicillin desensitization and treatment with benzathine penicillin G is recommended. Clinical evaluation and repeat serologic testing should be performed at 6 and 12 months follow-up, or more frequently if clinically indicated.5
- Pourang A, Fung MA, Tartar D, et al. Condyloma lata in secondary syphilis. JAAD Case Rep. 2021;10:18-21. doi:10.1016/j.jdcr.2021.01.025
- Liu Z, Wang L, Zhang G, et al. Warty mucosal lesions: oral condyloma lata of secondary syphilis. Indian J Dermatol Venereol Leprol. 2017;83:277. doi:10.4103/0378-6323.191129
- Rompalo AM, Joesoef MR, O’Donnell JA, et al; Syphilis and HIV Study Group. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis.2001;28:158-165.
- Kumar P, Das A, Mondal A. Secondary syphilis: an unusual presentation. Indian J Sex Transm Dis AIDS. 2017;38:98-99. doi:10.4103/0253-7184.194318
- Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70:1-187. doi:10.15585/mmwr.rr7004a1
The Diagnosis: Condyloma Latum
Laboratory test results were notable for a rapid plasma reagin titer of 1:512, a positive Treponema pallidum particle agglutination test, negative rectal nucleic acid amplification tests for gonorrhea and chlamydia, and a negative herpes simplex virus polymerase chain reaction. A VDRL test of cerebrospinal fluid from a lumbar puncture was negative. Histopathology of the punch biopsy sample revealed marked verrucous epidermal hyperplasia without keratinocytic atypia and with mixed inflammation (Figure 1), while immunohistochemical staining showed numerus T pallidum organisms (Figure 2). A diagnosis of condyloma latum was made based on the laboratory, lumbar puncture, and punch biopsy results. Due to a penicillin allergy, the patient was treated with oral doxycycline for 14 days. On follow-up at day 12 of therapy, he reported cessation of rectal pain, and resolution of anal lesions was noted on physical examination.
Condylomata lata are highly infectious cutaneous lesions that can manifest during secondary syphilis.1 They typically are described as white or gray, raised, flatappearing plaques and occur in moist areas or skin folds including the anus, scrotum, and vulva. However, these lesions also have been reported in the axillae, umbilicus, nasolabial folds, and other anatomic areas.1,2 The lesions can be painful and often manifest in multiples, especially in patients living with HIV.3
Condylomata lata can have a verrucous appearance and may mimic other anogenital lesions, such as condylomata acuminata, genital herpes, and malignant tumors, leading to an initial misdiagnosis.1,2 Condylomata lata should always be included in the differential when evaluating anogenital lesions. Other conditions in the differential diagnosis include psoriasis, typically manifesting as erythematous plaques with silver scale, and molluscum contagiosum, appearing as small umbilicated papules on physical examination.
Condylomata lata have been reported to occur in 6% to 23% of patients with secondary syphilis.1 Although secondary syphilis more typically manifests with a diffuse maculopapular rash, condylomata lata may be the sole dermatologic manifestation.4
Histopathology of condylomata lata consists of epithelial hyperplasia as well as lymphocytic and plasma cell infiltrates. It is diagnosed by serologic testing as well as immunohistochemical staining or dark-field microscopy.
First-line treatment of secondary syphilis is a single dose of benzathine penicillin G administered intramuscularly.5 However, a 14-day course of oral doxycycline can be used in patients with a penicillin allergy. When compliance and follow-up cannot be guaranteed, penicillin desensitization and treatment with benzathine penicillin G is recommended. Clinical evaluation and repeat serologic testing should be performed at 6 and 12 months follow-up, or more frequently if clinically indicated.5
The Diagnosis: Condyloma Latum
Laboratory test results were notable for a rapid plasma reagin titer of 1:512, a positive Treponema pallidum particle agglutination test, negative rectal nucleic acid amplification tests for gonorrhea and chlamydia, and a negative herpes simplex virus polymerase chain reaction. A VDRL test of cerebrospinal fluid from a lumbar puncture was negative. Histopathology of the punch biopsy sample revealed marked verrucous epidermal hyperplasia without keratinocytic atypia and with mixed inflammation (Figure 1), while immunohistochemical staining showed numerus T pallidum organisms (Figure 2). A diagnosis of condyloma latum was made based on the laboratory, lumbar puncture, and punch biopsy results. Due to a penicillin allergy, the patient was treated with oral doxycycline for 14 days. On follow-up at day 12 of therapy, he reported cessation of rectal pain, and resolution of anal lesions was noted on physical examination.
Condylomata lata are highly infectious cutaneous lesions that can manifest during secondary syphilis.1 They typically are described as white or gray, raised, flatappearing plaques and occur in moist areas or skin folds including the anus, scrotum, and vulva. However, these lesions also have been reported in the axillae, umbilicus, nasolabial folds, and other anatomic areas.1,2 The lesions can be painful and often manifest in multiples, especially in patients living with HIV.3
Condylomata lata can have a verrucous appearance and may mimic other anogenital lesions, such as condylomata acuminata, genital herpes, and malignant tumors, leading to an initial misdiagnosis.1,2 Condylomata lata should always be included in the differential when evaluating anogenital lesions. Other conditions in the differential diagnosis include psoriasis, typically manifesting as erythematous plaques with silver scale, and molluscum contagiosum, appearing as small umbilicated papules on physical examination.
Condylomata lata have been reported to occur in 6% to 23% of patients with secondary syphilis.1 Although secondary syphilis more typically manifests with a diffuse maculopapular rash, condylomata lata may be the sole dermatologic manifestation.4
Histopathology of condylomata lata consists of epithelial hyperplasia as well as lymphocytic and plasma cell infiltrates. It is diagnosed by serologic testing as well as immunohistochemical staining or dark-field microscopy.
First-line treatment of secondary syphilis is a single dose of benzathine penicillin G administered intramuscularly.5 However, a 14-day course of oral doxycycline can be used in patients with a penicillin allergy. When compliance and follow-up cannot be guaranteed, penicillin desensitization and treatment with benzathine penicillin G is recommended. Clinical evaluation and repeat serologic testing should be performed at 6 and 12 months follow-up, or more frequently if clinically indicated.5
- Pourang A, Fung MA, Tartar D, et al. Condyloma lata in secondary syphilis. JAAD Case Rep. 2021;10:18-21. doi:10.1016/j.jdcr.2021.01.025
- Liu Z, Wang L, Zhang G, et al. Warty mucosal lesions: oral condyloma lata of secondary syphilis. Indian J Dermatol Venereol Leprol. 2017;83:277. doi:10.4103/0378-6323.191129
- Rompalo AM, Joesoef MR, O’Donnell JA, et al; Syphilis and HIV Study Group. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis.2001;28:158-165.
- Kumar P, Das A, Mondal A. Secondary syphilis: an unusual presentation. Indian J Sex Transm Dis AIDS. 2017;38:98-99. doi:10.4103/0253-7184.194318
- Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70:1-187. doi:10.15585/mmwr.rr7004a1
- Pourang A, Fung MA, Tartar D, et al. Condyloma lata in secondary syphilis. JAAD Case Rep. 2021;10:18-21. doi:10.1016/j.jdcr.2021.01.025
- Liu Z, Wang L, Zhang G, et al. Warty mucosal lesions: oral condyloma lata of secondary syphilis. Indian J Dermatol Venereol Leprol. 2017;83:277. doi:10.4103/0378-6323.191129
- Rompalo AM, Joesoef MR, O’Donnell JA, et al; Syphilis and HIV Study Group. Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study. Sex Transm Dis.2001;28:158-165.
- Kumar P, Das A, Mondal A. Secondary syphilis: an unusual presentation. Indian J Sex Transm Dis AIDS. 2017;38:98-99. doi:10.4103/0253-7184.194318
- Workowski KA, Bachmann LH, Chan PA, et al. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70:1-187. doi:10.15585/mmwr.rr7004a1
A 24-year-old man presented to the emergency department with rectal pain and lesions of 3 weeks’ duration that were progressively worsening. He had a medical history of poorly controlled HIV, cerebral toxoplasmosis, and genital herpes, as well as a social history of sexual activity with other men.
He had been diagnosed with HIV 7 years prior and had been off therapy until 1 year prior to the current presentation, when he was hospitalized with encephalopathy (CD4 count, <50 cells/mm3). A diagnosis of cerebral toxoplasmosis was made, and he began a treatment regimen of sulfadiazine, pyrimethamine, and leucovorin, as well as bictegravir, emtricitabine, and tenofovir alafenamide. Since then, the patient admitted to difficulty with medication adherence.
Rapid plasma reagin, gonorrhea, and chlamydia testing were negative during a routine workup 6 months prior to the current presentation. He initially presented to an urgent care clinic for evaluation of the rectal pain and lesions and was treated empirically with topical podofilox. He presented to the emergency department 1 week later (3 weeks after symptom onset) with anal warts and apparent vesicular lesions. Empiric treatment with oral valacyclovir was prescribed.
Despite these treatments, the rectal pain became severe—especially upon sitting, defecation, and physical exertion—prompting further evaluation. Physical examination revealed soft, flat-topped, moist-appearing, gray plaques with minimal surrounding erythema at the anus. Laboratory test results demonstrated a CD4 count of 161 cells/mm3 and an HIV viral load of 137 copies/mL.
The Shield Sign of Cutaneous Metastases Is Associated With Carcinoma Hemorrhagiectoides
To the Editor:
We read with interest the Case Letter from Wang et al1 (Cutis. 2023;112:E13-E15) of a 60-year-old man whose metastatic salivary duct adenocarcinoma manifested with the shield sign as well as carcinoma hemorrhagiectoides. Cutaneous metastases have seldom been described in association with salivary duct carcinoma.2-7 In addition, carcinoma hemorrhagiectoides–associated shield sign has not been commonly reported.5,8-12
Salivary duct carcinoma—an uncommon head and neck malignancy characterized by androgen receptor expression—rarely is associated with cutaneous metastases. Based on a PubMed search of articles indexed for MEDLINE using the terms cutaneous, metastatic, salivary duct carcinoma, and/or skin, including the patient described by Wang et al,1 there have been 8 individuals with cutaneous metastases from this cancer. The morphology of the cutaneous metastases has varied from angiomatous to angiokeratomalike (black and keratotic) papules, bullae, macules (red), papules and nodules (erythematous and scaly), plaques (cellulitislike and confluent that were purpuric, hemorrhagic, and violaceous), pseudovesicles, purpuric papules, subcutaneous nodules, and an ulcer (superficial and mimicked a basal cell carcinoma).1-7 Remarkably, 4 of 8 patients (50%) with salivary duct carcinoma cutaneous metastases presented with a shield sign,5,7 including the case reported by Wang et al.1
The shield sign is a distinctive clinical manifestation of cutaneous metastasis.10 It was named to describe the skin metastases located predominantly on the chest area that would be covered by a medieval knight’s shield5,10,12; metastatic lesions also have been noted on the proximal arm and/or the upper back in a similar distribution.8,9 To date, based on a PubMed search of articles indexed for MEDLINE using the search terms breast cancer, carcinoma, hemorrhagiectoides, metastases, salivary duct carcinoma, shield, and/or sign, the shield sign has been described in 6 patients with cutaneous metastases either from salivary duct carcinoma (4 patients)1,5,7 or breast cancer (2 patients).8,9 The shield sign pathologically corresponds to carcinoma hemorrhagiectoides, an inflammatory pattern of cutaneous metastases.5,11
Inflammatory cutaneous metastatic carcinoma has 3 distinctive clinical and pathologic manifestations.11 Carcinoma erysipelatoides and carcinoma telangiectoides were the earlier described variants.11 In 2012, carcinoma hemorrhagiectoides was described as the third pattern of inflammatory cutaneous metastasis.5
Carcinoma erysipelatoides, which clinically mimics cutaneous streptococcal cellulitis, appears as a well-defined erythematous patch or plaque; the tumor cells can be found in the lymphatic vessels and either are absent or minimally present in the dermis. Carcinoma telangiectoides, which clinically mimics idiopathic telangiectases, appears as an erythematous patch with prominent telangiectases; the tumor cells can be found in the blood vessels and are either absent or minimally present in the dermis. Carcinoma hemorrhagiectoides appears as purpuric or violaceous indurated plaques; the tumor cells are not only found in the blood vessels, in the lymphatic vessels, or both, but also can be mildly to extensively present in the dermis.5,10,11
In conclusion, the shield sign is a unique presentation of inflammatory cutaneous metastatic carcinoma, which is associated with carcinoma hemorrhagiectoides. The clinical features of the infiltrated plaques correspond to the presence of tumor cells in the blood vessels, lymphatic vessels, and the dermis; in addition, the purpuric and violaceous appearance correlates with the presence of extravasated erythrocytes or hemorrhage in the dermis. To date, half of the patients with skin metastases from salivary duct carcinoma have presented with carcinoma hemorrhagiectoides–associated shield sign.
Authors’ Response
We appreciate and welcome the comments provided by the authors. Drawing attention to unusual pathologic manifestations of cutaneous metastatic salivary duct carcinoma manifesting with the shield sign, the authors present a comprehensive review of 3 distinctive presentations: carcinoma erysipelatoides, carcinoma telangiectoides, and carcinoma hemorrhagiectoides. The inclusion of these variants enriches the discussion and makes this letter a valuable addition to the literature on cutaneous metastatic carcinoma, particularly metastatic salivary duct carcinoma.
Xintong Wang, MD; William H. Westra, MD
From the Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
The authors report no conflict of interest.
- Wang X, Vyas NS, Alghamdi AA, et al. Cutaneous presentation of metastatic salivary duct carcinoma. Cutis. 2023;112:E13-E15.
- Pollock JL, Catalano E. Metastatic ductal carcinoma of the parotid gland in a patient with sarcoidosis. Arch Dermatol. 1979;115:1098-1099.
- Pollock JL. Metastatic carcinoma of the parotid gland resembling carcinoma of the breast. J Am Acad Dermatol. 1996;34:1093.
- Aygit AC, Top H, Cakir B, et al. Salivary duct carcinoma of the parotid gland metastasizing to the skin: a case report and review of the literature. Am J Dermatopathol. 2005;27:48-50.
- Cohen PR, Prieto VG, Piha-Paul SA, et al. The “shield sign” in two men with metastatic salivary duct carcinoma to the skin: cutaneous metastases presenting as carcinoma hemorrhagiectoides. J Clin Aesthet Dermatol. 2012;5:27-36.
- Chakari W, Andersen L, Anderson JL. Cutaneous metastases from salivary duct carcinoma of the submandibular gland. Case Rep Dermatol. 2017;9:254-258.
- Shin JY, Eun DH, Lee JY, et al. A case of cutaneous metastases of salivary duct carcinoma mimicking radiation recall dermatitis. Ann Dermatol. 2020;32:436-438.
- Aravena RC, Aravena DC, Velasco MJ, et al. Carcinoma hemorrhagiectoides: case report of an uncommon presentation of cutaneous metastatic breast carcinoma. Dermatol Online J. 2017;23:13030/qt3hn3z850.
- Smith KA, Basko-Plluska J, Kothari AD, et al. Cutaneous metastatic breast adenocarcinoma. Cutis. 2020;105:E20-E22.
- Cohen PR, Kurzrock R. Cutaneous metastatic cancer: carcinoma hemorrhagiectoides presenting as the shield sign. Cureus. 2021;13:e12627.
- Cohen PR. Pleomorphic appearance of breast cancer cutaneous metastases. Cureus. 2021;13:e20301.
- Cohen PR, Prieto VG, Kurzrock R. Tumor lysis syndrome: introduction of a cutaneous variant and a new classification system. Cureus. 2021;13:e13816.
To the Editor:
We read with interest the Case Letter from Wang et al1 (Cutis. 2023;112:E13-E15) of a 60-year-old man whose metastatic salivary duct adenocarcinoma manifested with the shield sign as well as carcinoma hemorrhagiectoides. Cutaneous metastases have seldom been described in association with salivary duct carcinoma.2-7 In addition, carcinoma hemorrhagiectoides–associated shield sign has not been commonly reported.5,8-12
Salivary duct carcinoma—an uncommon head and neck malignancy characterized by androgen receptor expression—rarely is associated with cutaneous metastases. Based on a PubMed search of articles indexed for MEDLINE using the terms cutaneous, metastatic, salivary duct carcinoma, and/or skin, including the patient described by Wang et al,1 there have been 8 individuals with cutaneous metastases from this cancer. The morphology of the cutaneous metastases has varied from angiomatous to angiokeratomalike (black and keratotic) papules, bullae, macules (red), papules and nodules (erythematous and scaly), plaques (cellulitislike and confluent that were purpuric, hemorrhagic, and violaceous), pseudovesicles, purpuric papules, subcutaneous nodules, and an ulcer (superficial and mimicked a basal cell carcinoma).1-7 Remarkably, 4 of 8 patients (50%) with salivary duct carcinoma cutaneous metastases presented with a shield sign,5,7 including the case reported by Wang et al.1
The shield sign is a distinctive clinical manifestation of cutaneous metastasis.10 It was named to describe the skin metastases located predominantly on the chest area that would be covered by a medieval knight’s shield5,10,12; metastatic lesions also have been noted on the proximal arm and/or the upper back in a similar distribution.8,9 To date, based on a PubMed search of articles indexed for MEDLINE using the search terms breast cancer, carcinoma, hemorrhagiectoides, metastases, salivary duct carcinoma, shield, and/or sign, the shield sign has been described in 6 patients with cutaneous metastases either from salivary duct carcinoma (4 patients)1,5,7 or breast cancer (2 patients).8,9 The shield sign pathologically corresponds to carcinoma hemorrhagiectoides, an inflammatory pattern of cutaneous metastases.5,11
Inflammatory cutaneous metastatic carcinoma has 3 distinctive clinical and pathologic manifestations.11 Carcinoma erysipelatoides and carcinoma telangiectoides were the earlier described variants.11 In 2012, carcinoma hemorrhagiectoides was described as the third pattern of inflammatory cutaneous metastasis.5
Carcinoma erysipelatoides, which clinically mimics cutaneous streptococcal cellulitis, appears as a well-defined erythematous patch or plaque; the tumor cells can be found in the lymphatic vessels and either are absent or minimally present in the dermis. Carcinoma telangiectoides, which clinically mimics idiopathic telangiectases, appears as an erythematous patch with prominent telangiectases; the tumor cells can be found in the blood vessels and are either absent or minimally present in the dermis. Carcinoma hemorrhagiectoides appears as purpuric or violaceous indurated plaques; the tumor cells are not only found in the blood vessels, in the lymphatic vessels, or both, but also can be mildly to extensively present in the dermis.5,10,11
In conclusion, the shield sign is a unique presentation of inflammatory cutaneous metastatic carcinoma, which is associated with carcinoma hemorrhagiectoides. The clinical features of the infiltrated plaques correspond to the presence of tumor cells in the blood vessels, lymphatic vessels, and the dermis; in addition, the purpuric and violaceous appearance correlates with the presence of extravasated erythrocytes or hemorrhage in the dermis. To date, half of the patients with skin metastases from salivary duct carcinoma have presented with carcinoma hemorrhagiectoides–associated shield sign.
Authors’ Response
We appreciate and welcome the comments provided by the authors. Drawing attention to unusual pathologic manifestations of cutaneous metastatic salivary duct carcinoma manifesting with the shield sign, the authors present a comprehensive review of 3 distinctive presentations: carcinoma erysipelatoides, carcinoma telangiectoides, and carcinoma hemorrhagiectoides. The inclusion of these variants enriches the discussion and makes this letter a valuable addition to the literature on cutaneous metastatic carcinoma, particularly metastatic salivary duct carcinoma.
Xintong Wang, MD; William H. Westra, MD
From the Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
The authors report no conflict of interest.
To the Editor:
We read with interest the Case Letter from Wang et al1 (Cutis. 2023;112:E13-E15) of a 60-year-old man whose metastatic salivary duct adenocarcinoma manifested with the shield sign as well as carcinoma hemorrhagiectoides. Cutaneous metastases have seldom been described in association with salivary duct carcinoma.2-7 In addition, carcinoma hemorrhagiectoides–associated shield sign has not been commonly reported.5,8-12
Salivary duct carcinoma—an uncommon head and neck malignancy characterized by androgen receptor expression—rarely is associated with cutaneous metastases. Based on a PubMed search of articles indexed for MEDLINE using the terms cutaneous, metastatic, salivary duct carcinoma, and/or skin, including the patient described by Wang et al,1 there have been 8 individuals with cutaneous metastases from this cancer. The morphology of the cutaneous metastases has varied from angiomatous to angiokeratomalike (black and keratotic) papules, bullae, macules (red), papules and nodules (erythematous and scaly), plaques (cellulitislike and confluent that were purpuric, hemorrhagic, and violaceous), pseudovesicles, purpuric papules, subcutaneous nodules, and an ulcer (superficial and mimicked a basal cell carcinoma).1-7 Remarkably, 4 of 8 patients (50%) with salivary duct carcinoma cutaneous metastases presented with a shield sign,5,7 including the case reported by Wang et al.1
The shield sign is a distinctive clinical manifestation of cutaneous metastasis.10 It was named to describe the skin metastases located predominantly on the chest area that would be covered by a medieval knight’s shield5,10,12; metastatic lesions also have been noted on the proximal arm and/or the upper back in a similar distribution.8,9 To date, based on a PubMed search of articles indexed for MEDLINE using the search terms breast cancer, carcinoma, hemorrhagiectoides, metastases, salivary duct carcinoma, shield, and/or sign, the shield sign has been described in 6 patients with cutaneous metastases either from salivary duct carcinoma (4 patients)1,5,7 or breast cancer (2 patients).8,9 The shield sign pathologically corresponds to carcinoma hemorrhagiectoides, an inflammatory pattern of cutaneous metastases.5,11
Inflammatory cutaneous metastatic carcinoma has 3 distinctive clinical and pathologic manifestations.11 Carcinoma erysipelatoides and carcinoma telangiectoides were the earlier described variants.11 In 2012, carcinoma hemorrhagiectoides was described as the third pattern of inflammatory cutaneous metastasis.5
Carcinoma erysipelatoides, which clinically mimics cutaneous streptococcal cellulitis, appears as a well-defined erythematous patch or plaque; the tumor cells can be found in the lymphatic vessels and either are absent or minimally present in the dermis. Carcinoma telangiectoides, which clinically mimics idiopathic telangiectases, appears as an erythematous patch with prominent telangiectases; the tumor cells can be found in the blood vessels and are either absent or minimally present in the dermis. Carcinoma hemorrhagiectoides appears as purpuric or violaceous indurated plaques; the tumor cells are not only found in the blood vessels, in the lymphatic vessels, or both, but also can be mildly to extensively present in the dermis.5,10,11
In conclusion, the shield sign is a unique presentation of inflammatory cutaneous metastatic carcinoma, which is associated with carcinoma hemorrhagiectoides. The clinical features of the infiltrated plaques correspond to the presence of tumor cells in the blood vessels, lymphatic vessels, and the dermis; in addition, the purpuric and violaceous appearance correlates with the presence of extravasated erythrocytes or hemorrhage in the dermis. To date, half of the patients with skin metastases from salivary duct carcinoma have presented with carcinoma hemorrhagiectoides–associated shield sign.
Authors’ Response
We appreciate and welcome the comments provided by the authors. Drawing attention to unusual pathologic manifestations of cutaneous metastatic salivary duct carcinoma manifesting with the shield sign, the authors present a comprehensive review of 3 distinctive presentations: carcinoma erysipelatoides, carcinoma telangiectoides, and carcinoma hemorrhagiectoides. The inclusion of these variants enriches the discussion and makes this letter a valuable addition to the literature on cutaneous metastatic carcinoma, particularly metastatic salivary duct carcinoma.
Xintong Wang, MD; William H. Westra, MD
From the Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
The authors report no conflict of interest.
- Wang X, Vyas NS, Alghamdi AA, et al. Cutaneous presentation of metastatic salivary duct carcinoma. Cutis. 2023;112:E13-E15.
- Pollock JL, Catalano E. Metastatic ductal carcinoma of the parotid gland in a patient with sarcoidosis. Arch Dermatol. 1979;115:1098-1099.
- Pollock JL. Metastatic carcinoma of the parotid gland resembling carcinoma of the breast. J Am Acad Dermatol. 1996;34:1093.
- Aygit AC, Top H, Cakir B, et al. Salivary duct carcinoma of the parotid gland metastasizing to the skin: a case report and review of the literature. Am J Dermatopathol. 2005;27:48-50.
- Cohen PR, Prieto VG, Piha-Paul SA, et al. The “shield sign” in two men with metastatic salivary duct carcinoma to the skin: cutaneous metastases presenting as carcinoma hemorrhagiectoides. J Clin Aesthet Dermatol. 2012;5:27-36.
- Chakari W, Andersen L, Anderson JL. Cutaneous metastases from salivary duct carcinoma of the submandibular gland. Case Rep Dermatol. 2017;9:254-258.
- Shin JY, Eun DH, Lee JY, et al. A case of cutaneous metastases of salivary duct carcinoma mimicking radiation recall dermatitis. Ann Dermatol. 2020;32:436-438.
- Aravena RC, Aravena DC, Velasco MJ, et al. Carcinoma hemorrhagiectoides: case report of an uncommon presentation of cutaneous metastatic breast carcinoma. Dermatol Online J. 2017;23:13030/qt3hn3z850.
- Smith KA, Basko-Plluska J, Kothari AD, et al. Cutaneous metastatic breast adenocarcinoma. Cutis. 2020;105:E20-E22.
- Cohen PR, Kurzrock R. Cutaneous metastatic cancer: carcinoma hemorrhagiectoides presenting as the shield sign. Cureus. 2021;13:e12627.
- Cohen PR. Pleomorphic appearance of breast cancer cutaneous metastases. Cureus. 2021;13:e20301.
- Cohen PR, Prieto VG, Kurzrock R. Tumor lysis syndrome: introduction of a cutaneous variant and a new classification system. Cureus. 2021;13:e13816.
- Wang X, Vyas NS, Alghamdi AA, et al. Cutaneous presentation of metastatic salivary duct carcinoma. Cutis. 2023;112:E13-E15.
- Pollock JL, Catalano E. Metastatic ductal carcinoma of the parotid gland in a patient with sarcoidosis. Arch Dermatol. 1979;115:1098-1099.
- Pollock JL. Metastatic carcinoma of the parotid gland resembling carcinoma of the breast. J Am Acad Dermatol. 1996;34:1093.
- Aygit AC, Top H, Cakir B, et al. Salivary duct carcinoma of the parotid gland metastasizing to the skin: a case report and review of the literature. Am J Dermatopathol. 2005;27:48-50.
- Cohen PR, Prieto VG, Piha-Paul SA, et al. The “shield sign” in two men with metastatic salivary duct carcinoma to the skin: cutaneous metastases presenting as carcinoma hemorrhagiectoides. J Clin Aesthet Dermatol. 2012;5:27-36.
- Chakari W, Andersen L, Anderson JL. Cutaneous metastases from salivary duct carcinoma of the submandibular gland. Case Rep Dermatol. 2017;9:254-258.
- Shin JY, Eun DH, Lee JY, et al. A case of cutaneous metastases of salivary duct carcinoma mimicking radiation recall dermatitis. Ann Dermatol. 2020;32:436-438.
- Aravena RC, Aravena DC, Velasco MJ, et al. Carcinoma hemorrhagiectoides: case report of an uncommon presentation of cutaneous metastatic breast carcinoma. Dermatol Online J. 2017;23:13030/qt3hn3z850.
- Smith KA, Basko-Plluska J, Kothari AD, et al. Cutaneous metastatic breast adenocarcinoma. Cutis. 2020;105:E20-E22.
- Cohen PR, Kurzrock R. Cutaneous metastatic cancer: carcinoma hemorrhagiectoides presenting as the shield sign. Cureus. 2021;13:e12627.
- Cohen PR. Pleomorphic appearance of breast cancer cutaneous metastases. Cureus. 2021;13:e20301.
- Cohen PR, Prieto VG, Kurzrock R. Tumor lysis syndrome: introduction of a cutaneous variant and a new classification system. Cureus. 2021;13:e13816.
Pruritic Rash on the Neck and Back
The Diagnosis: Prurigo Pigmentosa
A comprehensive metabolic panel collected from our patient 1 month earlier did not reveal any abnormalities. Serum methylmalonic acid and homocysteine were both elevated at 417 nmol/L (reference range [for those aged 2–59 years], 55–335 nmol/L) and 23 μmol/L (reference range, 5–15 μmol/L), respectively. Serum folate and 25-hydroxyvitamin D were low at 3.1 ng/mL (reference range, >4.8 ng/mL) and 5 ng/mL (reference range, 30–80 ng/mL), respectively. Vitamin B12 was within reference range. Two 4-mm punch biopsies collected from the upper back showed spongiotic dermatitis.
Our patient’s histopathology results along with the rash distribution and medical history of anorexia increased suspicion for prurigo pigmentosa. A trial of oral doxycycline 100 mg twice daily for 2 weeks was prescribed. At 2-week follow-up, the patient’s mother revealed a history of ketosis in her daughter, solidifying the diagnosis. The patient was counseled on maintaining a healthy diet to prevent future breakouts. The patient’s rash resolved with diet modification and doxycycline; however, it recurred upon relapse of anorexia 4 months later.
Prurigo pigmentosa, originally identified in Japan by Nagashima et al,1 is an uncommon recurrent inflammatory disorder predominantly observed in young adults of Asian descent. Subsequently, it was reported to occur among individuals from different ethnic backgrounds, indicating potential underdiagnosis or misdiagnosis in Western countries.2 Although a direct pathogenic cause for prurigo pigmentosa has not been identified, a strong association has been linked to diet, specifically when ketosis is induced, such as in ketogenic diets and anorexia nervosa.3-5 Other possible causes include sunlight exposure, clothing friction, and sweating.1,5 The disease course is characterized by intermittent flares and spontaneous resolution, with recurrence in most cases. During the active phase, intensely pruritic, papulovesicular or urticarial papules are predominant and most often are localized to the upper body and torso, including the back, shoulders, neck, and chest.5 These flares can persist for several days but eventually subside, leaving behind a characteristic reticular pigmentation that can persist for months.5 First-line treatment often involves the use of tetracycline antibiotics, such as minocycline or doxycycline. 2,4,5 Dapsone often is used with successful resolution. 6 Dietary modifications also have been found to be effective in treating prurigo pigmentosa, particularly in patients presenting with dietary insufficiency.6,7 Increased carbohydrate intake has been shown to promote resolution. 6 Topical corticosteroids demonstrate limited efficacy in controlling flares.6,8
Histopathology has been variably described, with initial findings reported as nonspecific.1 However, it was later described as a distinct inflammatory disease of the skin with histologically distinct stages.2,9 Early stages reveal scattered dermal, dermal papillary, and perivascular neutrophilic infiltration.9 The lesions then progress and become fully developed, at which point neutrophilic infiltration becomes more prominent, accompanied by the presence of intraepidermal neutrophils and spongiosis. As the lesions resolve, the infiltration transitions to lymphocytic, and lichenoid changes can sometimes be appreciated along with epidermal hyperplasia, hyperpigmentation, and dermal melanophages.9 Although these findings aid in the diagnosis of prurigo pigmentosa, a clinicopathologic correlation is necessary to establish a definitive diagnosis.
Because prurigo pigmentosa is rare, it often is misdiagnosed as another condition with a similar presentation and nonspecific biopsy findings.6 Allergic contact dermatitis is a common type IV delayed hypersensitivity reaction that manifests similar to prurigo pigmentosa with pruritus and a well-demarcated distribution10 that is related to the pattern of allergen exposure; in the case of allergic contact dermatitis related to textiles, a well-demarcated rash will appear in the distribution area of the associated clothing (eg, shirt, pants, shorts).11 Development of allergy involves exposure and sensitization to an allergen, followed by subsequent re-exposure that results in cutaneous T-cell activation and inflammation. 10 Histopathology shows nonspecific spongiotic inflammation, and the gold standard for diagnosis is patch testing to identify the causative substance(s). Definitive treatment includes avoidance of identified allergies; however, if patients are unable to avoid the allergen or the cause is unknown, then corticosteroids, antihistamines, and/or calcineurin inhibitors are beneficial in controlling symptoms and flares.10
Pityrosporum folliculitis (also known as Malassezia folliculitis) is a fungal acneform condition that arises from overgrowth of normal skin flora Malassezia yeast,12 which may be due to occlusion of follicles or disruption of the normal flora composition. Clinically, the manifestation may resemble prurigo pigmentosa in distribution and presence of intense pruritus. However, pustular lesions and involvement of the face can aid in differentiating Pityrosporum from prurigo pigmentosa, which can be confirmed via periodic acid–Schiff staining with numerous round yeasts within affected follicles. Oral antifungal therapy typically yields rapid improvement and resolution of symptoms.12
Urticaria and prurigo pigmentosa share similar clinical characteristics, with symptoms of intense pruritus and urticarial lesions on the trunk.2,13 Urticaria is an IgEmediated type I hypersensitivity reaction characterized by wheals (ie, edematous red or pink lesions of variable size and shape that typically resolve spontaneously within 24–48 hours).13 Notably, urticaria will improve and in some cases completely resolve with antihistamines or anti-IgE antibody treatment, which may aid in distinguishing it from prurigo pigmentosa, as the latter typically exhibits limited response to such treatment.2 Histopathology also can assist in the diagnosis by ruling out other causes of similar rash; however, biopsies are not routinely done unless other inflammatory conditions are of high suspicion.13
Bullous pemphigoid is an autoimmune, subepidermal, blistering dermatosis that is most common among the elderly.14 It is characterized by the presence of IgG antibodies that target BP180 and BP230, which initiate inflammatory cascades that lead to tissue damage and blister formation. It typically manifests as pruritic blistering eruptions, primarily on the limbs and trunk, but may involve the head, neck, or palmoplantar regions.14 Although blistering eruptions are the prodrome of the disease, some cases may present with nonspecific urticarial or eczematous lesions14,15 that may resemble prurigo pigmentosa. The diagnosis is confirmed through direct immunofluorescence microscopy of biopsied lesions, which reveals IgG and/or C3 deposits along the dermoepidermal junction.14 Management of bullous pemphigoid involves timely initiation of dapsone or systemic corticosteroids, which have demonstrated high efficacy in controlling the disease and its associated symptoms.15
Our patient achieved a favorable response to diet modification and doxycycline therapy consistent with the diagnosis of prurigo pigmentosa. Unfortunately, the condition recurred following a relapse of anorexia. Management of prurigo pigmentosa necessitates not only accurate diagnosis but also addressing any underlying factors that may contribute to disease exacerbation. We anticipate the eating disorder will pose a major challenge in achieving long-term control of prurigo pigmentosa.
- Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Jpn J Dermatol. 1971;81:38-39.
- Boer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease? Indian J Dermatol Venereol Leprol. 2006;72:405-409. doi:10.4103/0378-6323.29334
- Michaels JD, Hoss E, DiCaudo DJ, et al. Prurigo pigmentosa after a strict ketogenic diet. Pediatr Dermatol. 2013;32:248-251. doi:10.1111/pde.12275
- Teraki Y, Teraki E, Kawashima M, et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol. 1996;34:509-511. doi:10.1016/s0190-9622(96)90460-0
- Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2003;25:117-129. doi:10.1097/00000372-200304000-00005
- Mufti A, Mirali S, Abduelmula A, et al. Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): a systematic review of the literature. JAAD Int. 2021;3:79-87. doi:10.1016/j.jdin.2021.03.003
- Wong M, Lee E, Wu Y, et al. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawaii J Med Public Health. 2018;77:114-117.
- Almaani N, Al-Tarawneh AH, Msallam H. Prurigo pigmentosa: a clinicopathological report of three Middle Eastern patients. Case Rep Dermatol Med. 2018;2018:9406797. doi:10.1155/2018/9406797
- Kim JK, Chung WK, Chang SE, et al. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea. J Dermatol. 2012;39:891-897. doi:10.1111/j.1346-8138.2012.01640.x
- Mowad CM, Anderson B, Scheinman P, et al. Allergic contact dermatitis: patient diagnosis and evaluation. J Am Acad Dermatol. 2016;74:1029-1040. doi:10.1016/j.jaad.2015.02.1139
- Lazarov A, Cordoba M, Plosk N, et al. Atypical and unusual clinical manifestations of contact dermatitis to clothing (textile contact dermatitis)—case presentation and review of the literature. Dermatol Online J. 2003;9. doi:10.5070/d30kd1d259
- Rubenstein RM, Malerich SA. Malassezia (Pityrosporum) folliculitis. J Clin Aesthet Dermatol. 2014;7:37-41.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133:1270-1277. doi:10.1016/j.jaci.2014.02.036
- della Torre R, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. Br J Dermatol. 2012;167:1111-1117. doi:10.1111/j.1365-2133.2012.11108.x
- Alonso-Llamazares J, Rogers RS 3rd, Oursler JR, et al. Bullous pemphigoid presenting as generalized pruritus: observations in six patients. Int J Dermatol. 1998;37:508-514.
The Diagnosis: Prurigo Pigmentosa
A comprehensive metabolic panel collected from our patient 1 month earlier did not reveal any abnormalities. Serum methylmalonic acid and homocysteine were both elevated at 417 nmol/L (reference range [for those aged 2–59 years], 55–335 nmol/L) and 23 μmol/L (reference range, 5–15 μmol/L), respectively. Serum folate and 25-hydroxyvitamin D were low at 3.1 ng/mL (reference range, >4.8 ng/mL) and 5 ng/mL (reference range, 30–80 ng/mL), respectively. Vitamin B12 was within reference range. Two 4-mm punch biopsies collected from the upper back showed spongiotic dermatitis.
Our patient’s histopathology results along with the rash distribution and medical history of anorexia increased suspicion for prurigo pigmentosa. A trial of oral doxycycline 100 mg twice daily for 2 weeks was prescribed. At 2-week follow-up, the patient’s mother revealed a history of ketosis in her daughter, solidifying the diagnosis. The patient was counseled on maintaining a healthy diet to prevent future breakouts. The patient’s rash resolved with diet modification and doxycycline; however, it recurred upon relapse of anorexia 4 months later.
Prurigo pigmentosa, originally identified in Japan by Nagashima et al,1 is an uncommon recurrent inflammatory disorder predominantly observed in young adults of Asian descent. Subsequently, it was reported to occur among individuals from different ethnic backgrounds, indicating potential underdiagnosis or misdiagnosis in Western countries.2 Although a direct pathogenic cause for prurigo pigmentosa has not been identified, a strong association has been linked to diet, specifically when ketosis is induced, such as in ketogenic diets and anorexia nervosa.3-5 Other possible causes include sunlight exposure, clothing friction, and sweating.1,5 The disease course is characterized by intermittent flares and spontaneous resolution, with recurrence in most cases. During the active phase, intensely pruritic, papulovesicular or urticarial papules are predominant and most often are localized to the upper body and torso, including the back, shoulders, neck, and chest.5 These flares can persist for several days but eventually subside, leaving behind a characteristic reticular pigmentation that can persist for months.5 First-line treatment often involves the use of tetracycline antibiotics, such as minocycline or doxycycline. 2,4,5 Dapsone often is used with successful resolution. 6 Dietary modifications also have been found to be effective in treating prurigo pigmentosa, particularly in patients presenting with dietary insufficiency.6,7 Increased carbohydrate intake has been shown to promote resolution. 6 Topical corticosteroids demonstrate limited efficacy in controlling flares.6,8
Histopathology has been variably described, with initial findings reported as nonspecific.1 However, it was later described as a distinct inflammatory disease of the skin with histologically distinct stages.2,9 Early stages reveal scattered dermal, dermal papillary, and perivascular neutrophilic infiltration.9 The lesions then progress and become fully developed, at which point neutrophilic infiltration becomes more prominent, accompanied by the presence of intraepidermal neutrophils and spongiosis. As the lesions resolve, the infiltration transitions to lymphocytic, and lichenoid changes can sometimes be appreciated along with epidermal hyperplasia, hyperpigmentation, and dermal melanophages.9 Although these findings aid in the diagnosis of prurigo pigmentosa, a clinicopathologic correlation is necessary to establish a definitive diagnosis.
Because prurigo pigmentosa is rare, it often is misdiagnosed as another condition with a similar presentation and nonspecific biopsy findings.6 Allergic contact dermatitis is a common type IV delayed hypersensitivity reaction that manifests similar to prurigo pigmentosa with pruritus and a well-demarcated distribution10 that is related to the pattern of allergen exposure; in the case of allergic contact dermatitis related to textiles, a well-demarcated rash will appear in the distribution area of the associated clothing (eg, shirt, pants, shorts).11 Development of allergy involves exposure and sensitization to an allergen, followed by subsequent re-exposure that results in cutaneous T-cell activation and inflammation. 10 Histopathology shows nonspecific spongiotic inflammation, and the gold standard for diagnosis is patch testing to identify the causative substance(s). Definitive treatment includes avoidance of identified allergies; however, if patients are unable to avoid the allergen or the cause is unknown, then corticosteroids, antihistamines, and/or calcineurin inhibitors are beneficial in controlling symptoms and flares.10
Pityrosporum folliculitis (also known as Malassezia folliculitis) is a fungal acneform condition that arises from overgrowth of normal skin flora Malassezia yeast,12 which may be due to occlusion of follicles or disruption of the normal flora composition. Clinically, the manifestation may resemble prurigo pigmentosa in distribution and presence of intense pruritus. However, pustular lesions and involvement of the face can aid in differentiating Pityrosporum from prurigo pigmentosa, which can be confirmed via periodic acid–Schiff staining with numerous round yeasts within affected follicles. Oral antifungal therapy typically yields rapid improvement and resolution of symptoms.12
Urticaria and prurigo pigmentosa share similar clinical characteristics, with symptoms of intense pruritus and urticarial lesions on the trunk.2,13 Urticaria is an IgEmediated type I hypersensitivity reaction characterized by wheals (ie, edematous red or pink lesions of variable size and shape that typically resolve spontaneously within 24–48 hours).13 Notably, urticaria will improve and in some cases completely resolve with antihistamines or anti-IgE antibody treatment, which may aid in distinguishing it from prurigo pigmentosa, as the latter typically exhibits limited response to such treatment.2 Histopathology also can assist in the diagnosis by ruling out other causes of similar rash; however, biopsies are not routinely done unless other inflammatory conditions are of high suspicion.13
Bullous pemphigoid is an autoimmune, subepidermal, blistering dermatosis that is most common among the elderly.14 It is characterized by the presence of IgG antibodies that target BP180 and BP230, which initiate inflammatory cascades that lead to tissue damage and blister formation. It typically manifests as pruritic blistering eruptions, primarily on the limbs and trunk, but may involve the head, neck, or palmoplantar regions.14 Although blistering eruptions are the prodrome of the disease, some cases may present with nonspecific urticarial or eczematous lesions14,15 that may resemble prurigo pigmentosa. The diagnosis is confirmed through direct immunofluorescence microscopy of biopsied lesions, which reveals IgG and/or C3 deposits along the dermoepidermal junction.14 Management of bullous pemphigoid involves timely initiation of dapsone or systemic corticosteroids, which have demonstrated high efficacy in controlling the disease and its associated symptoms.15
Our patient achieved a favorable response to diet modification and doxycycline therapy consistent with the diagnosis of prurigo pigmentosa. Unfortunately, the condition recurred following a relapse of anorexia. Management of prurigo pigmentosa necessitates not only accurate diagnosis but also addressing any underlying factors that may contribute to disease exacerbation. We anticipate the eating disorder will pose a major challenge in achieving long-term control of prurigo pigmentosa.
The Diagnosis: Prurigo Pigmentosa
A comprehensive metabolic panel collected from our patient 1 month earlier did not reveal any abnormalities. Serum methylmalonic acid and homocysteine were both elevated at 417 nmol/L (reference range [for those aged 2–59 years], 55–335 nmol/L) and 23 μmol/L (reference range, 5–15 μmol/L), respectively. Serum folate and 25-hydroxyvitamin D were low at 3.1 ng/mL (reference range, >4.8 ng/mL) and 5 ng/mL (reference range, 30–80 ng/mL), respectively. Vitamin B12 was within reference range. Two 4-mm punch biopsies collected from the upper back showed spongiotic dermatitis.
Our patient’s histopathology results along with the rash distribution and medical history of anorexia increased suspicion for prurigo pigmentosa. A trial of oral doxycycline 100 mg twice daily for 2 weeks was prescribed. At 2-week follow-up, the patient’s mother revealed a history of ketosis in her daughter, solidifying the diagnosis. The patient was counseled on maintaining a healthy diet to prevent future breakouts. The patient’s rash resolved with diet modification and doxycycline; however, it recurred upon relapse of anorexia 4 months later.
Prurigo pigmentosa, originally identified in Japan by Nagashima et al,1 is an uncommon recurrent inflammatory disorder predominantly observed in young adults of Asian descent. Subsequently, it was reported to occur among individuals from different ethnic backgrounds, indicating potential underdiagnosis or misdiagnosis in Western countries.2 Although a direct pathogenic cause for prurigo pigmentosa has not been identified, a strong association has been linked to diet, specifically when ketosis is induced, such as in ketogenic diets and anorexia nervosa.3-5 Other possible causes include sunlight exposure, clothing friction, and sweating.1,5 The disease course is characterized by intermittent flares and spontaneous resolution, with recurrence in most cases. During the active phase, intensely pruritic, papulovesicular or urticarial papules are predominant and most often are localized to the upper body and torso, including the back, shoulders, neck, and chest.5 These flares can persist for several days but eventually subside, leaving behind a characteristic reticular pigmentation that can persist for months.5 First-line treatment often involves the use of tetracycline antibiotics, such as minocycline or doxycycline. 2,4,5 Dapsone often is used with successful resolution. 6 Dietary modifications also have been found to be effective in treating prurigo pigmentosa, particularly in patients presenting with dietary insufficiency.6,7 Increased carbohydrate intake has been shown to promote resolution. 6 Topical corticosteroids demonstrate limited efficacy in controlling flares.6,8
Histopathology has been variably described, with initial findings reported as nonspecific.1 However, it was later described as a distinct inflammatory disease of the skin with histologically distinct stages.2,9 Early stages reveal scattered dermal, dermal papillary, and perivascular neutrophilic infiltration.9 The lesions then progress and become fully developed, at which point neutrophilic infiltration becomes more prominent, accompanied by the presence of intraepidermal neutrophils and spongiosis. As the lesions resolve, the infiltration transitions to lymphocytic, and lichenoid changes can sometimes be appreciated along with epidermal hyperplasia, hyperpigmentation, and dermal melanophages.9 Although these findings aid in the diagnosis of prurigo pigmentosa, a clinicopathologic correlation is necessary to establish a definitive diagnosis.
Because prurigo pigmentosa is rare, it often is misdiagnosed as another condition with a similar presentation and nonspecific biopsy findings.6 Allergic contact dermatitis is a common type IV delayed hypersensitivity reaction that manifests similar to prurigo pigmentosa with pruritus and a well-demarcated distribution10 that is related to the pattern of allergen exposure; in the case of allergic contact dermatitis related to textiles, a well-demarcated rash will appear in the distribution area of the associated clothing (eg, shirt, pants, shorts).11 Development of allergy involves exposure and sensitization to an allergen, followed by subsequent re-exposure that results in cutaneous T-cell activation and inflammation. 10 Histopathology shows nonspecific spongiotic inflammation, and the gold standard for diagnosis is patch testing to identify the causative substance(s). Definitive treatment includes avoidance of identified allergies; however, if patients are unable to avoid the allergen or the cause is unknown, then corticosteroids, antihistamines, and/or calcineurin inhibitors are beneficial in controlling symptoms and flares.10
Pityrosporum folliculitis (also known as Malassezia folliculitis) is a fungal acneform condition that arises from overgrowth of normal skin flora Malassezia yeast,12 which may be due to occlusion of follicles or disruption of the normal flora composition. Clinically, the manifestation may resemble prurigo pigmentosa in distribution and presence of intense pruritus. However, pustular lesions and involvement of the face can aid in differentiating Pityrosporum from prurigo pigmentosa, which can be confirmed via periodic acid–Schiff staining with numerous round yeasts within affected follicles. Oral antifungal therapy typically yields rapid improvement and resolution of symptoms.12
Urticaria and prurigo pigmentosa share similar clinical characteristics, with symptoms of intense pruritus and urticarial lesions on the trunk.2,13 Urticaria is an IgEmediated type I hypersensitivity reaction characterized by wheals (ie, edematous red or pink lesions of variable size and shape that typically resolve spontaneously within 24–48 hours).13 Notably, urticaria will improve and in some cases completely resolve with antihistamines or anti-IgE antibody treatment, which may aid in distinguishing it from prurigo pigmentosa, as the latter typically exhibits limited response to such treatment.2 Histopathology also can assist in the diagnosis by ruling out other causes of similar rash; however, biopsies are not routinely done unless other inflammatory conditions are of high suspicion.13
Bullous pemphigoid is an autoimmune, subepidermal, blistering dermatosis that is most common among the elderly.14 It is characterized by the presence of IgG antibodies that target BP180 and BP230, which initiate inflammatory cascades that lead to tissue damage and blister formation. It typically manifests as pruritic blistering eruptions, primarily on the limbs and trunk, but may involve the head, neck, or palmoplantar regions.14 Although blistering eruptions are the prodrome of the disease, some cases may present with nonspecific urticarial or eczematous lesions14,15 that may resemble prurigo pigmentosa. The diagnosis is confirmed through direct immunofluorescence microscopy of biopsied lesions, which reveals IgG and/or C3 deposits along the dermoepidermal junction.14 Management of bullous pemphigoid involves timely initiation of dapsone or systemic corticosteroids, which have demonstrated high efficacy in controlling the disease and its associated symptoms.15
Our patient achieved a favorable response to diet modification and doxycycline therapy consistent with the diagnosis of prurigo pigmentosa. Unfortunately, the condition recurred following a relapse of anorexia. Management of prurigo pigmentosa necessitates not only accurate diagnosis but also addressing any underlying factors that may contribute to disease exacerbation. We anticipate the eating disorder will pose a major challenge in achieving long-term control of prurigo pigmentosa.
- Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Jpn J Dermatol. 1971;81:38-39.
- Boer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease? Indian J Dermatol Venereol Leprol. 2006;72:405-409. doi:10.4103/0378-6323.29334
- Michaels JD, Hoss E, DiCaudo DJ, et al. Prurigo pigmentosa after a strict ketogenic diet. Pediatr Dermatol. 2013;32:248-251. doi:10.1111/pde.12275
- Teraki Y, Teraki E, Kawashima M, et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol. 1996;34:509-511. doi:10.1016/s0190-9622(96)90460-0
- Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2003;25:117-129. doi:10.1097/00000372-200304000-00005
- Mufti A, Mirali S, Abduelmula A, et al. Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): a systematic review of the literature. JAAD Int. 2021;3:79-87. doi:10.1016/j.jdin.2021.03.003
- Wong M, Lee E, Wu Y, et al. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawaii J Med Public Health. 2018;77:114-117.
- Almaani N, Al-Tarawneh AH, Msallam H. Prurigo pigmentosa: a clinicopathological report of three Middle Eastern patients. Case Rep Dermatol Med. 2018;2018:9406797. doi:10.1155/2018/9406797
- Kim JK, Chung WK, Chang SE, et al. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea. J Dermatol. 2012;39:891-897. doi:10.1111/j.1346-8138.2012.01640.x
- Mowad CM, Anderson B, Scheinman P, et al. Allergic contact dermatitis: patient diagnosis and evaluation. J Am Acad Dermatol. 2016;74:1029-1040. doi:10.1016/j.jaad.2015.02.1139
- Lazarov A, Cordoba M, Plosk N, et al. Atypical and unusual clinical manifestations of contact dermatitis to clothing (textile contact dermatitis)—case presentation and review of the literature. Dermatol Online J. 2003;9. doi:10.5070/d30kd1d259
- Rubenstein RM, Malerich SA. Malassezia (Pityrosporum) folliculitis. J Clin Aesthet Dermatol. 2014;7:37-41.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133:1270-1277. doi:10.1016/j.jaci.2014.02.036
- della Torre R, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. Br J Dermatol. 2012;167:1111-1117. doi:10.1111/j.1365-2133.2012.11108.x
- Alonso-Llamazares J, Rogers RS 3rd, Oursler JR, et al. Bullous pemphigoid presenting as generalized pruritus: observations in six patients. Int J Dermatol. 1998;37:508-514.
- Nagashima M, Ohshiro A, Shimizu N. A peculiar pruriginous dermatosis with gross reticular pigmentation. Jpn J Dermatol. 1971;81:38-39.
- Boer A, Asgari M. Prurigo pigmentosa: an underdiagnosed disease? Indian J Dermatol Venereol Leprol. 2006;72:405-409. doi:10.4103/0378-6323.29334
- Michaels JD, Hoss E, DiCaudo DJ, et al. Prurigo pigmentosa after a strict ketogenic diet. Pediatr Dermatol. 2013;32:248-251. doi:10.1111/pde.12275
- Teraki Y, Teraki E, Kawashima M, et al. Ketosis is involved in the origin of prurigo pigmentosa. J Am Acad Dermatol. 1996;34:509-511. doi:10.1016/s0190-9622(96)90460-0
- Böer A, Misago N, Wolter M, et al. Prurigo pigmentosa: a distinctive inflammatory disease of the skin. Am J Dermatopathol. 2003;25:117-129. doi:10.1097/00000372-200304000-00005
- Mufti A, Mirali S, Abduelmula A, et al. Clinical manifestations and treatment outcomes in prurigo pigmentosa (Nagashima disease): a systematic review of the literature. JAAD Int. 2021;3:79-87. doi:10.1016/j.jdin.2021.03.003
- Wong M, Lee E, Wu Y, et al. Treatment of prurigo pigmentosa with diet modification: a medical case study. Hawaii J Med Public Health. 2018;77:114-117.
- Almaani N, Al-Tarawneh AH, Msallam H. Prurigo pigmentosa: a clinicopathological report of three Middle Eastern patients. Case Rep Dermatol Med. 2018;2018:9406797. doi:10.1155/2018/9406797
- Kim JK, Chung WK, Chang SE, et al. Prurigo pigmentosa: clinicopathological study and analysis of 50 cases in Korea. J Dermatol. 2012;39:891-897. doi:10.1111/j.1346-8138.2012.01640.x
- Mowad CM, Anderson B, Scheinman P, et al. Allergic contact dermatitis: patient diagnosis and evaluation. J Am Acad Dermatol. 2016;74:1029-1040. doi:10.1016/j.jaad.2015.02.1139
- Lazarov A, Cordoba M, Plosk N, et al. Atypical and unusual clinical manifestations of contact dermatitis to clothing (textile contact dermatitis)—case presentation and review of the literature. Dermatol Online J. 2003;9. doi:10.5070/d30kd1d259
- Rubenstein RM, Malerich SA. Malassezia (Pityrosporum) folliculitis. J Clin Aesthet Dermatol. 2014;7:37-41.
- Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133:1270-1277. doi:10.1016/j.jaci.2014.02.036
- della Torre R, Combescure C, Cortés B, et al. Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. Br J Dermatol. 2012;167:1111-1117. doi:10.1111/j.1365-2133.2012.11108.x
- Alonso-Llamazares J, Rogers RS 3rd, Oursler JR, et al. Bullous pemphigoid presenting as generalized pruritus: observations in six patients. Int J Dermatol. 1998;37:508-514.
A 43-year-old woman presented with a pruritic rash across the neck and back of 6 months’ duration that progressively worsened. She had a medical history of anorexia nervosa, herpes zoster with a recent flare, and peripheral neuropathy. Physical examination showed numerous red scaly papules across the upper back and shoulders that coalesced in a reticular pattern. No similar papules were seen elsewhere on the body.
Commentary: IL-13 in PsA, PsA Risk, and Exercise, August 2024
Age at psoriasis onset may influence the risk of developing PsA. Cheemalavagu and colleagues aimed to identify clinical factors associated with PsA development in patients with psoriasis. Using data from a registry that included 384 patients diagnosed with PsA either after or concurrently with their psoriasis diagnosis, they demonstrated that patients with psoriasis onset at the age of 42.6 vs 18.9 years had a 62% shorter time interval between psoriasis and PsA diagnoses and were ~4.6 times more likely to have a concurrent onset of PsA within 6 months of having psoriasis. Thus, older age at onset of psoriasis may indicate a higher risk of developing PsA. This result is consistent with the observation that psoriasis patients carrying the human leukocyte antigen (HLA) C*06:02 allele (associated with early-onset psoriasis) are at lower risk of developing PsA.
Most patients with PsA have psoriasis vulgaris. The differential risk of PsA with different psoriasis phenotypes is less well studied. Therefore, Gershater and colleagues conducted a population-based retrospective cohort study that included patients with psoriasis vulgaris (n = 35,281), pustulosis palmoplantaris (n = 9639), or generalized pustular psoriasis (n = 2281), and who were propensity score–matched with an equal number of control individuals without psoriasis. They demonstrated that compared with control individuals without psoriasis, patients with psoriasis vulgaris had the highest risk for incident PsA (hazard ratio [HR] 87.7), followed by those with generalized pustular psoriasis (HR 26.8) and pustulosis palmoplantaris (HR 15.3). Thus, the study confirms the highest risk for PsA with psoriasis vulgaris, as well as the estimated risk for other, less common forms of psoriasis.
Finally, a cross-sectional study by Toledano and colleagues showed that PsA patients with a sedentary lifestyle (<90 min of physical activity per week) had more enthesitis, fatigue, pain, higher disease activity, greater disease impact, and lower functionality compared with those having a nonsedentary lifestyle. The study indicates that PsA patients would benefit from >90 minutes of physical activity per week.
Additional References
- Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601 Source
- Zhao H, Zhou Y, Wang Z, et al. Plasma proteins and psoriatic arthritis: A proteome-wide Mendelian randomization study. Front Immunol. 2024;15:1417564. doi: 10.3389/fimmu.2024.1417564 Source
Age at psoriasis onset may influence the risk of developing PsA. Cheemalavagu and colleagues aimed to identify clinical factors associated with PsA development in patients with psoriasis. Using data from a registry that included 384 patients diagnosed with PsA either after or concurrently with their psoriasis diagnosis, they demonstrated that patients with psoriasis onset at the age of 42.6 vs 18.9 years had a 62% shorter time interval between psoriasis and PsA diagnoses and were ~4.6 times more likely to have a concurrent onset of PsA within 6 months of having psoriasis. Thus, older age at onset of psoriasis may indicate a higher risk of developing PsA. This result is consistent with the observation that psoriasis patients carrying the human leukocyte antigen (HLA) C*06:02 allele (associated with early-onset psoriasis) are at lower risk of developing PsA.
Most patients with PsA have psoriasis vulgaris. The differential risk of PsA with different psoriasis phenotypes is less well studied. Therefore, Gershater and colleagues conducted a population-based retrospective cohort study that included patients with psoriasis vulgaris (n = 35,281), pustulosis palmoplantaris (n = 9639), or generalized pustular psoriasis (n = 2281), and who were propensity score–matched with an equal number of control individuals without psoriasis. They demonstrated that compared with control individuals without psoriasis, patients with psoriasis vulgaris had the highest risk for incident PsA (hazard ratio [HR] 87.7), followed by those with generalized pustular psoriasis (HR 26.8) and pustulosis palmoplantaris (HR 15.3). Thus, the study confirms the highest risk for PsA with psoriasis vulgaris, as well as the estimated risk for other, less common forms of psoriasis.
Finally, a cross-sectional study by Toledano and colleagues showed that PsA patients with a sedentary lifestyle (<90 min of physical activity per week) had more enthesitis, fatigue, pain, higher disease activity, greater disease impact, and lower functionality compared with those having a nonsedentary lifestyle. The study indicates that PsA patients would benefit from >90 minutes of physical activity per week.
Additional References
- Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601 Source
- Zhao H, Zhou Y, Wang Z, et al. Plasma proteins and psoriatic arthritis: A proteome-wide Mendelian randomization study. Front Immunol. 2024;15:1417564. doi: 10.3389/fimmu.2024.1417564 Source
Age at psoriasis onset may influence the risk of developing PsA. Cheemalavagu and colleagues aimed to identify clinical factors associated with PsA development in patients with psoriasis. Using data from a registry that included 384 patients diagnosed with PsA either after or concurrently with their psoriasis diagnosis, they demonstrated that patients with psoriasis onset at the age of 42.6 vs 18.9 years had a 62% shorter time interval between psoriasis and PsA diagnoses and were ~4.6 times more likely to have a concurrent onset of PsA within 6 months of having psoriasis. Thus, older age at onset of psoriasis may indicate a higher risk of developing PsA. This result is consistent with the observation that psoriasis patients carrying the human leukocyte antigen (HLA) C*06:02 allele (associated with early-onset psoriasis) are at lower risk of developing PsA.
Most patients with PsA have psoriasis vulgaris. The differential risk of PsA with different psoriasis phenotypes is less well studied. Therefore, Gershater and colleagues conducted a population-based retrospective cohort study that included patients with psoriasis vulgaris (n = 35,281), pustulosis palmoplantaris (n = 9639), or generalized pustular psoriasis (n = 2281), and who were propensity score–matched with an equal number of control individuals without psoriasis. They demonstrated that compared with control individuals without psoriasis, patients with psoriasis vulgaris had the highest risk for incident PsA (hazard ratio [HR] 87.7), followed by those with generalized pustular psoriasis (HR 26.8) and pustulosis palmoplantaris (HR 15.3). Thus, the study confirms the highest risk for PsA with psoriasis vulgaris, as well as the estimated risk for other, less common forms of psoriasis.
Finally, a cross-sectional study by Toledano and colleagues showed that PsA patients with a sedentary lifestyle (<90 min of physical activity per week) had more enthesitis, fatigue, pain, higher disease activity, greater disease impact, and lower functionality compared with those having a nonsedentary lifestyle. The study indicates that PsA patients would benefit from >90 minutes of physical activity per week.
Additional References
- Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi: 10.1136/bmj.k601 Source
- Zhao H, Zhou Y, Wang Z, et al. Plasma proteins and psoriatic arthritis: A proteome-wide Mendelian randomization study. Front Immunol. 2024;15:1417564. doi: 10.3389/fimmu.2024.1417564 Source
Commentary: Medication Overuse, Diet, and Parenting in Migraine, August 2024
MOH involves many of the same features as migraine headaches: photophobia, nausea, vomiting, and sleep disturbances.1 Additionally, patients with migraine and comorbid MOH are at a higher risk for anxiety, depression, and emotional stress. MOH is difficult to treat, and symptom relapse after treatment is common. Results of a retrospective analysis published in July 2024 in The Journal of Headache and Facial Pain confirmed the effectiveness of calcitonin gene-related peptide (CGRP) antibody treatment in a real-world setting among migraine patients who had MOH. The study included a total of 291 patients who had been treated with either erenumab, fremanezumab, or galcanezumab. The majority of patients experienced a significant decline in monthly headache days, monthly migraine days, and monthly acute medication intake at 1 year. The researchers found that only 15.4% of the patients who initially met the criterion of chronic migraine with MOH relapsed, meeting the criterion for chronic migraine/MOH at the end of the 1-year follow-up period.
Lifestyle factors, such as diet, should be addressed when discussing migraine therapy with patients. Dietary factors, including a low–glycemic index diet, have been associated with promising results in migraine control. Results of a 10,359-patient cross-sectional study published in 2023 in the journal Nutrition confirmed that the inflammatory potential of patients' diet is associated with severe headache or migraine in US adults.2A more recent study, published in Frontiers in Nutrition in July 2024, examined dietary vitamin C intake of 13,445 individuals, of whom 20.42% had a severe headache or migraine. Vitamin C is a naturally occurring antioxidant and is also anti-inflammatory, found in foods such as citrus fruit, mangoes, strawberries, broccoli, and peppers. A subgroup analysis showed a significant association between vitamin C intake and severe headaches or migraines, with a reduced risk for severe headaches or migraines associated with an increased consumption of vitamin C. The authors noted that "each 1 mg/day increase in dietary vitamin C intake was significantly associated with a 6% lower risk for severe headache or migraine." Real-life application of this result for patients can involve encouraging patients to swap processed, low-nutrient foods in favor of fresh, nutrient-dense foods.
When treating migraine patients who are also parents, it is crucial to be persistent in searching for effective therapies to treat migraine and to treat or prevent MOH. According to a study published in 2018 in Headache, adolescents reported that parental migraine affected these factors in their lives: loss of parental support, reverse caregiving, emotional experience, interference with school, and missed activities and events.3 According to the authors of a more recent study, published in July 2024 in the Annals of General Psychiatry, parental migraine was significantly associated with an increased risk for attention-deficit/hyperactivity disorder, bipolar disorder, and depressive disorder among offspring of parents with migraine when compared with offspring of parents without migraine. The study authors noted that these outcomes could be the result of multiple factors, including psychosocial interactions, the burden of migraine on the family, and hereditary genetic traits. Nevertheless, even for offspring who may have a predisposition to these conditions because of genetic factors, effective treatment of parental migraine can relieve the day-to-day burden on the family, potentially reducing the effect of parental migraine on children. Parents who have migraine can become better equipped to provide attention to their children when their migraine symptoms are effectively treated. Furthermore, parents who have experienced improvement of their own migraine symptoms can offer hope and support if their children experience migraines, as migraine can be hereditary.
Additional References
1. Göçmez Yılmaz G, Ghouri R, et al. Complicated form of medication overuse headache is severe version of chronic migraine. J Clin Med. 2024;13(13):3696. doi: 10.3390/jcm13133696 Source
2. Liu H, Wang D, Wu F, et al. Association between inflammatory potential of diet and self-reported severe headache or migraine: A cross-sectional study of the National Health and Nutrition Examination Survey. Nutrition. 2023;113:112098. doi: 10.1016/j.nut.2023.112098 Source
3. Buse DC, Powers SW, Gelfand AA, et al. Adolescent perspectives on the burden of a parent's migraine: Results from the CaMEO Study. Headache. 2018;58(4):512-524. doi: 10.1111/head.13254 Source
MOH involves many of the same features as migraine headaches: photophobia, nausea, vomiting, and sleep disturbances.1 Additionally, patients with migraine and comorbid MOH are at a higher risk for anxiety, depression, and emotional stress. MOH is difficult to treat, and symptom relapse after treatment is common. Results of a retrospective analysis published in July 2024 in The Journal of Headache and Facial Pain confirmed the effectiveness of calcitonin gene-related peptide (CGRP) antibody treatment in a real-world setting among migraine patients who had MOH. The study included a total of 291 patients who had been treated with either erenumab, fremanezumab, or galcanezumab. The majority of patients experienced a significant decline in monthly headache days, monthly migraine days, and monthly acute medication intake at 1 year. The researchers found that only 15.4% of the patients who initially met the criterion of chronic migraine with MOH relapsed, meeting the criterion for chronic migraine/MOH at the end of the 1-year follow-up period.
Lifestyle factors, such as diet, should be addressed when discussing migraine therapy with patients. Dietary factors, including a low–glycemic index diet, have been associated with promising results in migraine control. Results of a 10,359-patient cross-sectional study published in 2023 in the journal Nutrition confirmed that the inflammatory potential of patients' diet is associated with severe headache or migraine in US adults.2A more recent study, published in Frontiers in Nutrition in July 2024, examined dietary vitamin C intake of 13,445 individuals, of whom 20.42% had a severe headache or migraine. Vitamin C is a naturally occurring antioxidant and is also anti-inflammatory, found in foods such as citrus fruit, mangoes, strawberries, broccoli, and peppers. A subgroup analysis showed a significant association between vitamin C intake and severe headaches or migraines, with a reduced risk for severe headaches or migraines associated with an increased consumption of vitamin C. The authors noted that "each 1 mg/day increase in dietary vitamin C intake was significantly associated with a 6% lower risk for severe headache or migraine." Real-life application of this result for patients can involve encouraging patients to swap processed, low-nutrient foods in favor of fresh, nutrient-dense foods.
When treating migraine patients who are also parents, it is crucial to be persistent in searching for effective therapies to treat migraine and to treat or prevent MOH. According to a study published in 2018 in Headache, adolescents reported that parental migraine affected these factors in their lives: loss of parental support, reverse caregiving, emotional experience, interference with school, and missed activities and events.3 According to the authors of a more recent study, published in July 2024 in the Annals of General Psychiatry, parental migraine was significantly associated with an increased risk for attention-deficit/hyperactivity disorder, bipolar disorder, and depressive disorder among offspring of parents with migraine when compared with offspring of parents without migraine. The study authors noted that these outcomes could be the result of multiple factors, including psychosocial interactions, the burden of migraine on the family, and hereditary genetic traits. Nevertheless, even for offspring who may have a predisposition to these conditions because of genetic factors, effective treatment of parental migraine can relieve the day-to-day burden on the family, potentially reducing the effect of parental migraine on children. Parents who have migraine can become better equipped to provide attention to their children when their migraine symptoms are effectively treated. Furthermore, parents who have experienced improvement of their own migraine symptoms can offer hope and support if their children experience migraines, as migraine can be hereditary.
Additional References
1. Göçmez Yılmaz G, Ghouri R, et al. Complicated form of medication overuse headache is severe version of chronic migraine. J Clin Med. 2024;13(13):3696. doi: 10.3390/jcm13133696 Source
2. Liu H, Wang D, Wu F, et al. Association between inflammatory potential of diet and self-reported severe headache or migraine: A cross-sectional study of the National Health and Nutrition Examination Survey. Nutrition. 2023;113:112098. doi: 10.1016/j.nut.2023.112098 Source
3. Buse DC, Powers SW, Gelfand AA, et al. Adolescent perspectives on the burden of a parent's migraine: Results from the CaMEO Study. Headache. 2018;58(4):512-524. doi: 10.1111/head.13254 Source
MOH involves many of the same features as migraine headaches: photophobia, nausea, vomiting, and sleep disturbances.1 Additionally, patients with migraine and comorbid MOH are at a higher risk for anxiety, depression, and emotional stress. MOH is difficult to treat, and symptom relapse after treatment is common. Results of a retrospective analysis published in July 2024 in The Journal of Headache and Facial Pain confirmed the effectiveness of calcitonin gene-related peptide (CGRP) antibody treatment in a real-world setting among migraine patients who had MOH. The study included a total of 291 patients who had been treated with either erenumab, fremanezumab, or galcanezumab. The majority of patients experienced a significant decline in monthly headache days, monthly migraine days, and monthly acute medication intake at 1 year. The researchers found that only 15.4% of the patients who initially met the criterion of chronic migraine with MOH relapsed, meeting the criterion for chronic migraine/MOH at the end of the 1-year follow-up period.
Lifestyle factors, such as diet, should be addressed when discussing migraine therapy with patients. Dietary factors, including a low–glycemic index diet, have been associated with promising results in migraine control. Results of a 10,359-patient cross-sectional study published in 2023 in the journal Nutrition confirmed that the inflammatory potential of patients' diet is associated with severe headache or migraine in US adults.2A more recent study, published in Frontiers in Nutrition in July 2024, examined dietary vitamin C intake of 13,445 individuals, of whom 20.42% had a severe headache or migraine. Vitamin C is a naturally occurring antioxidant and is also anti-inflammatory, found in foods such as citrus fruit, mangoes, strawberries, broccoli, and peppers. A subgroup analysis showed a significant association between vitamin C intake and severe headaches or migraines, with a reduced risk for severe headaches or migraines associated with an increased consumption of vitamin C. The authors noted that "each 1 mg/day increase in dietary vitamin C intake was significantly associated with a 6% lower risk for severe headache or migraine." Real-life application of this result for patients can involve encouraging patients to swap processed, low-nutrient foods in favor of fresh, nutrient-dense foods.
When treating migraine patients who are also parents, it is crucial to be persistent in searching for effective therapies to treat migraine and to treat or prevent MOH. According to a study published in 2018 in Headache, adolescents reported that parental migraine affected these factors in their lives: loss of parental support, reverse caregiving, emotional experience, interference with school, and missed activities and events.3 According to the authors of a more recent study, published in July 2024 in the Annals of General Psychiatry, parental migraine was significantly associated with an increased risk for attention-deficit/hyperactivity disorder, bipolar disorder, and depressive disorder among offspring of parents with migraine when compared with offspring of parents without migraine. The study authors noted that these outcomes could be the result of multiple factors, including psychosocial interactions, the burden of migraine on the family, and hereditary genetic traits. Nevertheless, even for offspring who may have a predisposition to these conditions because of genetic factors, effective treatment of parental migraine can relieve the day-to-day burden on the family, potentially reducing the effect of parental migraine on children. Parents who have migraine can become better equipped to provide attention to their children when their migraine symptoms are effectively treated. Furthermore, parents who have experienced improvement of their own migraine symptoms can offer hope and support if their children experience migraines, as migraine can be hereditary.
Additional References
1. Göçmez Yılmaz G, Ghouri R, et al. Complicated form of medication overuse headache is severe version of chronic migraine. J Clin Med. 2024;13(13):3696. doi: 10.3390/jcm13133696 Source
2. Liu H, Wang D, Wu F, et al. Association between inflammatory potential of diet and self-reported severe headache or migraine: A cross-sectional study of the National Health and Nutrition Examination Survey. Nutrition. 2023;113:112098. doi: 10.1016/j.nut.2023.112098 Source
3. Buse DC, Powers SW, Gelfand AA, et al. Adolescent perspectives on the burden of a parent's migraine: Results from the CaMEO Study. Headache. 2018;58(4):512-524. doi: 10.1111/head.13254 Source
Paclitaxel Drug-Drug Interactions in the Military Health System
Background
Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.1-9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.8-18
Two different chemotherapy drugs contain paclitaxel—paclitaxel and nab-paclitaxel—and the US Food and Drug Administration (FDA) recognizes them as separate entities.19-21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.20 It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination withbevacizumab) in 1994, 1997, 1999, and 2014, respectively.21 Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.19 Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.22-26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.19-32
One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.2,17,33-38 Therefore, many alternatives to polyethoxylated castor oil have been researched.
Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nanotechnological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.33,39-52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.33,53
Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.19-22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.54 Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.55 Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.56 In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 µmol/L.57 Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.58-64
The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.65-67
The Walter Reed National Military Medical Center in Bethesda, Maryland, institutionalreview board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.
METHODS
The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.
Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.
Data Extraction Design
The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.
Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).
Data Extraction Analysis
The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.
In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.70 Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.
RESULTS
The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).
There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined withdoxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).
Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 andP = .30, respectively) (Table 4).
Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).
Management Analysis and Reporting Tool Database
MHS data analysts provided data on diagnoses for 639 patients among 687 submitteddiagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).
The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.
MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).
The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).
DISCUSSION
As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.
Paclitaxel
Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.22-27
The generic name is not the same as a generic drug, which may have slight differences from the brand name product.71 The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.72 During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.
Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.73-76
Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.
Discontinued Treatment
Ten patients had prescribed Taxol that was changed due to AEs: 1 was switched to Abraxane and atezolizumab, 3 switched to Abraxane, 2 switched to docetaxel, 1 switched to doxorubicin, and 3 switched to pembrolizumab (based on physician’s comments). Of the 10 patients, 7 had Taxol reaction, 2 experienced disease progression, and 1 experienced high programmed death–ligand 1 expression (this patient with breast cancer was switched to Abraxane and atezolizumab during the accelerated FDA approval phase for atezolizumab, which was later revoked). Five patients were treated with carboplatin and Taxol for cancer of the anal canal (changed to pembrolizumab after disease progression), lung not otherwise specified (changed to carboplatin and pembrolizumab due to Taxol reaction), lower inner quadrant of the breast (changed to doxorubicin due to hypersensitivity reaction), corpus uteri (changed to Abraxane due to Taxol reaction), and ovary (changed to docetaxel due to Taxol reaction). Three patients were treated with doxorubicin, cyclophosphamide, and Taxol for breast cancer; 2 patients with breast cancer not otherwise specified switched to Abraxane due to cardiopulmonary hypersensitivity and Taxol reaction and 1 patient with cancer of the upper outer quadrant of the breast changed to docetaxel due to allergic reaction. One patient, who was treated with paclitaxel, ifosfamide, and cisplatin for metastasis of the lower lobe of the lung and kidney cancer, experienced complications due to infectious colitis (treated with ciprofloxacin) and then switched to pembrolizumab after the disease progressed. These AEs are known in paclitaxel medical literature on paclitaxel AEs.19-24,77-81
Combining 2 or more treatments to target cancer-inducing or cell-sustaining pathways is a cornerstone of chemotherapy.82-84 Most combinations are given on the same day, but some are not. For 3- or 4-drug combinations, doxorubicin and cyclophosphamide were given first, followed by paclitaxel with or withouttrastuzumab, carboplatin, or pembrolizumab. Only 16 patients (2%) were treated with paclitaxel alone; therefore, the completed and discontinued treatment groups are mostly concomitant treatment. As a result, the comparisons of the completed and discontinued treatment groups were almost the same for the diagnosis. The PDTS data have a better result because 2 exclusion criteria were applied before narrowing the analysis down to paclitaxel treatment specifically.
Antidepressants and Other Drugs
Drug response can vary from person to person and can lead to treatment failure related to AEs. One major factor in drug metabolism is CYP.85 CYP2C8 is the major pathway for paclitaxel and CYP3A4 is the minor pathway. When evaluating the noncancer drugs, there were no reports of CYP2C8 inhibition or induction.Over the years, many DDI warnings have been issued for paclitaxel with different drugs in various electronic resources.
Oncologists follow guidelines to prevent DDIs, as paclitaxel is known to have severe, moderate, and minor interactions with other drugs. Among 687 patients, 261 (38%) were prescribed any of 14 antidepressants. Eight of these antidepressants (amitriptyline, citalopram, desipramine, doxepin, venlafaxine, escitalopram, nortriptyline, and trazodone) are metabolized, 3 (mirtazapine, sertraline, and fluoxetine) are metabolized and inhibited, 2 (bupropion and duloxetine) are neither metabolized nor inhibited, and 1 (paroxetine) is inhibited by CYP3A4. Duloxetine, venlafaxine, and trazodone were more commonly dispensed (84, 78, and 42 patients, respectively) than others (≤ 33 patients).
Of 32 patients with documented AEs,14 (44%) had 168 dispensed drugs in the PDTS database. Six patients (19%) were treated with doxorubicin and cyclophosphamide followed by paclitaxel for breast cancer; 6 (19%) were treated with carboplatin and paclitaxel for cancer of the lung (n = 3), corpus uteri (n = 2), and ovary (n = 1); 1 patient (3%) was treated with carboplatin and paclitaxel, then switched to carboplatin, bevacizumab, and paclitaxel, and then completed treatment with carboplatin and paclitaxel for an unspecified female genital cancer; and 1 patient (3%) was treated with cisplatin, ifosfamide, and paclitaxel for metastasis of the lower lobe lung and kidney cancer.
The 14 patients with PDTS data had 18 cancer drugs dispensed. Eleven had moderate interaction reports and 7 had no interaction reports. A total of 165 noncancer drugs were dispensed, of which 3 were antidepressants and had no interactions reported, 8 had moderate interactions reported, and 2 had minor interactions with Taxol and Abraxane, respectively (Table 6).86-129
Of 3 patients who were dispensed bupropion, nortriptyline, or paroxetine, 1 patient with breast cancer was treated with doxorubicin andcyclophosphamide, followed by paclitaxel with bupropion, nortriptyline, pegfilgrastim,dexamethasone, and 17 other noncancer drugs that had no interaction report dispensed during paclitaxel treatment. Of 2 patients with lung cancer, 1 patient was treated with carboplatin and paclitaxel with nortriptyline, dexamethasone, and 13 additional medications, and the second patient was treated with paroxetine, cimetidine, dexamethasone, and 12 other medications. Patients were dispensed up to6 noncancer medications on the same day as paclitaxel administration to control the AEs, not including the prodrugs filled before the treatments. Paroxetine and cimetidine have weak inhibition, and dexamethasone has weak induction of CYP3A4. Therefore, while 1:1 DDIs might have little or no effect with weak inhibit/induce CYP3A4 drugs, 1:1:1 or more combinations could have a different outcome (confirmed in previous publications).65-67
Dispensed on the same day may not mean taken at the same time. One patient experienced an AE with dispensed 50 mg losartan, carboplatin plus paclitaxel, dexamethasone, and 6 other noncancer drugs. Losartan inhibits paclitaxel, which can lead to negative AEs.57,66,67 However, there were no blood or plasma samples taken to confirm the losartan was taken at the same time as the paclitaxel given this was not a clinical trial.
Conclusions
This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIsidentified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996-2022), enabling them to make informed decisions about paclitaxel treatment.
Acknowledgments
The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Brandon E. Jenkins, and Alexander G. Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Martin L. Boese, CDR Wesley R. Campbell, Maj. Abhimanyu Chandel, CDR Ling Ye, Chelsea N. Powers, Yaling Zhou, Elizabeth Schafer, Micah Stretch, Diane Beaner, and Adrienne Woodard.
1. American Chemical Society. Discovery of camptothecin and taxol. acs.org. Accessed June 4, 2024. https://www.acs.org/education/whatischemistry/landmarks/camptothecintaxol.html
2. Bocci G, Di Paolo A, Danesi R. The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis. 2013;16(3):481-492. doi:10.1007/s10456-013-9334-0.
3. Meštrovic T. Paclitaxel history. News Medical Life Sciences. Updated March 11, 2023. Accessed June 4, 2024. https://www.news-medical.net/health/Paclitaxel-History.aspx
4. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995;332(15):1004-1014. doi:10.1056/NEJM199504133321507
5. Walsh V, Goodman J. The billion dollar molecule: Taxol in historical and theoretical perspective. Clio Med. 2002;66:245-267. doi:10.1163/9789004333499_013
6. Perdue RE, Jr, Hartwell JL. The search for plant sources of anticancer drugs. Morris Arboretum Bull. 1969;20:35-53.
7. Wall ME, Wani MC. Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 1995;55:753-760.
8. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J Am Chem Soc. 1971;93(9):2325-2327. doi:10.1021/ja00738a045
9. Weaver BA. How taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25(18):2677-2681. doi:10.1091/mbc.E14-04-0916
10. Chen JG, Horwitz SB. Differential mitotic responses to microtubule-stabilizing and-destabilizing drugs. Cancer Res. 2002;62(7):1935-1938.
11. Singh S, Dash AK. Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges. Crit Rev Ther Drug Carrier Syst. 2009;26(4):333-372. doi:10.1615/critrevtherdrugcarriersyst.v26.i4.10
12. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277(5698):665-667. doi:10.1038/277665a0
13. Fuchs DA, Johnson RK. Cytologic evidence that taxol, an antineoplastic agent from taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep. 1978;62(8):1219-1222.
14. Walsh V, Goodman J. From taxol to taxol: the changing identities and ownership of an anti-cancer drug. Med Anthropol. 2002;21(3-4):307-336. doi:10.1080/01459740214074
15. Walsh V, Goodman J. Cancer chemotherapy, biodiversity, public and private property: the case of the anti-cancer drug taxol. Soc Sci Med. 1999;49(9):1215-1225. doi:10.1016/s0277-9536(99)00161-6
16. Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 1996;56(4):816-825.
17. Picard M, Castells MC. Re-visiting hypersensitivity reactions to taxanes: a comprehensive review. Clin Rev Allergy Immunol. 2015;49(2):177-191. doi:10.1007/s12016-014-8416-0
18. Zasadil LM, Andersen KA, Yeum D, et al. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med. 2014;6:229ra243. doi:10.1126/scitranslmed.3007965
19. National Cancer Institute. Carboplatin-Taxol. Published May 30, 2012. Updated March 22, 2023. Accessed June 4, 2024. https://www.cancer.gov/about-cancer/treatment/drugs/carboplatin-taxol
20. Taxol (paclitaxel). Prescribing information. Bristol-Myers Squibb; 2011. Accessed June 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf
21. Abraxane (paclitaxel). Prescribing information. Celgene Corporation; 2021. Accessed June 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf
22. Awosika AO, Farrar MC, Jacobs TF. Paclitaxel. StatPearls. Updated November 18, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK536917/
23. Gerriets V, Kasi A. Bevacizumab. StatPearls. Updated September 1, 2022. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482126/
24. American Cancer Society. Chemotherapy for endometrial cancer. Updated March 27, 2019. Accessed June 4, 2024. https://www.cancer.org/cancer/types/endometrial-cancer/treating/chemotherapy.html
25. US Food and Drug Administration. FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC. October 30, 2018. Updated December 14, 2018. Accessed June 4, 2024. https://www.fda.gov/drugs/fda-approves-pembrolizumab-combination-chemotherapy-first-line-treatment-metastatic-squamous-nsclc
26. US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. November 13, 2020. Accessed June 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple
27. US Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast. March 8, 2019. Updated March 18, 2019. Accessed June 5, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative
28. US Food and Drug Administration. FDA issues alert about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. September 8, 2020. Accessed June 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-issues-alert-about-efficacy-and-potential-safety-concerns-atezolizumab-combination-paclitaxel
29. Tan AR. Chemoimmunotherapy: still the standard of care for metastatic triple-negative breast cancer. ASCO Daily News. February 23, 2022. Accessed June 5, 2024. https://dailynews.ascopubs.org/do/chemoimmunotherapy-still-standard-care-metastatic-triple-negative-breast-cancer
30. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111(4):273-279. doi:10.7326/0003-4819-111-4-273
31. Milas L, Hunter NR, Kurdoglu B, et al. Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemother Pharmacol. 1995;35(4):297-303. doi:10.1007/BF00689448
32. Searle J, Collins DJ, Harmon B, Kerr JF. The spontaneous occurrence of apoptosis in squamous carcinomas of the uterine cervix. Pathology. 1973;5(2):163-169. doi:10.3109/00313027309060831
33. Gallego-Jara J, Lozano-Terol G, Sola-Martínez RA, Cánovas-Díaz M, de Diego Puente T. A compressive review about taxol®: history and future challenges. Molecules. 2020;25(24):5986. doi:10.3390/molecules25245986
34. Bernabeu E, Cagel M, Lagomarsino E, Moretton M, Chiappetta DA. Paclitaxel: What has been done and the challenges remain ahead. Int J Pharm. 2017;526(1-2):474-495. doi:10.1016/j.ijpharm.2017.05.016
35. Nehate C, Jain S, Saneja A, et al. Paclitaxel formulations: challenges and novel delivery options. Curr Drug Deliv. 2014;11(6):666-686. doi:10.2174/1567201811666140609154949
36. Gelderblom H, Verweij J, Nooter K, Sparreboom A, Cremophor EL. The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590-1598. doi:10.1016/S0959-8049(01)00171-x
37. Chowdhury MR, Moshikur RM, Wakabayashi R, et al. In vivo biocompatibility, pharmacokinetics, antitumor efficacy, and hypersensitivity evaluation of ionic liquid-mediated paclitaxel formulations. Int J Pharm. 2019;565:219-226. doi:10.1016/j.ijpharm.2019.05.020
38. Borgå O, Henriksson R, Bjermo H, Lilienberg E, Heldring N, Loman N. Maximum tolerated dose and pharmacokinetics of paclitaxel micellar in patients with recurrent malignant solid tumours: a dose-escalation study. Adv Ther. 2019;36(5):1150-1163. doi:10.1007/s12325-019-00909-6
39. Rouzier R, Rajan R, Wagner P, et al. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci USA. 2005;102(23):8315-8320. doi:10.1073/pnas.0408974102
40. Choudhury H, Gorain B, Tekade RK, Pandey M, Karmakar S, Pal TK. Safety against nephrotoxicity in paclitaxel treatment: oral nanocarrier as an effective tool in preclinical evaluation with marked in vivo antitumor activity. Regul Toxicol Pharmacol. 2017;91:179-189. doi:10.1016/j.yrtph.2017.10.023
41. Barkat MA, Beg S, Pottoo FH, Ahmad FJ. Nanopaclitaxel therapy: an evidence based review on the battle for next-generation formulation challenges. Nanomedicine (Lond). 2019;14(10):1323-1341. doi:10.2217/nnm-2018-0313
42. Sofias AM, Dunne M, Storm G, Allen C. The battle of “nano” paclitaxel. Adv Drug Deliv Rev. 2017;122:20-30. doi:10.1016/j.addr.2017.02.003
43. Yang N, Wang C, Wang J, et al. Aurora inase a stabilizes FOXM1 to enhance paclitaxel resistance in triple-negative breast cancer. J Cell Mol Med. 2019;23(9):6442-6453. doi:10.1111/jcmm.14538
44. Chowdhury MR, Moshikur RM, Wakabayashi R, et al. Ionic-liquid-based paclitaxel preparation: a new potential formulation for cancer treatment. Mol Pharm. 2018;15(16):2484-2488. doi:10.1021/acs.molpharmaceut.8b00305
45. Chung HJ, Kim HJ, Hong ST. Tumor-specific delivery of a paclitaxel-loading HSA-haemin nanoparticle for cancer treatment. Nanomedicine. 2020;23:102089. doi:10.1016/j.nano.2019.102089
46. Ye L, He J, Hu Z, et al. Antitumor effect and toxicity of lipusu in rat ovarian cancer xenografts. Food Chem Toxicol. 2013;52:200-206. doi:10.1016/j.fct.2012.11.004
47. Ma WW, Lam ET, Dy GK, et al. A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with arboplatin in patients with advanced solid tumors. J Clin Oncol. 2013;31:2557. doi:10.1200/jco.2013.31.15_suppl.2557
48. Micha JP, Goldstein BH, Birk CL, Rettenmaier MA, Brown JV. Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions. Gynecol Oncol. 2006;100(2):437-438. doi:10.1016/j.ygyno.2005.09.012
49. Ingle SG, Pai RV, Monpara JD, Vavia PR. Liposils: an effective strategy for stabilizing paclitaxel loaded liposomes by surface coating with silica. Eur J Pharm Sci. 2018;122:51-63. doi:10.1016/j.ejps.2018.06.025
50. Abriata JP, Turatti RC, Luiz MT, et al. Development, characterization and biological in vitro assays of paclitaxel-loaded PCL polymeric nanoparticles. Mater Sci Eng C Mater Biol Appl. 2019;96:347-355. doi:10.1016/j.msec.2018.11.035
51. Hu J, Fu S, Peng Q, et al. Paclitaxel-loaded polymeric nanoparticles combined with chronomodulated chemotherapy on lung cancer: in vitro and in vivo evaluation. Int J Pharm. 2017;516(1-2):313-322. doi:10.1016/j.ijpharm.2016.11.047
52. Dranitsaris G, Yu B, Wang L, et al. Abraxane® vs Taxol® for patients with advanced breast cancer: a prospective time and motion analysis from a chinese health care perspective. J Oncol Pharm Pract. 2016;22(2):205-211. doi:10.1177/1078155214556008
53. Pei Q, Hu X, Liu S, Li Y, Xie Z, Jing X. Paclitaxel dimers assembling nanomedicines for treatment of cervix carcinoma. J Control Release. 2017;254:23-33. doi:10.1016/j.jconrel.2017.03.391
54. Wang Y, Wang M, Qi H, et al. Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials. Drug Metab Dispos. 2014;42(4):782-795. doi:10.1124/dmd.113.053793
55. Shen F, Jiang G, Philips S, et al. Cytochrome P450 oxidoreductase (POR) associated with severe paclitaxel-induced peripheral neuropathy in patients of european ancestry from ECOG-ACRIN E5103. Clin Cancer Res. 2023;29(13):2494-2500. doi:10.1158/1078-0432.CCR-22-2431
56. Henningsson A, Marsh S, Loos WJ, et al. Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res. 2005;11(22):8097-8104. doi:10.1158/1078-0432.CCR-05-1152
57. Mukai Y, Senda A, Toda T, et al. Drug-drug interaction between losartan and paclitaxel in human liver microsomes with different CYP2C8 genotypes. Basic Clin Pharmacol Toxicol. 2015;116(6):493-498. doi:10.1111/bcpt.12355
58. Kawahara B, Faull KF, Janzen C, Mascharak PK. Carbon monoxide inhibits cytochrome P450 enzymes CYP3A4/2C8 in human breast cancer cells, increasing sensitivity to paclitaxel. J Med Chem. 2021;64(12):8437-8446. doi:10.1021/acs.jmedchem.1c00404
59. Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F. Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos. 2002;30(4):438-445. doi:10.1124/dmd.30.4.438
60. Taniguchi R, Kumai T, Matsumoto N, et al. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. J Pharmacol Sci. 2005;97(1):83-90. doi:10.1254/jphs.fp0040603
61. Nakayama A, Tsuchiya K, Xu L, Matsumoto T, Makino T. Drug-interaction between paclitaxel and goshajinkigan extract and its constituents. J Nat Med. 2022;76(1):59-67. doi:10.1007/s11418-021-01552-8
62. Monsarrat B, Chatelut E, Royer I, et al. Modification of paclitaxel metabolism in a cancer patient by induction of cytochrome P450 3A4. Drug Metab Dispos. 1998;26(3):229-233.
63. Walle T. Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro. Methods Enzymol. 1996;272:145-151. doi:10.1016/s0076-6879(96)72018-9
64. Hanioka N, Matsumoto K, Saito Y, Narimatsu S. Functional characterization of CYP2C8.13 and CYP2C8.14: catalytic activities toward paclitaxel. Basic Clin Pharmacol Toxicol. 2010;107(1):565-569. doi:10.1111/j.1742-7843.2010.00543.x
65. Luong TT, Powers CN, Reinhardt BJ, Weina PJ. Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. Curr Res Pharmacol Drug Discov. 2022;3:100112. doi:10.1016/j.crphar.2022.100112
66. Luong TT, McAnulty MJ, Evers DL, Reinhardt BJ, Weina PJ. Pre-clinical drug-drug interaction (DDI) of gefitinib or erlotinib with Cytochrome P450 (CYP) inhibiting drugs, fluoxetine and/or losartan. Curr Res Toxicol. 2021;2:217-224. doi:10.1016/j.crtox.2021.05.006
67. Luong TT, Powers CN, Reinhardt BJ, et al. Retrospective evaluation of drug-drug interactions with erlotinib and gefitinib use in the military health system. Fed Pract. 2023;40(suppl 3):S24-S34. doi:10.12788/fp.0401
68. Adamo M, Dickie L, Ruhl J. SEER program coding and staging manual 2016. National Cancer Institute. Accessed June 5, 2024. https://seer.cancer.gov/archive/manuals/2016/SPCSM_2016_maindoc.pdf
69. World Health Organization. International classification of diseases for oncology (ICD-O) 3rd ed, 1st revision. World Health Organization; 2013. Accessed June 5, 2024. https://apps.who.int/iris/handle/10665/96612
70. Z score calculator for 2 population proportions. Social science statistics. Accessed June 5, 2024. https://www.socscistatistics.com/tests/ztest/default2.aspx
71. US Food and Drug Administration. Generic drugs: question & answers. FDA.gov. Accessed June 5, 2024. https://www.fda.gov/drugs/frequently-asked-questions-popular-topics/generic-drugs-questions-answers
72. Oura M, Saito H, Nishikawa Y. Shortage of nab-paclitaxel in Japan and around the world: issues in global information sharing. JMA J. 2023;6(2):192-195. doi:10.31662/jmaj.2022-0179
73. Yuan H, Guo H, Luan X, et al. Albumin nanoparticle of paclitaxel (abraxane) decreases while taxol increases breast cancer stem cells in treatment of triple negative breast cancer. Mol Pharm. 2020;17(7):2275-2286. doi:10.1021/acs.molpharmaceut.9b01221
74. Dranitsaris G, Yu B, Wang L, et al. Abraxane® versus Taxol® for patients with advanced breast cancer: a prospective time and motion analysis from a Chinese health care perspective. J Oncol Pharm Pract. 2016;22(2):205-211. doi:10.1177/1078155214556008
75. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794-7803. doi:10.1200/JCO.2005.04.
76. Liu M, Liu S, Yang L, Wang S. Comparison between nab-paclitaxel and solvent-based taxanes as neoadjuvant therapy in breast cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):118. doi:10.1186/s12885-021-07831-7
77. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (taxol). Semin Oncol. 1993;20(4 Suppl 3):1-15.
78. Banerji A, Lax T, Guyer A, Hurwitz S, Camargo CA Jr, Long AA. Management of hypersensitivity reactions to carboplatin and paclitaxel in an outpatient oncology infusion center: a 5-year review. J Allergy Clin Immunol Pract. 2014;2(4):428-433. doi:10.1016/j.jaip.2014.04.010
79. Staff NP, Fehrenbacher JC, Caillaud M, Damaj MI, Segal RA, Rieger S. Pathogenesis of paclitaxel-induced peripheral neuropathy: a current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol. 2020;324:113121. doi:10.1016/j.expneurol.2019.113121
80. Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM, Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol. 1995;6(5):489-494. doi:10.1093/oxfordjournals.annonc.a059220
81. Liu JM, Chen YM, Chao Y, et al. Paclitaxel-induced severe neuropathy in patients with previous radiotherapy to the head and neck region. J Natl Cancer Inst. 1996;88(14):1000-1002. doi:10.1093/jnci/88.14.1000-a
82. Bayat Mokhtari R, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022-38043. doi:10.18632/oncotarget.16723
83. Blagosklonny MV. Analysis of FDA approved anticancer drugs reveals the future of cancer therapy. Cell Cycle. 2004;3(8):1035-1042.
84. Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592-1605. doi:10.1200/JCO.2011.37.6418
85. Gilani B, Cassagnol M. Biochemistry, Cytochrome P450. StatPearls. Updated April 24, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK557698/
86. LiverTox: clinical and research information on drug-induced liver injury; 2012. Carboplatin. Updated September 15, 2020. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548565/
87. Carboplatin. Prescribing information. Teva Parenteral Medicines; 2012. Accessed June 5, 204. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/077139Orig1s016lbl.pdf
88. Johnson-Arbor K, Dubey R. Doxorubicin. StatPearls. Updated August 8, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK459232/
89. Doxorubicin hydrochloride injection. Prescribing information. Pfizer; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/050467s078,050629s030lbl.pdf
90. Gor, PP, Su, HI, Gray, RJ, et al. Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res. 2010;12(3):R26. doi:10.1186/bcr2570
91. Cyclophosphamide. Prescribing information. Ingenus Pharmaceuticals; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212501s000lbl.pdf
92. Gemcitabine. Prescribing information. Hospira; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/200795Orig1s010lbl.pdf
93. Ifex (ifosfamide). Prescribing information. Baxter; 2012. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf
94. Cisplatin. Prescribing information. WG Critical Care; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018057s089lbl.pdf
95. Gerriets V, Kasi A. Bevacizumab. StatPearls. Updated August 28, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482126/
96. Avastin (bevacizumab). Prescribing information. Genentech; 2022. Accessed June 5, 2024. https://www.accessdata .fda.gov/drugsatfda_docs/label/2022/125085s340lbl.pdf
97. Keytruda (pembrolizumab). Prescribing information. Merck; 2021. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf
98. Dean L, Kane M. Capecitabine therapy and DPYD genotype. National Center for Biotechnology Information (US); 2012. Updated November 2, 2020. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK385155/
99. Xeloda (capecitabine). Prescribing information. Roche; 2000. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20896lbl.pdf
100. Pemetrexed injection. Prescribing information. Fareva Unterach; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214657s000lbl.pdf
101. Topotecan Injection. Prescribing information. Zydus Hospira Oncology; 2014. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200582s001lbl.pdf
102. Ibrance (palbociclib). Prescribing information. Pfizer; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf
103. Navelbine (vinorelbine) injection. Prescribing information. Pierre Fabre Médicament; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020388s037lbl.pdf
104. LiverTox: clinical and research information on drug-induced liver injury; 2012. Letrozole. Updated July 25, 2017. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548381/
105. Femara (letrozole). Prescribing information. Novartis; 2014. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf
106. Soltamox (tamoxifen citrate). Prescribing information. Rosemont Pharmaceuticals; 2018. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf
107. LiverTox: clinical and research information on drug-induced liver injury; 2012. Anastrozole. Updated July 25, 2017. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548189/
108. Grimm SW, Dyroff MC. Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase. Drug Metab Dispos. 1997;25(5):598-602.
109. Arimidex (anastrozole). Prescribing information. AstraZeneca; 2010. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020541s026lbl.pdf
110. Megace (megestrol acetate). Prescribing information. Endo Pharmaceuticals; 2018. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021778s024lbl.pdf
111. Imfinzi (durvalumab). Prescribing information. AstraZeneca; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf
112. Merwar G, Gibbons JR, Hosseini SA, et al. Nortriptyline. StatPearls. Updated June 5, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482214/
113. Pamelor (nortriptyline HCl). Prescribing information. Patheon Inc.; 2012. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018012s029,018013s061lbl.pdf
114. Wellbutrin (bupropion hydrochloride). Prescribing information. GlaxoSmithKline; 2017. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018644s052lbl.pdf
115. Paxil (paroxetine). Prescribing information. Apotex Inc.; 2021. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020031s077lbl.pdf
116. Johnson DB, Lopez MJ, Kelley B. Dexamethasone. StatPearls. Updated May 2, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482130/
117. Hemady (dexamethasone). Prescribing information. Dexcel Pharma; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211379s000lbl.pdf
118. Parker SD, King N, Jacobs TF. Pegfilgrastim. StatPearls. Updated May 9, 2024. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK532893/
119. Fylnetra (pegfilgrastim-pbbk). Prescribing information. Kashiv BioSciences; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761084s000lbl.pdf
120. Emend (aprepitant). Prescribing information. Merck; 2015. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207865lbl.pdf
121. Lipitor (atorvastatin calcium). Prescribing information. Viatris Specialty; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020702Orig1s079correctedlbl.pdf
122. Cipro (ciprofloxacin hydrochloride). Prescribing information. Bayer HealthCare Pharmaceuticals Inc.; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/019537s090,020780s047lbl.pdf
123. Pino MA, Azer SA. Cimetidine. StatPearls. Updated March 6, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK544255/
124. Tagament (Cimetidine). Prescribing information. Mylan; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020238Orig1s024lbl.pdf
125. Neupogen (filgrastim). Prescribing information. Amgen Inc.; 2015. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103353s5184lbl.pdf
126. Flagyl (metronidazole). Prescribing information. Pfizer; 2013. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020334s008lbl.pdf
127. Zymaxid (gatifloxacin ophthalmic solution). Prescribing information. Allergan; 2016. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022548s002lbl.pdf
128. Macrobid (nitrofurantoin monohydrate). Prescribing information. Procter and Gamble Pharmaceutical Inc.; 2009. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf
129. Hyzaar (losartan). Prescribing information. Merck; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020387s067lbl.pdf
Background
Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.1-9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.8-18
Two different chemotherapy drugs contain paclitaxel—paclitaxel and nab-paclitaxel—and the US Food and Drug Administration (FDA) recognizes them as separate entities.19-21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.20 It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination withbevacizumab) in 1994, 1997, 1999, and 2014, respectively.21 Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.19 Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.22-26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.19-32
One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.2,17,33-38 Therefore, many alternatives to polyethoxylated castor oil have been researched.
Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nanotechnological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.33,39-52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.33,53
Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.19-22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.54 Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.55 Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.56 In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 µmol/L.57 Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.58-64
The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.65-67
The Walter Reed National Military Medical Center in Bethesda, Maryland, institutionalreview board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.
METHODS
The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.
Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.
Data Extraction Design
The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.
Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).
Data Extraction Analysis
The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.
In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.70 Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.
RESULTS
The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).
There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined withdoxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).
Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 andP = .30, respectively) (Table 4).
Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).
Management Analysis and Reporting Tool Database
MHS data analysts provided data on diagnoses for 639 patients among 687 submitteddiagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).
The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.
MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).
The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).
DISCUSSION
As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.
Paclitaxel
Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.22-27
The generic name is not the same as a generic drug, which may have slight differences from the brand name product.71 The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.72 During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.
Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.73-76
Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.
Discontinued Treatment
Ten patients had prescribed Taxol that was changed due to AEs: 1 was switched to Abraxane and atezolizumab, 3 switched to Abraxane, 2 switched to docetaxel, 1 switched to doxorubicin, and 3 switched to pembrolizumab (based on physician’s comments). Of the 10 patients, 7 had Taxol reaction, 2 experienced disease progression, and 1 experienced high programmed death–ligand 1 expression (this patient with breast cancer was switched to Abraxane and atezolizumab during the accelerated FDA approval phase for atezolizumab, which was later revoked). Five patients were treated with carboplatin and Taxol for cancer of the anal canal (changed to pembrolizumab after disease progression), lung not otherwise specified (changed to carboplatin and pembrolizumab due to Taxol reaction), lower inner quadrant of the breast (changed to doxorubicin due to hypersensitivity reaction), corpus uteri (changed to Abraxane due to Taxol reaction), and ovary (changed to docetaxel due to Taxol reaction). Three patients were treated with doxorubicin, cyclophosphamide, and Taxol for breast cancer; 2 patients with breast cancer not otherwise specified switched to Abraxane due to cardiopulmonary hypersensitivity and Taxol reaction and 1 patient with cancer of the upper outer quadrant of the breast changed to docetaxel due to allergic reaction. One patient, who was treated with paclitaxel, ifosfamide, and cisplatin for metastasis of the lower lobe of the lung and kidney cancer, experienced complications due to infectious colitis (treated with ciprofloxacin) and then switched to pembrolizumab after the disease progressed. These AEs are known in paclitaxel medical literature on paclitaxel AEs.19-24,77-81
Combining 2 or more treatments to target cancer-inducing or cell-sustaining pathways is a cornerstone of chemotherapy.82-84 Most combinations are given on the same day, but some are not. For 3- or 4-drug combinations, doxorubicin and cyclophosphamide were given first, followed by paclitaxel with or withouttrastuzumab, carboplatin, or pembrolizumab. Only 16 patients (2%) were treated with paclitaxel alone; therefore, the completed and discontinued treatment groups are mostly concomitant treatment. As a result, the comparisons of the completed and discontinued treatment groups were almost the same for the diagnosis. The PDTS data have a better result because 2 exclusion criteria were applied before narrowing the analysis down to paclitaxel treatment specifically.
Antidepressants and Other Drugs
Drug response can vary from person to person and can lead to treatment failure related to AEs. One major factor in drug metabolism is CYP.85 CYP2C8 is the major pathway for paclitaxel and CYP3A4 is the minor pathway. When evaluating the noncancer drugs, there were no reports of CYP2C8 inhibition or induction.Over the years, many DDI warnings have been issued for paclitaxel with different drugs in various electronic resources.
Oncologists follow guidelines to prevent DDIs, as paclitaxel is known to have severe, moderate, and minor interactions with other drugs. Among 687 patients, 261 (38%) were prescribed any of 14 antidepressants. Eight of these antidepressants (amitriptyline, citalopram, desipramine, doxepin, venlafaxine, escitalopram, nortriptyline, and trazodone) are metabolized, 3 (mirtazapine, sertraline, and fluoxetine) are metabolized and inhibited, 2 (bupropion and duloxetine) are neither metabolized nor inhibited, and 1 (paroxetine) is inhibited by CYP3A4. Duloxetine, venlafaxine, and trazodone were more commonly dispensed (84, 78, and 42 patients, respectively) than others (≤ 33 patients).
Of 32 patients with documented AEs,14 (44%) had 168 dispensed drugs in the PDTS database. Six patients (19%) were treated with doxorubicin and cyclophosphamide followed by paclitaxel for breast cancer; 6 (19%) were treated with carboplatin and paclitaxel for cancer of the lung (n = 3), corpus uteri (n = 2), and ovary (n = 1); 1 patient (3%) was treated with carboplatin and paclitaxel, then switched to carboplatin, bevacizumab, and paclitaxel, and then completed treatment with carboplatin and paclitaxel for an unspecified female genital cancer; and 1 patient (3%) was treated with cisplatin, ifosfamide, and paclitaxel for metastasis of the lower lobe lung and kidney cancer.
The 14 patients with PDTS data had 18 cancer drugs dispensed. Eleven had moderate interaction reports and 7 had no interaction reports. A total of 165 noncancer drugs were dispensed, of which 3 were antidepressants and had no interactions reported, 8 had moderate interactions reported, and 2 had minor interactions with Taxol and Abraxane, respectively (Table 6).86-129
Of 3 patients who were dispensed bupropion, nortriptyline, or paroxetine, 1 patient with breast cancer was treated with doxorubicin andcyclophosphamide, followed by paclitaxel with bupropion, nortriptyline, pegfilgrastim,dexamethasone, and 17 other noncancer drugs that had no interaction report dispensed during paclitaxel treatment. Of 2 patients with lung cancer, 1 patient was treated with carboplatin and paclitaxel with nortriptyline, dexamethasone, and 13 additional medications, and the second patient was treated with paroxetine, cimetidine, dexamethasone, and 12 other medications. Patients were dispensed up to6 noncancer medications on the same day as paclitaxel administration to control the AEs, not including the prodrugs filled before the treatments. Paroxetine and cimetidine have weak inhibition, and dexamethasone has weak induction of CYP3A4. Therefore, while 1:1 DDIs might have little or no effect with weak inhibit/induce CYP3A4 drugs, 1:1:1 or more combinations could have a different outcome (confirmed in previous publications).65-67
Dispensed on the same day may not mean taken at the same time. One patient experienced an AE with dispensed 50 mg losartan, carboplatin plus paclitaxel, dexamethasone, and 6 other noncancer drugs. Losartan inhibits paclitaxel, which can lead to negative AEs.57,66,67 However, there were no blood or plasma samples taken to confirm the losartan was taken at the same time as the paclitaxel given this was not a clinical trial.
Conclusions
This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIsidentified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996-2022), enabling them to make informed decisions about paclitaxel treatment.
Acknowledgments
The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Brandon E. Jenkins, and Alexander G. Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Martin L. Boese, CDR Wesley R. Campbell, Maj. Abhimanyu Chandel, CDR Ling Ye, Chelsea N. Powers, Yaling Zhou, Elizabeth Schafer, Micah Stretch, Diane Beaner, and Adrienne Woodard.
Background
Paclitaxel was first derived from the bark of the yew tree (Taxus brevifolia). It was discovered as part of a National Cancer Institute program screen of plants and natural products with putative anticancer activity during the 1960s.1-9 Paclitaxel works by suppressing spindle microtube dynamics, which results in the blockage of the metaphase-anaphase transitions, inhibition of mitosis, and induction of apoptosis in a broad spectrum of cancer cells. Paclitaxel also displayed additional anticancer activities, including the suppression of cell proliferation and antiangiogenic effects. However, since the growth of normal body cells may also be affected, other adverse effects (AEs) will also occur.8-18
Two different chemotherapy drugs contain paclitaxel—paclitaxel and nab-paclitaxel—and the US Food and Drug Administration (FDA) recognizes them as separate entities.19-21 Taxol (paclitaxel) was approved by the FDA in 1992 for treating advanced ovarian cancer.20 It has since been approved for the treatment of metastatic breast cancer, AIDS-related Kaposi sarcoma (as an orphan drug), non-small cell lung cancer (NSCLC), and cervical cancers (in combination withbevacizumab) in 1994, 1997, 1999, and 2014, respectively.21 Since 2002, a generic version of Taxol, known as paclitaxel injectable, has been FDA-approved from different manufacturers. According to the National Cancer Institute, a combination of carboplatin and Taxol is approved to treat carcinoma of unknown primary, cervical, endometrial, NSCLC, ovarian, and thymoma cancers.19 Abraxane (nab-paclitaxel) was FDA-approved to treat metastatic breast cancer in 2005. It was later approved for first-line treatment of advanced NSCLC and late-stage pancreatic cancer in 2012 and 2013, respectively. In 2018 and 2020, both Taxol and Abraxane were approved for first-line treatment of metastatic squamous cell NSCLC in combination with carboplatin and pembrolizumab and metastatic triple-negative breast cancer in combination with pembrolizumab, respectively.22-26 In 2019, Abraxane was approved with atezolizumab to treat metastatic triple-negative breast cancer, but this approval was withdrawn in 2021. In 2022, a generic version of Abraxane, known as paclitaxel protein-bound, was released in the United States. Furthermore, paclitaxel-containing formulations also are being studied in the treatment of other types of cancer.19-32
One of the main limitations of paclitaxel is its low solubility in water, which complicates its drug supply. To distribute this hydrophobic anticancer drug efficiently, paclitaxel is formulated and administered to patients via polyethoxylated castor oil or albumin-bound (nab-paclitaxel). However, polyethoxylated castor oil induces complement activation and is the cause of common hypersensitivity reactions related to paclitaxel use.2,17,33-38 Therefore, many alternatives to polyethoxylated castor oil have been researched.
Since 2000, new paclitaxel formulations have emerged using nanomedicine techniques. The difference between these formulations is the drug vehicle. Different paclitaxel-based nanotechnological vehicles have been developed and approved, such as albumin-based nanoparticles, polymeric lipidic nanoparticles, polymeric micelles, and liposomes, with many others in clinical trial phases.3,37 Albumin-based nanoparticles have a high response rate (33%), whereas the response rate for polyethoxylated castor oil is 25% in patients with metastatic breast cancer.33,39-52 The use of paclitaxel dimer nanoparticles also has been proposed as a method for increasing drug solubility.33,53
Paclitaxel is metabolized by cytochrome P450 (CYP) isoenzymes 2C8 and 3A4. When administering paclitaxel with known inhibitors, inducers, or substrates of CYP2C8 or CYP3A4, caution is required.19-22 Regulations for CYP research were not issued until 2008, so potential interactions between paclitaxel and other drugs have not been extensively evaluated in clinical trials. A study of 12 kinase inhibitors showed strong inhibition of CYP2C8 and/or CYP3A4 pathways by these inhibitors, which could alter the ratio of paclitaxel metabolites in vivo, leading to clinically relevant changes.54 Differential metabolism has been linked to paclitaxel-induced neurotoxicity in patients with cancer.55 Nonetheless, variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not account for significant interindividual variability in paclitaxel pharmacokinetics.56 In liver microsomes, losartan inhibited paclitaxel metabolism when used at concentrations > 50 µmol/L.57 Many drug-drug interaction (DDI) studies of CYP2C8 and CYP3A4 have shown similar results for paclitaxel.58-64
The goals of this study are to investigate prescribed drugs used with paclitaxel and determine patient outcomes through several Military Health System (MHS) databases. The investigation focused on (1) the functions of paclitaxel; (2) identifying AEs that patients experienced; (3) evaluating differences when paclitaxel is used alone vs concomitantly and between the completed vs discontinued treatment groups; (4) identifying all drugs used during paclitaxel treatment; and (5) evaluating DDIs with antidepressants (that have an FDA boxed warning and are known to have DDIs confirmed in previous publications) and other drugs.65-67
The Walter Reed National Military Medical Center in Bethesda, Maryland, institutionalreview board approved the study protocol and ensured compliance with the Health Insurance Portability and Accountability Act as an exempt protocol. The Joint Pathology Center (JPC) of the US Department of Defense (DoD) Cancer Registry Program and MHS data experts from the Comprehensive Ambulatory/Professional Encounter Record (CAPER) and the Pharmacy Data Transaction Service (PDTS) provided data for the analysis.
METHODS
The DoD Cancer Registry Program was established in 1986 and currently contains data from 1998 to 2024. CAPER and PDTS are part of the MHS Data Repository/Management Analysis and Reporting Tool database. Each observation in the CAPER record represents an ambulatory encounter at a military treatment facility (MTF). CAPER includes data from 2003 to 2024.
Each observation in the PDTS record represents a prescription filled for an MHS beneficiary at an MTF through the TRICARE mail-order program or a US retail pharmacy. Missing from this record are prescriptions filled at international civilian pharmacies and inpatient pharmacy prescriptions. The MHS Data Repository PDTS record is available from 2002 to 2024. The legacy Composite Health Care System is being replaced by GENESIS at MTFs.
Data Extraction Design
The study design involved a cross-sectional analysis. We requested data extraction for paclitaxel from 1998 to 2022. Data from the DoD Cancer Registry Program were used to identify patients who received cancer treatment. Once patients were identified, the CAPER database was searched for diagnoses to identify other health conditions, whereas the PDTS database was used to populate a list of prescription medications filled during chemotherapy treatment.
Data collected from the JPC included cancer treatment, cancer information, demographics, and physicians’ comments on AEs. Collected data from the MHS include diagnosis and filled prescription history from initiation to completion of the therapy period (or 2 years after the diagnosis date). For the analysis of the DoD Cancer Registry Program and CAPER databases, we used all collected data without excluding any. When analyzing PDTS data, we excluded patients with PDTS data but without a record of paclitaxel being filled, or medications filled outside the chemotherapy period (by evaluating the dispensed date and day of supply).
Data Extraction Analysis
The Surveillance, Epidemiology, and End Results Program Coding and Staging Manual 2016 and the International Classification of Diseases for Oncology, 3rd edition, 1st revision, were used to decode disease and cancer types.68,69 Data sorting and analysis were performed using Microsoft Excel. The percentage for the total was calculated by using the number of patients or data available within the paclitaxel groups divided by the total number of patients or data variables. The subgroup percentage was calculated by using the number of patients or data available within the subgroup divided by the total number of patients in that subgroup.
In alone vs concomitant and completed vs discontinued treatment groups, a 2-tailed, 2-sample z test was used to statistical significance (P < .05) using a statistics website.70 Concomitant was defined as paclitaxel taken with other antineoplastic agent(s) before, after, or at the same time as cancer therapy. For the retrospective data analysis, physicians’ notes with a period, comma, forward slash, semicolon, or space between medication names were interpreted as concurrent, whereas plus (+), minus/plus (-/+), or “and” between drug names that were dispensed on the same day were interpreted as combined with known common combinations: 2 drugs (DM886 paclitaxel and carboplatin and DM881-TC-1 paclitaxel and cisplatin) or 3 drugs (DM887-ACT doxorubicin, cyclophosphamide, and paclitaxel). Completed treatment was defined as paclitaxel as the last medication the patient took without recorded AEs; switching or experiencing AEs was defined as discontinued treatment.
RESULTS
The JPC provided 702 entries for 687 patients with a mean age of 56 years (range, 2 months to 88 years) who were treated with paclitaxel from March 1996 to October 2021. Fifteen patients had duplicate entries because they had multiple cancer sites or occurrences. There were 623 patients (89%) who received paclitaxel for FDA-approved indications. The most common types of cancer identified were 344 patients with breast cancer (49%), 91 patients with lung cancer (13%), 79 patients with ovarian cancer (11%), and 75 patients with endometrial cancer (11%) (Table 1). Seventy-nine patients (11%) received paclitaxel for cancers that were not for FDA-approved indications, including 19 for cancers of the fallopian tube (3%) and 17 for esophageal cancer (2%) (Table 2).
There were 477 patients (68%) aged > 50 years. A total of 304 patients (43%) had a stage III or IV cancer diagnosis and 398 (57%) had stage II or lower (combination of data for stages 0, I, and II; not applicable; and unknown) cancer diagnosis. For systemic treatment, 16 patients (2%) were treated with paclitaxel alone and 686 patients (98%) received paclitaxel concomitantly with additional chemotherapy: 59 patients (9%) in the before or after group, 410 patients (58%) had a 2-drug combination, 212 patients (30%) had a 3-drug combination, and 5 patients (1%) had a 4-drug combination. In addition, for doublet therapies, paclitaxel combined with carboplatin, trastuzumab, gemcitabine, or cisplatin had more patients (318, 58, 12, and 11, respectively) than other combinations (≤ 4 patients). For triplet therapies, paclitaxel combined withdoxorubicin plus cyclophosphamide or carboplatin plus bevacizumab had more patients (174 and 20, respectively) than other combinations, including quadruplet therapies (≤ 4 patients) (Table 3).
Patients were more likely to discontinue paclitaxel if they received concomitant treatment. None of the 16 patients receiving paclitaxel monotherapy experienced AEs, whereas 364 of 686 patients (53%) treated concomitantly discontinued (P < .001). Comparisons of 1 drug vs combination (2 to 4 drugs) and use for treating cancers that were FDA-approved indications vs off-label use were significant (P < .001), whereas comparisons of stage II or lower vs stage III and IV cancer and of those aged ≤ 50 years vs aged > 50 years were not significant (P = .50 andP = .30, respectively) (Table 4).
Among the 364 patients who had concomitant treatment and had discontinued their treatment, 332 (91%) switched treatments with no AEs documented and 32 (9%) experienced fatigue with pneumonia, mucositis, neuropathy, neurotoxicity, neutropenia, pneumonitis, allergic or hypersensitivity reaction, or an unknown AE. Patients who discontinued treatment because of unknown AEs had a physician’s note that detailed progressive disease, a significant decline in performance status, and another unknown adverse effect due to a previous sinus tract infection and infectious colitis (Table 5).
Management Analysis and Reporting Tool Database
MHS data analysts provided data on diagnoses for 639 patients among 687 submitteddiagnoses, with 294 patients completing and 345 discontinuing paclitaxel treatment. Patients in the completed treatment group had 3 to 258 unique health conditions documented, while patients in the discontinued treatment group had 4 to 181 unique health conditions documented. The MHS reported 3808 unique diagnosis conditions for the completed group and 3714 for the discontinued group (P = .02).
The mean (SD) number of diagnoses was 51 (31) for the completed and 55 (28) for the discontinued treatment groups (Figure). Among 639 patients who received paclitaxel, the top 5 diagnoses were administrative, including encounters for other administrative examinations; antineoplastic chemotherapy; administrative examination for unspecified; other specified counseling; and adjustment and management of vascular access device. The database does not differentiate between administrative and clinically significant diagnoses.
MHS data analysts provided data for 336 of 687 submitted patients who were prescribed paclitaxel; 46 patients had no PDTS data, and 305 patients had PDTS data without paclitaxel, Taxol, or Abraxane dispensed. Medications that were filled outside the chemotherapy period were removed by evaluating the dispensed date and day of supply. Among these 336 patients, 151 completed the treatment and 185 discontinued, with 14 patients experiencing documented AEs. Patients in the completed treatment group filled 9 to 56 prescriptions while patients in the discontinued treatment group filled 6 to 70 prescriptions.Patients in the discontinued group filled more prescriptions than those who completed treatment: 793 vs 591, respectively (P = .34).
The mean (SD) number of filled prescription drugs was 24 (9) for the completed and 34 (12) for the discontinued treatment group. The 5 most filled prescriptions with paclitaxel from 336 patients with PDTS data were dexamethasone (324 prescriptions with 14 recorded AEs), diphenhydramine (296 prescriptions with 12 recorded AEs), ondansetron (277 prescriptions with 11 recorded AEs), prochlorperazine (265 prescriptions with 12 recorded AEs), and sodium chloride (232 prescriptions with 11 recorded AEs).
DISCUSSION
As a retrospective review, this study is more limited in the strength of its conclusions when compared to randomized control trials. The DoD Cancer Registry Program only contains information about cancer types, stages, treatment regimens, and physicians’ notes. Therefore, noncancer drugs are based solely on the PDTS database. In most cases, physicians' notes on AEs were not detailed. There was no distinction between initial vs later lines of therapy and dosage reductions. The change in status or appearance of a new medical condition did not indicate whether paclitaxel caused the changes to develop or directly worsen a pre-existing condition. The PDTS records prescriptions filled, but that may not reflect patients taking prescriptions.
Paclitaxel
Paclitaxel has a long list of both approved and off-label uses in malignancies as a primary agent and in conjunction with other drugs. The FDA prescribing information for Taxol and Abraxane was last updated in April 2011 and September 2020, respectively.20,21 The National Institutes of Health National Library of Medicine has the current update for paclitaxel on July 2023.19,22 Thus, the prescribed information for paclitaxel referenced in the database may not always be up to date. The combinations of paclitaxel with bevacizumab, carboplatin, or carboplatin and pembrolizumab were not in the Taxol prescribing information. Likewise, a combination of nab-paclitaxel with atezolizumab or carboplatin and pembrolizumab is missing in the Abraxane prescribing information.22-27
The generic name is not the same as a generic drug, which may have slight differences from the brand name product.71 The generic drug versions of Taxol and Abraxane have been approved by the FDA as paclitaxel injectable and paclitaxel-protein bound, respectively. There was a global shortage of nab-paclitaxel from October 2021 to June 2022 because of a manufacturing problem.72 During this shortage, data showed similar comments from physician documents that treatment switched to Taxol due to the Abraxane shortage.
Of 336 patients in the PDTS database with dispensed paclitaxel prescriptions, 276 received paclitaxel (year dispensed, 2013-2022), 27 received Abraxane (year dispensed, 2013-2022), 47 received Taxol (year dispensed, 2004-2015), 8 received both Abraxane and paclitaxel, and 6 received both Taxol and paclitaxel. Based on this information, it appears that the distinction between the drugs was not made in the PDTS until after 2015, 10 years after Abraxane received FDA approval. Abraxane was prescribed in the MHS in 2013, 8 years after FDA approval. There were a few comparison studies of Abraxane and Taxol.73-76
Safety and effectiveness in pediatric patients have not been established for paclitaxel. According to the DoD Cancer Registry Program, the youngest patient was aged 2 months. In 2021, this patient was diagnosed with corpus uteri and treated with carboplatin and Taxol in course 1; in course 2, the patient reacted to Taxol; in course 3, Taxol was replaced with Abraxane; in courses 4 to 7, the patient was treated with carboplatin only.
Discontinued Treatment
Ten patients had prescribed Taxol that was changed due to AEs: 1 was switched to Abraxane and atezolizumab, 3 switched to Abraxane, 2 switched to docetaxel, 1 switched to doxorubicin, and 3 switched to pembrolizumab (based on physician’s comments). Of the 10 patients, 7 had Taxol reaction, 2 experienced disease progression, and 1 experienced high programmed death–ligand 1 expression (this patient with breast cancer was switched to Abraxane and atezolizumab during the accelerated FDA approval phase for atezolizumab, which was later revoked). Five patients were treated with carboplatin and Taxol for cancer of the anal canal (changed to pembrolizumab after disease progression), lung not otherwise specified (changed to carboplatin and pembrolizumab due to Taxol reaction), lower inner quadrant of the breast (changed to doxorubicin due to hypersensitivity reaction), corpus uteri (changed to Abraxane due to Taxol reaction), and ovary (changed to docetaxel due to Taxol reaction). Three patients were treated with doxorubicin, cyclophosphamide, and Taxol for breast cancer; 2 patients with breast cancer not otherwise specified switched to Abraxane due to cardiopulmonary hypersensitivity and Taxol reaction and 1 patient with cancer of the upper outer quadrant of the breast changed to docetaxel due to allergic reaction. One patient, who was treated with paclitaxel, ifosfamide, and cisplatin for metastasis of the lower lobe of the lung and kidney cancer, experienced complications due to infectious colitis (treated with ciprofloxacin) and then switched to pembrolizumab after the disease progressed. These AEs are known in paclitaxel medical literature on paclitaxel AEs.19-24,77-81
Combining 2 or more treatments to target cancer-inducing or cell-sustaining pathways is a cornerstone of chemotherapy.82-84 Most combinations are given on the same day, but some are not. For 3- or 4-drug combinations, doxorubicin and cyclophosphamide were given first, followed by paclitaxel with or withouttrastuzumab, carboplatin, or pembrolizumab. Only 16 patients (2%) were treated with paclitaxel alone; therefore, the completed and discontinued treatment groups are mostly concomitant treatment. As a result, the comparisons of the completed and discontinued treatment groups were almost the same for the diagnosis. The PDTS data have a better result because 2 exclusion criteria were applied before narrowing the analysis down to paclitaxel treatment specifically.
Antidepressants and Other Drugs
Drug response can vary from person to person and can lead to treatment failure related to AEs. One major factor in drug metabolism is CYP.85 CYP2C8 is the major pathway for paclitaxel and CYP3A4 is the minor pathway. When evaluating the noncancer drugs, there were no reports of CYP2C8 inhibition or induction.Over the years, many DDI warnings have been issued for paclitaxel with different drugs in various electronic resources.
Oncologists follow guidelines to prevent DDIs, as paclitaxel is known to have severe, moderate, and minor interactions with other drugs. Among 687 patients, 261 (38%) were prescribed any of 14 antidepressants. Eight of these antidepressants (amitriptyline, citalopram, desipramine, doxepin, venlafaxine, escitalopram, nortriptyline, and trazodone) are metabolized, 3 (mirtazapine, sertraline, and fluoxetine) are metabolized and inhibited, 2 (bupropion and duloxetine) are neither metabolized nor inhibited, and 1 (paroxetine) is inhibited by CYP3A4. Duloxetine, venlafaxine, and trazodone were more commonly dispensed (84, 78, and 42 patients, respectively) than others (≤ 33 patients).
Of 32 patients with documented AEs,14 (44%) had 168 dispensed drugs in the PDTS database. Six patients (19%) were treated with doxorubicin and cyclophosphamide followed by paclitaxel for breast cancer; 6 (19%) were treated with carboplatin and paclitaxel for cancer of the lung (n = 3), corpus uteri (n = 2), and ovary (n = 1); 1 patient (3%) was treated with carboplatin and paclitaxel, then switched to carboplatin, bevacizumab, and paclitaxel, and then completed treatment with carboplatin and paclitaxel for an unspecified female genital cancer; and 1 patient (3%) was treated with cisplatin, ifosfamide, and paclitaxel for metastasis of the lower lobe lung and kidney cancer.
The 14 patients with PDTS data had 18 cancer drugs dispensed. Eleven had moderate interaction reports and 7 had no interaction reports. A total of 165 noncancer drugs were dispensed, of which 3 were antidepressants and had no interactions reported, 8 had moderate interactions reported, and 2 had minor interactions with Taxol and Abraxane, respectively (Table 6).86-129
Of 3 patients who were dispensed bupropion, nortriptyline, or paroxetine, 1 patient with breast cancer was treated with doxorubicin andcyclophosphamide, followed by paclitaxel with bupropion, nortriptyline, pegfilgrastim,dexamethasone, and 17 other noncancer drugs that had no interaction report dispensed during paclitaxel treatment. Of 2 patients with lung cancer, 1 patient was treated with carboplatin and paclitaxel with nortriptyline, dexamethasone, and 13 additional medications, and the second patient was treated with paroxetine, cimetidine, dexamethasone, and 12 other medications. Patients were dispensed up to6 noncancer medications on the same day as paclitaxel administration to control the AEs, not including the prodrugs filled before the treatments. Paroxetine and cimetidine have weak inhibition, and dexamethasone has weak induction of CYP3A4. Therefore, while 1:1 DDIs might have little or no effect with weak inhibit/induce CYP3A4 drugs, 1:1:1 or more combinations could have a different outcome (confirmed in previous publications).65-67
Dispensed on the same day may not mean taken at the same time. One patient experienced an AE with dispensed 50 mg losartan, carboplatin plus paclitaxel, dexamethasone, and 6 other noncancer drugs. Losartan inhibits paclitaxel, which can lead to negative AEs.57,66,67 However, there were no blood or plasma samples taken to confirm the losartan was taken at the same time as the paclitaxel given this was not a clinical trial.
Conclusions
This retrospective study discusses the use of paclitaxel in the MHS and the potential DDIs associated with it. The study population consisted mostly of active-duty personnel, who are required to be healthy or have controlled or nonactive medical diagnoses and be physically fit. This group is mixed with dependents and retirees that are more reflective of the average US population. As a result, this patient population is healthier than the general population, with a lower prevalence of common illnesses such as diabetes and obesity. The study aimed to identify drugs used alongside paclitaxel treatment. While further research is needed to identify potential DDIs among patients who experienced AEs, in vitro testing will need to be conducted before confirming causality. The low number of AEs experienced by only 32 of 702 patients (5%), with no deaths during paclitaxel treatment, indicates that the drug is generally well tolerated. Although this study cannot conclude that concomitant use with noncancer drugs led to the discontinuation of paclitaxel, we can conclude that there seems to be no significant DDIsidentified between paclitaxel and antidepressants. This comprehensive overview provides clinicians with a complete picture of paclitaxel use for 27 years (1996-2022), enabling them to make informed decisions about paclitaxel treatment.
Acknowledgments
The Department of Research Program funds at Walter Reed National Military Medical Center supported this protocol. We sincerely appreciate the contribution of data extraction from the Joint Pathology Center teams (Francisco J. Rentas, John D. McGeeney, Beatriz A. Hallo, and Johnny P. Beason) and the MHS database personnel (Maj Ryan Costantino, Brandon E. Jenkins, and Alexander G. Rittel). We gratefully thank you for the protocol support from the Department of Research programs: CDR Martin L. Boese, CDR Wesley R. Campbell, Maj. Abhimanyu Chandel, CDR Ling Ye, Chelsea N. Powers, Yaling Zhou, Elizabeth Schafer, Micah Stretch, Diane Beaner, and Adrienne Woodard.
1. American Chemical Society. Discovery of camptothecin and taxol. acs.org. Accessed June 4, 2024. https://www.acs.org/education/whatischemistry/landmarks/camptothecintaxol.html
2. Bocci G, Di Paolo A, Danesi R. The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis. 2013;16(3):481-492. doi:10.1007/s10456-013-9334-0.
3. Meštrovic T. Paclitaxel history. News Medical Life Sciences. Updated March 11, 2023. Accessed June 4, 2024. https://www.news-medical.net/health/Paclitaxel-History.aspx
4. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995;332(15):1004-1014. doi:10.1056/NEJM199504133321507
5. Walsh V, Goodman J. The billion dollar molecule: Taxol in historical and theoretical perspective. Clio Med. 2002;66:245-267. doi:10.1163/9789004333499_013
6. Perdue RE, Jr, Hartwell JL. The search for plant sources of anticancer drugs. Morris Arboretum Bull. 1969;20:35-53.
7. Wall ME, Wani MC. Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 1995;55:753-760.
8. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J Am Chem Soc. 1971;93(9):2325-2327. doi:10.1021/ja00738a045
9. Weaver BA. How taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25(18):2677-2681. doi:10.1091/mbc.E14-04-0916
10. Chen JG, Horwitz SB. Differential mitotic responses to microtubule-stabilizing and-destabilizing drugs. Cancer Res. 2002;62(7):1935-1938.
11. Singh S, Dash AK. Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges. Crit Rev Ther Drug Carrier Syst. 2009;26(4):333-372. doi:10.1615/critrevtherdrugcarriersyst.v26.i4.10
12. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277(5698):665-667. doi:10.1038/277665a0
13. Fuchs DA, Johnson RK. Cytologic evidence that taxol, an antineoplastic agent from taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep. 1978;62(8):1219-1222.
14. Walsh V, Goodman J. From taxol to taxol: the changing identities and ownership of an anti-cancer drug. Med Anthropol. 2002;21(3-4):307-336. doi:10.1080/01459740214074
15. Walsh V, Goodman J. Cancer chemotherapy, biodiversity, public and private property: the case of the anti-cancer drug taxol. Soc Sci Med. 1999;49(9):1215-1225. doi:10.1016/s0277-9536(99)00161-6
16. Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 1996;56(4):816-825.
17. Picard M, Castells MC. Re-visiting hypersensitivity reactions to taxanes: a comprehensive review. Clin Rev Allergy Immunol. 2015;49(2):177-191. doi:10.1007/s12016-014-8416-0
18. Zasadil LM, Andersen KA, Yeum D, et al. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med. 2014;6:229ra243. doi:10.1126/scitranslmed.3007965
19. National Cancer Institute. Carboplatin-Taxol. Published May 30, 2012. Updated March 22, 2023. Accessed June 4, 2024. https://www.cancer.gov/about-cancer/treatment/drugs/carboplatin-taxol
20. Taxol (paclitaxel). Prescribing information. Bristol-Myers Squibb; 2011. Accessed June 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf
21. Abraxane (paclitaxel). Prescribing information. Celgene Corporation; 2021. Accessed June 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf
22. Awosika AO, Farrar MC, Jacobs TF. Paclitaxel. StatPearls. Updated November 18, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK536917/
23. Gerriets V, Kasi A. Bevacizumab. StatPearls. Updated September 1, 2022. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482126/
24. American Cancer Society. Chemotherapy for endometrial cancer. Updated March 27, 2019. Accessed June 4, 2024. https://www.cancer.org/cancer/types/endometrial-cancer/treating/chemotherapy.html
25. US Food and Drug Administration. FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC. October 30, 2018. Updated December 14, 2018. Accessed June 4, 2024. https://www.fda.gov/drugs/fda-approves-pembrolizumab-combination-chemotherapy-first-line-treatment-metastatic-squamous-nsclc
26. US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. November 13, 2020. Accessed June 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple
27. US Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast. March 8, 2019. Updated March 18, 2019. Accessed June 5, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative
28. US Food and Drug Administration. FDA issues alert about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. September 8, 2020. Accessed June 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-issues-alert-about-efficacy-and-potential-safety-concerns-atezolizumab-combination-paclitaxel
29. Tan AR. Chemoimmunotherapy: still the standard of care for metastatic triple-negative breast cancer. ASCO Daily News. February 23, 2022. Accessed June 5, 2024. https://dailynews.ascopubs.org/do/chemoimmunotherapy-still-standard-care-metastatic-triple-negative-breast-cancer
30. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111(4):273-279. doi:10.7326/0003-4819-111-4-273
31. Milas L, Hunter NR, Kurdoglu B, et al. Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemother Pharmacol. 1995;35(4):297-303. doi:10.1007/BF00689448
32. Searle J, Collins DJ, Harmon B, Kerr JF. The spontaneous occurrence of apoptosis in squamous carcinomas of the uterine cervix. Pathology. 1973;5(2):163-169. doi:10.3109/00313027309060831
33. Gallego-Jara J, Lozano-Terol G, Sola-Martínez RA, Cánovas-Díaz M, de Diego Puente T. A compressive review about taxol®: history and future challenges. Molecules. 2020;25(24):5986. doi:10.3390/molecules25245986
34. Bernabeu E, Cagel M, Lagomarsino E, Moretton M, Chiappetta DA. Paclitaxel: What has been done and the challenges remain ahead. Int J Pharm. 2017;526(1-2):474-495. doi:10.1016/j.ijpharm.2017.05.016
35. Nehate C, Jain S, Saneja A, et al. Paclitaxel formulations: challenges and novel delivery options. Curr Drug Deliv. 2014;11(6):666-686. doi:10.2174/1567201811666140609154949
36. Gelderblom H, Verweij J, Nooter K, Sparreboom A, Cremophor EL. The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590-1598. doi:10.1016/S0959-8049(01)00171-x
37. Chowdhury MR, Moshikur RM, Wakabayashi R, et al. In vivo biocompatibility, pharmacokinetics, antitumor efficacy, and hypersensitivity evaluation of ionic liquid-mediated paclitaxel formulations. Int J Pharm. 2019;565:219-226. doi:10.1016/j.ijpharm.2019.05.020
38. Borgå O, Henriksson R, Bjermo H, Lilienberg E, Heldring N, Loman N. Maximum tolerated dose and pharmacokinetics of paclitaxel micellar in patients with recurrent malignant solid tumours: a dose-escalation study. Adv Ther. 2019;36(5):1150-1163. doi:10.1007/s12325-019-00909-6
39. Rouzier R, Rajan R, Wagner P, et al. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci USA. 2005;102(23):8315-8320. doi:10.1073/pnas.0408974102
40. Choudhury H, Gorain B, Tekade RK, Pandey M, Karmakar S, Pal TK. Safety against nephrotoxicity in paclitaxel treatment: oral nanocarrier as an effective tool in preclinical evaluation with marked in vivo antitumor activity. Regul Toxicol Pharmacol. 2017;91:179-189. doi:10.1016/j.yrtph.2017.10.023
41. Barkat MA, Beg S, Pottoo FH, Ahmad FJ. Nanopaclitaxel therapy: an evidence based review on the battle for next-generation formulation challenges. Nanomedicine (Lond). 2019;14(10):1323-1341. doi:10.2217/nnm-2018-0313
42. Sofias AM, Dunne M, Storm G, Allen C. The battle of “nano” paclitaxel. Adv Drug Deliv Rev. 2017;122:20-30. doi:10.1016/j.addr.2017.02.003
43. Yang N, Wang C, Wang J, et al. Aurora inase a stabilizes FOXM1 to enhance paclitaxel resistance in triple-negative breast cancer. J Cell Mol Med. 2019;23(9):6442-6453. doi:10.1111/jcmm.14538
44. Chowdhury MR, Moshikur RM, Wakabayashi R, et al. Ionic-liquid-based paclitaxel preparation: a new potential formulation for cancer treatment. Mol Pharm. 2018;15(16):2484-2488. doi:10.1021/acs.molpharmaceut.8b00305
45. Chung HJ, Kim HJ, Hong ST. Tumor-specific delivery of a paclitaxel-loading HSA-haemin nanoparticle for cancer treatment. Nanomedicine. 2020;23:102089. doi:10.1016/j.nano.2019.102089
46. Ye L, He J, Hu Z, et al. Antitumor effect and toxicity of lipusu in rat ovarian cancer xenografts. Food Chem Toxicol. 2013;52:200-206. doi:10.1016/j.fct.2012.11.004
47. Ma WW, Lam ET, Dy GK, et al. A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with arboplatin in patients with advanced solid tumors. J Clin Oncol. 2013;31:2557. doi:10.1200/jco.2013.31.15_suppl.2557
48. Micha JP, Goldstein BH, Birk CL, Rettenmaier MA, Brown JV. Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions. Gynecol Oncol. 2006;100(2):437-438. doi:10.1016/j.ygyno.2005.09.012
49. Ingle SG, Pai RV, Monpara JD, Vavia PR. Liposils: an effective strategy for stabilizing paclitaxel loaded liposomes by surface coating with silica. Eur J Pharm Sci. 2018;122:51-63. doi:10.1016/j.ejps.2018.06.025
50. Abriata JP, Turatti RC, Luiz MT, et al. Development, characterization and biological in vitro assays of paclitaxel-loaded PCL polymeric nanoparticles. Mater Sci Eng C Mater Biol Appl. 2019;96:347-355. doi:10.1016/j.msec.2018.11.035
51. Hu J, Fu S, Peng Q, et al. Paclitaxel-loaded polymeric nanoparticles combined with chronomodulated chemotherapy on lung cancer: in vitro and in vivo evaluation. Int J Pharm. 2017;516(1-2):313-322. doi:10.1016/j.ijpharm.2016.11.047
52. Dranitsaris G, Yu B, Wang L, et al. Abraxane® vs Taxol® for patients with advanced breast cancer: a prospective time and motion analysis from a chinese health care perspective. J Oncol Pharm Pract. 2016;22(2):205-211. doi:10.1177/1078155214556008
53. Pei Q, Hu X, Liu S, Li Y, Xie Z, Jing X. Paclitaxel dimers assembling nanomedicines for treatment of cervix carcinoma. J Control Release. 2017;254:23-33. doi:10.1016/j.jconrel.2017.03.391
54. Wang Y, Wang M, Qi H, et al. Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials. Drug Metab Dispos. 2014;42(4):782-795. doi:10.1124/dmd.113.053793
55. Shen F, Jiang G, Philips S, et al. Cytochrome P450 oxidoreductase (POR) associated with severe paclitaxel-induced peripheral neuropathy in patients of european ancestry from ECOG-ACRIN E5103. Clin Cancer Res. 2023;29(13):2494-2500. doi:10.1158/1078-0432.CCR-22-2431
56. Henningsson A, Marsh S, Loos WJ, et al. Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res. 2005;11(22):8097-8104. doi:10.1158/1078-0432.CCR-05-1152
57. Mukai Y, Senda A, Toda T, et al. Drug-drug interaction between losartan and paclitaxel in human liver microsomes with different CYP2C8 genotypes. Basic Clin Pharmacol Toxicol. 2015;116(6):493-498. doi:10.1111/bcpt.12355
58. Kawahara B, Faull KF, Janzen C, Mascharak PK. Carbon monoxide inhibits cytochrome P450 enzymes CYP3A4/2C8 in human breast cancer cells, increasing sensitivity to paclitaxel. J Med Chem. 2021;64(12):8437-8446. doi:10.1021/acs.jmedchem.1c00404
59. Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F. Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos. 2002;30(4):438-445. doi:10.1124/dmd.30.4.438
60. Taniguchi R, Kumai T, Matsumoto N, et al. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. J Pharmacol Sci. 2005;97(1):83-90. doi:10.1254/jphs.fp0040603
61. Nakayama A, Tsuchiya K, Xu L, Matsumoto T, Makino T. Drug-interaction between paclitaxel and goshajinkigan extract and its constituents. J Nat Med. 2022;76(1):59-67. doi:10.1007/s11418-021-01552-8
62. Monsarrat B, Chatelut E, Royer I, et al. Modification of paclitaxel metabolism in a cancer patient by induction of cytochrome P450 3A4. Drug Metab Dispos. 1998;26(3):229-233.
63. Walle T. Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro. Methods Enzymol. 1996;272:145-151. doi:10.1016/s0076-6879(96)72018-9
64. Hanioka N, Matsumoto K, Saito Y, Narimatsu S. Functional characterization of CYP2C8.13 and CYP2C8.14: catalytic activities toward paclitaxel. Basic Clin Pharmacol Toxicol. 2010;107(1):565-569. doi:10.1111/j.1742-7843.2010.00543.x
65. Luong TT, Powers CN, Reinhardt BJ, Weina PJ. Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. Curr Res Pharmacol Drug Discov. 2022;3:100112. doi:10.1016/j.crphar.2022.100112
66. Luong TT, McAnulty MJ, Evers DL, Reinhardt BJ, Weina PJ. Pre-clinical drug-drug interaction (DDI) of gefitinib or erlotinib with Cytochrome P450 (CYP) inhibiting drugs, fluoxetine and/or losartan. Curr Res Toxicol. 2021;2:217-224. doi:10.1016/j.crtox.2021.05.006
67. Luong TT, Powers CN, Reinhardt BJ, et al. Retrospective evaluation of drug-drug interactions with erlotinib and gefitinib use in the military health system. Fed Pract. 2023;40(suppl 3):S24-S34. doi:10.12788/fp.0401
68. Adamo M, Dickie L, Ruhl J. SEER program coding and staging manual 2016. National Cancer Institute. Accessed June 5, 2024. https://seer.cancer.gov/archive/manuals/2016/SPCSM_2016_maindoc.pdf
69. World Health Organization. International classification of diseases for oncology (ICD-O) 3rd ed, 1st revision. World Health Organization; 2013. Accessed June 5, 2024. https://apps.who.int/iris/handle/10665/96612
70. Z score calculator for 2 population proportions. Social science statistics. Accessed June 5, 2024. https://www.socscistatistics.com/tests/ztest/default2.aspx
71. US Food and Drug Administration. Generic drugs: question & answers. FDA.gov. Accessed June 5, 2024. https://www.fda.gov/drugs/frequently-asked-questions-popular-topics/generic-drugs-questions-answers
72. Oura M, Saito H, Nishikawa Y. Shortage of nab-paclitaxel in Japan and around the world: issues in global information sharing. JMA J. 2023;6(2):192-195. doi:10.31662/jmaj.2022-0179
73. Yuan H, Guo H, Luan X, et al. Albumin nanoparticle of paclitaxel (abraxane) decreases while taxol increases breast cancer stem cells in treatment of triple negative breast cancer. Mol Pharm. 2020;17(7):2275-2286. doi:10.1021/acs.molpharmaceut.9b01221
74. Dranitsaris G, Yu B, Wang L, et al. Abraxane® versus Taxol® for patients with advanced breast cancer: a prospective time and motion analysis from a Chinese health care perspective. J Oncol Pharm Pract. 2016;22(2):205-211. doi:10.1177/1078155214556008
75. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794-7803. doi:10.1200/JCO.2005.04.
76. Liu M, Liu S, Yang L, Wang S. Comparison between nab-paclitaxel and solvent-based taxanes as neoadjuvant therapy in breast cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):118. doi:10.1186/s12885-021-07831-7
77. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (taxol). Semin Oncol. 1993;20(4 Suppl 3):1-15.
78. Banerji A, Lax T, Guyer A, Hurwitz S, Camargo CA Jr, Long AA. Management of hypersensitivity reactions to carboplatin and paclitaxel in an outpatient oncology infusion center: a 5-year review. J Allergy Clin Immunol Pract. 2014;2(4):428-433. doi:10.1016/j.jaip.2014.04.010
79. Staff NP, Fehrenbacher JC, Caillaud M, Damaj MI, Segal RA, Rieger S. Pathogenesis of paclitaxel-induced peripheral neuropathy: a current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol. 2020;324:113121. doi:10.1016/j.expneurol.2019.113121
80. Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM, Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol. 1995;6(5):489-494. doi:10.1093/oxfordjournals.annonc.a059220
81. Liu JM, Chen YM, Chao Y, et al. Paclitaxel-induced severe neuropathy in patients with previous radiotherapy to the head and neck region. J Natl Cancer Inst. 1996;88(14):1000-1002. doi:10.1093/jnci/88.14.1000-a
82. Bayat Mokhtari R, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022-38043. doi:10.18632/oncotarget.16723
83. Blagosklonny MV. Analysis of FDA approved anticancer drugs reveals the future of cancer therapy. Cell Cycle. 2004;3(8):1035-1042.
84. Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592-1605. doi:10.1200/JCO.2011.37.6418
85. Gilani B, Cassagnol M. Biochemistry, Cytochrome P450. StatPearls. Updated April 24, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK557698/
86. LiverTox: clinical and research information on drug-induced liver injury; 2012. Carboplatin. Updated September 15, 2020. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548565/
87. Carboplatin. Prescribing information. Teva Parenteral Medicines; 2012. Accessed June 5, 204. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/077139Orig1s016lbl.pdf
88. Johnson-Arbor K, Dubey R. Doxorubicin. StatPearls. Updated August 8, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK459232/
89. Doxorubicin hydrochloride injection. Prescribing information. Pfizer; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/050467s078,050629s030lbl.pdf
90. Gor, PP, Su, HI, Gray, RJ, et al. Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res. 2010;12(3):R26. doi:10.1186/bcr2570
91. Cyclophosphamide. Prescribing information. Ingenus Pharmaceuticals; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212501s000lbl.pdf
92. Gemcitabine. Prescribing information. Hospira; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/200795Orig1s010lbl.pdf
93. Ifex (ifosfamide). Prescribing information. Baxter; 2012. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf
94. Cisplatin. Prescribing information. WG Critical Care; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018057s089lbl.pdf
95. Gerriets V, Kasi A. Bevacizumab. StatPearls. Updated August 28, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482126/
96. Avastin (bevacizumab). Prescribing information. Genentech; 2022. Accessed June 5, 2024. https://www.accessdata .fda.gov/drugsatfda_docs/label/2022/125085s340lbl.pdf
97. Keytruda (pembrolizumab). Prescribing information. Merck; 2021. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf
98. Dean L, Kane M. Capecitabine therapy and DPYD genotype. National Center for Biotechnology Information (US); 2012. Updated November 2, 2020. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK385155/
99. Xeloda (capecitabine). Prescribing information. Roche; 2000. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20896lbl.pdf
100. Pemetrexed injection. Prescribing information. Fareva Unterach; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214657s000lbl.pdf
101. Topotecan Injection. Prescribing information. Zydus Hospira Oncology; 2014. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200582s001lbl.pdf
102. Ibrance (palbociclib). Prescribing information. Pfizer; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf
103. Navelbine (vinorelbine) injection. Prescribing information. Pierre Fabre Médicament; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020388s037lbl.pdf
104. LiverTox: clinical and research information on drug-induced liver injury; 2012. Letrozole. Updated July 25, 2017. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548381/
105. Femara (letrozole). Prescribing information. Novartis; 2014. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf
106. Soltamox (tamoxifen citrate). Prescribing information. Rosemont Pharmaceuticals; 2018. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf
107. LiverTox: clinical and research information on drug-induced liver injury; 2012. Anastrozole. Updated July 25, 2017. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548189/
108. Grimm SW, Dyroff MC. Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase. Drug Metab Dispos. 1997;25(5):598-602.
109. Arimidex (anastrozole). Prescribing information. AstraZeneca; 2010. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020541s026lbl.pdf
110. Megace (megestrol acetate). Prescribing information. Endo Pharmaceuticals; 2018. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021778s024lbl.pdf
111. Imfinzi (durvalumab). Prescribing information. AstraZeneca; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf
112. Merwar G, Gibbons JR, Hosseini SA, et al. Nortriptyline. StatPearls. Updated June 5, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482214/
113. Pamelor (nortriptyline HCl). Prescribing information. Patheon Inc.; 2012. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018012s029,018013s061lbl.pdf
114. Wellbutrin (bupropion hydrochloride). Prescribing information. GlaxoSmithKline; 2017. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018644s052lbl.pdf
115. Paxil (paroxetine). Prescribing information. Apotex Inc.; 2021. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020031s077lbl.pdf
116. Johnson DB, Lopez MJ, Kelley B. Dexamethasone. StatPearls. Updated May 2, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482130/
117. Hemady (dexamethasone). Prescribing information. Dexcel Pharma; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211379s000lbl.pdf
118. Parker SD, King N, Jacobs TF. Pegfilgrastim. StatPearls. Updated May 9, 2024. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK532893/
119. Fylnetra (pegfilgrastim-pbbk). Prescribing information. Kashiv BioSciences; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761084s000lbl.pdf
120. Emend (aprepitant). Prescribing information. Merck; 2015. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207865lbl.pdf
121. Lipitor (atorvastatin calcium). Prescribing information. Viatris Specialty; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020702Orig1s079correctedlbl.pdf
122. Cipro (ciprofloxacin hydrochloride). Prescribing information. Bayer HealthCare Pharmaceuticals Inc.; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/019537s090,020780s047lbl.pdf
123. Pino MA, Azer SA. Cimetidine. StatPearls. Updated March 6, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK544255/
124. Tagament (Cimetidine). Prescribing information. Mylan; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020238Orig1s024lbl.pdf
125. Neupogen (filgrastim). Prescribing information. Amgen Inc.; 2015. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103353s5184lbl.pdf
126. Flagyl (metronidazole). Prescribing information. Pfizer; 2013. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020334s008lbl.pdf
127. Zymaxid (gatifloxacin ophthalmic solution). Prescribing information. Allergan; 2016. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022548s002lbl.pdf
128. Macrobid (nitrofurantoin monohydrate). Prescribing information. Procter and Gamble Pharmaceutical Inc.; 2009. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf
129. Hyzaar (losartan). Prescribing information. Merck; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020387s067lbl.pdf
1. American Chemical Society. Discovery of camptothecin and taxol. acs.org. Accessed June 4, 2024. https://www.acs.org/education/whatischemistry/landmarks/camptothecintaxol.html
2. Bocci G, Di Paolo A, Danesi R. The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis. 2013;16(3):481-492. doi:10.1007/s10456-013-9334-0.
3. Meštrovic T. Paclitaxel history. News Medical Life Sciences. Updated March 11, 2023. Accessed June 4, 2024. https://www.news-medical.net/health/Paclitaxel-History.aspx
4. Rowinsky EK, Donehower RC. Paclitaxel (taxol). N Engl J Med. 1995;332(15):1004-1014. doi:10.1056/NEJM199504133321507
5. Walsh V, Goodman J. The billion dollar molecule: Taxol in historical and theoretical perspective. Clio Med. 2002;66:245-267. doi:10.1163/9789004333499_013
6. Perdue RE, Jr, Hartwell JL. The search for plant sources of anticancer drugs. Morris Arboretum Bull. 1969;20:35-53.
7. Wall ME, Wani MC. Camptothecin and taxol: discovery to clinic—thirteenth Bruce F. Cain Memorial Award lecture. Cancer Res. 1995;55:753-760.
8. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from taxus brevifolia. J Am Chem Soc. 1971;93(9):2325-2327. doi:10.1021/ja00738a045
9. Weaver BA. How taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25(18):2677-2681. doi:10.1091/mbc.E14-04-0916
10. Chen JG, Horwitz SB. Differential mitotic responses to microtubule-stabilizing and-destabilizing drugs. Cancer Res. 2002;62(7):1935-1938.
11. Singh S, Dash AK. Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges. Crit Rev Ther Drug Carrier Syst. 2009;26(4):333-372. doi:10.1615/critrevtherdrugcarriersyst.v26.i4.10
12. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979;277(5698):665-667. doi:10.1038/277665a0
13. Fuchs DA, Johnson RK. Cytologic evidence that taxol, an antineoplastic agent from taxus brevifolia, acts as a mitotic spindle poison. Cancer Treat Rep. 1978;62(8):1219-1222.
14. Walsh V, Goodman J. From taxol to taxol: the changing identities and ownership of an anti-cancer drug. Med Anthropol. 2002;21(3-4):307-336. doi:10.1080/01459740214074
15. Walsh V, Goodman J. Cancer chemotherapy, biodiversity, public and private property: the case of the anti-cancer drug taxol. Soc Sci Med. 1999;49(9):1215-1225. doi:10.1016/s0277-9536(99)00161-6
16. Jordan MA, Wendell K, Gardiner S, Derry WB, Copp H, Wilson L. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 1996;56(4):816-825.
17. Picard M, Castells MC. Re-visiting hypersensitivity reactions to taxanes: a comprehensive review. Clin Rev Allergy Immunol. 2015;49(2):177-191. doi:10.1007/s12016-014-8416-0
18. Zasadil LM, Andersen KA, Yeum D, et al. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med. 2014;6:229ra243. doi:10.1126/scitranslmed.3007965
19. National Cancer Institute. Carboplatin-Taxol. Published May 30, 2012. Updated March 22, 2023. Accessed June 4, 2024. https://www.cancer.gov/about-cancer/treatment/drugs/carboplatin-taxol
20. Taxol (paclitaxel). Prescribing information. Bristol-Myers Squibb; 2011. Accessed June 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf
21. Abraxane (paclitaxel). Prescribing information. Celgene Corporation; 2021. Accessed June 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021660s047lbl.pdf
22. Awosika AO, Farrar MC, Jacobs TF. Paclitaxel. StatPearls. Updated November 18, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK536917/
23. Gerriets V, Kasi A. Bevacizumab. StatPearls. Updated September 1, 2022. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482126/
24. American Cancer Society. Chemotherapy for endometrial cancer. Updated March 27, 2019. Accessed June 4, 2024. https://www.cancer.org/cancer/types/endometrial-cancer/treating/chemotherapy.html
25. US Food and Drug Administration. FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC. October 30, 2018. Updated December 14, 2018. Accessed June 4, 2024. https://www.fda.gov/drugs/fda-approves-pembrolizumab-combination-chemotherapy-first-line-treatment-metastatic-squamous-nsclc
26. US Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. November 13, 2020. Accessed June 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple
27. US Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast. March 8, 2019. Updated March 18, 2019. Accessed June 5, 2024. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative
28. US Food and Drug Administration. FDA issues alert about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for treatment of breast cancer. September 8, 2020. Accessed June 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-issues-alert-about-efficacy-and-potential-safety-concerns-atezolizumab-combination-paclitaxel
29. Tan AR. Chemoimmunotherapy: still the standard of care for metastatic triple-negative breast cancer. ASCO Daily News. February 23, 2022. Accessed June 5, 2024. https://dailynews.ascopubs.org/do/chemoimmunotherapy-still-standard-care-metastatic-triple-negative-breast-cancer
30. McGuire WP, Rowinsky EK, Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989;111(4):273-279. doi:10.7326/0003-4819-111-4-273
31. Milas L, Hunter NR, Kurdoglu B, et al. Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemother Pharmacol. 1995;35(4):297-303. doi:10.1007/BF00689448
32. Searle J, Collins DJ, Harmon B, Kerr JF. The spontaneous occurrence of apoptosis in squamous carcinomas of the uterine cervix. Pathology. 1973;5(2):163-169. doi:10.3109/00313027309060831
33. Gallego-Jara J, Lozano-Terol G, Sola-Martínez RA, Cánovas-Díaz M, de Diego Puente T. A compressive review about taxol®: history and future challenges. Molecules. 2020;25(24):5986. doi:10.3390/molecules25245986
34. Bernabeu E, Cagel M, Lagomarsino E, Moretton M, Chiappetta DA. Paclitaxel: What has been done and the challenges remain ahead. Int J Pharm. 2017;526(1-2):474-495. doi:10.1016/j.ijpharm.2017.05.016
35. Nehate C, Jain S, Saneja A, et al. Paclitaxel formulations: challenges and novel delivery options. Curr Drug Deliv. 2014;11(6):666-686. doi:10.2174/1567201811666140609154949
36. Gelderblom H, Verweij J, Nooter K, Sparreboom A, Cremophor EL. The drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590-1598. doi:10.1016/S0959-8049(01)00171-x
37. Chowdhury MR, Moshikur RM, Wakabayashi R, et al. In vivo biocompatibility, pharmacokinetics, antitumor efficacy, and hypersensitivity evaluation of ionic liquid-mediated paclitaxel formulations. Int J Pharm. 2019;565:219-226. doi:10.1016/j.ijpharm.2019.05.020
38. Borgå O, Henriksson R, Bjermo H, Lilienberg E, Heldring N, Loman N. Maximum tolerated dose and pharmacokinetics of paclitaxel micellar in patients with recurrent malignant solid tumours: a dose-escalation study. Adv Ther. 2019;36(5):1150-1163. doi:10.1007/s12325-019-00909-6
39. Rouzier R, Rajan R, Wagner P, et al. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci USA. 2005;102(23):8315-8320. doi:10.1073/pnas.0408974102
40. Choudhury H, Gorain B, Tekade RK, Pandey M, Karmakar S, Pal TK. Safety against nephrotoxicity in paclitaxel treatment: oral nanocarrier as an effective tool in preclinical evaluation with marked in vivo antitumor activity. Regul Toxicol Pharmacol. 2017;91:179-189. doi:10.1016/j.yrtph.2017.10.023
41. Barkat MA, Beg S, Pottoo FH, Ahmad FJ. Nanopaclitaxel therapy: an evidence based review on the battle for next-generation formulation challenges. Nanomedicine (Lond). 2019;14(10):1323-1341. doi:10.2217/nnm-2018-0313
42. Sofias AM, Dunne M, Storm G, Allen C. The battle of “nano” paclitaxel. Adv Drug Deliv Rev. 2017;122:20-30. doi:10.1016/j.addr.2017.02.003
43. Yang N, Wang C, Wang J, et al. Aurora inase a stabilizes FOXM1 to enhance paclitaxel resistance in triple-negative breast cancer. J Cell Mol Med. 2019;23(9):6442-6453. doi:10.1111/jcmm.14538
44. Chowdhury MR, Moshikur RM, Wakabayashi R, et al. Ionic-liquid-based paclitaxel preparation: a new potential formulation for cancer treatment. Mol Pharm. 2018;15(16):2484-2488. doi:10.1021/acs.molpharmaceut.8b00305
45. Chung HJ, Kim HJ, Hong ST. Tumor-specific delivery of a paclitaxel-loading HSA-haemin nanoparticle for cancer treatment. Nanomedicine. 2020;23:102089. doi:10.1016/j.nano.2019.102089
46. Ye L, He J, Hu Z, et al. Antitumor effect and toxicity of lipusu in rat ovarian cancer xenografts. Food Chem Toxicol. 2013;52:200-206. doi:10.1016/j.fct.2012.11.004
47. Ma WW, Lam ET, Dy GK, et al. A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with arboplatin in patients with advanced solid tumors. J Clin Oncol. 2013;31:2557. doi:10.1200/jco.2013.31.15_suppl.2557
48. Micha JP, Goldstein BH, Birk CL, Rettenmaier MA, Brown JV. Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions. Gynecol Oncol. 2006;100(2):437-438. doi:10.1016/j.ygyno.2005.09.012
49. Ingle SG, Pai RV, Monpara JD, Vavia PR. Liposils: an effective strategy for stabilizing paclitaxel loaded liposomes by surface coating with silica. Eur J Pharm Sci. 2018;122:51-63. doi:10.1016/j.ejps.2018.06.025
50. Abriata JP, Turatti RC, Luiz MT, et al. Development, characterization and biological in vitro assays of paclitaxel-loaded PCL polymeric nanoparticles. Mater Sci Eng C Mater Biol Appl. 2019;96:347-355. doi:10.1016/j.msec.2018.11.035
51. Hu J, Fu S, Peng Q, et al. Paclitaxel-loaded polymeric nanoparticles combined with chronomodulated chemotherapy on lung cancer: in vitro and in vivo evaluation. Int J Pharm. 2017;516(1-2):313-322. doi:10.1016/j.ijpharm.2016.11.047
52. Dranitsaris G, Yu B, Wang L, et al. Abraxane® vs Taxol® for patients with advanced breast cancer: a prospective time and motion analysis from a chinese health care perspective. J Oncol Pharm Pract. 2016;22(2):205-211. doi:10.1177/1078155214556008
53. Pei Q, Hu X, Liu S, Li Y, Xie Z, Jing X. Paclitaxel dimers assembling nanomedicines for treatment of cervix carcinoma. J Control Release. 2017;254:23-33. doi:10.1016/j.jconrel.2017.03.391
54. Wang Y, Wang M, Qi H, et al. Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials. Drug Metab Dispos. 2014;42(4):782-795. doi:10.1124/dmd.113.053793
55. Shen F, Jiang G, Philips S, et al. Cytochrome P450 oxidoreductase (POR) associated with severe paclitaxel-induced peripheral neuropathy in patients of european ancestry from ECOG-ACRIN E5103. Clin Cancer Res. 2023;29(13):2494-2500. doi:10.1158/1078-0432.CCR-22-2431
56. Henningsson A, Marsh S, Loos WJ, et al. Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res. 2005;11(22):8097-8104. doi:10.1158/1078-0432.CCR-05-1152
57. Mukai Y, Senda A, Toda T, et al. Drug-drug interaction between losartan and paclitaxel in human liver microsomes with different CYP2C8 genotypes. Basic Clin Pharmacol Toxicol. 2015;116(6):493-498. doi:10.1111/bcpt.12355
58. Kawahara B, Faull KF, Janzen C, Mascharak PK. Carbon monoxide inhibits cytochrome P450 enzymes CYP3A4/2C8 in human breast cancer cells, increasing sensitivity to paclitaxel. J Med Chem. 2021;64(12):8437-8446. doi:10.1021/acs.jmedchem.1c00404
59. Cresteil T, Monsarrat B, Dubois J, Sonnier M, Alvinerie P, Gueritte F. Regioselective metabolism of taxoids by human CYP3A4 and 2C8: structure-activity relationship. Drug Metab Dispos. 2002;30(4):438-445. doi:10.1124/dmd.30.4.438
60. Taniguchi R, Kumai T, Matsumoto N, et al. Utilization of human liver microsomes to explain individual differences in paclitaxel metabolism by CYP2C8 and CYP3A4. J Pharmacol Sci. 2005;97(1):83-90. doi:10.1254/jphs.fp0040603
61. Nakayama A, Tsuchiya K, Xu L, Matsumoto T, Makino T. Drug-interaction between paclitaxel and goshajinkigan extract and its constituents. J Nat Med. 2022;76(1):59-67. doi:10.1007/s11418-021-01552-8
62. Monsarrat B, Chatelut E, Royer I, et al. Modification of paclitaxel metabolism in a cancer patient by induction of cytochrome P450 3A4. Drug Metab Dispos. 1998;26(3):229-233.
63. Walle T. Assays of CYP2C8- and CYP3A4-mediated metabolism of taxol in vivo and in vitro. Methods Enzymol. 1996;272:145-151. doi:10.1016/s0076-6879(96)72018-9
64. Hanioka N, Matsumoto K, Saito Y, Narimatsu S. Functional characterization of CYP2C8.13 and CYP2C8.14: catalytic activities toward paclitaxel. Basic Clin Pharmacol Toxicol. 2010;107(1):565-569. doi:10.1111/j.1742-7843.2010.00543.x
65. Luong TT, Powers CN, Reinhardt BJ, Weina PJ. Pre-clinical drug-drug interactions (DDIs) of gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. Curr Res Pharmacol Drug Discov. 2022;3:100112. doi:10.1016/j.crphar.2022.100112
66. Luong TT, McAnulty MJ, Evers DL, Reinhardt BJ, Weina PJ. Pre-clinical drug-drug interaction (DDI) of gefitinib or erlotinib with Cytochrome P450 (CYP) inhibiting drugs, fluoxetine and/or losartan. Curr Res Toxicol. 2021;2:217-224. doi:10.1016/j.crtox.2021.05.006
67. Luong TT, Powers CN, Reinhardt BJ, et al. Retrospective evaluation of drug-drug interactions with erlotinib and gefitinib use in the military health system. Fed Pract. 2023;40(suppl 3):S24-S34. doi:10.12788/fp.0401
68. Adamo M, Dickie L, Ruhl J. SEER program coding and staging manual 2016. National Cancer Institute. Accessed June 5, 2024. https://seer.cancer.gov/archive/manuals/2016/SPCSM_2016_maindoc.pdf
69. World Health Organization. International classification of diseases for oncology (ICD-O) 3rd ed, 1st revision. World Health Organization; 2013. Accessed June 5, 2024. https://apps.who.int/iris/handle/10665/96612
70. Z score calculator for 2 population proportions. Social science statistics. Accessed June 5, 2024. https://www.socscistatistics.com/tests/ztest/default2.aspx
71. US Food and Drug Administration. Generic drugs: question & answers. FDA.gov. Accessed June 5, 2024. https://www.fda.gov/drugs/frequently-asked-questions-popular-topics/generic-drugs-questions-answers
72. Oura M, Saito H, Nishikawa Y. Shortage of nab-paclitaxel in Japan and around the world: issues in global information sharing. JMA J. 2023;6(2):192-195. doi:10.31662/jmaj.2022-0179
73. Yuan H, Guo H, Luan X, et al. Albumin nanoparticle of paclitaxel (abraxane) decreases while taxol increases breast cancer stem cells in treatment of triple negative breast cancer. Mol Pharm. 2020;17(7):2275-2286. doi:10.1021/acs.molpharmaceut.9b01221
74. Dranitsaris G, Yu B, Wang L, et al. Abraxane® versus Taxol® for patients with advanced breast cancer: a prospective time and motion analysis from a Chinese health care perspective. J Oncol Pharm Pract. 2016;22(2):205-211. doi:10.1177/1078155214556008
75. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794-7803. doi:10.1200/JCO.2005.04.
76. Liu M, Liu S, Yang L, Wang S. Comparison between nab-paclitaxel and solvent-based taxanes as neoadjuvant therapy in breast cancer: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):118. doi:10.1186/s12885-021-07831-7
77. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. Clinical toxicities encountered with paclitaxel (taxol). Semin Oncol. 1993;20(4 Suppl 3):1-15.
78. Banerji A, Lax T, Guyer A, Hurwitz S, Camargo CA Jr, Long AA. Management of hypersensitivity reactions to carboplatin and paclitaxel in an outpatient oncology infusion center: a 5-year review. J Allergy Clin Immunol Pract. 2014;2(4):428-433. doi:10.1016/j.jaip.2014.04.010
79. Staff NP, Fehrenbacher JC, Caillaud M, Damaj MI, Segal RA, Rieger S. Pathogenesis of paclitaxel-induced peripheral neuropathy: a current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol. 2020;324:113121. doi:10.1016/j.expneurol.2019.113121
80. Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM, Heimans JJ. Paclitaxel-induced neuropathy. Ann Oncol. 1995;6(5):489-494. doi:10.1093/oxfordjournals.annonc.a059220
81. Liu JM, Chen YM, Chao Y, et al. Paclitaxel-induced severe neuropathy in patients with previous radiotherapy to the head and neck region. J Natl Cancer Inst. 1996;88(14):1000-1002. doi:10.1093/jnci/88.14.1000-a
82. Bayat Mokhtari R, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022-38043. doi:10.18632/oncotarget.16723
83. Blagosklonny MV. Analysis of FDA approved anticancer drugs reveals the future of cancer therapy. Cell Cycle. 2004;3(8):1035-1042.
84. Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31(12):1592-1605. doi:10.1200/JCO.2011.37.6418
85. Gilani B, Cassagnol M. Biochemistry, Cytochrome P450. StatPearls. Updated April 24, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK557698/
86. LiverTox: clinical and research information on drug-induced liver injury; 2012. Carboplatin. Updated September 15, 2020. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548565/
87. Carboplatin. Prescribing information. Teva Parenteral Medicines; 2012. Accessed June 5, 204. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/077139Orig1s016lbl.pdf
88. Johnson-Arbor K, Dubey R. Doxorubicin. StatPearls. Updated August 8, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK459232/
89. Doxorubicin hydrochloride injection. Prescribing information. Pfizer; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/050467s078,050629s030lbl.pdf
90. Gor, PP, Su, HI, Gray, RJ, et al. Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. Breast Cancer Res. 2010;12(3):R26. doi:10.1186/bcr2570
91. Cyclophosphamide. Prescribing information. Ingenus Pharmaceuticals; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212501s000lbl.pdf
92. Gemcitabine. Prescribing information. Hospira; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/200795Orig1s010lbl.pdf
93. Ifex (ifosfamide). Prescribing information. Baxter; 2012. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019763s017lbl.pdf
94. Cisplatin. Prescribing information. WG Critical Care; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018057s089lbl.pdf
95. Gerriets V, Kasi A. Bevacizumab. StatPearls. Updated August 28, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482126/
96. Avastin (bevacizumab). Prescribing information. Genentech; 2022. Accessed June 5, 2024. https://www.accessdata .fda.gov/drugsatfda_docs/label/2022/125085s340lbl.pdf
97. Keytruda (pembrolizumab). Prescribing information. Merck; 2021. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf
98. Dean L, Kane M. Capecitabine therapy and DPYD genotype. National Center for Biotechnology Information (US); 2012. Updated November 2, 2020. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK385155/
99. Xeloda (capecitabine). Prescribing information. Roche; 2000. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20896lbl.pdf
100. Pemetrexed injection. Prescribing information. Fareva Unterach; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214657s000lbl.pdf
101. Topotecan Injection. Prescribing information. Zydus Hospira Oncology; 2014. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200582s001lbl.pdf
102. Ibrance (palbociclib). Prescribing information. Pfizer; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf
103. Navelbine (vinorelbine) injection. Prescribing information. Pierre Fabre Médicament; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020388s037lbl.pdf
104. LiverTox: clinical and research information on drug-induced liver injury; 2012. Letrozole. Updated July 25, 2017. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548381/
105. Femara (letrozole). Prescribing information. Novartis; 2014. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf
106. Soltamox (tamoxifen citrate). Prescribing information. Rosemont Pharmaceuticals; 2018. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021807s005lbl.pdf
107. LiverTox: clinical and research information on drug-induced liver injury; 2012. Anastrozole. Updated July 25, 2017. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548189/
108. Grimm SW, Dyroff MC. Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase. Drug Metab Dispos. 1997;25(5):598-602.
109. Arimidex (anastrozole). Prescribing information. AstraZeneca; 2010. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020541s026lbl.pdf
110. Megace (megestrol acetate). Prescribing information. Endo Pharmaceuticals; 2018. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021778s024lbl.pdf
111. Imfinzi (durvalumab). Prescribing information. AstraZeneca; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf
112. Merwar G, Gibbons JR, Hosseini SA, et al. Nortriptyline. StatPearls. Updated June 5, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482214/
113. Pamelor (nortriptyline HCl). Prescribing information. Patheon Inc.; 2012. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/018012s029,018013s061lbl.pdf
114. Wellbutrin (bupropion hydrochloride). Prescribing information. GlaxoSmithKline; 2017. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018644s052lbl.pdf
115. Paxil (paroxetine). Prescribing information. Apotex Inc.; 2021. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020031s077lbl.pdf
116. Johnson DB, Lopez MJ, Kelley B. Dexamethasone. StatPearls. Updated May 2, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482130/
117. Hemady (dexamethasone). Prescribing information. Dexcel Pharma; 2019. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211379s000lbl.pdf
118. Parker SD, King N, Jacobs TF. Pegfilgrastim. StatPearls. Updated May 9, 2024. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK532893/
119. Fylnetra (pegfilgrastim-pbbk). Prescribing information. Kashiv BioSciences; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761084s000lbl.pdf
120. Emend (aprepitant). Prescribing information. Merck; 2015. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207865lbl.pdf
121. Lipitor (atorvastatin calcium). Prescribing information. Viatris Specialty; 2022. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020702Orig1s079correctedlbl.pdf
122. Cipro (ciprofloxacin hydrochloride). Prescribing information. Bayer HealthCare Pharmaceuticals Inc.; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/019537s090,020780s047lbl.pdf
123. Pino MA, Azer SA. Cimetidine. StatPearls. Updated March 6, 2023. Accessed June 5, 2024. https://www.ncbi.nlm.nih.gov/books/NBK544255/
124. Tagament (Cimetidine). Prescribing information. Mylan; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020238Orig1s024lbl.pdf
125. Neupogen (filgrastim). Prescribing information. Amgen Inc.; 2015. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103353s5184lbl.pdf
126. Flagyl (metronidazole). Prescribing information. Pfizer; 2013. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020334s008lbl.pdf
127. Zymaxid (gatifloxacin ophthalmic solution). Prescribing information. Allergan; 2016. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022548s002lbl.pdf
128. Macrobid (nitrofurantoin monohydrate). Prescribing information. Procter and Gamble Pharmaceutical Inc.; 2009. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf
129. Hyzaar (losartan). Prescribing information. Merck; 2020. Accessed June 5, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020387s067lbl.pdf
Open Clinical Trials for Patients With Prostate Cancer
The clinical trials listed below are all open as of July 12, 2024; have ≥ 1 US Department of Veterans Affairs (VA) medical center (VAMC) or US Department of Defense (DoD) military treatment facility location recruiting patients; and are focused on treatments for prostate cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.
Actively Recruiting
Patient Decision Making About Precision Oncology in Veterans With Advanced Prostate Cancer
This clinical trial explores and implements methods to improve informed decision making regarding precision oncology tests among veterans with prostate cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Precision oncology, the use of germline genetic testing and tumor-based molecular assays to inform cancer care, has become an important aspect of evidence-based care for men with advanced prostate cancer. Veterans with metastatic castrate-resistant prostate cancer may not be carrying out informed decision making due to unmet decisional needs. An informed decision is a choice based on complete and accurate information. The information gained from this study will help researchers develop a decision support intervention and implement the intervention. A decision support intervention may serve as a valuable tool to reduce ongoing racial disparities in genetic testing and encourage enrollment to precision oncology trials.
ID: NCT05396872
Sponsor; Collaborator: University of California, San Francisco; DoD
Location: San Francisco VAMC
DeADT - Living Well With Prostate Cancer
The goal of this pilot randomized implementation trial is to compare 2 strategies to reduce low-value androgen deprivation therapy (ADT) use for prostate cancer care. The aim of the study is to compare implementation of the 2 strategies: use of a clinical reminder order check intervention vs a clinician script/patient education approach, and their impacts on low-value ADT use after 6 months. The main goal of both interventions will be to decrease ADT overuse for patients with prostate cancer, but to do this in a way that is acceptable to the provider who treat these patients. Provider participants will engage with 1 of the interventions triggered in the electronic health record when their patients are deemed likely to receive low-value ADT. Provider participants receive only 1 intervention. The intervention is triggered for every clinic visit involving a patient deemed to be receiving low-value ADT, so provider participants may receive their assigned intervention multiple times. Researchers will compare provider use of both strategies to determine implementation outcomes and whether 1 was more effective in reducing low-value ADT use.
ID: NCT06199986
Sponsor; Collaborator: University of Michigan; VA, National Cancer Institute
Location: VA Ann Arbor Healthcare System
VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for Oligometastatic Prostate Cancer (VA STARPORT)
This is a prospective, open-label, multicenter, seamless phase II to phase III randomized clinical trial designed to compare somatostatin with or without positron emission tomography (PET)-directed local therapy in improving the castration-resistant prostate cancer-free survival for veterans with oligometastatic prostate cancer. Oligometastasis will be defined as 1 to 10 sites of metastatic disease based on the clinical determination.
ID: NCT04787744
Sponsor; Investigators: VA Office of Research and Development; Abhishek Solani, MD, MS, Edward Hines Jr.
Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VAMC, Baltimore VAMC, VA Boston Healthcare System, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VAMC, VA New Jersey Healthcare System, VA NY Harbor Healthcare System, Durham VAMC, Louis Stokes VAMC, Corporal Michael J. Crescenz VAMC, Michael E. DeBakey VAMC, Hunter Holmes McGuire VAMC, William S. Middleton Memorial Veterans Hospital, Clement J. Zablocki VAMC
The Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS)
Prostate cancer is the most common non-skin cancer among veterans and the second leading cause of male cancer death. Current methods of screening men for prostate cancer are inaccurate and cannot identify which men do not have prostate cancer or have low-grade cases that will not cause harm and which men have significant prostate cancer needing treatment. False-positive screening tests can result in unnecessary prostate biopsies for men who do not need them. However, new genetic testing might help identify which men are at highest risk for prostate cancer. This study will examine whether a genetic test helps identify men at risk for significant prostate cancer while helping men who are at low risk for prostate cancer avoid unnecessary biopsies. If this genetic test proves beneficial, it will improve the way that health care providers screen male veterans for prostate cancer.
ID: NCT05926102
Sponsor; Investigator: VA Office of Research and Development; Jason L. Vassy, MD, MPH
Location: VA Boston Healthcare System
Prostate Active Surveillance Study (PASS)
This research study is for men who have chosen active surveillance as a management plan for their prostate cancer. Active surveillance is defined as close monitoring of prostate cancer with the offer of treatment if there are changes in test results. This study seeks to discover markers that will identify cancers that are more aggressive from those tumors that grow slowly.
ID: NCT00756665
Sponsor; Collaborators: University of Washington; Canary Foundation, Early Detection Research Network
Locations: VA San Francisco Health Care System, VA Puget Sound Health Care System
A Study of Checkpoint Inhibitors in Men With Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation (CHOMP)
The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in veterans with metastatic castration-resistant prostate cancer characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to prostate-specific antigen progression, maximal prostate-specific antigen response, time to initiation of alternative antineoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pretreatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.
ID: NCT04104893
Sponsor; Collaborator: VA Office of Research and Development; Merck Sharp & Dohme LLC
Locations: San Francisco VAMC, VA Greater Los Angeles Healthcare System, Washington DC VAMC, Bay Pines VA Healthcare System Jesse Brown VAMC, VA Ann Arbor Healthcare System, James J. Peter VAMC, VA NY Harbor Healthcare System, Durham VAMC, Corporal Michael J. Crescenz VAMC, Hunter Holmes McGuire VAMC, VA Puget Sound Health Care System
A Single-Arm Phase II Study of Neoadjuvant Intensified Androgen Deprivation (Leuprolideand Abiraterone Acetate) in Combination With AKT Inhibition (Capivasertib) for High-Risk Localized Prostate Cancer With PTEN Loss (SNARE)
The purpose of this study is to learn about how an investigational drug intervention completed before doing prostate surgery (specifically, radical prostatectomy with lymph node dissection) may help in the treatment of high-risk localized prostate cancers that are most resistant to standard treatments. This is a phase II research study. For this study, capivasertib, the study drug, will be taken with intensified androgen deprivation therapy drugs (iADT; abiraterone and leuprolide) prior to radical prostatectomy. This study drug treatment will be evaluated to see if it is effective in shrinking and destroying prostate cancer tumors prior to surgery and to further evaluate its safety prior to prostate cancer surgery.
ID: NCT05593497
Sponsor; Investigator: VA Office of Research and Development; Ryan P. Kopp, MD
Locations: VA Greater Los Angeles Healthcare System, James J. Peters VAMC, VA Portland Health Care System, South Texas Veterans Health Care System, VA Puget Sound Health Care System
Active, Not Recruiting
Intramuscular Mechanisms of Androgen Deprivation-related Sarcopenia
Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes androgen deprivation therapy (ADT), or the lowering of the levels of the hormone testosterone as much as possible. Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as “sarcopenia,” and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because the investigators do not understand the mechanisms that cause it. The mitochondria are part of the cells responsible for providing energy to muscles, but to this date, the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT.
ID: NCT03867357
Sponsor; Collaborators: Seattle Institute for Biomedical and Clinical Research; DoD, University of Washington
Location: VA Puget Sound Health Care System
Radiation Therapy With or Without Androgen-Deprivation Therapy in Treating Patients With Prostate Cancer
RATIONALE: Radiation therapy uses high-energy X-rays and other types of radiation to kill tumor cells and shrink tumors. Androgens can cause the growth of prostate cancer cells. Androgen deprivation therapy (ADT) may lessen the amount of androgens made by the body. It is not yet known whether radiation therapy is more effective with or without ADT in treating patients with prostate cancer.
PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with ADT in treating patients with prostate cancer.
ID: NCT00936390
Sponsor; Collaborators: Radiation Therapy Oncology Group; National Cancer Institute, NRG Oncology
Locations: 518 locations, James A. Haley VA Hospital
Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer
This randomized phase III trial studies enzalutamide to see how well it works compared to enzalutamide, abiraterone, and prednisone in treating patients with castration-resistant metastatic prostate cancer. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, abiraterone acetate, and prednisone, may lessen the amount of androgens made by the body.
ID: NCT01949337
Sponsor; Collaborators: Alliance for Clinical Trials in Oncology; NCI, Astellas Pharma US, Inc., Medivation, Inc., Biologics, Inc.
Locations: 539 locations, including VA Connecticut Healthcare System
S1216, Phase III ADT+TAK-700 vs ADT+Bicalutamide for Metastatic Prostate Cancer (S1216)
The purpose of this study is to compare overall survival in newly diagnosed metastatic prostate cancer patients randomly assigned to ADT + TAK-700 vs androgen deprivation therapy (ADT) + bicalutamide.
ID: NCT01809691
Sponsor; Collaborators: SWOG Cancer Research Network; Millennium Pharmaceuticals, Inc., NCI
Locations: 560 locations, including VA New York Harbor Healthcare System
Androgen Ablation Therapy With or Without Chemotherapy in Treating Patients With Metastatic Prostate Cancer (CHAARTED)
RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen ablation therapy may stop the adrenal glands from making androgens. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether androgen-ablation therapy is more effective with or without docetaxel in treating metastatic prostate cancer.
PURPOSE: This randomized phase III trial is studying androgen ablation therapy and chemotherapy to see how well they work compared to androgen ablation therapy alone in treating patients with metastatic prostate cancer.
ID: NCT00309985
Sponsor; Collaborator: ECOG-ACRIN Cancer Research Group; NCI
Locations: 343 locations, including Mather VAMC
Not Yet Recruiting
biraterone, Enzalutamide, or Apalutamide in Castrate-Sensitive Prostate Cancer
The investigators have used national Veterans Health Administration (VHA) data to demonstrate real-world efficacy of abiraterone and enzalutamide in veterans with metastatic castration-resistant prostate cancer. In the real world that is the VHA, the investigators have successfully estimated g values that accurately predict overall survival, and the use of this metric in other settings should now be explored. In the egalitarian system that is the VHA, the treatment of prostate cancer is excellent, uniform across the US and indifferent to race. The choices made are clearly personalized, given not all men received all therapies, and younger veterans were treated more aggressively.
ID: NCT05422911
Sponsor: James J. Peters VAMC
Location: James J. Peters VAMC
18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)
The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires, and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.
ID: NCT04390880
Sponsor, Investigator: VA Greater Los Angeles Healthcare System; Gholam Berenji, MD
Location: VA Greater Los Angeles Healthcare System
18F-DCFPyL PET-CT Scan and Prostate Cancer
The primary objective of this study is to assess the efficacy of 18F-DCFPyL PET-CT for initial staging of prostate cancer in veterans compared to conventional imaging (99mTc-MDP bone scan and diagnostic CT or MRI). The primary clinical endpoint of our study is the percentage of veterans with prostate cancer in which the 18F-DCFPyL PET-CT identifies M1 disease at initial staging. Secondary objectives included frequency of the change in primary treatment plan after initial staging.
ID: NCT03852654
Sponsor, Investigator: Lida Jafari, MD
Location: VA Greater Los Angeles Healthcare System
Neoadjuvant Therapy With Docetaxel and Ketoconazole in Patients With High-Risk Prostate Cancer: A Pilot Study (IST 16167)
Eligible patients with high-risk prostate cancer who are scheduled to undergo radical prostatectomy will receive 4 cycles of therapy with ketoconazole and docetaxel prior to surgery resection. A cycle of therapy is defined as 21 days (3 weeks). Pharmacokinetic analysis will be performed during the first and second cycles of therapy. All patients will be evaluated for toxicity, tumor response, and recurrence.
ID: NCT00870714
Sponsor, Collaborator: Kansas City VAMC; Sanofi
Location: Kansas City VAMC
A Study of Epirubicin With Estramustine Phosphate and Celecoxib for the Treatment of Prostate Cancer
The purpose of this clinical trial is to find out the effect of epirubicin with estramustine phosphate and celecoxib on PSA and objective response in patients with hormone-resistant prostate cancer, as well as to evaluate the toxicity and quality of life of this combination. Celecoxib is an FDA-approved drug that treats arthritis. Epirubicin, alone or with estramustine phosphate, has been used in the treatment of hormone-resistant prostate cancer. These drugs have demonstrated evidence of tumor blood vessel suppression and a combination of these 3 drugs could possibly arrest further tumor growth or even make the tumor decrease in size.
ID: NCT00218205
Sponsor, Collaborator; Investigator: VA New Jersey Health Care System; Pfizer; Basil Kasimis, MD
Location: VA New Jersey Health Care System
A Phase II Trial of Combination Therapy With Celecoxib and Taxotere for the Treatment of Stage D3 Prostate Cancer
The purpose of this clinical trial is to find out the safety and effectiveness as well as the patient’s quality of life while taking the combination of Taxotere and celecoxib on patients with hormone refractory prostate cancer. Celecoxib (Celebrex) is an FDA-approved drug that treats arthritis. Taxotere (Docetaxel) is an FDA-approved chemotherapy drug to treat certain forms of cancer. Both drugs have demonstrated evidences of tumor blood vessel suppression and combination of these 2 drugs could possibly arrest further tumor growth or make the tumor decrease in size.
ID: NCT00215345
Sponsor, Collaborator; Investigator: Department of Veterans Affairs, New Jersey; Pfizer, Sanofi; Basil Kasimis, MD
Location: VA New Jersey Health Care System
A Yoga Program for Patients Undergoing Prostate Cancer Surgery
Men with localized prostate cancer are often treated with surgery, a treatment that is associated with high rates of adverse effects such as erectile dysfunction (ED) and urinary incontinence (UI) which impact quality of life. Yoga may improve control of UI and improve ED by bringing awareness to and strengthening the pelvic floor musculature. The randomized controlled pilot study is to assess the feasibility of an innovative hybrid (in-person and virtual) twice-weekly yoga program that includes a prehabilitation component and to obtain preliminary data that will help assess its potential effectiveness in alleviating prostate cancer treatment symptom burden (primarily ED and UI). The long-term goal is to develop a scalable and sustainable yoga program that helps cancer survivors manage their treatment side effects.
ID: NCT05929300
Sponsor, Investigator: VA Office of Research and Development; Abigail Silva, PhD, MPH
Location: Edward Hines Jr. VA Hospital
The clinical trials listed below are all open as of July 12, 2024; have ≥ 1 US Department of Veterans Affairs (VA) medical center (VAMC) or US Department of Defense (DoD) military treatment facility location recruiting patients; and are focused on treatments for prostate cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.
Actively Recruiting
Patient Decision Making About Precision Oncology in Veterans With Advanced Prostate Cancer
This clinical trial explores and implements methods to improve informed decision making regarding precision oncology tests among veterans with prostate cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Precision oncology, the use of germline genetic testing and tumor-based molecular assays to inform cancer care, has become an important aspect of evidence-based care for men with advanced prostate cancer. Veterans with metastatic castrate-resistant prostate cancer may not be carrying out informed decision making due to unmet decisional needs. An informed decision is a choice based on complete and accurate information. The information gained from this study will help researchers develop a decision support intervention and implement the intervention. A decision support intervention may serve as a valuable tool to reduce ongoing racial disparities in genetic testing and encourage enrollment to precision oncology trials.
ID: NCT05396872
Sponsor; Collaborator: University of California, San Francisco; DoD
Location: San Francisco VAMC
DeADT - Living Well With Prostate Cancer
The goal of this pilot randomized implementation trial is to compare 2 strategies to reduce low-value androgen deprivation therapy (ADT) use for prostate cancer care. The aim of the study is to compare implementation of the 2 strategies: use of a clinical reminder order check intervention vs a clinician script/patient education approach, and their impacts on low-value ADT use after 6 months. The main goal of both interventions will be to decrease ADT overuse for patients with prostate cancer, but to do this in a way that is acceptable to the provider who treat these patients. Provider participants will engage with 1 of the interventions triggered in the electronic health record when their patients are deemed likely to receive low-value ADT. Provider participants receive only 1 intervention. The intervention is triggered for every clinic visit involving a patient deemed to be receiving low-value ADT, so provider participants may receive their assigned intervention multiple times. Researchers will compare provider use of both strategies to determine implementation outcomes and whether 1 was more effective in reducing low-value ADT use.
ID: NCT06199986
Sponsor; Collaborator: University of Michigan; VA, National Cancer Institute
Location: VA Ann Arbor Healthcare System
VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for Oligometastatic Prostate Cancer (VA STARPORT)
This is a prospective, open-label, multicenter, seamless phase II to phase III randomized clinical trial designed to compare somatostatin with or without positron emission tomography (PET)-directed local therapy in improving the castration-resistant prostate cancer-free survival for veterans with oligometastatic prostate cancer. Oligometastasis will be defined as 1 to 10 sites of metastatic disease based on the clinical determination.
ID: NCT04787744
Sponsor; Investigators: VA Office of Research and Development; Abhishek Solani, MD, MS, Edward Hines Jr.
Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VAMC, Baltimore VAMC, VA Boston Healthcare System, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VAMC, VA New Jersey Healthcare System, VA NY Harbor Healthcare System, Durham VAMC, Louis Stokes VAMC, Corporal Michael J. Crescenz VAMC, Michael E. DeBakey VAMC, Hunter Holmes McGuire VAMC, William S. Middleton Memorial Veterans Hospital, Clement J. Zablocki VAMC
The Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS)
Prostate cancer is the most common non-skin cancer among veterans and the second leading cause of male cancer death. Current methods of screening men for prostate cancer are inaccurate and cannot identify which men do not have prostate cancer or have low-grade cases that will not cause harm and which men have significant prostate cancer needing treatment. False-positive screening tests can result in unnecessary prostate biopsies for men who do not need them. However, new genetic testing might help identify which men are at highest risk for prostate cancer. This study will examine whether a genetic test helps identify men at risk for significant prostate cancer while helping men who are at low risk for prostate cancer avoid unnecessary biopsies. If this genetic test proves beneficial, it will improve the way that health care providers screen male veterans for prostate cancer.
ID: NCT05926102
Sponsor; Investigator: VA Office of Research and Development; Jason L. Vassy, MD, MPH
Location: VA Boston Healthcare System
Prostate Active Surveillance Study (PASS)
This research study is for men who have chosen active surveillance as a management plan for their prostate cancer. Active surveillance is defined as close monitoring of prostate cancer with the offer of treatment if there are changes in test results. This study seeks to discover markers that will identify cancers that are more aggressive from those tumors that grow slowly.
ID: NCT00756665
Sponsor; Collaborators: University of Washington; Canary Foundation, Early Detection Research Network
Locations: VA San Francisco Health Care System, VA Puget Sound Health Care System
A Study of Checkpoint Inhibitors in Men With Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation (CHOMP)
The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in veterans with metastatic castration-resistant prostate cancer characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to prostate-specific antigen progression, maximal prostate-specific antigen response, time to initiation of alternative antineoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pretreatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.
ID: NCT04104893
Sponsor; Collaborator: VA Office of Research and Development; Merck Sharp & Dohme LLC
Locations: San Francisco VAMC, VA Greater Los Angeles Healthcare System, Washington DC VAMC, Bay Pines VA Healthcare System Jesse Brown VAMC, VA Ann Arbor Healthcare System, James J. Peter VAMC, VA NY Harbor Healthcare System, Durham VAMC, Corporal Michael J. Crescenz VAMC, Hunter Holmes McGuire VAMC, VA Puget Sound Health Care System
A Single-Arm Phase II Study of Neoadjuvant Intensified Androgen Deprivation (Leuprolideand Abiraterone Acetate) in Combination With AKT Inhibition (Capivasertib) for High-Risk Localized Prostate Cancer With PTEN Loss (SNARE)
The purpose of this study is to learn about how an investigational drug intervention completed before doing prostate surgery (specifically, radical prostatectomy with lymph node dissection) may help in the treatment of high-risk localized prostate cancers that are most resistant to standard treatments. This is a phase II research study. For this study, capivasertib, the study drug, will be taken with intensified androgen deprivation therapy drugs (iADT; abiraterone and leuprolide) prior to radical prostatectomy. This study drug treatment will be evaluated to see if it is effective in shrinking and destroying prostate cancer tumors prior to surgery and to further evaluate its safety prior to prostate cancer surgery.
ID: NCT05593497
Sponsor; Investigator: VA Office of Research and Development; Ryan P. Kopp, MD
Locations: VA Greater Los Angeles Healthcare System, James J. Peters VAMC, VA Portland Health Care System, South Texas Veterans Health Care System, VA Puget Sound Health Care System
Active, Not Recruiting
Intramuscular Mechanisms of Androgen Deprivation-related Sarcopenia
Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes androgen deprivation therapy (ADT), or the lowering of the levels of the hormone testosterone as much as possible. Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as “sarcopenia,” and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because the investigators do not understand the mechanisms that cause it. The mitochondria are part of the cells responsible for providing energy to muscles, but to this date, the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT.
ID: NCT03867357
Sponsor; Collaborators: Seattle Institute for Biomedical and Clinical Research; DoD, University of Washington
Location: VA Puget Sound Health Care System
Radiation Therapy With or Without Androgen-Deprivation Therapy in Treating Patients With Prostate Cancer
RATIONALE: Radiation therapy uses high-energy X-rays and other types of radiation to kill tumor cells and shrink tumors. Androgens can cause the growth of prostate cancer cells. Androgen deprivation therapy (ADT) may lessen the amount of androgens made by the body. It is not yet known whether radiation therapy is more effective with or without ADT in treating patients with prostate cancer.
PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with ADT in treating patients with prostate cancer.
ID: NCT00936390
Sponsor; Collaborators: Radiation Therapy Oncology Group; National Cancer Institute, NRG Oncology
Locations: 518 locations, James A. Haley VA Hospital
Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer
This randomized phase III trial studies enzalutamide to see how well it works compared to enzalutamide, abiraterone, and prednisone in treating patients with castration-resistant metastatic prostate cancer. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, abiraterone acetate, and prednisone, may lessen the amount of androgens made by the body.
ID: NCT01949337
Sponsor; Collaborators: Alliance for Clinical Trials in Oncology; NCI, Astellas Pharma US, Inc., Medivation, Inc., Biologics, Inc.
Locations: 539 locations, including VA Connecticut Healthcare System
S1216, Phase III ADT+TAK-700 vs ADT+Bicalutamide for Metastatic Prostate Cancer (S1216)
The purpose of this study is to compare overall survival in newly diagnosed metastatic prostate cancer patients randomly assigned to ADT + TAK-700 vs androgen deprivation therapy (ADT) + bicalutamide.
ID: NCT01809691
Sponsor; Collaborators: SWOG Cancer Research Network; Millennium Pharmaceuticals, Inc., NCI
Locations: 560 locations, including VA New York Harbor Healthcare System
Androgen Ablation Therapy With or Without Chemotherapy in Treating Patients With Metastatic Prostate Cancer (CHAARTED)
RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen ablation therapy may stop the adrenal glands from making androgens. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether androgen-ablation therapy is more effective with or without docetaxel in treating metastatic prostate cancer.
PURPOSE: This randomized phase III trial is studying androgen ablation therapy and chemotherapy to see how well they work compared to androgen ablation therapy alone in treating patients with metastatic prostate cancer.
ID: NCT00309985
Sponsor; Collaborator: ECOG-ACRIN Cancer Research Group; NCI
Locations: 343 locations, including Mather VAMC
Not Yet Recruiting
biraterone, Enzalutamide, or Apalutamide in Castrate-Sensitive Prostate Cancer
The investigators have used national Veterans Health Administration (VHA) data to demonstrate real-world efficacy of abiraterone and enzalutamide in veterans with metastatic castration-resistant prostate cancer. In the real world that is the VHA, the investigators have successfully estimated g values that accurately predict overall survival, and the use of this metric in other settings should now be explored. In the egalitarian system that is the VHA, the treatment of prostate cancer is excellent, uniform across the US and indifferent to race. The choices made are clearly personalized, given not all men received all therapies, and younger veterans were treated more aggressively.
ID: NCT05422911
Sponsor: James J. Peters VAMC
Location: James J. Peters VAMC
18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)
The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires, and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.
ID: NCT04390880
Sponsor, Investigator: VA Greater Los Angeles Healthcare System; Gholam Berenji, MD
Location: VA Greater Los Angeles Healthcare System
18F-DCFPyL PET-CT Scan and Prostate Cancer
The primary objective of this study is to assess the efficacy of 18F-DCFPyL PET-CT for initial staging of prostate cancer in veterans compared to conventional imaging (99mTc-MDP bone scan and diagnostic CT or MRI). The primary clinical endpoint of our study is the percentage of veterans with prostate cancer in which the 18F-DCFPyL PET-CT identifies M1 disease at initial staging. Secondary objectives included frequency of the change in primary treatment plan after initial staging.
ID: NCT03852654
Sponsor, Investigator: Lida Jafari, MD
Location: VA Greater Los Angeles Healthcare System
Neoadjuvant Therapy With Docetaxel and Ketoconazole in Patients With High-Risk Prostate Cancer: A Pilot Study (IST 16167)
Eligible patients with high-risk prostate cancer who are scheduled to undergo radical prostatectomy will receive 4 cycles of therapy with ketoconazole and docetaxel prior to surgery resection. A cycle of therapy is defined as 21 days (3 weeks). Pharmacokinetic analysis will be performed during the first and second cycles of therapy. All patients will be evaluated for toxicity, tumor response, and recurrence.
ID: NCT00870714
Sponsor, Collaborator: Kansas City VAMC; Sanofi
Location: Kansas City VAMC
A Study of Epirubicin With Estramustine Phosphate and Celecoxib for the Treatment of Prostate Cancer
The purpose of this clinical trial is to find out the effect of epirubicin with estramustine phosphate and celecoxib on PSA and objective response in patients with hormone-resistant prostate cancer, as well as to evaluate the toxicity and quality of life of this combination. Celecoxib is an FDA-approved drug that treats arthritis. Epirubicin, alone or with estramustine phosphate, has been used in the treatment of hormone-resistant prostate cancer. These drugs have demonstrated evidence of tumor blood vessel suppression and a combination of these 3 drugs could possibly arrest further tumor growth or even make the tumor decrease in size.
ID: NCT00218205
Sponsor, Collaborator; Investigator: VA New Jersey Health Care System; Pfizer; Basil Kasimis, MD
Location: VA New Jersey Health Care System
A Phase II Trial of Combination Therapy With Celecoxib and Taxotere for the Treatment of Stage D3 Prostate Cancer
The purpose of this clinical trial is to find out the safety and effectiveness as well as the patient’s quality of life while taking the combination of Taxotere and celecoxib on patients with hormone refractory prostate cancer. Celecoxib (Celebrex) is an FDA-approved drug that treats arthritis. Taxotere (Docetaxel) is an FDA-approved chemotherapy drug to treat certain forms of cancer. Both drugs have demonstrated evidences of tumor blood vessel suppression and combination of these 2 drugs could possibly arrest further tumor growth or make the tumor decrease in size.
ID: NCT00215345
Sponsor, Collaborator; Investigator: Department of Veterans Affairs, New Jersey; Pfizer, Sanofi; Basil Kasimis, MD
Location: VA New Jersey Health Care System
A Yoga Program for Patients Undergoing Prostate Cancer Surgery
Men with localized prostate cancer are often treated with surgery, a treatment that is associated with high rates of adverse effects such as erectile dysfunction (ED) and urinary incontinence (UI) which impact quality of life. Yoga may improve control of UI and improve ED by bringing awareness to and strengthening the pelvic floor musculature. The randomized controlled pilot study is to assess the feasibility of an innovative hybrid (in-person and virtual) twice-weekly yoga program that includes a prehabilitation component and to obtain preliminary data that will help assess its potential effectiveness in alleviating prostate cancer treatment symptom burden (primarily ED and UI). The long-term goal is to develop a scalable and sustainable yoga program that helps cancer survivors manage their treatment side effects.
ID: NCT05929300
Sponsor, Investigator: VA Office of Research and Development; Abigail Silva, PhD, MPH
Location: Edward Hines Jr. VA Hospital
The clinical trials listed below are all open as of July 12, 2024; have ≥ 1 US Department of Veterans Affairs (VA) medical center (VAMC) or US Department of Defense (DoD) military treatment facility location recruiting patients; and are focused on treatments for prostate cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.
Actively Recruiting
Patient Decision Making About Precision Oncology in Veterans With Advanced Prostate Cancer
This clinical trial explores and implements methods to improve informed decision making regarding precision oncology tests among veterans with prostate cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Precision oncology, the use of germline genetic testing and tumor-based molecular assays to inform cancer care, has become an important aspect of evidence-based care for men with advanced prostate cancer. Veterans with metastatic castrate-resistant prostate cancer may not be carrying out informed decision making due to unmet decisional needs. An informed decision is a choice based on complete and accurate information. The information gained from this study will help researchers develop a decision support intervention and implement the intervention. A decision support intervention may serve as a valuable tool to reduce ongoing racial disparities in genetic testing and encourage enrollment to precision oncology trials.
ID: NCT05396872
Sponsor; Collaborator: University of California, San Francisco; DoD
Location: San Francisco VAMC
DeADT - Living Well With Prostate Cancer
The goal of this pilot randomized implementation trial is to compare 2 strategies to reduce low-value androgen deprivation therapy (ADT) use for prostate cancer care. The aim of the study is to compare implementation of the 2 strategies: use of a clinical reminder order check intervention vs a clinician script/patient education approach, and their impacts on low-value ADT use after 6 months. The main goal of both interventions will be to decrease ADT overuse for patients with prostate cancer, but to do this in a way that is acceptable to the provider who treat these patients. Provider participants will engage with 1 of the interventions triggered in the electronic health record when their patients are deemed likely to receive low-value ADT. Provider participants receive only 1 intervention. The intervention is triggered for every clinic visit involving a patient deemed to be receiving low-value ADT, so provider participants may receive their assigned intervention multiple times. Researchers will compare provider use of both strategies to determine implementation outcomes and whether 1 was more effective in reducing low-value ADT use.
ID: NCT06199986
Sponsor; Collaborator: University of Michigan; VA, National Cancer Institute
Location: VA Ann Arbor Healthcare System
VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for Oligometastatic Prostate Cancer (VA STARPORT)
This is a prospective, open-label, multicenter, seamless phase II to phase III randomized clinical trial designed to compare somatostatin with or without positron emission tomography (PET)-directed local therapy in improving the castration-resistant prostate cancer-free survival for veterans with oligometastatic prostate cancer. Oligometastasis will be defined as 1 to 10 sites of metastatic disease based on the clinical determination.
ID: NCT04787744
Sponsor; Investigators: VA Office of Research and Development; Abhishek Solani, MD, MS, Edward Hines Jr.
Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VAMC, Baltimore VAMC, VA Boston Healthcare System, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VAMC, VA New Jersey Healthcare System, VA NY Harbor Healthcare System, Durham VAMC, Louis Stokes VAMC, Corporal Michael J. Crescenz VAMC, Michael E. DeBakey VAMC, Hunter Holmes McGuire VAMC, William S. Middleton Memorial Veterans Hospital, Clement J. Zablocki VAMC
The Prostate Cancer, Genetic Risk, and Equitable Screening Study (ProGRESS)
Prostate cancer is the most common non-skin cancer among veterans and the second leading cause of male cancer death. Current methods of screening men for prostate cancer are inaccurate and cannot identify which men do not have prostate cancer or have low-grade cases that will not cause harm and which men have significant prostate cancer needing treatment. False-positive screening tests can result in unnecessary prostate biopsies for men who do not need them. However, new genetic testing might help identify which men are at highest risk for prostate cancer. This study will examine whether a genetic test helps identify men at risk for significant prostate cancer while helping men who are at low risk for prostate cancer avoid unnecessary biopsies. If this genetic test proves beneficial, it will improve the way that health care providers screen male veterans for prostate cancer.
ID: NCT05926102
Sponsor; Investigator: VA Office of Research and Development; Jason L. Vassy, MD, MPH
Location: VA Boston Healthcare System
Prostate Active Surveillance Study (PASS)
This research study is for men who have chosen active surveillance as a management plan for their prostate cancer. Active surveillance is defined as close monitoring of prostate cancer with the offer of treatment if there are changes in test results. This study seeks to discover markers that will identify cancers that are more aggressive from those tumors that grow slowly.
ID: NCT00756665
Sponsor; Collaborators: University of Washington; Canary Foundation, Early Detection Research Network
Locations: VA San Francisco Health Care System, VA Puget Sound Health Care System
A Study of Checkpoint Inhibitors in Men With Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation (CHOMP)
The primary objective is to assess the activity and efficacy of pembrolizumab, a checkpoint inhibitor, in veterans with metastatic castration-resistant prostate cancer characterized by either mismatch repair deficiency (dMMR) or biallelic inactivation of CDK12 (CDK12-/-). The secondary objectives involve determining the frequency with which dMMR and CDK12-/- occur in this patient population, as well as the effects of pembrolizumab on various clinical endpoints (time to prostate-specific antigen progression, maximal prostate-specific antigen response, time to initiation of alternative antineoplastic therapy, time to radiographic progression, overall survival, and safety and tolerability). Lastly, the study will compare the pretreatment and at-progression metastatic tumor biopsies to investigate the molecular correlates of resistance and sensitivity to pembrolizumab via RNA-sequencing, exome-sequencing, selected protein analyses, and multiplexed immunofluorescence.
ID: NCT04104893
Sponsor; Collaborator: VA Office of Research and Development; Merck Sharp & Dohme LLC
Locations: San Francisco VAMC, VA Greater Los Angeles Healthcare System, Washington DC VAMC, Bay Pines VA Healthcare System Jesse Brown VAMC, VA Ann Arbor Healthcare System, James J. Peter VAMC, VA NY Harbor Healthcare System, Durham VAMC, Corporal Michael J. Crescenz VAMC, Hunter Holmes McGuire VAMC, VA Puget Sound Health Care System
A Single-Arm Phase II Study of Neoadjuvant Intensified Androgen Deprivation (Leuprolideand Abiraterone Acetate) in Combination With AKT Inhibition (Capivasertib) for High-Risk Localized Prostate Cancer With PTEN Loss (SNARE)
The purpose of this study is to learn about how an investigational drug intervention completed before doing prostate surgery (specifically, radical prostatectomy with lymph node dissection) may help in the treatment of high-risk localized prostate cancers that are most resistant to standard treatments. This is a phase II research study. For this study, capivasertib, the study drug, will be taken with intensified androgen deprivation therapy drugs (iADT; abiraterone and leuprolide) prior to radical prostatectomy. This study drug treatment will be evaluated to see if it is effective in shrinking and destroying prostate cancer tumors prior to surgery and to further evaluate its safety prior to prostate cancer surgery.
ID: NCT05593497
Sponsor; Investigator: VA Office of Research and Development; Ryan P. Kopp, MD
Locations: VA Greater Los Angeles Healthcare System, James J. Peters VAMC, VA Portland Health Care System, South Texas Veterans Health Care System, VA Puget Sound Health Care System
Active, Not Recruiting
Intramuscular Mechanisms of Androgen Deprivation-related Sarcopenia
Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes androgen deprivation therapy (ADT), or the lowering of the levels of the hormone testosterone as much as possible. Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as “sarcopenia,” and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because the investigators do not understand the mechanisms that cause it. The mitochondria are part of the cells responsible for providing energy to muscles, but to this date, the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT.
ID: NCT03867357
Sponsor; Collaborators: Seattle Institute for Biomedical and Clinical Research; DoD, University of Washington
Location: VA Puget Sound Health Care System
Radiation Therapy With or Without Androgen-Deprivation Therapy in Treating Patients With Prostate Cancer
RATIONALE: Radiation therapy uses high-energy X-rays and other types of radiation to kill tumor cells and shrink tumors. Androgens can cause the growth of prostate cancer cells. Androgen deprivation therapy (ADT) may lessen the amount of androgens made by the body. It is not yet known whether radiation therapy is more effective with or without ADT in treating patients with prostate cancer.
PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with ADT in treating patients with prostate cancer.
ID: NCT00936390
Sponsor; Collaborators: Radiation Therapy Oncology Group; National Cancer Institute, NRG Oncology
Locations: 518 locations, James A. Haley VA Hospital
Enzalutamide With or Without Abiraterone and Prednisone in Treating Patients With Castration-Resistant Metastatic Prostate Cancer
This randomized phase III trial studies enzalutamide to see how well it works compared to enzalutamide, abiraterone, and prednisone in treating patients with castration-resistant metastatic prostate cancer. Androgens can cause the growth of prostate cancer cells. Drugs, such as enzalutamide, abiraterone acetate, and prednisone, may lessen the amount of androgens made by the body.
ID: NCT01949337
Sponsor; Collaborators: Alliance for Clinical Trials in Oncology; NCI, Astellas Pharma US, Inc., Medivation, Inc., Biologics, Inc.
Locations: 539 locations, including VA Connecticut Healthcare System
S1216, Phase III ADT+TAK-700 vs ADT+Bicalutamide for Metastatic Prostate Cancer (S1216)
The purpose of this study is to compare overall survival in newly diagnosed metastatic prostate cancer patients randomly assigned to ADT + TAK-700 vs androgen deprivation therapy (ADT) + bicalutamide.
ID: NCT01809691
Sponsor; Collaborators: SWOG Cancer Research Network; Millennium Pharmaceuticals, Inc., NCI
Locations: 560 locations, including VA New York Harbor Healthcare System
Androgen Ablation Therapy With or Without Chemotherapy in Treating Patients With Metastatic Prostate Cancer (CHAARTED)
RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen ablation therapy may stop the adrenal glands from making androgens. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether androgen-ablation therapy is more effective with or without docetaxel in treating metastatic prostate cancer.
PURPOSE: This randomized phase III trial is studying androgen ablation therapy and chemotherapy to see how well they work compared to androgen ablation therapy alone in treating patients with metastatic prostate cancer.
ID: NCT00309985
Sponsor; Collaborator: ECOG-ACRIN Cancer Research Group; NCI
Locations: 343 locations, including Mather VAMC
Not Yet Recruiting
biraterone, Enzalutamide, or Apalutamide in Castrate-Sensitive Prostate Cancer
The investigators have used national Veterans Health Administration (VHA) data to demonstrate real-world efficacy of abiraterone and enzalutamide in veterans with metastatic castration-resistant prostate cancer. In the real world that is the VHA, the investigators have successfully estimated g values that accurately predict overall survival, and the use of this metric in other settings should now be explored. In the egalitarian system that is the VHA, the treatment of prostate cancer is excellent, uniform across the US and indifferent to race. The choices made are clearly personalized, given not all men received all therapies, and younger veterans were treated more aggressively.
ID: NCT05422911
Sponsor: James J. Peters VAMC
Location: James J. Peters VAMC
18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)
The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires, and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.
ID: NCT04390880
Sponsor, Investigator: VA Greater Los Angeles Healthcare System; Gholam Berenji, MD
Location: VA Greater Los Angeles Healthcare System
18F-DCFPyL PET-CT Scan and Prostate Cancer
The primary objective of this study is to assess the efficacy of 18F-DCFPyL PET-CT for initial staging of prostate cancer in veterans compared to conventional imaging (99mTc-MDP bone scan and diagnostic CT or MRI). The primary clinical endpoint of our study is the percentage of veterans with prostate cancer in which the 18F-DCFPyL PET-CT identifies M1 disease at initial staging. Secondary objectives included frequency of the change in primary treatment plan after initial staging.
ID: NCT03852654
Sponsor, Investigator: Lida Jafari, MD
Location: VA Greater Los Angeles Healthcare System
Neoadjuvant Therapy With Docetaxel and Ketoconazole in Patients With High-Risk Prostate Cancer: A Pilot Study (IST 16167)
Eligible patients with high-risk prostate cancer who are scheduled to undergo radical prostatectomy will receive 4 cycles of therapy with ketoconazole and docetaxel prior to surgery resection. A cycle of therapy is defined as 21 days (3 weeks). Pharmacokinetic analysis will be performed during the first and second cycles of therapy. All patients will be evaluated for toxicity, tumor response, and recurrence.
ID: NCT00870714
Sponsor, Collaborator: Kansas City VAMC; Sanofi
Location: Kansas City VAMC
A Study of Epirubicin With Estramustine Phosphate and Celecoxib for the Treatment of Prostate Cancer
The purpose of this clinical trial is to find out the effect of epirubicin with estramustine phosphate and celecoxib on PSA and objective response in patients with hormone-resistant prostate cancer, as well as to evaluate the toxicity and quality of life of this combination. Celecoxib is an FDA-approved drug that treats arthritis. Epirubicin, alone or with estramustine phosphate, has been used in the treatment of hormone-resistant prostate cancer. These drugs have demonstrated evidence of tumor blood vessel suppression and a combination of these 3 drugs could possibly arrest further tumor growth or even make the tumor decrease in size.
ID: NCT00218205
Sponsor, Collaborator; Investigator: VA New Jersey Health Care System; Pfizer; Basil Kasimis, MD
Location: VA New Jersey Health Care System
A Phase II Trial of Combination Therapy With Celecoxib and Taxotere for the Treatment of Stage D3 Prostate Cancer
The purpose of this clinical trial is to find out the safety and effectiveness as well as the patient’s quality of life while taking the combination of Taxotere and celecoxib on patients with hormone refractory prostate cancer. Celecoxib (Celebrex) is an FDA-approved drug that treats arthritis. Taxotere (Docetaxel) is an FDA-approved chemotherapy drug to treat certain forms of cancer. Both drugs have demonstrated evidences of tumor blood vessel suppression and combination of these 2 drugs could possibly arrest further tumor growth or make the tumor decrease in size.
ID: NCT00215345
Sponsor, Collaborator; Investigator: Department of Veterans Affairs, New Jersey; Pfizer, Sanofi; Basil Kasimis, MD
Location: VA New Jersey Health Care System
A Yoga Program for Patients Undergoing Prostate Cancer Surgery
Men with localized prostate cancer are often treated with surgery, a treatment that is associated with high rates of adverse effects such as erectile dysfunction (ED) and urinary incontinence (UI) which impact quality of life. Yoga may improve control of UI and improve ED by bringing awareness to and strengthening the pelvic floor musculature. The randomized controlled pilot study is to assess the feasibility of an innovative hybrid (in-person and virtual) twice-weekly yoga program that includes a prehabilitation component and to obtain preliminary data that will help assess its potential effectiveness in alleviating prostate cancer treatment symptom burden (primarily ED and UI). The long-term goal is to develop a scalable and sustainable yoga program that helps cancer survivors manage their treatment side effects.
ID: NCT05929300
Sponsor, Investigator: VA Office of Research and Development; Abigail Silva, PhD, MPH
Location: Edward Hines Jr. VA Hospital
Acquired Factor VIII Deficiency Presenting as Compartment Syndrome
Compartment syndrome occurs when the interstitial tissue pressures within a confined space are elevated to a level at which the arterial perfusion is diminished. Multiple etiologies exist and can be extrinsic (a cast that is too tight or prolonged compression on a limb), iatrogenic (aggressive resuscitation, drug infiltration, arterial puncture, or a spontaneous bleed from anticoagulation), and traumatic (fracture, snake envenomation, circumferential burn, or electrocution). If the compartments are not released, irreversible changes happen to the cells, including nerve and muscle death.1 Definitive management of this emergency requires prompt fasciotomy to decompress the compartment(s).1-3
Case Presentation
A 76-year-old right-handed woman with a history of chronic obstructive pulmonary disease, hypertension, and hyperlipidemia presented to the emergency department with 2 days of extensive right upper extremity ecchymosis and severe pain that was localized to her forearm (Figure 1). She was taking low-dose aspirin (81 mg/d) for left subclavian stenosis and over-the-counter ginkgo biloba. Leading up to the presentation, the patient was able to perform routine household chores, including yard work, cleaning, and taking care of her cats. Wrist and elbow X-rays were negative for a fracture. An upper extremity ultrasound found no venous occlusion. A computed tomography (CT) angiogram of her arm and chest found diffuse edema around the right elbow and forearm without pulmonary or right upper extremity emboli, fractures, hematoma, abscess, or air in the tissues.
The plastic surgery service was consulted. The patient was found to have a very tense forearm and pain to passive digital extension. The 2-point discrimination and pulses were intact. The patient was diagnosed with compartment syndrome based on the examination alone and gave consent for an emergent forearm and hand fasciotomy. A carpal tunnel release and a standard S-shaped volar forearm fasciotomy release were performed, which provided immediate decompression (Figure 2). The rest of the hand and extremity were soft. Edematous, healthy flexor muscle belly was identified without a hematoma. Most of the forearm wound was left open because the skin could not be reapproximated. Oxidized regenerated cellulose (Surgicel) was placed around the wound edges and the muscle was covered with a nonadherent dressing. Hemoglobin on admission was 12.9 g/dL(reference range, 12 to 16 g/dL). Kidney function was within normal limits. The rest of the complete blood count was unremarkable. Postoperative hemoglobin was 8.6 g/dL. Over the next several days, the patient's skin edges and muscle bellies continued to slowly bleed, and her hemoglobin fell to 5.6 g/dL by postoperative Day 2. The bleeding was managed with topical oxidized regenerated cellulose, thrombin spray, a hemostatic dressing made with kaolin (QuikClot), and a transfusion of 2 units of packed red blood cells.
A hematology consultation was requested. The patient was noted to have an elevated partial thromboplastin time (PTT) since admission measuring between 39.9 to 61.7 seconds (reference range, 26.2 to 37.2 seconds) and a normal prothrombin time test with an international normalized ratio. A PTT measured 17 months prior to admission was within the normal range. She reported no personal or family history of bleeding disorders. Until recently, she had never had easy bruisability. She reported no history of heavy menses or epistaxis. The patient had no children and had never been pregnant. She had tolerated an exploratory laparotomy 40 years prior to admission without bleeding complications and had never required blood transfusions before. A PTT 1:1 mixing study revealed incomplete correction. Subsequent workup included factor VIII (FVIII) activity, factor IX activity, factor XI activity, von Willebrand factor antigen, ristocetin cofactor assay, and von Willebrand factor multimers. FVIII activity was severely reduced at 7.8% (reference, > 54%) with a positive Bethesda assay of 300 to 400 Bodansky units (BU), indicating a strong FVIII inhibitor was present and establishing a diagnosis of acquired hemophilia A. Further workup for secondary causes of acquired hemophilia A including abdominal and pelvic CT, serum protein electrophoresis, and serum free light chains, were negative. She was started on prednisone 1 mg/kg daily and rituximab 375 mg/m2. Her hemoglobin stabilized, and she required no further blood transfusions.
The patient underwent wound closure on postoperative Day 11. At the time of the second surgery, there was still no improvement in her FVIII levels or PTT; therefore, 70 mcg/kg of recombinant coagulation-activated FVII was given just before surgery with no bleeding complications. The skin was closed primarily except for the most distal 3 cm (Figure 3). Due to concerns regarding further bleeding with skin graft, the remaining wound was allowed to close by secondary intention. As a precaution, the wound was covered with oxidized regenerated cellulose and thrombin spray. The patient continued to progress postoperatively without bleeding complications or a need for additional transfusions. She was seen by the hand therapist before and after the second surgery to help with edema management and joint mobility. She completed 4 weekly doses of 375 mg/m² rituximab and prednisone was tapered by 10 mg weekly.
Three weeks after starting treatment, her PTT normalized, and her FVIII increased to 33.7%. The Bethesda assay remained high at 198 BU, although it was lower than at admission. She was discharged home with dressing changes and monthly follow-up appointments. The wounds were fully closed at her 3-month appointment when she proudly demonstrated full digital extension and flexion into her palm.
Discussion
Forearm compartment syndrome is most often caused by fractures—distal radius in adults and supracondylar in children.2 This case initially presented as a diagnostic puzzle to the emergency department due to the patient’s lucid review of several days of nontraumatic injury.
The clinical hallmarks of compartment syndrome are the 5 Ps: pain, pallor, paresthesia, paralysis, and pulselessness. Patients will describe the pain as out of proportion to the nature of the injury; the compartments will be tense and swollen, they will have pain to passive muscle stretch, and sensation will progressively diminish. Distal pulses are the last to go, and permanent tissue damage can still occur when pulses are present.1
Compartment Syndrome
Compartment syndrome is generally a clinical diagnosis; however, in patients who are sedated or uncooperative, or if the clinical findings are equivocal, the examination can be supplemented with intercompartmental pressures using an arterial line transducer system.2 In general, a tissue pressure of 30 mm Hg or a 20- to 30-mm Hg difference between the diastolic and compartment pressures are indications for fasciotomy.1 The hand is treated with an open carpal tunnel release, interosseous muscle release through 2 dorsal hand incisions, and thenar and hypothenar muscle release. The forearm is treated through a curved volar incision that usually decompresses the dorsal compartment, as it did in our patient. If pressures are still high in the forearm, a longitudinal dorsal incision over the mobile wad is necessary. Wounds can be closed primarily days later, left open to close by secondary intention, or reconstructed with skin grafts.2 In our patient, compartment syndrome was isolated to her forearm and the carpal tunnel release was performed prophylactically since it did not add significant time or morbidity to the surgery.
Nontraumatic upper extremity compartment syndrome is rare. A 2021 review of acute nontraumatic upper extremity compartment syndrome found a bleeding disorder as the etiology in 3 cases published in the literature between 1993 and 2016.4 One of these cases was secondary to a known diagnosis of hemophilia A in a teenager.5 Ogrodnik and colleagues described a spontaneous hand hematoma secondary to previously undiagnosed acquired hemophilia A and Waldenström macroglobulinemia.4 Ilyas and colleagues described a spontaneous hematoma in the forearm dorsal compartment in a 67-year-old woman, which presented as compartment syndrome and elevated PTT and led to a diagnosis of acquired FVIII inhibitor. The authors recommended prompt hematology consultation to coordinate treatment once this diagnosis issuspected.6 Compartment syndrome also has been found to develop slowly over weeks in patients with acquired FVIII deficiency, suggesting a high index of suspicion and frequent examinations are needed when patients with known acquired hemophilia A present with a painful extremity.7
Nontraumatic compartment syndrome in the lower extremity in patients with previously undiagnosed acquired hemophilia A has also been described in the literature.8-11 Case reports describe the delay in diagnosis as the patients were originally seen by clinicians for lower extremity pain and swelling within days of presenting to the emergency room with compartment syndrome. Persistent bleeding and abnormal laboratory results prompted further tests and examinations.8,9,11 This underscores the need to be suspicious of this unusual pathology without a history of trauma.
Acquired Hemophilia A
Acquired hemophilia A is an autoimmune disease most often found in older individuals, with a mean age of approximately 70 years.12 It is caused by the spontaneous production of neutralizing immunoglobin autoantibodies that target endogenous FVIII. Many cases are idiopathic; however, up to 50% of cases are associated with underlying autoimmunity, malignancy (especially lymphoproliferative disorders), or pregnancy. It often presents as bleeding that is subcutaneous or in the gastrointestinal system, muscle, retroperitoneal space, or genitourinary system. Unlike congenital hemophilia A, joint bleeding is rare.13
The diagnosis is suspected with an isolated elevated PTT in the absence of other coagulation abnormalities. A 1:1 mixing study will typically show incomplete correction, which suggests the presence of an inhibitor. FVIII activity is reduced, and the FVIII inhibitor is confirmed with the Bethesda assay. Clinically active bleeding is treated with bypassing agents such as recombinant coagulation-activated FVII, activated prothrombin complex concentrates such as anti-inhibitor coagulant complex (FEIBA), or recombinant porcine FVIII.12,14 Not all patients require hemostatic treatment, but close monitoring, education, recognition, and immediate treatment, if needed, are indicated.13 Immunosuppressive therapy (corticosteroids, rituximab, and/or cyclophosphamide) is prescribed to eradicate the antibodies and induce remission.12
Conclusions
An older woman without a preceding trauma was diagnosed with an unusual case of acute compartment syndrome in the forearm. No hematoma was found, but muscle and skin bleeding plus an elevated PTT prompted a hematology workup, and, ultimately, the diagnosis of FVIII inhibitor secondary to acquired hemophilia A.
While a nontraumatic cause of compartment syndrome is rare, it should be considered in differential diagnosis for clinicians who see hand and upper extremity emergencies. An isolated elevated PTT in a patient with a bleed should raise suspicions and trigger immediate further evaluation. Once suspected, multidisciplinary treatment is indicated for immediate and long-term successful outcomes.
Acknowledgments
This manuscript is the result of work supported withresources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.
1. Leversedge FJ, Moore TJ, Peterson BC, Seiler JG 3rd. Compartment syndrome of the upper extremity. J Hand Surg Am. 2011;36:544-559. doi:10.1016/j.jhsa.2010.12.008
2. Kalyani BS, Fisher BE, Roberts CS, Giannoudis PV. Compartment syndrome of the forearm: a systematic review. J Hand Surg Am. 2011;36:535-543. doi:10.1016/j.jhsa.2010.12.007
3. Steadman W, Wu R, Hamilton AT, Richardson MD, Wall CJ. Review article: a comprehensive review of unusual causes of acute limb compartment syndrome. Emerg Med Australas. 2022;34:871-876. doi:10.1111/1742-6723.14098
4. Ogrodnik J, Oliver JD, Cani D, Boczar D, Huayllani MT, Restrepo DJ, et al. Clinical case of acute non-traumatic hand compartment syndrome and systematic review for the upper extremity. Hand (N Y). 2021;16:285-291. doi:10.1177/1558944719856106
5. Kim J, Zelken J, Sacks JM. Case report. Spontaneous forearm compartment syndrome in a boy with hemophilia a: a therapeutic dilemma. Eplasty. 2013:13:e16.
6. Ilyas AM, Wisbeck JM, Shaffer GW, Thoder JJ. Upper extremity compartment syndrome secondary to acquired factor VIII inhibitor. A case report. J Bone Joint Surg Am. 2005;87:1606-1608. doi:10.2106/JBJS.C.01720
7. Adeclat GJ, Hayes M, Amick M, Kahan J, Halim A. Acute forearm compartment syndrome in the setting of acquired hemophilia A. Case Reports Plast Surg Hand Surg. 2022;9:140-144. doi:10.1080/23320885.2022.2071274
8. Abudaqqa RY, Arun KP, Mas AJA, Abushaaban FA. Acute atraumatic compartment syndrome of the thigh due to acquired coagulopathy disorder: a case report in known healthy patient. J Orthop Case Rep. 2021;11:59-62. doi:10.13107/jocr.2021.v11.i08.2366
9. Alidoost M, Conte GA, Chaudry R, Nahum K, Marchesani D. A unique presentation of spontaneous compartment syndrome due to acquired hemophilia A and associated malignancy: case report and literature review. World J Oncol. 2020;11:72-75. doi:10.14740/wjon1260
10. Jentzsch T, Brand-Staufer B, Schäfer FP, Wanner GA, Simmen H-P. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report. J Med Case Rep. 2014;8:132. doi:10.1186/1752-1947-8-132
11. Pham TV, Sorenson CA, Nable JV. Acquired factor VIII deficiency presenting with compartment syndrome. Am J Emerg Med. 2014;32:195.e1-2. doi:10.1016/j.ajem.2013.09.022
12. Tiede A, Zieger B, Lisman T. Acquired bleeding disorders. Haemophilia. 2022;28(suppl 4):68-76. doi:10.1111/hae.14548
13. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705. doi:10.1002/ajh.24777
14. Ilkhchoui Y, Koshkin E, Windsor JJ, Petersen TR, Charles M, Pack JD. Perioperative management of acquired hemophilia A: a case report and review of literature. Anesth Pain Med. 2013;4:e11906. doi:10.5812/aapm.11906
Compartment syndrome occurs when the interstitial tissue pressures within a confined space are elevated to a level at which the arterial perfusion is diminished. Multiple etiologies exist and can be extrinsic (a cast that is too tight or prolonged compression on a limb), iatrogenic (aggressive resuscitation, drug infiltration, arterial puncture, or a spontaneous bleed from anticoagulation), and traumatic (fracture, snake envenomation, circumferential burn, or electrocution). If the compartments are not released, irreversible changes happen to the cells, including nerve and muscle death.1 Definitive management of this emergency requires prompt fasciotomy to decompress the compartment(s).1-3
Case Presentation
A 76-year-old right-handed woman with a history of chronic obstructive pulmonary disease, hypertension, and hyperlipidemia presented to the emergency department with 2 days of extensive right upper extremity ecchymosis and severe pain that was localized to her forearm (Figure 1). She was taking low-dose aspirin (81 mg/d) for left subclavian stenosis and over-the-counter ginkgo biloba. Leading up to the presentation, the patient was able to perform routine household chores, including yard work, cleaning, and taking care of her cats. Wrist and elbow X-rays were negative for a fracture. An upper extremity ultrasound found no venous occlusion. A computed tomography (CT) angiogram of her arm and chest found diffuse edema around the right elbow and forearm without pulmonary or right upper extremity emboli, fractures, hematoma, abscess, or air in the tissues.
The plastic surgery service was consulted. The patient was found to have a very tense forearm and pain to passive digital extension. The 2-point discrimination and pulses were intact. The patient was diagnosed with compartment syndrome based on the examination alone and gave consent for an emergent forearm and hand fasciotomy. A carpal tunnel release and a standard S-shaped volar forearm fasciotomy release were performed, which provided immediate decompression (Figure 2). The rest of the hand and extremity were soft. Edematous, healthy flexor muscle belly was identified without a hematoma. Most of the forearm wound was left open because the skin could not be reapproximated. Oxidized regenerated cellulose (Surgicel) was placed around the wound edges and the muscle was covered with a nonadherent dressing. Hemoglobin on admission was 12.9 g/dL(reference range, 12 to 16 g/dL). Kidney function was within normal limits. The rest of the complete blood count was unremarkable. Postoperative hemoglobin was 8.6 g/dL. Over the next several days, the patient's skin edges and muscle bellies continued to slowly bleed, and her hemoglobin fell to 5.6 g/dL by postoperative Day 2. The bleeding was managed with topical oxidized regenerated cellulose, thrombin spray, a hemostatic dressing made with kaolin (QuikClot), and a transfusion of 2 units of packed red blood cells.
A hematology consultation was requested. The patient was noted to have an elevated partial thromboplastin time (PTT) since admission measuring between 39.9 to 61.7 seconds (reference range, 26.2 to 37.2 seconds) and a normal prothrombin time test with an international normalized ratio. A PTT measured 17 months prior to admission was within the normal range. She reported no personal or family history of bleeding disorders. Until recently, she had never had easy bruisability. She reported no history of heavy menses or epistaxis. The patient had no children and had never been pregnant. She had tolerated an exploratory laparotomy 40 years prior to admission without bleeding complications and had never required blood transfusions before. A PTT 1:1 mixing study revealed incomplete correction. Subsequent workup included factor VIII (FVIII) activity, factor IX activity, factor XI activity, von Willebrand factor antigen, ristocetin cofactor assay, and von Willebrand factor multimers. FVIII activity was severely reduced at 7.8% (reference, > 54%) with a positive Bethesda assay of 300 to 400 Bodansky units (BU), indicating a strong FVIII inhibitor was present and establishing a diagnosis of acquired hemophilia A. Further workup for secondary causes of acquired hemophilia A including abdominal and pelvic CT, serum protein electrophoresis, and serum free light chains, were negative. She was started on prednisone 1 mg/kg daily and rituximab 375 mg/m2. Her hemoglobin stabilized, and she required no further blood transfusions.
The patient underwent wound closure on postoperative Day 11. At the time of the second surgery, there was still no improvement in her FVIII levels or PTT; therefore, 70 mcg/kg of recombinant coagulation-activated FVII was given just before surgery with no bleeding complications. The skin was closed primarily except for the most distal 3 cm (Figure 3). Due to concerns regarding further bleeding with skin graft, the remaining wound was allowed to close by secondary intention. As a precaution, the wound was covered with oxidized regenerated cellulose and thrombin spray. The patient continued to progress postoperatively without bleeding complications or a need for additional transfusions. She was seen by the hand therapist before and after the second surgery to help with edema management and joint mobility. She completed 4 weekly doses of 375 mg/m² rituximab and prednisone was tapered by 10 mg weekly.
Three weeks after starting treatment, her PTT normalized, and her FVIII increased to 33.7%. The Bethesda assay remained high at 198 BU, although it was lower than at admission. She was discharged home with dressing changes and monthly follow-up appointments. The wounds were fully closed at her 3-month appointment when she proudly demonstrated full digital extension and flexion into her palm.
Discussion
Forearm compartment syndrome is most often caused by fractures—distal radius in adults and supracondylar in children.2 This case initially presented as a diagnostic puzzle to the emergency department due to the patient’s lucid review of several days of nontraumatic injury.
The clinical hallmarks of compartment syndrome are the 5 Ps: pain, pallor, paresthesia, paralysis, and pulselessness. Patients will describe the pain as out of proportion to the nature of the injury; the compartments will be tense and swollen, they will have pain to passive muscle stretch, and sensation will progressively diminish. Distal pulses are the last to go, and permanent tissue damage can still occur when pulses are present.1
Compartment Syndrome
Compartment syndrome is generally a clinical diagnosis; however, in patients who are sedated or uncooperative, or if the clinical findings are equivocal, the examination can be supplemented with intercompartmental pressures using an arterial line transducer system.2 In general, a tissue pressure of 30 mm Hg or a 20- to 30-mm Hg difference between the diastolic and compartment pressures are indications for fasciotomy.1 The hand is treated with an open carpal tunnel release, interosseous muscle release through 2 dorsal hand incisions, and thenar and hypothenar muscle release. The forearm is treated through a curved volar incision that usually decompresses the dorsal compartment, as it did in our patient. If pressures are still high in the forearm, a longitudinal dorsal incision over the mobile wad is necessary. Wounds can be closed primarily days later, left open to close by secondary intention, or reconstructed with skin grafts.2 In our patient, compartment syndrome was isolated to her forearm and the carpal tunnel release was performed prophylactically since it did not add significant time or morbidity to the surgery.
Nontraumatic upper extremity compartment syndrome is rare. A 2021 review of acute nontraumatic upper extremity compartment syndrome found a bleeding disorder as the etiology in 3 cases published in the literature between 1993 and 2016.4 One of these cases was secondary to a known diagnosis of hemophilia A in a teenager.5 Ogrodnik and colleagues described a spontaneous hand hematoma secondary to previously undiagnosed acquired hemophilia A and Waldenström macroglobulinemia.4 Ilyas and colleagues described a spontaneous hematoma in the forearm dorsal compartment in a 67-year-old woman, which presented as compartment syndrome and elevated PTT and led to a diagnosis of acquired FVIII inhibitor. The authors recommended prompt hematology consultation to coordinate treatment once this diagnosis issuspected.6 Compartment syndrome also has been found to develop slowly over weeks in patients with acquired FVIII deficiency, suggesting a high index of suspicion and frequent examinations are needed when patients with known acquired hemophilia A present with a painful extremity.7
Nontraumatic compartment syndrome in the lower extremity in patients with previously undiagnosed acquired hemophilia A has also been described in the literature.8-11 Case reports describe the delay in diagnosis as the patients were originally seen by clinicians for lower extremity pain and swelling within days of presenting to the emergency room with compartment syndrome. Persistent bleeding and abnormal laboratory results prompted further tests and examinations.8,9,11 This underscores the need to be suspicious of this unusual pathology without a history of trauma.
Acquired Hemophilia A
Acquired hemophilia A is an autoimmune disease most often found in older individuals, with a mean age of approximately 70 years.12 It is caused by the spontaneous production of neutralizing immunoglobin autoantibodies that target endogenous FVIII. Many cases are idiopathic; however, up to 50% of cases are associated with underlying autoimmunity, malignancy (especially lymphoproliferative disorders), or pregnancy. It often presents as bleeding that is subcutaneous or in the gastrointestinal system, muscle, retroperitoneal space, or genitourinary system. Unlike congenital hemophilia A, joint bleeding is rare.13
The diagnosis is suspected with an isolated elevated PTT in the absence of other coagulation abnormalities. A 1:1 mixing study will typically show incomplete correction, which suggests the presence of an inhibitor. FVIII activity is reduced, and the FVIII inhibitor is confirmed with the Bethesda assay. Clinically active bleeding is treated with bypassing agents such as recombinant coagulation-activated FVII, activated prothrombin complex concentrates such as anti-inhibitor coagulant complex (FEIBA), or recombinant porcine FVIII.12,14 Not all patients require hemostatic treatment, but close monitoring, education, recognition, and immediate treatment, if needed, are indicated.13 Immunosuppressive therapy (corticosteroids, rituximab, and/or cyclophosphamide) is prescribed to eradicate the antibodies and induce remission.12
Conclusions
An older woman without a preceding trauma was diagnosed with an unusual case of acute compartment syndrome in the forearm. No hematoma was found, but muscle and skin bleeding plus an elevated PTT prompted a hematology workup, and, ultimately, the diagnosis of FVIII inhibitor secondary to acquired hemophilia A.
While a nontraumatic cause of compartment syndrome is rare, it should be considered in differential diagnosis for clinicians who see hand and upper extremity emergencies. An isolated elevated PTT in a patient with a bleed should raise suspicions and trigger immediate further evaluation. Once suspected, multidisciplinary treatment is indicated for immediate and long-term successful outcomes.
Acknowledgments
This manuscript is the result of work supported withresources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.
Compartment syndrome occurs when the interstitial tissue pressures within a confined space are elevated to a level at which the arterial perfusion is diminished. Multiple etiologies exist and can be extrinsic (a cast that is too tight or prolonged compression on a limb), iatrogenic (aggressive resuscitation, drug infiltration, arterial puncture, or a spontaneous bleed from anticoagulation), and traumatic (fracture, snake envenomation, circumferential burn, or electrocution). If the compartments are not released, irreversible changes happen to the cells, including nerve and muscle death.1 Definitive management of this emergency requires prompt fasciotomy to decompress the compartment(s).1-3
Case Presentation
A 76-year-old right-handed woman with a history of chronic obstructive pulmonary disease, hypertension, and hyperlipidemia presented to the emergency department with 2 days of extensive right upper extremity ecchymosis and severe pain that was localized to her forearm (Figure 1). She was taking low-dose aspirin (81 mg/d) for left subclavian stenosis and over-the-counter ginkgo biloba. Leading up to the presentation, the patient was able to perform routine household chores, including yard work, cleaning, and taking care of her cats. Wrist and elbow X-rays were negative for a fracture. An upper extremity ultrasound found no venous occlusion. A computed tomography (CT) angiogram of her arm and chest found diffuse edema around the right elbow and forearm without pulmonary or right upper extremity emboli, fractures, hematoma, abscess, or air in the tissues.
The plastic surgery service was consulted. The patient was found to have a very tense forearm and pain to passive digital extension. The 2-point discrimination and pulses were intact. The patient was diagnosed with compartment syndrome based on the examination alone and gave consent for an emergent forearm and hand fasciotomy. A carpal tunnel release and a standard S-shaped volar forearm fasciotomy release were performed, which provided immediate decompression (Figure 2). The rest of the hand and extremity were soft. Edematous, healthy flexor muscle belly was identified without a hematoma. Most of the forearm wound was left open because the skin could not be reapproximated. Oxidized regenerated cellulose (Surgicel) was placed around the wound edges and the muscle was covered with a nonadherent dressing. Hemoglobin on admission was 12.9 g/dL(reference range, 12 to 16 g/dL). Kidney function was within normal limits. The rest of the complete blood count was unremarkable. Postoperative hemoglobin was 8.6 g/dL. Over the next several days, the patient's skin edges and muscle bellies continued to slowly bleed, and her hemoglobin fell to 5.6 g/dL by postoperative Day 2. The bleeding was managed with topical oxidized regenerated cellulose, thrombin spray, a hemostatic dressing made with kaolin (QuikClot), and a transfusion of 2 units of packed red blood cells.
A hematology consultation was requested. The patient was noted to have an elevated partial thromboplastin time (PTT) since admission measuring between 39.9 to 61.7 seconds (reference range, 26.2 to 37.2 seconds) and a normal prothrombin time test with an international normalized ratio. A PTT measured 17 months prior to admission was within the normal range. She reported no personal or family history of bleeding disorders. Until recently, she had never had easy bruisability. She reported no history of heavy menses or epistaxis. The patient had no children and had never been pregnant. She had tolerated an exploratory laparotomy 40 years prior to admission without bleeding complications and had never required blood transfusions before. A PTT 1:1 mixing study revealed incomplete correction. Subsequent workup included factor VIII (FVIII) activity, factor IX activity, factor XI activity, von Willebrand factor antigen, ristocetin cofactor assay, and von Willebrand factor multimers. FVIII activity was severely reduced at 7.8% (reference, > 54%) with a positive Bethesda assay of 300 to 400 Bodansky units (BU), indicating a strong FVIII inhibitor was present and establishing a diagnosis of acquired hemophilia A. Further workup for secondary causes of acquired hemophilia A including abdominal and pelvic CT, serum protein electrophoresis, and serum free light chains, were negative. She was started on prednisone 1 mg/kg daily and rituximab 375 mg/m2. Her hemoglobin stabilized, and she required no further blood transfusions.
The patient underwent wound closure on postoperative Day 11. At the time of the second surgery, there was still no improvement in her FVIII levels or PTT; therefore, 70 mcg/kg of recombinant coagulation-activated FVII was given just before surgery with no bleeding complications. The skin was closed primarily except for the most distal 3 cm (Figure 3). Due to concerns regarding further bleeding with skin graft, the remaining wound was allowed to close by secondary intention. As a precaution, the wound was covered with oxidized regenerated cellulose and thrombin spray. The patient continued to progress postoperatively without bleeding complications or a need for additional transfusions. She was seen by the hand therapist before and after the second surgery to help with edema management and joint mobility. She completed 4 weekly doses of 375 mg/m² rituximab and prednisone was tapered by 10 mg weekly.
Three weeks after starting treatment, her PTT normalized, and her FVIII increased to 33.7%. The Bethesda assay remained high at 198 BU, although it was lower than at admission. She was discharged home with dressing changes and monthly follow-up appointments. The wounds were fully closed at her 3-month appointment when she proudly demonstrated full digital extension and flexion into her palm.
Discussion
Forearm compartment syndrome is most often caused by fractures—distal radius in adults and supracondylar in children.2 This case initially presented as a diagnostic puzzle to the emergency department due to the patient’s lucid review of several days of nontraumatic injury.
The clinical hallmarks of compartment syndrome are the 5 Ps: pain, pallor, paresthesia, paralysis, and pulselessness. Patients will describe the pain as out of proportion to the nature of the injury; the compartments will be tense and swollen, they will have pain to passive muscle stretch, and sensation will progressively diminish. Distal pulses are the last to go, and permanent tissue damage can still occur when pulses are present.1
Compartment Syndrome
Compartment syndrome is generally a clinical diagnosis; however, in patients who are sedated or uncooperative, or if the clinical findings are equivocal, the examination can be supplemented with intercompartmental pressures using an arterial line transducer system.2 In general, a tissue pressure of 30 mm Hg or a 20- to 30-mm Hg difference between the diastolic and compartment pressures are indications for fasciotomy.1 The hand is treated with an open carpal tunnel release, interosseous muscle release through 2 dorsal hand incisions, and thenar and hypothenar muscle release. The forearm is treated through a curved volar incision that usually decompresses the dorsal compartment, as it did in our patient. If pressures are still high in the forearm, a longitudinal dorsal incision over the mobile wad is necessary. Wounds can be closed primarily days later, left open to close by secondary intention, or reconstructed with skin grafts.2 In our patient, compartment syndrome was isolated to her forearm and the carpal tunnel release was performed prophylactically since it did not add significant time or morbidity to the surgery.
Nontraumatic upper extremity compartment syndrome is rare. A 2021 review of acute nontraumatic upper extremity compartment syndrome found a bleeding disorder as the etiology in 3 cases published in the literature between 1993 and 2016.4 One of these cases was secondary to a known diagnosis of hemophilia A in a teenager.5 Ogrodnik and colleagues described a spontaneous hand hematoma secondary to previously undiagnosed acquired hemophilia A and Waldenström macroglobulinemia.4 Ilyas and colleagues described a spontaneous hematoma in the forearm dorsal compartment in a 67-year-old woman, which presented as compartment syndrome and elevated PTT and led to a diagnosis of acquired FVIII inhibitor. The authors recommended prompt hematology consultation to coordinate treatment once this diagnosis issuspected.6 Compartment syndrome also has been found to develop slowly over weeks in patients with acquired FVIII deficiency, suggesting a high index of suspicion and frequent examinations are needed when patients with known acquired hemophilia A present with a painful extremity.7
Nontraumatic compartment syndrome in the lower extremity in patients with previously undiagnosed acquired hemophilia A has also been described in the literature.8-11 Case reports describe the delay in diagnosis as the patients were originally seen by clinicians for lower extremity pain and swelling within days of presenting to the emergency room with compartment syndrome. Persistent bleeding and abnormal laboratory results prompted further tests and examinations.8,9,11 This underscores the need to be suspicious of this unusual pathology without a history of trauma.
Acquired Hemophilia A
Acquired hemophilia A is an autoimmune disease most often found in older individuals, with a mean age of approximately 70 years.12 It is caused by the spontaneous production of neutralizing immunoglobin autoantibodies that target endogenous FVIII. Many cases are idiopathic; however, up to 50% of cases are associated with underlying autoimmunity, malignancy (especially lymphoproliferative disorders), or pregnancy. It often presents as bleeding that is subcutaneous or in the gastrointestinal system, muscle, retroperitoneal space, or genitourinary system. Unlike congenital hemophilia A, joint bleeding is rare.13
The diagnosis is suspected with an isolated elevated PTT in the absence of other coagulation abnormalities. A 1:1 mixing study will typically show incomplete correction, which suggests the presence of an inhibitor. FVIII activity is reduced, and the FVIII inhibitor is confirmed with the Bethesda assay. Clinically active bleeding is treated with bypassing agents such as recombinant coagulation-activated FVII, activated prothrombin complex concentrates such as anti-inhibitor coagulant complex (FEIBA), or recombinant porcine FVIII.12,14 Not all patients require hemostatic treatment, but close monitoring, education, recognition, and immediate treatment, if needed, are indicated.13 Immunosuppressive therapy (corticosteroids, rituximab, and/or cyclophosphamide) is prescribed to eradicate the antibodies and induce remission.12
Conclusions
An older woman without a preceding trauma was diagnosed with an unusual case of acute compartment syndrome in the forearm. No hematoma was found, but muscle and skin bleeding plus an elevated PTT prompted a hematology workup, and, ultimately, the diagnosis of FVIII inhibitor secondary to acquired hemophilia A.
While a nontraumatic cause of compartment syndrome is rare, it should be considered in differential diagnosis for clinicians who see hand and upper extremity emergencies. An isolated elevated PTT in a patient with a bleed should raise suspicions and trigger immediate further evaluation. Once suspected, multidisciplinary treatment is indicated for immediate and long-term successful outcomes.
Acknowledgments
This manuscript is the result of work supported withresources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.
1. Leversedge FJ, Moore TJ, Peterson BC, Seiler JG 3rd. Compartment syndrome of the upper extremity. J Hand Surg Am. 2011;36:544-559. doi:10.1016/j.jhsa.2010.12.008
2. Kalyani BS, Fisher BE, Roberts CS, Giannoudis PV. Compartment syndrome of the forearm: a systematic review. J Hand Surg Am. 2011;36:535-543. doi:10.1016/j.jhsa.2010.12.007
3. Steadman W, Wu R, Hamilton AT, Richardson MD, Wall CJ. Review article: a comprehensive review of unusual causes of acute limb compartment syndrome. Emerg Med Australas. 2022;34:871-876. doi:10.1111/1742-6723.14098
4. Ogrodnik J, Oliver JD, Cani D, Boczar D, Huayllani MT, Restrepo DJ, et al. Clinical case of acute non-traumatic hand compartment syndrome and systematic review for the upper extremity. Hand (N Y). 2021;16:285-291. doi:10.1177/1558944719856106
5. Kim J, Zelken J, Sacks JM. Case report. Spontaneous forearm compartment syndrome in a boy with hemophilia a: a therapeutic dilemma. Eplasty. 2013:13:e16.
6. Ilyas AM, Wisbeck JM, Shaffer GW, Thoder JJ. Upper extremity compartment syndrome secondary to acquired factor VIII inhibitor. A case report. J Bone Joint Surg Am. 2005;87:1606-1608. doi:10.2106/JBJS.C.01720
7. Adeclat GJ, Hayes M, Amick M, Kahan J, Halim A. Acute forearm compartment syndrome in the setting of acquired hemophilia A. Case Reports Plast Surg Hand Surg. 2022;9:140-144. doi:10.1080/23320885.2022.2071274
8. Abudaqqa RY, Arun KP, Mas AJA, Abushaaban FA. Acute atraumatic compartment syndrome of the thigh due to acquired coagulopathy disorder: a case report in known healthy patient. J Orthop Case Rep. 2021;11:59-62. doi:10.13107/jocr.2021.v11.i08.2366
9. Alidoost M, Conte GA, Chaudry R, Nahum K, Marchesani D. A unique presentation of spontaneous compartment syndrome due to acquired hemophilia A and associated malignancy: case report and literature review. World J Oncol. 2020;11:72-75. doi:10.14740/wjon1260
10. Jentzsch T, Brand-Staufer B, Schäfer FP, Wanner GA, Simmen H-P. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report. J Med Case Rep. 2014;8:132. doi:10.1186/1752-1947-8-132
11. Pham TV, Sorenson CA, Nable JV. Acquired factor VIII deficiency presenting with compartment syndrome. Am J Emerg Med. 2014;32:195.e1-2. doi:10.1016/j.ajem.2013.09.022
12. Tiede A, Zieger B, Lisman T. Acquired bleeding disorders. Haemophilia. 2022;28(suppl 4):68-76. doi:10.1111/hae.14548
13. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705. doi:10.1002/ajh.24777
14. Ilkhchoui Y, Koshkin E, Windsor JJ, Petersen TR, Charles M, Pack JD. Perioperative management of acquired hemophilia A: a case report and review of literature. Anesth Pain Med. 2013;4:e11906. doi:10.5812/aapm.11906
1. Leversedge FJ, Moore TJ, Peterson BC, Seiler JG 3rd. Compartment syndrome of the upper extremity. J Hand Surg Am. 2011;36:544-559. doi:10.1016/j.jhsa.2010.12.008
2. Kalyani BS, Fisher BE, Roberts CS, Giannoudis PV. Compartment syndrome of the forearm: a systematic review. J Hand Surg Am. 2011;36:535-543. doi:10.1016/j.jhsa.2010.12.007
3. Steadman W, Wu R, Hamilton AT, Richardson MD, Wall CJ. Review article: a comprehensive review of unusual causes of acute limb compartment syndrome. Emerg Med Australas. 2022;34:871-876. doi:10.1111/1742-6723.14098
4. Ogrodnik J, Oliver JD, Cani D, Boczar D, Huayllani MT, Restrepo DJ, et al. Clinical case of acute non-traumatic hand compartment syndrome and systematic review for the upper extremity. Hand (N Y). 2021;16:285-291. doi:10.1177/1558944719856106
5. Kim J, Zelken J, Sacks JM. Case report. Spontaneous forearm compartment syndrome in a boy with hemophilia a: a therapeutic dilemma. Eplasty. 2013:13:e16.
6. Ilyas AM, Wisbeck JM, Shaffer GW, Thoder JJ. Upper extremity compartment syndrome secondary to acquired factor VIII inhibitor. A case report. J Bone Joint Surg Am. 2005;87:1606-1608. doi:10.2106/JBJS.C.01720
7. Adeclat GJ, Hayes M, Amick M, Kahan J, Halim A. Acute forearm compartment syndrome in the setting of acquired hemophilia A. Case Reports Plast Surg Hand Surg. 2022;9:140-144. doi:10.1080/23320885.2022.2071274
8. Abudaqqa RY, Arun KP, Mas AJA, Abushaaban FA. Acute atraumatic compartment syndrome of the thigh due to acquired coagulopathy disorder: a case report in known healthy patient. J Orthop Case Rep. 2021;11:59-62. doi:10.13107/jocr.2021.v11.i08.2366
9. Alidoost M, Conte GA, Chaudry R, Nahum K, Marchesani D. A unique presentation of spontaneous compartment syndrome due to acquired hemophilia A and associated malignancy: case report and literature review. World J Oncol. 2020;11:72-75. doi:10.14740/wjon1260
10. Jentzsch T, Brand-Staufer B, Schäfer FP, Wanner GA, Simmen H-P. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report. J Med Case Rep. 2014;8:132. doi:10.1186/1752-1947-8-132
11. Pham TV, Sorenson CA, Nable JV. Acquired factor VIII deficiency presenting with compartment syndrome. Am J Emerg Med. 2014;32:195.e1-2. doi:10.1016/j.ajem.2013.09.022
12. Tiede A, Zieger B, Lisman T. Acquired bleeding disorders. Haemophilia. 2022;28(suppl 4):68-76. doi:10.1111/hae.14548
13. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705. doi:10.1002/ajh.24777
14. Ilkhchoui Y, Koshkin E, Windsor JJ, Petersen TR, Charles M, Pack JD. Perioperative management of acquired hemophilia A: a case report and review of literature. Anesth Pain Med. 2013;4:e11906. doi:10.5812/aapm.11906