Sarcoma & GIST

Broader cancer screening of individuals with Li-Fraumeni syndrome (LFS), with or without whole-body magnetic resonance imaging, has a good diagnostic yield and identifies a wide range of cancers, according to a preliminary analysis of the ongoing LIFSCREEN phase 3, randomized, controlled trial.

Investigators led by Olivier Caron, MD, chair of the oncogenetics committee, department of medical oncology, at the Gustave Roussy University Hospital in Villejuif, France, enrolled in the trial 107 individuals from 75 families carrying a TP53 mutation, a genetic aberration commonly present in LFS that confers heightened risk of a variety of malignancies.

Participants had a median age at baseline of 32.9 years, with a range from 5 to 67 years. Fully 98% had a family history of cancer, and 48% had a personal history of cancer.

The participants were assigned to 5 years of standard screening – annual clinical examination, abdomen and pelvis ultrasound, brain MRI, complete blood cell count, and, for women older than 20 years, breast ultrasound and MRI – or intensive screening, entailing the addition of diffusion whole-body MRI.

At the time of the preliminary analysis, 15 patients had undergone only one round of screening; 35, two rounds; 19, three rounds; 24, four rounds; and 7, five rounds, Dr. Caron and associates reported in a research letter (JAMA Oncol. 2017; Aug 3 doi: 10.1001/jamaoncol.2017.1358).

Collectively, this amounted to 226.4 person-years of follow-up.

Screening with either trial strategy (with or without whole-body MRI) led to diagnosis of 23 new primary cancers in 20 patients. Nearly half of the total (12 cancers) were detected at the first round. Patients had a median age of 39.8 at the new cancer diagnosis, with a range from 6 to 70 years.

Of the new cancers, 10 belonged to the core LFS spectrum of breast cancer, sarcoma, and brain tumors. However, the other 13 were outside that spectrum, for example, lung adenocarcinomas, all seen in never or light smokers, and leukemias. Screening also detected three relapses of previous cancers.

Analyses further showed that prior cancer diagnosis was not a reliable marker for risk of new primaries. Although 12 of the patients with a screening-detected new primary had a personal cancer history, 8 did not (P = .22).

“The proportion and diversity of off–core LFS spectrum cancers detected in TP53 mutation carriers as reported by others give growing evidence of a broader LFS spectrum, in agreement with the permissive role of TP53 mutations,” write Dr. Caron and colleagues, who report having no relevant disclosures. “Our observations seem to support recent moves toward broader cancer screening in TP53 mutation carriers.”

The investigators continue to collect data in LIFSCREEN and plan to undertake main analysis later this year. “Our final analysis will help to determine the benefits and drawbacks (mostly related to false-positive test results) of whole-body MRI in TP53 mutation carrier surveillance,” they conclude. “Studies focused on TP53 mutation penetrance, using methods limiting selection bias, are required to refine cancer risks to improve TP53 mutation carrier management.”

Broader cancer screening of individuals with Li-Fraumeni syndrome (LFS), with or without whole-body magnetic resonance imaging, has a good diagnostic yield and identifies a wide range of cancers, according to a preliminary analysis of the ongoing LIFSCREEN phase 3, randomized, controlled trial.

Investigators led by Olivier Caron, MD, chair of the oncogenetics committee, department of medical oncology, at the Gustave Roussy University Hospital in Villejuif, France, enrolled in the trial 107 individuals from 75 families carrying a TP53 mutation, a genetic aberration commonly present in LFS that confers heightened risk of a variety of malignancies.

Participants had a median age at baseline of 32.9 years, with a range from 5 to 67 years. Fully 98% had a family history of cancer, and 48% had a personal history of cancer.

The participants were assigned to 5 years of standard screening – annual clinical examination, abdomen and pelvis ultrasound, brain MRI, complete blood cell count, and, for women older than 20 years, breast ultrasound and MRI – or intensive screening, entailing the addition of diffusion whole-body MRI.

At the time of the preliminary analysis, 15 patients had undergone only one round of screening; 35, two rounds; 19, three rounds; 24, four rounds; and 7, five rounds, Dr. Caron and associates reported in a research letter (JAMA Oncol. 2017; Aug 3 doi: 10.1001/jamaoncol.2017.1358).

Collectively, this amounted to 226.4 person-years of follow-up.

Screening with either trial strategy (with or without whole-body MRI) led to diagnosis of 23 new primary cancers in 20 patients. Nearly half of the total (12 cancers) were detected at the first round. Patients had a median age of 39.8 at the new cancer diagnosis, with a range from 6 to 70 years.

Of the new cancers, 10 belonged to the core LFS spectrum of breast cancer, sarcoma, and brain tumors. However, the other 13 were outside that spectrum, for example, lung adenocarcinomas, all seen in never or light smokers, and leukemias. Screening also detected three relapses of previous cancers.

Analyses further showed that prior cancer diagnosis was not a reliable marker for risk of new primaries. Although 12 of the patients with a screening-detected new primary had a personal cancer history, 8 did not (P = .22).

“The proportion and diversity of off–core LFS spectrum cancers detected in TP53 mutation carriers as reported by others give growing evidence of a broader LFS spectrum, in agreement with the permissive role of TP53 mutations,” write Dr. Caron and colleagues, who report having no relevant disclosures. “Our observations seem to support recent moves toward broader cancer screening in TP53 mutation carriers.”

The investigators continue to collect data in LIFSCREEN and plan to undertake main analysis later this year. “Our final analysis will help to determine the benefits and drawbacks (mostly related to false-positive test results) of whole-body MRI in TP53 mutation carrier surveillance,” they conclude. “Studies focused on TP53 mutation penetrance, using methods limiting selection bias, are required to refine cancer risks to improve TP53 mutation carrier management.”

Broader cancer screening of individuals with Li-Fraumeni syndrome (LFS), with or without whole-body magnetic resonance imaging, has a good diagnostic yield and identifies a wide range of cancers, according to a preliminary analysis of the ongoing LIFSCREEN phase 3, randomized, controlled trial.

Investigators led by Olivier Caron, MD, chair of the oncogenetics committee, department of medical oncology, at the Gustave Roussy University Hospital in Villejuif, France, enrolled in the trial 107 individuals from 75 families carrying a TP53 mutation, a genetic aberration commonly present in LFS that confers heightened risk of a variety of malignancies.

Participants had a median age at baseline of 32.9 years, with a range from 5 to 67 years. Fully 98% had a family history of cancer, and 48% had a personal history of cancer.

The participants were assigned to 5 years of standard screening – annual clinical examination, abdomen and pelvis ultrasound, brain MRI, complete blood cell count, and, for women older than 20 years, breast ultrasound and MRI – or intensive screening, entailing the addition of diffusion whole-body MRI.

At the time of the preliminary analysis, 15 patients had undergone only one round of screening; 35, two rounds; 19, three rounds; 24, four rounds; and 7, five rounds, Dr. Caron and associates reported in a research letter (JAMA Oncol. 2017; Aug 3 doi: 10.1001/jamaoncol.2017.1358).

Collectively, this amounted to 226.4 person-years of follow-up.

Screening with either trial strategy (with or without whole-body MRI) led to diagnosis of 23 new primary cancers in 20 patients. Nearly half of the total (12 cancers) were detected at the first round. Patients had a median age of 39.8 at the new cancer diagnosis, with a range from 6 to 70 years.

Of the new cancers, 10 belonged to the core LFS spectrum of breast cancer, sarcoma, and brain tumors. However, the other 13 were outside that spectrum, for example, lung adenocarcinomas, all seen in never or light smokers, and leukemias. Screening also detected three relapses of previous cancers.

Analyses further showed that prior cancer diagnosis was not a reliable marker for risk of new primaries. Although 12 of the patients with a screening-detected new primary had a personal cancer history, 8 did not (P = .22).

“The proportion and diversity of off–core LFS spectrum cancers detected in TP53 mutation carriers as reported by others give growing evidence of a broader LFS spectrum, in agreement with the permissive role of TP53 mutations,” write Dr. Caron and colleagues, who report having no relevant disclosures. “Our observations seem to support recent moves toward broader cancer screening in TP53 mutation carriers.”

The investigators continue to collect data in LIFSCREEN and plan to undertake main analysis later this year. “Our final analysis will help to determine the benefits and drawbacks (mostly related to false-positive test results) of whole-body MRI in TP53 mutation carrier surveillance,” they conclude. “Studies focused on TP53 mutation penetrance, using methods limiting selection bias, are required to refine cancer risks to improve TP53 mutation carrier management.”

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-8 (HHV-8). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremities, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹ We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm³; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia. The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.
 

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.² Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.³ Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴ Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

Kaposi sarcoma is an AIDS-defining illness associated with human herpes virus-8 (HHV-8) co-infection. It was described in 1872 by the Hungarian dermatologist Mortiz Kaposi, and was an isolated and sporadic occurrence before the emergence of HIV infection and AIDS.¹ It was first affiliated as an AIDS-associated neoplasm in 1981.¹ Kaposi sarcoma is a systemic disease that can present with cutaneous lesions with or without internal involvement. There are four subtypes: Classic, African endemic, AIDS-related (CD4 count, <200), and Kaposi sarcoma in iatrogenically immunosuppressed patients. The disease has the propensity to manifest in the skin and gastro-intestinal and respiratory tracts, and osseous involvement is rarely encountered. We present here the case of an AIDS-positive man with generalized bone pain as a result of metastasis from Kaposi sarcoma. Our discussion includes the epidemiological, clinical, pathological, and radiological facets of AIDS-related Kaposi sarcoma, and the anomaly of osseous involvement.

Case presentation and summary

A 26-year-old African American man with a history of AIDS (CD4 count, 13 cells/mm³ [normal, 500-1,600 cells/mm³]) who was noncompliant with HAART (highly active antiretroviral therapy), presented to the emergency department in January 2016 with chest, abdominal, and back pain. His HAART regimen included darunavir 8 mL oral suspension daily, emtricitabine 4 mL oral suspension daily, and ritonavir 100 mg tab daily. A computed-tomography (CT) scan of the man’s abdomen revealed axillary, mediastinal, and abdominal lymphadenopathy, with splenomegaly and innumerable osseous lucent spinal lesions. A left axillary lymph node biopsy was positive for Kaposi sarcoma; pathology showed fascicles of spindle, oval- to round-shaped atypical cells positive for HHV-8 (granular nuclear staining), CD31, and CD34 (partial; Figure 1). Serum and urine protein electrophoresis showed no paraproteins.

He restarted his previous HAART regimen in March 2016, and was subsequently started on chemotherapy with liposomal doxorubicin (50 mg [20 mg/m²] in 250 ml D5W IV every 2 weeks) because of his extensive disease.² He completed 6 cycles by June 2016. However, he returned in July 2016 with worsening back pain. A repeat CT scan revealed significant improvement in the disseminated lymphadenopathy, but worsening osseous metastatic disease was seen in the lumbar, thoracic, and pelvic regions. A pelvic lytic lesion biopsy revealed Kaposi sarcoma; pathology showed spindle cells positive for CD34, CD31, and HHV-8 (Figure 2). The patient received palliative radiation to the spine, aiding in pain management and ambulatory dysfunction. He continued with his noncompliance with all medications and outpatient follow-ups, and succumbed to his disease burden.

Discussion

Kaposi sarcoma is a low-grade mesenchymal tumor that involves the blood and lymphatic vessels.³ Its association with AIDS was revealed in the early 1980s at the start of the HIV epidemic in the United States. In 1994, Chang and colleagues discovered the association between Karposi sarcoma and HHV-8 by isolating DNA fragments of HHV in Kaposi sarcoma tumors from AIDS patients.⁴ The mode of transmission of HHV-8 has not been fully decoded. It has been presumed that adult homosexual contact continues to be an important route of transmission, inferring a common route of infection. In 1990, the overall risk of developing Kaposi sarcoma in AIDS patients was 20,000 times greater than it was in the general population, and 300 times greater than in other immunosuppressed patients.⁵ This suggests an increase in incidence, in direct relation, with a decrease in the CD4 count.

Kaposi sarcoma can present with a range of clinical features, from negligible cutaneous lesions to a hastily progressing neoplasm. Involvement in the musculoskeletal system is infrequent, but encountered increasingly in the AIDS-related subtype. Moreover, it is recurrently observed in the African population.⁶ In one of the largest reviews to date exploring Kaposi sarcoma involving the musculoskeletal system, Caponetti and colleagues observed the greatest osseous involvement distinctly in patients with CD4 and T-cell counts below 100 cells/mm³.⁶

Kaposi sarcoma musculoskeletal involvement, specifically bone, is atypical. If it does occur, it usually manifests as a result of contiguous invasion from an adjacent nonosseous lesion. Caponetti and colleagues that isolated osseous Kaposi sarcoma lesions (with no overlying skin lesion) were found to be more likely to be associated with AIDS in the review by Caponetti and colleagues.⁶ As in our patient, it is also typically a manifestation of more widely disseminated disease.⁷

Most of the osseous lytic lesions in AIDS patients are located in the axial skeleton. Radiological features of musculoskeletal Kaposi sarcoma are variable. As observed by Caponetti and colleagues, Kaposi sarcoma lesions can appear as a periosteal reaction, cortical erosions, osteolysis, or osseous destruction, with irregular-shaped cortical erosions being most typical.⁶ Despite their osteolytic features, Kaposi sarcoma lesions are often not visualized by conventional radiography.⁶ The preferred imaging for identification of lytic bone changes is CT (Figure 3). Magnetic resonance imaging can also help distinguish marrow abnormalities as well as adjacent soft tissues masses. Radiologically, Kaposi sarcoma osseous lesions have parallel features to bacillary angiomatosis, tuberculosis, or lymphoma.⁸ Therefore, biopsy of the lesion is essential in establishing the diagnosis of Kaposi sarcoma.

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

Susan London/Frontline Medical News

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

Susan London/Frontline Medical News

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”

Study details

For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

Susan London/Frontline Medical News

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

Susan London/Frontline Medical News

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”

Study details

For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

Susan London/Frontline Medical News

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

Susan London/Frontline Medical News

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”

Study details

For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.

CHICAGO – Genomic testing for all cancer patients was shown to be feasible and productive in a recent study, with a trend toward longer survival among those patients who received recommended targeted treatment.

Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).

“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.

[email protected]
On Twitter @karioakes

CHICAGO – Genomic testing for all cancer patients was shown to be feasible and productive in a recent study, with a trend toward longer survival among those patients who received recommended targeted treatment.

Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).

“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.

[email protected]
On Twitter @karioakes

CHICAGO – Genomic testing for all cancer patients was shown to be feasible and productive in a recent study, with a trend toward longer survival among those patients who received recommended targeted treatment.

Molecular profiling, including genetic sequencing and copy number variation analysis, was performed in 1944 tumors from patients with advanced tumors enrolled in the profiLER study. Of the tumors screened, mutations deemed actionable were identified in 1,004 (52%), with 394 patients having two or more actionable targets, and the remainder having one identified targeted treatment. A molecular targeted treatment was recommended for 676 patients (35% of those tested).

“We showed that the patients who did receive the molecular targeted agents were doing better in terms of overall survival,” said Olivier Tredan, MD, PhD, the study’s lead investigator. Noting that these are trends as the trial was not randomized, he reported that the overall survival (OS) for those receiving targeted treatments was 53.7% at 3 years, compared with 46.1% for those who did not receive targeted treatment. The trend continued out to 5 years, with the OS for the targeted treatment group at 34.8%, compared with 28.1% OS for those who did not receive targeted treatment, he said at the annual meeting of the American Society of Clinical Oncology.

[email protected]
On Twitter @karioakes

AMSTERDAM – Pathological fractures are prognostic of poor outcomes in adults with osteosarcoma, but not in children with osteosarcoma, investigators have found.

A retrospective review of data on consecutive patients treated over the course of 30 years showed that among patients of all ages, both 5-year and 10-year overall survival (OS) rates were worse among patients who had pathological fractures.

But in an analysis stratified by age, the survival difference attributable to fractures was limited entirely to patients who were 18 or older at the time of an osteosarcoma diagnosis, reported Lisa Kelley, a medical student at the Ludwig-Maximilians Universität in Munich.

AMSTERDAM – Pathological fractures are prognostic of poor outcomes in adults with osteosarcoma, but not in children with osteosarcoma, investigators have found.

A retrospective review of data on consecutive patients treated over the course of 30 years showed that among patients of all ages, both 5-year and 10-year overall survival (OS) rates were worse among patients who had pathological fractures.

But in an analysis stratified by age, the survival difference attributable to fractures was limited entirely to patients who were 18 or older at the time of an osteosarcoma diagnosis, reported Lisa Kelley, a medical student at the Ludwig-Maximilians Universität in Munich.

AMSTERDAM – Pathological fractures are prognostic of poor outcomes in adults with osteosarcoma, but not in children with osteosarcoma, investigators have found.

A retrospective review of data on consecutive patients treated over the course of 30 years showed that among patients of all ages, both 5-year and 10-year overall survival (OS) rates were worse among patients who had pathological fractures.

But in an analysis stratified by age, the survival difference attributable to fractures was limited entirely to patients who were 18 or older at the time of an osteosarcoma diagnosis, reported Lisa Kelley, a medical student at the Ludwig-Maximilians Universität in Munich.

AMSTERDAM – Immune checkpoint inhibitors targeted against programmed death–1 (PD-1) and its ligand (PD-L1) show strong activity against several different tumor types, but unfortunately may have only limited efficacy against soft tissue and bone sarcomas, investigators reported.

“We found that the clinical expression of PD-1, PD-L1, and CD8 is sarcoma subtype dependent,” said Anke van Erp, a PhD candidate in oncology at Radboud University Medical Center in Nijmegen, the Netherlands.

[email protected]

AMSTERDAM – Immune checkpoint inhibitors targeted against programmed death–1 (PD-1) and its ligand (PD-L1) show strong activity against several different tumor types, but unfortunately may have only limited efficacy against soft tissue and bone sarcomas, investigators reported.

“We found that the clinical expression of PD-1, PD-L1, and CD8 is sarcoma subtype dependent,” said Anke van Erp, a PhD candidate in oncology at Radboud University Medical Center in Nijmegen, the Netherlands.

[email protected]

AMSTERDAM – Immune checkpoint inhibitors targeted against programmed death–1 (PD-1) and its ligand (PD-L1) show strong activity against several different tumor types, but unfortunately may have only limited efficacy against soft tissue and bone sarcomas, investigators reported.

“We found that the clinical expression of PD-1, PD-L1, and CD8 is sarcoma subtype dependent,” said Anke van Erp, a PhD candidate in oncology at Radboud University Medical Center in Nijmegen, the Netherlands.

[email protected]

INTRODUCTION

Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.¹ Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.¹ Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.²

EPIDEMIOLOGY AND CLASSIFICATION

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.³ Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.⁴

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.^5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).⁷

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.⁸ Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.⁹

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.¹⁰ Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.¹⁰

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.¹¹ GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).¹² GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).¹¹ The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).² A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.² GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.¹²

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.

CLINICAL EVALUATION

CASE PRESENTATION

Initial Presentation and History

A 55-year-old man presents to his primary care physician with a painless mass in his anterior thigh. The mass has been present for the past 3 months and he believes that it is enlarging. The patient has a history of well-controlled hypertension and hyperlipidemia. His medications include atorvastatin and hydrochlorothiazide. He has no known drug allergies. Family history is notable for diabetes and hypertension. He drinks 4 to 5 alcoholic drinks a week and he is a former smoker. He quit smoking in his 30s and only smoked intermittently prior to quitting. He denies any illicit drug use. He works as a high school principal. Currently, he feels well. His review of systems is otherwise noncontributory.

Physical Examination

On physical exam, he is afebrile with a blood pressure of 132/75 mm Hg, respiratory rate of 10 breaths/min, and oxygen saturation of 99% on room air. He is a well appearing, overweight male. His head and neck exam is unremarkable. Lung exam reveals clear breath sounds, and cardiac exam reveals a regular rate and rhythm. His abdomen is obese, soft, and without hepatosplenomegaly. There is a large, fixed mass on the anterior lateral aspect of his right thigh. He has no appreciable lymphadenopathy. His neurological exam is unremarkable.

• What are risk factors for sarcoma?

There are few known risk factors for sarcoma. Established risks factors include prior radiation therapy, chronic lymphedema, viruses, and genetic cancer syndromes including Li-Fraumeni syndrome, hereditary retinoblastoma, and NF-1. Other environmental exposures include phenoxyacetic acids and chlorophenols.¹⁴ The majority of cases are sporadic, with only a minority of patients having one of these known risk factors.¹⁵ Up to one third of sarcomas have a specific translocation and are driven by fusion oncogenes (Table 1).

A painless mass is the most typical presenting symptom. Size at presentation varies based on location, with extremity and head and neck locations typically presenting at smaller sizes than retroperitoneal tumors.¹⁴ Patients may experience pain and numbness as the mass enlarges and impinges on surrounding structures including nerves and vasculature. The vast majority of patients are without systemic symptoms.

• How is sarcoma staged?

The American Joint Committee on Cancer (AJCC) staging system is the most widely used staging system in the United States. The latest AJCC manual was updated in 2010 to include a 3-tiered grading system where the tumor is classified according to tumor size, lymph node involvement, metastases, and grade at time of diagnosis (Table 2 and Table 3). Additionally, tumor depth in relation to deep fascia is also taken into account, with superficial tumors being assigned a designation of “a” and deep tumors a designation of “b.”

Previously, 2 of the most widely used grading systems were the National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems, both 3-tier grading systems. The main components that determine the NCI grade are the tumor’s histologic type and location and the amount of tumor necrosis. The FNCLCC system evaluation focuses on tumor differentiation, mitotic rate, and amount of tumor necrosis. A study that compared the NCI and FNCLCC grading systems found that FNCLCC was a better predictor of mortality and distant metastasis.¹⁶ Previously, the AJCC was a 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading system. Additionally, the AJCC system has reclassified single lymph node disease as stage III as it confers better survival than metastatic disease.¹⁷ It is important that pathology be evaluated by a sarcoma specialist as disagreements with regard to histologic subtype and grade are common.^18,19

• What are the most important prognostic factors?

Prognostic factors include grade, size, and presence of metastases at presentation. Best survival is associated with low-grade, small tumors with no metastases at time of diagnosis.¹⁴

Imaging should be undertaken to help differentiate between benign and malignant lesions. Ideally, it should be undertaken before a biopsy is planned as the imaging can be used to plan biopsy as well as provide invaluable prognostic information. There are several imaging modalities that should be considered during the preliminary work-up and staging of STSs. Conventional imaging includes magnetic resonance imaging (MRI) of the original tumor site; computed tomography (CT) to evaluate for pulmonary metastases and, depending on location, liver metastases; and in the case of small, low-grade tumors, chest radiography. MRI is considered the test of choice for soft tissue masses and can help delineate benign masses such as hematomas, lipomas, and hemangiomas from sarcomas.²⁰ It is difficult to compare the accuracy of positron emission tomography (PET)/CT to CT and MRI because most studies have evaluated PET/CT in parallel with CT and MRI.²¹ Tateishi et al compared the accuracy of conventional imaging, PET/CT, and PET/CT combined with conventional imaging at determining the TNM staging for 117 patients. They found that conventional imaging correctly classified 77% of patients, PET alone correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined with conventional imaging correctly staged 87%.²²

• Which subtypes are most likely to metastasize?

Although the vast majority of sarcomas spread hematogenously, 3 have a propensity to spread lymphogenously: epithelioid sarcoma, rhabdomyosarcoma, and clear-cell sarcoma. Additionally, certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarcomas, and epithelioid sarcomas.²³ Sarcomas metastasize to the lungs more frequently than to the liver. The metastatic pattern is defined primarily by sarcoma subtype and site of primary tumor. Sarcomas rarely metastasize to the brain (~1%).

MANAGEMENT

CASE CONTINUED

The patient undergoes an ultrasound to better visualize the mass. Given the heterogeneous character of the mass, he is referred for an MRI to evaluate the mass and a CT scan of the chest, abdomen, and pelvis to evaluate for distant metastases. MRI reveals a 5.1 cm × 4.6 cm heterogeneous mass invading the superficial fascia of the rectus femoris muscle. No suspicious lymph nodes or other masses are identified on imaging. The patient next undergoes an image-guided core needle biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, grade 3, dedifferentiated liposarcoma.

• What is the best management approach for this patient?

SURGERY

Surgery is the mainstay of treatment for STS. Patients with the best prognosis are those who undergo complete resection with negative surgical margins.^24,25 Goal tumor-free margin is 1 to 3 cm.²⁶ Complete resection confers the best long-term survival. Both local and metastatic recurrence is higher in patients with incomplete resection and positive margins.^24,25 In a study that analyzed 2084 localized primary STSs, patients with negative margins had a local recurrence rate of 15% versus a rate of 28% in patients with positive margins. This translated into higher 5-year local recurrence-free survival for patients with negative surgical margins (82%) compared to patients with positive margins (65%).²⁷ Another study similarly found that patients with negative margins at referral to their institution who underwent postoperative radiation had high local control rates of 93% (95% confidence interval [CI] 87% to 97%) at 5, 10, and 15 years.²⁶ Although radiation improves local control, neither preoperative or postoperative radiation has been shown to improve progression-free or overall survival.²⁸ Other factors that are associated with risk of recurrence are tumor location, history of previous recurrence, age of patient, histopathology, tumor grade, and tumor size. Approximately 40% to 50% of patients with high-grade tumors (defined as size > 5 cm, deep location, and high grade) will develop distant metastases.²⁹

Zagars et al found that positive or uncertain resection margin had a relative risk of local recurrence of 2.0 (95% CI 1.3 to 3.1; P = 0.002), and presentation with locally recurrent disease (vs new tumor) had a relative risk of local recurrence of 2.0 (95% CI 1.2 to 3.4; P = 0.013).²⁶ Patients with STS of head and neck and deep trunk have higher recurrence rates than those with superficial trunk and extremity STS. A single-institution retrospective review demonstrated that patients with completely resectable retroperitoneal sarcomas have longer median survival (103 months) compared to patients with incompletely resected abdominal sarcomas (18 months).²⁵

CASE CONTINUED

The patient is referred for limb-sparing surgery after presentation at a multidisciplinary tumor board. Prior to undergoing resection of the tumor, he is also referred to radiation-oncology to discuss the risks and benefits of combination radiotherapy and surgery as opposed to surgical resection alone.

• What is the evidence for radiation therapy?

RADIATION THERAPY

Radiation therapy is used in the preoperative, intraoperative, and postoperative settings to reduce the risk of local recurrence. There are several options for radiation, including external beam radiation therapy (EBRT), intraoperative radiation, and brachytherapy. A newer strategy, intensity-modulated radiation therapy (IMRT), utilizes 3-dimensional modeling to reduce radiation dosages. Overall there are no differences in overall survival or local recurrence rates between preoperative and postoperative radiation in STS.²⁸

The rationale behind preoperative radiation is that it reduces seeding of tumor cells, especially at the time of surgery.³⁰ Additionally, for EBRT, preoperative radiation has smaller field sizes and lower radiation doses. It can also help to reduce the size of the tumor prior to resection. Intraoperative radiation is often paired with preoperative radiation as a boost dose given only to the area of residual tumor.

Suit et al reviewed patients treated at a single institution with limb-sparing surgery and different radiation strategies. Local control rates between preoperative and postoperative radiation groups were not statistically significant. Local recurrence was linked to grade and size of the tumor in both groups. The authors did note, however, that the preoperative radiation group tended to have larger tumor sizes at baseline compared to the patients who received postoperative radiation.³⁰ A study that compared 190 patients who received preoperative and postoperative EBRT or brachytherapy (primary end point was wound complications, and local control was a secondary end point) showed a trend towards greater local control with preoperative radiation; however, the preoperative radiation group had significantly more wound complications compared to the postoperative radiation group.³¹

Yang et al found that postoperative EBRT decreases rates of local recurrence compared to surgery alone in high-grade extremity sarcomas.³² However, there were no differences in rates of distant metastases and overall survival between the 2 treatment groups. Similarly, in patients with low-grade sarcoma, there were fewer local recurrences in those who received EBRT and surgery as compared to surgery alone.³² Another study that evaluated 164 patients who received either adjuvant brachytherapy or no further therapy after complete resection found that brachytherapy reduced local recurrence in high-grade sarcomas. No difference in local recurrence rates was found in patients with low-grade sarcomas, nor was a significant difference found in the rates of distant metastases and overall survival between the 2 treatment groups.³³ With regards to IMRT, a single institution cohort experience with 41 patients who received IMRT following limb-sparing surgery had similar local control rates when compared to historical controls.³⁴

CASE CONTINUED

After discussion of the risks and benefits of radiation therapy, the patient opts for preoperative radiation prior to resection of his liposarcoma. He receives 50 Gy of EBRT prior to undergoing resection. Resection results in R1 margin consistent with microscopic disease. He receives 16 Gy of EBRT as a boost after recovery from his resection.²

• What is the evidence for neoadjuvant and adjuvant chemotherapy for stage I tumors?

CHEMOTHERAPY

Localized Sarcoma

For localized sarcoma, limb-sparing resection with or without radiation forms the backbone of treatment. Studies have evaluated chemotherapy in both the neoadjuvant and adjuvant settings, with the vast majority of studies evaluating doxorubicin-based chemotherapy regimens in the adjuvant settings. Due to the rare nature of sarcomas, most studies are not sufficiently powered to detect significant benefit from chemotherapy. Several trials evaluating chemotherapy regimens in the neoadjuvant and adjuvant settings needed to be terminated prematurely due to inadequate enrollment into the study. ^35,36

For stage IA (T1a-Tb, N0, M0, low grade) tumors, no additional therapy is recommended after limb-sparing surgery with appropriate surgical margins. For stage IB (T2a-2b, N0, M0, low grade) tumors with insufficient margins, re-resection and radiation therapy should be considered, while for stage IIA (T1a-1b, N0, M0, G2-3) tumors preoperative or postoperative radiation therapy is recommended.² Studies have not found benefit of adjuvant chemotherapy in these low-grade, stage I tumors in terms of progression-free survival and overall survival.³⁷

• At what stage should chemotherapy be considered?

For stage IIb and stage III tumors, surgery and radiation therapy again form the backbone of therapy; however, neoadjuvant and adjuvant chemotherapy are also recommended as considerations. Anthracycline-based chemotherapy with either single-agent doxorubicin or doxorubicin and ifosfamide in combination are considered first-line chemotherapy agents in locally advanced STS.^2,29,37

Evidence regarding the efficacy of both neoadjuvant and adjuvant chemotherapy regimens in the setting of locally advanced high-grade STS has been mixed. The Sarcoma Meta-analysis Collaboration evaluated 14 trials of doxorubicin-based adjuvant chemotherapy and found a trend towards overall survival in the treatment groups that received chemotherapy.³⁷ All trials included in the meta-analysis compared patients with localized resectable soft-tissue sarcomas who were randomized to either adjuvant chemotherapy or no adjuvant chemotherapy after limb-sparing surgery with or without radiation therapy. None of the individual trials showed a significant benefit, and all trials had large confidence intervals; however, the meta-analysis showed significant benefit in the chemotherapy treatment groups with regard to local recurrence, distant recurrence, and progression-free survival. No significant difference in overall survival was found.³⁷ Pervais et al updated the Sarcoma Meta-analysis Collaboration’s 1997 meta-analysis with the inclusion of 4 new trials that evaluated doxorubicin combined with ifosfamide and found that both patients who received doxorubicin-based regimens or doxorubicin with ifosfamide had significant decreases in distant and overall recurrences. Only the trials that utilized doxorubicin and ifosfamide had an improved overall survival that was statistically significant (hazard ratio 0.56 [95% CI 0.36 to 0.85]; P = 0.01).²⁹ Although no significant heterogeneity was found among the trials included in either meta-analysis, a variety of sarcomas were included in each clinical trial evaluated. Given the extremely small number of each sarcoma subtype present in each trial, subgroup analysis is difficult and prone to inaccuracies. As a result, it is not known if certain histological subtypes are more or less responsive to chemotherapy.^37–39

One randomized controlled trial evaluated neoadjuvant chemotherapy in high-risk sarcomas defined as tumors greater than 8 cm or grade II/III tumors. This study evaluated doxorubicin and ifosfamide and found no significant difference in disease-free and overall survival in the neoadjuvant therapy group compared to the control group.³⁵ There remains controversy in the literature with regards to adjuvant chemotherapy. Many oncologists offer adjuvant chemotherapy to patients with certain stage III subtypes. Examples of subtypes that may be offered adjuvant therapy include myxoid liposarcomas, synovial sarcomas, and leiomyosarcomas.² With regards to how many cycles of chemotherapy should be considered, a noninferiority study compared 3 cycles of epirubicin and ifosfamide to 5 cycles of epirubicin and ifosfamide in patients with high-risk locally advanced adult STSs. Three cycles of preoperative epirubicin and ifosfamide was found to be noninferior to 5 cycles with regards to overall survival.³⁸

• What is this patient’s risk for recurrence?

The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.³⁹ The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.⁴⁰ For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.⁴¹ Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5 (95% CI 1.0 to 2.0).³⁹

• What are the recommendations for surveillance?

Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.² For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.²

CASE CONTINUED

The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dyspnea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.

• Should this patient undergo metastectomy?

An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.⁴² For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.²

CASE CONTINUED

Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.

• What are treatment options for unresectable or metastatic disease?

Metastatic Disease

Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.⁴³ In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.⁴⁴ In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.⁴⁵ Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.⁴³ Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.

The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.⁴⁶ Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.⁴⁶

• What are second-line treatment options?

Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.⁴⁷ However, Omura et al

Several additional regimens have undergone evaluation in metastatic and recurrent STSs. Gemcitabine has been used both as a single agent and as part of combination therapy in many studies. Studies with gemcitabine in combination with either docetaxel or DTIC have been the most efficacious. In a phase 2 trial, patients with metastatic STS were randomly assigned to either gemcitabine alone or gemcitabine and docetaxel. Combination therapy had a higher response rate (16% versus 8%) and longer overall survival (17.9 months versus 11.5 months) than gemcitabine alone.⁵⁰ Furthermore, a phase 2 trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma showed an overall response rate of 56%, with 3 complete and 15 partial responses among the 34 patients enrolled in the study.⁵¹

A phase 2 trial randomly assigned patients with unresectable or metastatic STS to either DTIC or combination gemcitabine and DTIC.⁵² Gemcitabine-DTIC had a superior progression-free survival at 3 months (56% [95% CI 43% to 69%]) as compared to DTIC alone (37% [95% CI 23.5% to 50%]). Furthermore, mean progression-free survival and overall survival were improved in the gemcitabine-DTIC group (4.2 months and 16.8 months) as compared to the DTIC group (2.0 months and 8.2 months).⁵² DTIC has a single-agent response rate of 16%, but has been shown to be particularly effective in the setting of leiomyosarcomas.⁴⁹

• Does response to treatment regimens differ by histologic subtype?

The majority of STS trials include many different histologic subtypes. Given the rarity of sarcomas as a whole, many trials have had difficulty recruiting adequate numbers of patients to have sufficient power to definitely determine if the treatment under investigation has clinical benefit. Furthermore, the patients recruited have been heterogeneous with regard to subtype. Many older studies hypothesized that the efficacy of chemotherapeutic agents vary based on histologic subtype; however, for most subtypes the number of individuals included in those trials was too low to evaluate efficacy based on subtype.

Some exceptions exist, however. For example, both gemcitabine-DTIC and gemcitabine-docetaxel have been found to be particularly effective in the treatment of leiomyosarcomas.^50,52 Additionally, a retrospective study found a 51% overall response rate for patients with myxoid liposarcomas treated with trabectedin.⁵³ Studies of patients with angiosarcoma treated with paclitaxel have demonstrated response rates of 43% and 53%.^54,55

• What are the newest approved and investigational agents?

A recently approved agent is trabectedin, a tris tetrahydroisoquinoline alkaloid isolated from ascidians that binds to the minor groove of DNA and causes disruptions in the cell cycle. Samuels et al reported data from a single-arm, open-label expanded access trial that evaluated patients with advanced metastatic sarcomas.⁵⁶ In this study, patients with liposarcomas and leiomyosarcomas had an objective response rate of 6.9% (95% CI 4.8 to 9.6) as compared to a rate of 5.9% (95% CI 4.4 to 7.8) for all assessable patients. Median survival was 11.9 months for all patients, with improved median survivals for liposarcoma and leiomyosarcomas of 16.2 months (95% CI 14.1 to 19.5) compared to 8.4 months (95% CI 7.1 to 10.7 months) for other subtypes.⁵⁶

Schöffski et al evaluated eribulin, a chemotherapeutic agent that affects microtubule dynamics, in a phase 2 trial of patients with progressive or high-grade STS with progression on previous chemotherapy. They found a median progression-free survival of 2.6 months (95% CI 1.7 to 6.2) for adipocytic sarcoma, 2.9 months (95% CI 2.4 to 4.6) for leiomyosarcoma, 2.6 months (95% CI 2.3 to 4.3) for synovial sarcoma, and 2.1 months (95% CI 1.4 to 2.9) for other sarcomas.⁵⁷

Van der Graaf and colleagues randomly assigned patients with metastatic nonadipocytic STS to pazopanib or placebo in a phase 3 trial. Pazopanib is a small-molecule endothelial growth factor inhibitor with activity against vascular endothelial growth factors 1, 2, and 3 as well as platelet-derived growth factors. Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) with pazopanib compared to 1.6 months (95% CI 0.9 to 1.8) with placebo.⁵⁸ Adipocytic sarcomas (liposarcomas) were excluded from the trial because phase 2 trials had found a lower rate of progression-free survival (26%) for them compared to other subtypes.

Toxicities were seen with each of the regimens studied and were common in the randomized trials, with higher rates of toxicities in the combination chemotherapy regimens. The most common toxicities are myelosuppression, nausea, and vomiting. In the doxorubicin trials, the most common toxicities were myelosuppression, nausea, and vomiting.⁴⁴

Ifosfamide both as an individual agent and in combination with doxorubicin has higher rates and higher grades of toxicity than doxorubicin alone. Myelosuppression is the most common toxicity associated with ifosfamide, and the most commonly affected cell line is leukocytes.⁴⁴ Combination doxorubicin and ifosfamide also had high rates of nausea and vomiting (95%) and alopecia (100%).³⁵

Neutropenia is the most common toxicity associated with gemcitabine and dacarbazine, while their most common nonhematologic toxicities are fatigue and nausea.^52,59 Trabectedin’s most common toxicities are nausea (29%), neutropenia (24%), and fatigue (23%). It has also been shown to cause increased alkaline phosphatase (20%) and alanine aminotransferase (19%) levels.⁵⁶ In a phase 2 study of eribulin, 50% of patients had neutropenia, and other toxicities included fatigue, alopecia, nausea, sensory neuropathy, and thrombocytopenia.⁵⁷ Pazopanib is generally well tolerated; the most common toxicities are fatigue (65%), diarrhea (58%), nausea (54%), and hypertension (41%).⁵⁸ Higher rates of neutropenia, mucositis, nausea, vomiting, diarrhea, and transfusion reactions were seen with olaratumab and doxorubicin compared to doxorubicin alone in phase 1b and 2 studies.⁴⁶

CASE CONCLUSION

Given his poor prognosis with unresectable metastatic undifferentiated liposarcoma, the patient considers a clinical trial prior to undergoing combined therapy with doxorubicin and ifosfamide. He tolerates therapy well with stable disease at 6 months.

CONCLUSION

STSs are a heterogeneous collection of rare tumors. Low-grade, localized tumors have the best prognosis, and patients who undergo complete resection have the best long-term survival. Due to the rarity of STSs, trials often have limited enrollment, and little progress has been made with regards to treatment and survival rates for metastatic and unresectable disease. All patients should be evaluated and treated at specialized sarcoma centers. This case highlights the need for continued research and clinical trials to improve overall survival of patients with sarcoma.

INTRODUCTION

Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.¹ Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.¹ Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.²

EPIDEMIOLOGY AND CLASSIFICATION

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.³ Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.⁴

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.^5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).⁷

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.⁸ Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.⁹

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.¹⁰ Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.¹⁰

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.¹¹ GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).¹² GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).¹¹ The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).² A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.² GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.¹²

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.

CLINICAL EVALUATION

CASE PRESENTATION

Initial Presentation and History

A 55-year-old man presents to his primary care physician with a painless mass in his anterior thigh. The mass has been present for the past 3 months and he believes that it is enlarging. The patient has a history of well-controlled hypertension and hyperlipidemia. His medications include atorvastatin and hydrochlorothiazide. He has no known drug allergies. Family history is notable for diabetes and hypertension. He drinks 4 to 5 alcoholic drinks a week and he is a former smoker. He quit smoking in his 30s and only smoked intermittently prior to quitting. He denies any illicit drug use. He works as a high school principal. Currently, he feels well. His review of systems is otherwise noncontributory.

Physical Examination

On physical exam, he is afebrile with a blood pressure of 132/75 mm Hg, respiratory rate of 10 breaths/min, and oxygen saturation of 99% on room air. He is a well appearing, overweight male. His head and neck exam is unremarkable. Lung exam reveals clear breath sounds, and cardiac exam reveals a regular rate and rhythm. His abdomen is obese, soft, and without hepatosplenomegaly. There is a large, fixed mass on the anterior lateral aspect of his right thigh. He has no appreciable lymphadenopathy. His neurological exam is unremarkable.

• What are risk factors for sarcoma?

There are few known risk factors for sarcoma. Established risks factors include prior radiation therapy, chronic lymphedema, viruses, and genetic cancer syndromes including Li-Fraumeni syndrome, hereditary retinoblastoma, and NF-1. Other environmental exposures include phenoxyacetic acids and chlorophenols.¹⁴ The majority of cases are sporadic, with only a minority of patients having one of these known risk factors.¹⁵ Up to one third of sarcomas have a specific translocation and are driven by fusion oncogenes (Table 1).

A painless mass is the most typical presenting symptom. Size at presentation varies based on location, with extremity and head and neck locations typically presenting at smaller sizes than retroperitoneal tumors.¹⁴ Patients may experience pain and numbness as the mass enlarges and impinges on surrounding structures including nerves and vasculature. The vast majority of patients are without systemic symptoms.

• How is sarcoma staged?

The American Joint Committee on Cancer (AJCC) staging system is the most widely used staging system in the United States. The latest AJCC manual was updated in 2010 to include a 3-tiered grading system where the tumor is classified according to tumor size, lymph node involvement, metastases, and grade at time of diagnosis (Table 2 and Table 3). Additionally, tumor depth in relation to deep fascia is also taken into account, with superficial tumors being assigned a designation of “a” and deep tumors a designation of “b.”

Previously, 2 of the most widely used grading systems were the National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems, both 3-tier grading systems. The main components that determine the NCI grade are the tumor’s histologic type and location and the amount of tumor necrosis. The FNCLCC system evaluation focuses on tumor differentiation, mitotic rate, and amount of tumor necrosis. A study that compared the NCI and FNCLCC grading systems found that FNCLCC was a better predictor of mortality and distant metastasis.¹⁶ Previously, the AJCC was a 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading system. Additionally, the AJCC system has reclassified single lymph node disease as stage III as it confers better survival than metastatic disease.¹⁷ It is important that pathology be evaluated by a sarcoma specialist as disagreements with regard to histologic subtype and grade are common.^18,19

• What are the most important prognostic factors?

Prognostic factors include grade, size, and presence of metastases at presentation. Best survival is associated with low-grade, small tumors with no metastases at time of diagnosis.¹⁴

Imaging should be undertaken to help differentiate between benign and malignant lesions. Ideally, it should be undertaken before a biopsy is planned as the imaging can be used to plan biopsy as well as provide invaluable prognostic information. There are several imaging modalities that should be considered during the preliminary work-up and staging of STSs. Conventional imaging includes magnetic resonance imaging (MRI) of the original tumor site; computed tomography (CT) to evaluate for pulmonary metastases and, depending on location, liver metastases; and in the case of small, low-grade tumors, chest radiography. MRI is considered the test of choice for soft tissue masses and can help delineate benign masses such as hematomas, lipomas, and hemangiomas from sarcomas.²⁰ It is difficult to compare the accuracy of positron emission tomography (PET)/CT to CT and MRI because most studies have evaluated PET/CT in parallel with CT and MRI.²¹ Tateishi et al compared the accuracy of conventional imaging, PET/CT, and PET/CT combined with conventional imaging at determining the TNM staging for 117 patients. They found that conventional imaging correctly classified 77% of patients, PET alone correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined with conventional imaging correctly staged 87%.²²

• Which subtypes are most likely to metastasize?

Although the vast majority of sarcomas spread hematogenously, 3 have a propensity to spread lymphogenously: epithelioid sarcoma, rhabdomyosarcoma, and clear-cell sarcoma. Additionally, certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarcomas, and epithelioid sarcomas.²³ Sarcomas metastasize to the lungs more frequently than to the liver. The metastatic pattern is defined primarily by sarcoma subtype and site of primary tumor. Sarcomas rarely metastasize to the brain (~1%).

MANAGEMENT

CASE CONTINUED

The patient undergoes an ultrasound to better visualize the mass. Given the heterogeneous character of the mass, he is referred for an MRI to evaluate the mass and a CT scan of the chest, abdomen, and pelvis to evaluate for distant metastases. MRI reveals a 5.1 cm × 4.6 cm heterogeneous mass invading the superficial fascia of the rectus femoris muscle. No suspicious lymph nodes or other masses are identified on imaging. The patient next undergoes an image-guided core needle biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, grade 3, dedifferentiated liposarcoma.

• What is the best management approach for this patient?

SURGERY

Surgery is the mainstay of treatment for STS. Patients with the best prognosis are those who undergo complete resection with negative surgical margins.^24,25 Goal tumor-free margin is 1 to 3 cm.²⁶ Complete resection confers the best long-term survival. Both local and metastatic recurrence is higher in patients with incomplete resection and positive margins.^24,25 In a study that analyzed 2084 localized primary STSs, patients with negative margins had a local recurrence rate of 15% versus a rate of 28% in patients with positive margins. This translated into higher 5-year local recurrence-free survival for patients with negative surgical margins (82%) compared to patients with positive margins (65%).²⁷ Another study similarly found that patients with negative margins at referral to their institution who underwent postoperative radiation had high local control rates of 93% (95% confidence interval [CI] 87% to 97%) at 5, 10, and 15 years.²⁶ Although radiation improves local control, neither preoperative or postoperative radiation has been shown to improve progression-free or overall survival.²⁸ Other factors that are associated with risk of recurrence are tumor location, history of previous recurrence, age of patient, histopathology, tumor grade, and tumor size. Approximately 40% to 50% of patients with high-grade tumors (defined as size > 5 cm, deep location, and high grade) will develop distant metastases.²⁹

Zagars et al found that positive or uncertain resection margin had a relative risk of local recurrence of 2.0 (95% CI 1.3 to 3.1; P = 0.002), and presentation with locally recurrent disease (vs new tumor) had a relative risk of local recurrence of 2.0 (95% CI 1.2 to 3.4; P = 0.013).²⁶ Patients with STS of head and neck and deep trunk have higher recurrence rates than those with superficial trunk and extremity STS. A single-institution retrospective review demonstrated that patients with completely resectable retroperitoneal sarcomas have longer median survival (103 months) compared to patients with incompletely resected abdominal sarcomas (18 months).²⁵

CASE CONTINUED

The patient is referred for limb-sparing surgery after presentation at a multidisciplinary tumor board. Prior to undergoing resection of the tumor, he is also referred to radiation-oncology to discuss the risks and benefits of combination radiotherapy and surgery as opposed to surgical resection alone.

• What is the evidence for radiation therapy?

RADIATION THERAPY

Radiation therapy is used in the preoperative, intraoperative, and postoperative settings to reduce the risk of local recurrence. There are several options for radiation, including external beam radiation therapy (EBRT), intraoperative radiation, and brachytherapy. A newer strategy, intensity-modulated radiation therapy (IMRT), utilizes 3-dimensional modeling to reduce radiation dosages. Overall there are no differences in overall survival or local recurrence rates between preoperative and postoperative radiation in STS.²⁸

The rationale behind preoperative radiation is that it reduces seeding of tumor cells, especially at the time of surgery.³⁰ Additionally, for EBRT, preoperative radiation has smaller field sizes and lower radiation doses. It can also help to reduce the size of the tumor prior to resection. Intraoperative radiation is often paired with preoperative radiation as a boost dose given only to the area of residual tumor.

Suit et al reviewed patients treated at a single institution with limb-sparing surgery and different radiation strategies. Local control rates between preoperative and postoperative radiation groups were not statistically significant. Local recurrence was linked to grade and size of the tumor in both groups. The authors did note, however, that the preoperative radiation group tended to have larger tumor sizes at baseline compared to the patients who received postoperative radiation.³⁰ A study that compared 190 patients who received preoperative and postoperative EBRT or brachytherapy (primary end point was wound complications, and local control was a secondary end point) showed a trend towards greater local control with preoperative radiation; however, the preoperative radiation group had significantly more wound complications compared to the postoperative radiation group.³¹

Yang et al found that postoperative EBRT decreases rates of local recurrence compared to surgery alone in high-grade extremity sarcomas.³² However, there were no differences in rates of distant metastases and overall survival between the 2 treatment groups. Similarly, in patients with low-grade sarcoma, there were fewer local recurrences in those who received EBRT and surgery as compared to surgery alone.³² Another study that evaluated 164 patients who received either adjuvant brachytherapy or no further therapy after complete resection found that brachytherapy reduced local recurrence in high-grade sarcomas. No difference in local recurrence rates was found in patients with low-grade sarcomas, nor was a significant difference found in the rates of distant metastases and overall survival between the 2 treatment groups.³³ With regards to IMRT, a single institution cohort experience with 41 patients who received IMRT following limb-sparing surgery had similar local control rates when compared to historical controls.³⁴

CASE CONTINUED

After discussion of the risks and benefits of radiation therapy, the patient opts for preoperative radiation prior to resection of his liposarcoma. He receives 50 Gy of EBRT prior to undergoing resection. Resection results in R1 margin consistent with microscopic disease. He receives 16 Gy of EBRT as a boost after recovery from his resection.²

• What is the evidence for neoadjuvant and adjuvant chemotherapy for stage I tumors?

CHEMOTHERAPY

Localized Sarcoma

For localized sarcoma, limb-sparing resection with or without radiation forms the backbone of treatment. Studies have evaluated chemotherapy in both the neoadjuvant and adjuvant settings, with the vast majority of studies evaluating doxorubicin-based chemotherapy regimens in the adjuvant settings. Due to the rare nature of sarcomas, most studies are not sufficiently powered to detect significant benefit from chemotherapy. Several trials evaluating chemotherapy regimens in the neoadjuvant and adjuvant settings needed to be terminated prematurely due to inadequate enrollment into the study. ^35,36

For stage IA (T1a-Tb, N0, M0, low grade) tumors, no additional therapy is recommended after limb-sparing surgery with appropriate surgical margins. For stage IB (T2a-2b, N0, M0, low grade) tumors with insufficient margins, re-resection and radiation therapy should be considered, while for stage IIA (T1a-1b, N0, M0, G2-3) tumors preoperative or postoperative radiation therapy is recommended.² Studies have not found benefit of adjuvant chemotherapy in these low-grade, stage I tumors in terms of progression-free survival and overall survival.³⁷

• At what stage should chemotherapy be considered?

For stage IIb and stage III tumors, surgery and radiation therapy again form the backbone of therapy; however, neoadjuvant and adjuvant chemotherapy are also recommended as considerations. Anthracycline-based chemotherapy with either single-agent doxorubicin or doxorubicin and ifosfamide in combination are considered first-line chemotherapy agents in locally advanced STS.^2,29,37

Evidence regarding the efficacy of both neoadjuvant and adjuvant chemotherapy regimens in the setting of locally advanced high-grade STS has been mixed. The Sarcoma Meta-analysis Collaboration evaluated 14 trials of doxorubicin-based adjuvant chemotherapy and found a trend towards overall survival in the treatment groups that received chemotherapy.³⁷ All trials included in the meta-analysis compared patients with localized resectable soft-tissue sarcomas who were randomized to either adjuvant chemotherapy or no adjuvant chemotherapy after limb-sparing surgery with or without radiation therapy. None of the individual trials showed a significant benefit, and all trials had large confidence intervals; however, the meta-analysis showed significant benefit in the chemotherapy treatment groups with regard to local recurrence, distant recurrence, and progression-free survival. No significant difference in overall survival was found.³⁷ Pervais et al updated the Sarcoma Meta-analysis Collaboration’s 1997 meta-analysis with the inclusion of 4 new trials that evaluated doxorubicin combined with ifosfamide and found that both patients who received doxorubicin-based regimens or doxorubicin with ifosfamide had significant decreases in distant and overall recurrences. Only the trials that utilized doxorubicin and ifosfamide had an improved overall survival that was statistically significant (hazard ratio 0.56 [95% CI 0.36 to 0.85]; P = 0.01).²⁹ Although no significant heterogeneity was found among the trials included in either meta-analysis, a variety of sarcomas were included in each clinical trial evaluated. Given the extremely small number of each sarcoma subtype present in each trial, subgroup analysis is difficult and prone to inaccuracies. As a result, it is not known if certain histological subtypes are more or less responsive to chemotherapy.^37–39

One randomized controlled trial evaluated neoadjuvant chemotherapy in high-risk sarcomas defined as tumors greater than 8 cm or grade II/III tumors. This study evaluated doxorubicin and ifosfamide and found no significant difference in disease-free and overall survival in the neoadjuvant therapy group compared to the control group.³⁵ There remains controversy in the literature with regards to adjuvant chemotherapy. Many oncologists offer adjuvant chemotherapy to patients with certain stage III subtypes. Examples of subtypes that may be offered adjuvant therapy include myxoid liposarcomas, synovial sarcomas, and leiomyosarcomas.² With regards to how many cycles of chemotherapy should be considered, a noninferiority study compared 3 cycles of epirubicin and ifosfamide to 5 cycles of epirubicin and ifosfamide in patients with high-risk locally advanced adult STSs. Three cycles of preoperative epirubicin and ifosfamide was found to be noninferior to 5 cycles with regards to overall survival.³⁸

• What is this patient’s risk for recurrence?

The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.³⁹ The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.⁴⁰ For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.⁴¹ Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5 (95% CI 1.0 to 2.0).³⁹

• What are the recommendations for surveillance?

Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.² For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.²

CASE CONTINUED

The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dyspnea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.

• Should this patient undergo metastectomy?

An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.⁴² For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.²

CASE CONTINUED

Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.

• What are treatment options for unresectable or metastatic disease?

Metastatic Disease

Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.⁴³ In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.⁴⁴ In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.⁴⁵ Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.⁴³ Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.

The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.⁴⁶ Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.⁴⁶

• What are second-line treatment options?

Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.⁴⁷ However, Omura et al

Several additional regimens have undergone evaluation in metastatic and recurrent STSs. Gemcitabine has been used both as a single agent and as part of combination therapy in many studies. Studies with gemcitabine in combination with either docetaxel or DTIC have been the most efficacious. In a phase 2 trial, patients with metastatic STS were randomly assigned to either gemcitabine alone or gemcitabine and docetaxel. Combination therapy had a higher response rate (16% versus 8%) and longer overall survival (17.9 months versus 11.5 months) than gemcitabine alone.⁵⁰ Furthermore, a phase 2 trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma showed an overall response rate of 56%, with 3 complete and 15 partial responses among the 34 patients enrolled in the study.⁵¹

A phase 2 trial randomly assigned patients with unresectable or metastatic STS to either DTIC or combination gemcitabine and DTIC.⁵² Gemcitabine-DTIC had a superior progression-free survival at 3 months (56% [95% CI 43% to 69%]) as compared to DTIC alone (37% [95% CI 23.5% to 50%]). Furthermore, mean progression-free survival and overall survival were improved in the gemcitabine-DTIC group (4.2 months and 16.8 months) as compared to the DTIC group (2.0 months and 8.2 months).⁵² DTIC has a single-agent response rate of 16%, but has been shown to be particularly effective in the setting of leiomyosarcomas.⁴⁹

• Does response to treatment regimens differ by histologic subtype?

The majority of STS trials include many different histologic subtypes. Given the rarity of sarcomas as a whole, many trials have had difficulty recruiting adequate numbers of patients to have sufficient power to definitely determine if the treatment under investigation has clinical benefit. Furthermore, the patients recruited have been heterogeneous with regard to subtype. Many older studies hypothesized that the efficacy of chemotherapeutic agents vary based on histologic subtype; however, for most subtypes the number of individuals included in those trials was too low to evaluate efficacy based on subtype.

Some exceptions exist, however. For example, both gemcitabine-DTIC and gemcitabine-docetaxel have been found to be particularly effective in the treatment of leiomyosarcomas.^50,52 Additionally, a retrospective study found a 51% overall response rate for patients with myxoid liposarcomas treated with trabectedin.⁵³ Studies of patients with angiosarcoma treated with paclitaxel have demonstrated response rates of 43% and 53%.^54,55

• What are the newest approved and investigational agents?

A recently approved agent is trabectedin, a tris tetrahydroisoquinoline alkaloid isolated from ascidians that binds to the minor groove of DNA and causes disruptions in the cell cycle. Samuels et al reported data from a single-arm, open-label expanded access trial that evaluated patients with advanced metastatic sarcomas.⁵⁶ In this study, patients with liposarcomas and leiomyosarcomas had an objective response rate of 6.9% (95% CI 4.8 to 9.6) as compared to a rate of 5.9% (95% CI 4.4 to 7.8) for all assessable patients. Median survival was 11.9 months for all patients, with improved median survivals for liposarcoma and leiomyosarcomas of 16.2 months (95% CI 14.1 to 19.5) compared to 8.4 months (95% CI 7.1 to 10.7 months) for other subtypes.⁵⁶

Schöffski et al evaluated eribulin, a chemotherapeutic agent that affects microtubule dynamics, in a phase 2 trial of patients with progressive or high-grade STS with progression on previous chemotherapy. They found a median progression-free survival of 2.6 months (95% CI 1.7 to 6.2) for adipocytic sarcoma, 2.9 months (95% CI 2.4 to 4.6) for leiomyosarcoma, 2.6 months (95% CI 2.3 to 4.3) for synovial sarcoma, and 2.1 months (95% CI 1.4 to 2.9) for other sarcomas.⁵⁷

Van der Graaf and colleagues randomly assigned patients with metastatic nonadipocytic STS to pazopanib or placebo in a phase 3 trial. Pazopanib is a small-molecule endothelial growth factor inhibitor with activity against vascular endothelial growth factors 1, 2, and 3 as well as platelet-derived growth factors. Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) with pazopanib compared to 1.6 months (95% CI 0.9 to 1.8) with placebo.⁵⁸ Adipocytic sarcomas (liposarcomas) were excluded from the trial because phase 2 trials had found a lower rate of progression-free survival (26%) for them compared to other subtypes.

Toxicities were seen with each of the regimens studied and were common in the randomized trials, with higher rates of toxicities in the combination chemotherapy regimens. The most common toxicities are myelosuppression, nausea, and vomiting. In the doxorubicin trials, the most common toxicities were myelosuppression, nausea, and vomiting.⁴⁴

Ifosfamide both as an individual agent and in combination with doxorubicin has higher rates and higher grades of toxicity than doxorubicin alone. Myelosuppression is the most common toxicity associated with ifosfamide, and the most commonly affected cell line is leukocytes.⁴⁴ Combination doxorubicin and ifosfamide also had high rates of nausea and vomiting (95%) and alopecia (100%).³⁵

Neutropenia is the most common toxicity associated with gemcitabine and dacarbazine, while their most common nonhematologic toxicities are fatigue and nausea.^52,59 Trabectedin’s most common toxicities are nausea (29%), neutropenia (24%), and fatigue (23%). It has also been shown to cause increased alkaline phosphatase (20%) and alanine aminotransferase (19%) levels.⁵⁶ In a phase 2 study of eribulin, 50% of patients had neutropenia, and other toxicities included fatigue, alopecia, nausea, sensory neuropathy, and thrombocytopenia.⁵⁷ Pazopanib is generally well tolerated; the most common toxicities are fatigue (65%), diarrhea (58%), nausea (54%), and hypertension (41%).⁵⁸ Higher rates of neutropenia, mucositis, nausea, vomiting, diarrhea, and transfusion reactions were seen with olaratumab and doxorubicin compared to doxorubicin alone in phase 1b and 2 studies.⁴⁶

CASE CONCLUSION

Given his poor prognosis with unresectable metastatic undifferentiated liposarcoma, the patient considers a clinical trial prior to undergoing combined therapy with doxorubicin and ifosfamide. He tolerates therapy well with stable disease at 6 months.

CONCLUSION

STSs are a heterogeneous collection of rare tumors. Low-grade, localized tumors have the best prognosis, and patients who undergo complete resection have the best long-term survival. Due to the rarity of STSs, trials often have limited enrollment, and little progress has been made with regards to treatment and survival rates for metastatic and unresectable disease. All patients should be evaluated and treated at specialized sarcoma centers. This case highlights the need for continued research and clinical trials to improve overall survival of patients with sarcoma.

INTRODUCTION

Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.¹ Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.¹ Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.²

EPIDEMIOLOGY AND CLASSIFICATION

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.³ Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.⁴

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.^5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).⁷

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.⁸ Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.⁹

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.¹⁰ Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.¹⁰

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.¹¹ GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).¹² GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).¹¹ The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).² A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.² GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.¹²

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.

CLINICAL EVALUATION

CASE PRESENTATION

Initial Presentation and History

A 55-year-old man presents to his primary care physician with a painless mass in his anterior thigh. The mass has been present for the past 3 months and he believes that it is enlarging. The patient has a history of well-controlled hypertension and hyperlipidemia. His medications include atorvastatin and hydrochlorothiazide. He has no known drug allergies. Family history is notable for diabetes and hypertension. He drinks 4 to 5 alcoholic drinks a week and he is a former smoker. He quit smoking in his 30s and only smoked intermittently prior to quitting. He denies any illicit drug use. He works as a high school principal. Currently, he feels well. His review of systems is otherwise noncontributory.

Physical Examination

On physical exam, he is afebrile with a blood pressure of 132/75 mm Hg, respiratory rate of 10 breaths/min, and oxygen saturation of 99% on room air. He is a well appearing, overweight male. His head and neck exam is unremarkable. Lung exam reveals clear breath sounds, and cardiac exam reveals a regular rate and rhythm. His abdomen is obese, soft, and without hepatosplenomegaly. There is a large, fixed mass on the anterior lateral aspect of his right thigh. He has no appreciable lymphadenopathy. His neurological exam is unremarkable.

• What are risk factors for sarcoma?

There are few known risk factors for sarcoma. Established risks factors include prior radiation therapy, chronic lymphedema, viruses, and genetic cancer syndromes including Li-Fraumeni syndrome, hereditary retinoblastoma, and NF-1. Other environmental exposures include phenoxyacetic acids and chlorophenols.¹⁴ The majority of cases are sporadic, with only a minority of patients having one of these known risk factors.¹⁵ Up to one third of sarcomas have a specific translocation and are driven by fusion oncogenes (Table 1).

A painless mass is the most typical presenting symptom. Size at presentation varies based on location, with extremity and head and neck locations typically presenting at smaller sizes than retroperitoneal tumors.¹⁴ Patients may experience pain and numbness as the mass enlarges and impinges on surrounding structures including nerves and vasculature. The vast majority of patients are without systemic symptoms.

• How is sarcoma staged?

The American Joint Committee on Cancer (AJCC) staging system is the most widely used staging system in the United States. The latest AJCC manual was updated in 2010 to include a 3-tiered grading system where the tumor is classified according to tumor size, lymph node involvement, metastases, and grade at time of diagnosis (Table 2 and Table 3). Additionally, tumor depth in relation to deep fascia is also taken into account, with superficial tumors being assigned a designation of “a” and deep tumors a designation of “b.”

Previously, 2 of the most widely used grading systems were the National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems, both 3-tier grading systems. The main components that determine the NCI grade are the tumor’s histologic type and location and the amount of tumor necrosis. The FNCLCC system evaluation focuses on tumor differentiation, mitotic rate, and amount of tumor necrosis. A study that compared the NCI and FNCLCC grading systems found that FNCLCC was a better predictor of mortality and distant metastasis.¹⁶ Previously, the AJCC was a 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading system. Additionally, the AJCC system has reclassified single lymph node disease as stage III as it confers better survival than metastatic disease.¹⁷ It is important that pathology be evaluated by a sarcoma specialist as disagreements with regard to histologic subtype and grade are common.^18,19

• What are the most important prognostic factors?

Prognostic factors include grade, size, and presence of metastases at presentation. Best survival is associated with low-grade, small tumors with no metastases at time of diagnosis.¹⁴

Imaging should be undertaken to help differentiate between benign and malignant lesions. Ideally, it should be undertaken before a biopsy is planned as the imaging can be used to plan biopsy as well as provide invaluable prognostic information. There are several imaging modalities that should be considered during the preliminary work-up and staging of STSs. Conventional imaging includes magnetic resonance imaging (MRI) of the original tumor site; computed tomography (CT) to evaluate for pulmonary metastases and, depending on location, liver metastases; and in the case of small, low-grade tumors, chest radiography. MRI is considered the test of choice for soft tissue masses and can help delineate benign masses such as hematomas, lipomas, and hemangiomas from sarcomas.²⁰ It is difficult to compare the accuracy of positron emission tomography (PET)/CT to CT and MRI because most studies have evaluated PET/CT in parallel with CT and MRI.²¹ Tateishi et al compared the accuracy of conventional imaging, PET/CT, and PET/CT combined with conventional imaging at determining the TNM staging for 117 patients. They found that conventional imaging correctly classified 77% of patients, PET alone correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined with conventional imaging correctly staged 87%.²²

• Which subtypes are most likely to metastasize?

Although the vast majority of sarcomas spread hematogenously, 3 have a propensity to spread lymphogenously: epithelioid sarcoma, rhabdomyosarcoma, and clear-cell sarcoma. Additionally, certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarcomas, and epithelioid sarcomas.²³ Sarcomas metastasize to the lungs more frequently than to the liver. The metastatic pattern is defined primarily by sarcoma subtype and site of primary tumor. Sarcomas rarely metastasize to the brain (~1%).

MANAGEMENT

CASE CONTINUED

The patient undergoes an ultrasound to better visualize the mass. Given the heterogeneous character of the mass, he is referred for an MRI to evaluate the mass and a CT scan of the chest, abdomen, and pelvis to evaluate for distant metastases. MRI reveals a 5.1 cm × 4.6 cm heterogeneous mass invading the superficial fascia of the rectus femoris muscle. No suspicious lymph nodes or other masses are identified on imaging. The patient next undergoes an image-guided core needle biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, grade 3, dedifferentiated liposarcoma.

• What is the best management approach for this patient?

SURGERY

Surgery is the mainstay of treatment for STS. Patients with the best prognosis are those who undergo complete resection with negative surgical margins.^24,25 Goal tumor-free margin is 1 to 3 cm.²⁶ Complete resection confers the best long-term survival. Both local and metastatic recurrence is higher in patients with incomplete resection and positive margins.^24,25 In a study that analyzed 2084 localized primary STSs, patients with negative margins had a local recurrence rate of 15% versus a rate of 28% in patients with positive margins. This translated into higher 5-year local recurrence-free survival for patients with negative surgical margins (82%) compared to patients with positive margins (65%).²⁷ Another study similarly found that patients with negative margins at referral to their institution who underwent postoperative radiation had high local control rates of 93% (95% confidence interval [CI] 87% to 97%) at 5, 10, and 15 years.²⁶ Although radiation improves local control, neither preoperative or postoperative radiation has been shown to improve progression-free or overall survival.²⁸ Other factors that are associated with risk of recurrence are tumor location, history of previous recurrence, age of patient, histopathology, tumor grade, and tumor size. Approximately 40% to 50% of patients with high-grade tumors (defined as size > 5 cm, deep location, and high grade) will develop distant metastases.²⁹

Zagars et al found that positive or uncertain resection margin had a relative risk of local recurrence of 2.0 (95% CI 1.3 to 3.1; P = 0.002), and presentation with locally recurrent disease (vs new tumor) had a relative risk of local recurrence of 2.0 (95% CI 1.2 to 3.4; P = 0.013).²⁶ Patients with STS of head and neck and deep trunk have higher recurrence rates than those with superficial trunk and extremity STS. A single-institution retrospective review demonstrated that patients with completely resectable retroperitoneal sarcomas have longer median survival (103 months) compared to patients with incompletely resected abdominal sarcomas (18 months).²⁵

CASE CONTINUED

The patient is referred for limb-sparing surgery after presentation at a multidisciplinary tumor board. Prior to undergoing resection of the tumor, he is also referred to radiation-oncology to discuss the risks and benefits of combination radiotherapy and surgery as opposed to surgical resection alone.

• What is the evidence for radiation therapy?

RADIATION THERAPY

Radiation therapy is used in the preoperative, intraoperative, and postoperative settings to reduce the risk of local recurrence. There are several options for radiation, including external beam radiation therapy (EBRT), intraoperative radiation, and brachytherapy. A newer strategy, intensity-modulated radiation therapy (IMRT), utilizes 3-dimensional modeling to reduce radiation dosages. Overall there are no differences in overall survival or local recurrence rates between preoperative and postoperative radiation in STS.²⁸

The rationale behind preoperative radiation is that it reduces seeding of tumor cells, especially at the time of surgery.³⁰ Additionally, for EBRT, preoperative radiation has smaller field sizes and lower radiation doses. It can also help to reduce the size of the tumor prior to resection. Intraoperative radiation is often paired with preoperative radiation as a boost dose given only to the area of residual tumor.

Suit et al reviewed patients treated at a single institution with limb-sparing surgery and different radiation strategies. Local control rates between preoperative and postoperative radiation groups were not statistically significant. Local recurrence was linked to grade and size of the tumor in both groups. The authors did note, however, that the preoperative radiation group tended to have larger tumor sizes at baseline compared to the patients who received postoperative radiation.³⁰ A study that compared 190 patients who received preoperative and postoperative EBRT or brachytherapy (primary end point was wound complications, and local control was a secondary end point) showed a trend towards greater local control with preoperative radiation; however, the preoperative radiation group had significantly more wound complications compared to the postoperative radiation group.³¹

Yang et al found that postoperative EBRT decreases rates of local recurrence compared to surgery alone in high-grade extremity sarcomas.³² However, there were no differences in rates of distant metastases and overall survival between the 2 treatment groups. Similarly, in patients with low-grade sarcoma, there were fewer local recurrences in those who received EBRT and surgery as compared to surgery alone.³² Another study that evaluated 164 patients who received either adjuvant brachytherapy or no further therapy after complete resection found that brachytherapy reduced local recurrence in high-grade sarcomas. No difference in local recurrence rates was found in patients with low-grade sarcomas, nor was a significant difference found in the rates of distant metastases and overall survival between the 2 treatment groups.³³ With regards to IMRT, a single institution cohort experience with 41 patients who received IMRT following limb-sparing surgery had similar local control rates when compared to historical controls.³⁴

CASE CONTINUED

After discussion of the risks and benefits of radiation therapy, the patient opts for preoperative radiation prior to resection of his liposarcoma. He receives 50 Gy of EBRT prior to undergoing resection. Resection results in R1 margin consistent with microscopic disease. He receives 16 Gy of EBRT as a boost after recovery from his resection.²

• What is the evidence for neoadjuvant and adjuvant chemotherapy for stage I tumors?

CHEMOTHERAPY

Localized Sarcoma

For localized sarcoma, limb-sparing resection with or without radiation forms the backbone of treatment. Studies have evaluated chemotherapy in both the neoadjuvant and adjuvant settings, with the vast majority of studies evaluating doxorubicin-based chemotherapy regimens in the adjuvant settings. Due to the rare nature of sarcomas, most studies are not sufficiently powered to detect significant benefit from chemotherapy. Several trials evaluating chemotherapy regimens in the neoadjuvant and adjuvant settings needed to be terminated prematurely due to inadequate enrollment into the study. ^35,36

For stage IA (T1a-Tb, N0, M0, low grade) tumors, no additional therapy is recommended after limb-sparing surgery with appropriate surgical margins. For stage IB (T2a-2b, N0, M0, low grade) tumors with insufficient margins, re-resection and radiation therapy should be considered, while for stage IIA (T1a-1b, N0, M0, G2-3) tumors preoperative or postoperative radiation therapy is recommended.² Studies have not found benefit of adjuvant chemotherapy in these low-grade, stage I tumors in terms of progression-free survival and overall survival.³⁷

• At what stage should chemotherapy be considered?

For stage IIb and stage III tumors, surgery and radiation therapy again form the backbone of therapy; however, neoadjuvant and adjuvant chemotherapy are also recommended as considerations. Anthracycline-based chemotherapy with either single-agent doxorubicin or doxorubicin and ifosfamide in combination are considered first-line chemotherapy agents in locally advanced STS.^2,29,37

Evidence regarding the efficacy of both neoadjuvant and adjuvant chemotherapy regimens in the setting of locally advanced high-grade STS has been mixed. The Sarcoma Meta-analysis Collaboration evaluated 14 trials of doxorubicin-based adjuvant chemotherapy and found a trend towards overall survival in the treatment groups that received chemotherapy.³⁷ All trials included in the meta-analysis compared patients with localized resectable soft-tissue sarcomas who were randomized to either adjuvant chemotherapy or no adjuvant chemotherapy after limb-sparing surgery with or without radiation therapy. None of the individual trials showed a significant benefit, and all trials had large confidence intervals; however, the meta-analysis showed significant benefit in the chemotherapy treatment groups with regard to local recurrence, distant recurrence, and progression-free survival. No significant difference in overall survival was found.³⁷ Pervais et al updated the Sarcoma Meta-analysis Collaboration’s 1997 meta-analysis with the inclusion of 4 new trials that evaluated doxorubicin combined with ifosfamide and found that both patients who received doxorubicin-based regimens or doxorubicin with ifosfamide had significant decreases in distant and overall recurrences. Only the trials that utilized doxorubicin and ifosfamide had an improved overall survival that was statistically significant (hazard ratio 0.56 [95% CI 0.36 to 0.85]; P = 0.01).²⁹ Although no significant heterogeneity was found among the trials included in either meta-analysis, a variety of sarcomas were included in each clinical trial evaluated. Given the extremely small number of each sarcoma subtype present in each trial, subgroup analysis is difficult and prone to inaccuracies. As a result, it is not known if certain histological subtypes are more or less responsive to chemotherapy.^37–39

One randomized controlled trial evaluated neoadjuvant chemotherapy in high-risk sarcomas defined as tumors greater than 8 cm or grade II/III tumors. This study evaluated doxorubicin and ifosfamide and found no significant difference in disease-free and overall survival in the neoadjuvant therapy group compared to the control group.³⁵ There remains controversy in the literature with regards to adjuvant chemotherapy. Many oncologists offer adjuvant chemotherapy to patients with certain stage III subtypes. Examples of subtypes that may be offered adjuvant therapy include myxoid liposarcomas, synovial sarcomas, and leiomyosarcomas.² With regards to how many cycles of chemotherapy should be considered, a noninferiority study compared 3 cycles of epirubicin and ifosfamide to 5 cycles of epirubicin and ifosfamide in patients with high-risk locally advanced adult STSs. Three cycles of preoperative epirubicin and ifosfamide was found to be noninferior to 5 cycles with regards to overall survival.³⁸

• What is this patient’s risk for recurrence?

The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.³⁹ The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.⁴⁰ For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.⁴¹ Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5 (95% CI 1.0 to 2.0).³⁹

• What are the recommendations for surveillance?

Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.² For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.²

CASE CONTINUED

The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dyspnea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.

• Should this patient undergo metastectomy?

An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.⁴² For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.²

CASE CONTINUED

Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.

• What are treatment options for unresectable or metastatic disease?

Metastatic Disease

Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.⁴³ In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.⁴⁴ In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.⁴⁵ Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.⁴³ Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.

The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.⁴⁶ Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.⁴⁶

• What are second-line treatment options?

Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.⁴⁷ However, Omura et al

Several additional regimens have undergone evaluation in metastatic and recurrent STSs. Gemcitabine has been used both as a single agent and as part of combination therapy in many studies. Studies with gemcitabine in combination with either docetaxel or DTIC have been the most efficacious. In a phase 2 trial, patients with metastatic STS were randomly assigned to either gemcitabine alone or gemcitabine and docetaxel. Combination therapy had a higher response rate (16% versus 8%) and longer overall survival (17.9 months versus 11.5 months) than gemcitabine alone.⁵⁰ Furthermore, a phase 2 trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma showed an overall response rate of 56%, with 3 complete and 15 partial responses among the 34 patients enrolled in the study.⁵¹

A phase 2 trial randomly assigned patients with unresectable or metastatic STS to either DTIC or combination gemcitabine and DTIC.⁵² Gemcitabine-DTIC had a superior progression-free survival at 3 months (56% [95% CI 43% to 69%]) as compared to DTIC alone (37% [95% CI 23.5% to 50%]). Furthermore, mean progression-free survival and overall survival were improved in the gemcitabine-DTIC group (4.2 months and 16.8 months) as compared to the DTIC group (2.0 months and 8.2 months).⁵² DTIC has a single-agent response rate of 16%, but has been shown to be particularly effective in the setting of leiomyosarcomas.⁴⁹

• Does response to treatment regimens differ by histologic subtype?

The majority of STS trials include many different histologic subtypes. Given the rarity of sarcomas as a whole, many trials have had difficulty recruiting adequate numbers of patients to have sufficient power to definitely determine if the treatment under investigation has clinical benefit. Furthermore, the patients recruited have been heterogeneous with regard to subtype. Many older studies hypothesized that the efficacy of chemotherapeutic agents vary based on histologic subtype; however, for most subtypes the number of individuals included in those trials was too low to evaluate efficacy based on subtype.

Some exceptions exist, however. For example, both gemcitabine-DTIC and gemcitabine-docetaxel have been found to be particularly effective in the treatment of leiomyosarcomas.^50,52 Additionally, a retrospective study found a 51% overall response rate for patients with myxoid liposarcomas treated with trabectedin.⁵³ Studies of patients with angiosarcoma treated with paclitaxel have demonstrated response rates of 43% and 53%.^54,55

• What are the newest approved and investigational agents?

A recently approved agent is trabectedin, a tris tetrahydroisoquinoline alkaloid isolated from ascidians that binds to the minor groove of DNA and causes disruptions in the cell cycle. Samuels et al reported data from a single-arm, open-label expanded access trial that evaluated patients with advanced metastatic sarcomas.⁵⁶ In this study, patients with liposarcomas and leiomyosarcomas had an objective response rate of 6.9% (95% CI 4.8 to 9.6) as compared to a rate of 5.9% (95% CI 4.4 to 7.8) for all assessable patients. Median survival was 11.9 months for all patients, with improved median survivals for liposarcoma and leiomyosarcomas of 16.2 months (95% CI 14.1 to 19.5) compared to 8.4 months (95% CI 7.1 to 10.7 months) for other subtypes.⁵⁶

Schöffski et al evaluated eribulin, a chemotherapeutic agent that affects microtubule dynamics, in a phase 2 trial of patients with progressive or high-grade STS with progression on previous chemotherapy. They found a median progression-free survival of 2.6 months (95% CI 1.7 to 6.2) for adipocytic sarcoma, 2.9 months (95% CI 2.4 to 4.6) for leiomyosarcoma, 2.6 months (95% CI 2.3 to 4.3) for synovial sarcoma, and 2.1 months (95% CI 1.4 to 2.9) for other sarcomas.⁵⁷

Van der Graaf and colleagues randomly assigned patients with metastatic nonadipocytic STS to pazopanib or placebo in a phase 3 trial. Pazopanib is a small-molecule endothelial growth factor inhibitor with activity against vascular endothelial growth factors 1, 2, and 3 as well as platelet-derived growth factors. Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) with pazopanib compared to 1.6 months (95% CI 0.9 to 1.8) with placebo.⁵⁸ Adipocytic sarcomas (liposarcomas) were excluded from the trial because phase 2 trials had found a lower rate of progression-free survival (26%) for them compared to other subtypes.

Toxicities were seen with each of the regimens studied and were common in the randomized trials, with higher rates of toxicities in the combination chemotherapy regimens. The most common toxicities are myelosuppression, nausea, and vomiting. In the doxorubicin trials, the most common toxicities were myelosuppression, nausea, and vomiting.⁴⁴

Ifosfamide both as an individual agent and in combination with doxorubicin has higher rates and higher grades of toxicity than doxorubicin alone. Myelosuppression is the most common toxicity associated with ifosfamide, and the most commonly affected cell line is leukocytes.⁴⁴ Combination doxorubicin and ifosfamide also had high rates of nausea and vomiting (95%) and alopecia (100%).³⁵

Neutropenia is the most common toxicity associated with gemcitabine and dacarbazine, while their most common nonhematologic toxicities are fatigue and nausea.^52,59 Trabectedin’s most common toxicities are nausea (29%), neutropenia (24%), and fatigue (23%). It has also been shown to cause increased alkaline phosphatase (20%) and alanine aminotransferase (19%) levels.⁵⁶ In a phase 2 study of eribulin, 50% of patients had neutropenia, and other toxicities included fatigue, alopecia, nausea, sensory neuropathy, and thrombocytopenia.⁵⁷ Pazopanib is generally well tolerated; the most common toxicities are fatigue (65%), diarrhea (58%), nausea (54%), and hypertension (41%).⁵⁸ Higher rates of neutropenia, mucositis, nausea, vomiting, diarrhea, and transfusion reactions were seen with olaratumab and doxorubicin compared to doxorubicin alone in phase 1b and 2 studies.⁴⁶

CASE CONCLUSION

Given his poor prognosis with unresectable metastatic undifferentiated liposarcoma, the patient considers a clinical trial prior to undergoing combined therapy with doxorubicin and ifosfamide. He tolerates therapy well with stable disease at 6 months.

CONCLUSION

STSs are a heterogeneous collection of rare tumors. Low-grade, localized tumors have the best prognosis, and patients who undergo complete resection have the best long-term survival. Due to the rarity of STSs, trials often have limited enrollment, and little progress has been made with regards to treatment and survival rates for metastatic and unresectable disease. All patients should be evaluated and treated at specialized sarcoma centers. This case highlights the need for continued research and clinical trials to improve overall survival of patients with sarcoma.

Oral pomalidomide, a derivative of thalidomide with immunomodulatory, antiangiogenic, and antiproliferative properties, proved to be well tolerated and effective against Kaposi’s sarcoma (KS) in a small phase I/II study, investigators reported in the Journal of Clinical Oncology.

There is a substantial need for oral therapies for KS, which often recurs and requires treatment, at least intermittently, for years. Existing treatments are cytotoxic agents, such as anthracyclines that are poorly tolerated and unsuitable for long-term use, said Mark N. Polizzotto, MD, of the National Cancer Institute, Bethesda, Md., and his associates.

They examined the tolerability and efficacy of pomalidomide against KS in a single-center, open-label trial involving 21 men and 1 transgender woman who had at least five evaluable cutaneous lesions. Fifteen of these participants had HIV infection. All of the patients were heavily pretreated with antiretrovirals and other agents, including thalidomide or lenalidomide, and most (17) had advanced KS with tumor-associated edema. The study participants received 5-mg oral pomalidomide once daily for 21 days in 28-day cycles for up to 12 cycles.

Sixteen patients showed an objective tumor response (overall response rate, 73%), including four who achieved a complete response (ORR, 18%). All 7 of the participants who didn’t have HIV showed an objective tumor response (ORR, 100%), as did 9 of the 15 HIV-infected participants (ORR, 60%). Three more participants, including one who was nonadeherent and lost to follow-up, achieved a partial tumor response.

Tumor responses included a decrease in the number of lesions and a decrease in the number of nodular lesions, as well as complete flattening of lesions, resolution of edema, and improvement in appearance. “The latter is particularly important because visible KS is a major source of stigma,” Dr. Polizzotto and his associates said (J Clin Oncol. 2016 Oct 3;34[34]:4125-32).

Two patients reported substantial subjective improvement in foot pain and appearance; one said he was pleased to be able to resume wearing closed shoes, the investigators noted. Treatment response generally was rapid, often commencing before the first follow-up at 4 weeks.

Pomalidomide was generally well tolerated. Adverse effects were frequent but mild and self-limiting, and they included neutropenia, constipation, anemia, fatigue, and rash. No patients required hospitalization, and there were no thromboembolic events. Three study participants developed malignancies after treatment: an Epstein-Barr-virus–associated Hodgkin lymphoma 1 year after the trial, a primary effusion lymphoma 15 months after, and a squamous-cell skin carcinoma. These probably reflect the patients’ underlying immunodeficiency, but the possibility that pomalidomide could contribute to malignancies in this high-risk population should be carefully explored in future studies, the investigators said.

“In resource-rich regions, pomalidomide may be of particular use in HIV-uninfected patients, in patients who have received substantial cumulative doses of anthracyclines, and in patients with less extensive but symptomatic disease for whom avoidance of cytotoxic chemotherapy would be beneficial. In resource-limited regions, there is an urgent need for effective and tolerable oral agents; with appropriate safeguards and monitoring, pomalidomide could address this,” Dr. Polizzotto and his associates wrote.

“Confirmatory studies of pomalidomide, alone and in combination with cytotoxic chemotherapy, are planned, including in sub-Saharan Africa,” they added.

[email protected]

Oral pomalidomide, a derivative of thalidomide with immunomodulatory, antiangiogenic, and antiproliferative properties, proved to be well tolerated and effective against Kaposi’s sarcoma (KS) in a small phase I/II study, investigators reported in the Journal of Clinical Oncology.

There is a substantial need for oral therapies for KS, which often recurs and requires treatment, at least intermittently, for years. Existing treatments are cytotoxic agents, such as anthracyclines that are poorly tolerated and unsuitable for long-term use, said Mark N. Polizzotto, MD, of the National Cancer Institute, Bethesda, Md., and his associates.

They examined the tolerability and efficacy of pomalidomide against KS in a single-center, open-label trial involving 21 men and 1 transgender woman who had at least five evaluable cutaneous lesions. Fifteen of these participants had HIV infection. All of the patients were heavily pretreated with antiretrovirals and other agents, including thalidomide or lenalidomide, and most (17) had advanced KS with tumor-associated edema. The study participants received 5-mg oral pomalidomide once daily for 21 days in 28-day cycles for up to 12 cycles.

Sixteen patients showed an objective tumor response (overall response rate, 73%), including four who achieved a complete response (ORR, 18%). All 7 of the participants who didn’t have HIV showed an objective tumor response (ORR, 100%), as did 9 of the 15 HIV-infected participants (ORR, 60%). Three more participants, including one who was nonadeherent and lost to follow-up, achieved a partial tumor response.

Tumor responses included a decrease in the number of lesions and a decrease in the number of nodular lesions, as well as complete flattening of lesions, resolution of edema, and improvement in appearance. “The latter is particularly important because visible KS is a major source of stigma,” Dr. Polizzotto and his associates said (J Clin Oncol. 2016 Oct 3;34[34]:4125-32).

Two patients reported substantial subjective improvement in foot pain and appearance; one said he was pleased to be able to resume wearing closed shoes, the investigators noted. Treatment response generally was rapid, often commencing before the first follow-up at 4 weeks.

Pomalidomide was generally well tolerated. Adverse effects were frequent but mild and self-limiting, and they included neutropenia, constipation, anemia, fatigue, and rash. No patients required hospitalization, and there were no thromboembolic events. Three study participants developed malignancies after treatment: an Epstein-Barr-virus–associated Hodgkin lymphoma 1 year after the trial, a primary effusion lymphoma 15 months after, and a squamous-cell skin carcinoma. These probably reflect the patients’ underlying immunodeficiency, but the possibility that pomalidomide could contribute to malignancies in this high-risk population should be carefully explored in future studies, the investigators said.

“In resource-rich regions, pomalidomide may be of particular use in HIV-uninfected patients, in patients who have received substantial cumulative doses of anthracyclines, and in patients with less extensive but symptomatic disease for whom avoidance of cytotoxic chemotherapy would be beneficial. In resource-limited regions, there is an urgent need for effective and tolerable oral agents; with appropriate safeguards and monitoring, pomalidomide could address this,” Dr. Polizzotto and his associates wrote.

“Confirmatory studies of pomalidomide, alone and in combination with cytotoxic chemotherapy, are planned, including in sub-Saharan Africa,” they added.

[email protected]

Oral pomalidomide, a derivative of thalidomide with immunomodulatory, antiangiogenic, and antiproliferative properties, proved to be well tolerated and effective against Kaposi’s sarcoma (KS) in a small phase I/II study, investigators reported in the Journal of Clinical Oncology.

There is a substantial need for oral therapies for KS, which often recurs and requires treatment, at least intermittently, for years. Existing treatments are cytotoxic agents, such as anthracyclines that are poorly tolerated and unsuitable for long-term use, said Mark N. Polizzotto, MD, of the National Cancer Institute, Bethesda, Md., and his associates.

They examined the tolerability and efficacy of pomalidomide against KS in a single-center, open-label trial involving 21 men and 1 transgender woman who had at least five evaluable cutaneous lesions. Fifteen of these participants had HIV infection. All of the patients were heavily pretreated with antiretrovirals and other agents, including thalidomide or lenalidomide, and most (17) had advanced KS with tumor-associated edema. The study participants received 5-mg oral pomalidomide once daily for 21 days in 28-day cycles for up to 12 cycles.

Sixteen patients showed an objective tumor response (overall response rate, 73%), including four who achieved a complete response (ORR, 18%). All 7 of the participants who didn’t have HIV showed an objective tumor response (ORR, 100%), as did 9 of the 15 HIV-infected participants (ORR, 60%). Three more participants, including one who was nonadeherent and lost to follow-up, achieved a partial tumor response.

Tumor responses included a decrease in the number of lesions and a decrease in the number of nodular lesions, as well as complete flattening of lesions, resolution of edema, and improvement in appearance. “The latter is particularly important because visible KS is a major source of stigma,” Dr. Polizzotto and his associates said (J Clin Oncol. 2016 Oct 3;34[34]:4125-32).

Two patients reported substantial subjective improvement in foot pain and appearance; one said he was pleased to be able to resume wearing closed shoes, the investigators noted. Treatment response generally was rapid, often commencing before the first follow-up at 4 weeks.

Pomalidomide was generally well tolerated. Adverse effects were frequent but mild and self-limiting, and they included neutropenia, constipation, anemia, fatigue, and rash. No patients required hospitalization, and there were no thromboembolic events. Three study participants developed malignancies after treatment: an Epstein-Barr-virus–associated Hodgkin lymphoma 1 year after the trial, a primary effusion lymphoma 15 months after, and a squamous-cell skin carcinoma. These probably reflect the patients’ underlying immunodeficiency, but the possibility that pomalidomide could contribute to malignancies in this high-risk population should be carefully explored in future studies, the investigators said.

“In resource-rich regions, pomalidomide may be of particular use in HIV-uninfected patients, in patients who have received substantial cumulative doses of anthracyclines, and in patients with less extensive but symptomatic disease for whom avoidance of cytotoxic chemotherapy would be beneficial. In resource-limited regions, there is an urgent need for effective and tolerable oral agents; with appropriate safeguards and monitoring, pomalidomide could address this,” Dr. Polizzotto and his associates wrote.

“Confirmatory studies of pomalidomide, alone and in combination with cytotoxic chemotherapy, are planned, including in sub-Saharan Africa,” they added.

[email protected]

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.

Adding low-dose metronomic chemotherapy (oral cyclophosphamide and methotrexate) to standard methotrexate, adriamycin, and platinum (MAP) maintenance treatment did not extend event-free survival in adolescents and young adults with high-grade, resectable osteosarcoma of the extremities, according to investigators.

“In pediatric tumors such as localized osteosarcomas, in situ tumor angiogenesis and levels of circulating angiogenic factors correlate with metastatic disease and a poor prognosis,” noted Andreza A. Senerchia, MD, of the Institute of Pediatric Oncology/Support Group for Adolescents and Children With Cancer, Federal University of Sao Paulo (Brazil), and her associates.

Since metronomic chemotherapy can prevent tumor angiogenesis and is a readily available, low-cost treatment with low toxicity, it could serve as a useful add-on to established MAP maintenance therapy in this patient population, they speculated.

The investigators assessed this approach in a prospective clinical trial involving 296 patients aged younger than 30 (mean age, 14 years; range, 0-29 years) who were treated at 27 medical centers in Brazil, Argentina, and Uruguay. All the study participants had high-grade but nonmetastatic operable osteosarcomas of the extremities, and all underwent preoperative chemotherapy followed by surgical resection, with limb salvage whenever possible.

A total of 139 patients were then randomly assigned to receive MAP plus metronomic chemotherapy (intervention group) and 157 to receive MAP alone (control group). However, 35% of the intervention group never started metronomic chemotherapy for a variety of reasons, and another 10% stopped the treatment very early.

At 5 years, cumulative event-free survival was 61% with MAP plus metronomic chemotherapy and 64% with MAP alone, a nonsignificant difference. When the analysis was restricted to only the patients in the intervention group who actually received metronomic chemotherapy, there still was no evidence that the add-on treatment made any difference in event-free survival. Similarly, mean overall survival was not significantly different between the two study groups, at 76% and 73%, respectively, Dr. Senerchia and her associates wrote (Cancer 2016 Nov 7. doi: 10.1002/cncr.30411).

There were 27 deaths (19%) in the intervention group, 81% of which were due to disease progression and 11% of which were due to treatment-related toxicity. Similarly, there were 24 deaths (15%) in the control group, of which 83% were due to disease progression and 17% to treatment-related toxicity.

These findings “do not support the routine use of cyclophosphamide and methotrexate as metronomic agents after standard chemotherapy for nonmetastatic osteosarcoma. However, our results should not preclude further investigation into the potential of maintenance for patients with osteosarcoma ... The combination tested here may not be optimal. In addition, adding a targeted-like effect through drug repositioning could allow more potent treatment with the addition of, for instance, valproic acid or beta-blockers,” the investigators said.