Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract and arise from the interstitial cells of Cajal of the myenteric plexus. These tumors are rare, with about 1 case per 100,000 persons diagnosed in the United States annually, but may be incidentally discovered in up to 1 in 5 autopsy specimens of older adults.^1,2 Epidemiologic risk factors include increasing age, with a peak incidence between age 60 and 65 years, male gender, black race, and non-Hispanic white ethnicity. Germline predisposition can also increase the risk of developing GISTs; molecular drivers of GIST include gain-of-function mutations in the KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) gene, which both encode structurally similar tyrosine kinase receptors; germline mutations of succinate dehydrogenase (SDH) subunit genes; and mutations associated with neurofibromatosis type 1.

GISTs most commonly involve the stomach, followed by the small intestine, but can arise anywhere within the GI tract (esophagus, colon, rectum, and anus). They can also develop outside the GI tract, arising from the mesentery, omentum, and retroperitoneum. The majority of cases are localized or locoregional, whereas about 20% are metastatic at presentation.¹ GISTs can occur in children, adolescents, and young adults. Pediatric GISTs represent a distinct subset marked by female predominance and gastric origin, are often multifocal, can sometimes have lymph node involvement, and typically lack mutations in the KIT and PDGFRA genes.

This review is the first of 2 articles focusing on the diagnosis and management of GISTs. Here, we review the evaluation and diagnosis of GISTs along with management of localized disease. Management of advanced disease is reviewed in a separate article.

Case Presentation

A 64-year-old African American man with progressive iron deficiency and abdominal discomfort undergoes upper and lower endoscopy and is found to have a bulging mass within his abdominal cavity. He undergoes a computed tomography (CT) evaluation of the chest, abdomen, and pelvis with contrast, which reveals the presence of a 10-cm gastric mass, with no other lesions identified. He undergoes surgical resection of the mass and presents for review of his pathology and to discuss his treatment plan.

What histopathologic features are consistent with GIST?

What factors are used for risk stratification and to predict likelihood of recurrence?

Clinical Presentation and Diagnosis

Most patients present with symptoms of overt or occult GI bleeding or abdominal discomfort, but a significant proportion of GISTs are discovered incidentally. Lymph node involvement is not typical, except for GISTs occurring in children and/or with rare syndromes. Most syndromic GISTs are multifocal and multicentric. After surgical resection, GISTs usually recur or metastasize within the abdominal cavity, including the omentum, peritoneum, or liver. These tumors rarely spread to the lungs, brain, or bones; when tumor spread does occur, it tends to be in heavily pre-treated patients with advanced disease who have been on multiple lines of therapy for a long duration of time.

The diagnosis usually can be made by histopathology. Specimens can be obtained by endoscopic ultrasound (EUS)– or CT-guided methods, the latter of which carries a very small risk of contamination from percutaneous biopsy. In terms of morphology, GISTs can be spindle cell, epithelioid, or mixed neoplasms. Epithelioid tumors are more commonly seen in the stomach and are often PDGFRA-mutated or SDH-deficient. The differential diagnosis includes other soft-tissue GI wall tumors such as leiomyosarcomas/leiomyomas, germ cell tumors, lymphomas, fibromatosis, and neuroendocrine and neurogenic tumors. A unique feature of GISTs that differentiates them from leiomyomas is near universal expression of CD117 by immunohistochemistry (IHC); this characteristic has allowed pathologists and providers to accurately distinguish true GISTs from other GI mesenchymal tumors.³ Recently, DOG1 (discovered on GIST1) immunoreactivity has been found to be helpful in identifying patients with CD117-negative GISTs. Initially identified through gene expression analysis of GISTs, DOG1 IHC can identify the common mutant c-Kit-driven CD117-positive GISTs as well as the rare CD117-negative GISTs, which are often driven by mutated PDGFRA.⁴ Importantly, IHC for KIT and DOG1 are not surrogates for mutational status, nor are they predictive of tyrosine kinase inhibitor (TKI) sensitivity. If IHC of a tumor specimen is CD117- and DOG1-negative, the specimen can be sent for KIT and PDGFRA mutational analysis to confirm the diagnosis. If analysis reveals that these genes are wild-type, then IHC staining for SDH B (SDHB) should follow to assess for an SDH-deficient GIST (negative staining).

Risk Stratification for Recurrence

The clinical behavior of GISTs can be variable. Some are indolent, while others behave more aggressively, with a greater malignant potential and a higher propensity to recur and metastasize. Clinical and pathologic features can provide important prognostic information that allows providers to risk-stratify patients. Various institutions have assessed prognostic variables for GISTs. In 2001, the National Institutes of Health (NIH) held a GIST workshop that proposed an approach to estimating metastatic risk based on tumor size and mitotic index (NIH or Fletcher criteria).⁵ Joensuu et al later proposed a modification of the NIH risk classification to include tumor location and tumor rupture (modified NIH criteria or Joensuu criteria).^6-8 Similarly, the Armed Forces Institute of Pathology (AFIP) identified tumor site as a prognostic factor, with gastric GISTs having the best prognosis (AFIP-Miettinen criteria).^9-11 Tabular schemes were designed which stratified patients into discrete groups with ranges for mitotic rate and tumor size. Nomograms for ease of use were then constructed utilizing a bimodal mitotic rate and included tumor site and size.¹² Finally, contour maps were developed, which have the advantage of evaluating mitotic rate and tumor size as continuous nonlinear variables and also include tumor site and rupture (associated with a high risk of peritoneal metastasis) separately, further improving risk assessment. These contour maps have been validated against pooled data from 10 series (2560 patients).¹³ High-risk features identified from these studies include tumor location, size, mitotic rate and tumor rupture and are now used for deciding on the use of adjuvant imatinib and as requirements to enter clinical trials assessing adjuvant therapy for resected GISTs.

Case Continued

The patient’s operative and pathology reports indicate that the tumor is a spindle cell neoplasm of the stomach that is positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. Resection margins are negative. There are 10 mitoses per 50 high-power fields (HPF). Per the operative report, there was no intraoperative or intraperitoneal tumor rupture. Thus, while his GIST was gastric, which generally has a more favorable prognosis, the tumor harbors high-risk features based on its size and mitotic index.

What further testing should be requested?

Molecular Alterations

It is recommended that a mutational analysis be performed as part of the diagnostic work-up of all GISTs.¹⁴ Mutational analysis can provide prognostic and predictive information for sensitivity to imatinib and should be considered standard of care. It may also be useful for confirming a GIST diagnosis, or, if negative, lead to further evaluation with an IHC stain for SDHB. The c-Kit receptor is a member of the tyrosine kinase family and, through direct interactions with stem cell factor (SCF), can upregulate the PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK-STAT pathways, resulting in transcription and translation of genes that enhance cell growth and survival.¹⁵ The cell of origin of GISTs, the interstitial cells of Cajal, are dependent on the SCF–c-Kit interaction for development.¹⁶ Likewise, the large majority of GISTs (about 70%) are driven by upregulation and constitutive activation of c-Kit, which is normally autoinhibited. About 80% of KIT mutations involve exon 11; these GISTs are most often associated with a gastric location and are associated with a favorable recurrence-free survival (RFS) rate with surgery alone.¹⁷KIT exon 9 mutations are much less common, encompassing only about 10% of GIST KIT mutations, and GISTs with these mutations are more likely to arise from the small bowel.¹⁷

About 8% of GISTs harbor gain-of-function PDGFRA driver mutations rendering constitutively active PDGFRA.¹⁸PDGFRA mutations are mutually exclusive from KIT mutations, and PDGFRA-mutated tumors most often occur in the stomach. PDGFRA mutations generally are associated with a lower mitotic rate and gastric location. Identification of the PDGFRA D842V mutation on exon 18, which is the most common, is important, as it is associated with imatinib resistance, and these patients should not be offered imatinib.¹⁹

Several other mutations associated with GISTs outside of the KIT and PDGFRA spectrum have been identified. About 10% of GISTs are wildtype for KIT and PDGFRA, and not all KIT/PDGFRA-wildtype GISTs are imatinib-sensitive and/or respond to other TKIs.¹⁸ These tumors may harbor aberrations in SDH and NF1, or less commonly, BRAF V600E, FGFR, and NTRK.^20,21 SDH subunits B, C and D play a role in the Krebs cycle and electron transport chain. Germline mutations in these SDH subunits can result in the Carney-Stratakis syndrome characterized by the dyad of multifocal GISTs and multicentric paragangliomas.²² This syndrome is most likely to manifest in the pediatric or young adult population. In contradistinction is the Carney triad, which is associated with acquired loss of function of the SDHC gene due to promoter hypermethylation. This syndrome classically occurs in young women and is characterized by an indolent-behaving triad of multicentric GISTs, non-adrenal paragangliomas, and pulmonary chondromas.²³ Like PDGFRA D842V–mutated GISTs, SDH-deficient and NF1-associated GISTs are considered imatinib resistant, and these patients should not be offered imatinib therapy.¹⁴

Case Continued

The patient’s GIST is found to harbor a KIT exon 11 single codon deletion. He appears anxious and asks to have everything done to prevent his GIST from coming back and to improve his lifespan.

Management

A multidisciplinary team approach to the management of all GISTs is essential and includes input from radiology, gastroenterology, pathology, medical and surgical oncology, nuclear medicine, and nursing.

Surgical Resection

Small esophagogastric and duodenal GISTs ≤ 2 cm can be asymptomatic and managed with serial endoscopic surveillance, typically every 6 to 12 months, with biopsies if the tumors increase in size. GISTs larger than 2 cm require surgical resection, with resection of the full pseudocapsule and an R0 resection, if possible, since larger GISTs carry a higher risk of growth and recurrence. If an R0 resection would lead to significant morbidity or functional sequelae, an R1 may suffice. Rectal GISTs are an exception, where microscopic margins have been shown to be associated with an increased risk of local failure.²⁴ It is important to explore the abdomen thoroughly for peritoneal, rectovaginal, and vesicular implants and metastasis to the liver. A formal lymph node dissection is not necessary because lymph nodes are rarely involved and should only be removed when clinically suspicious. Tumor rupture must be avoided. A laparoscopic approach should only be considered for smaller tumors, since there is a risk of tumor rupture with larger tumors.¹⁴

When is adjuvant imatinib indicated?

Adjuvant Imatinib

Among patients with local or locally advanced GISTs, the risk of death from recurrence with surgery alone can be high, with a historical 5-year overall survival (OS) of about 35%.²⁵ As a result, multiple studies have assessed the benefit of adjuvant imatinib, which is now considered standard of care for patients with imatinib-sensitive, high-risk GISTs. In addition to inhibiting BCR-ABL, imatinib mesylate inhibits multiple other receptor tyrosine kinases, including PDGFR, SCF and c-Kit. As a result, imatinib has demonstrated in vitro inhibition of cell proliferation and apoptosis and clinical activity against GISTs expressing CD117.²⁶ Importantly, adjuvant imatinib should only be offered to patients with imatinib-sensitive mutations, such as KIT exon 11 and KIT exon 9 mutations. Adjuvant imatinib should not be offered to patients with imatinib-insensitive mutations such as PDGFR 842V, NF1, or BRAF-related or SDH-deficient GISTs.

The ACOSOG Z9000 was the first study of adjuvant imatinib in patients with resected GISTs.²⁵ This was a single-arm, phase 2 study involving 106 patients with surgically resected GISTs deemed high-risk for recurrence, defined as size > 10 cm, tumor rupture, or up to 4 peritoneal implants. Patients were treated with imatinib 400 mg daily for 1 year. The primary and secondary endpoints were OS and RFS, respectively. Long-term follow-up of this study demonstrated 1-, 3-, and 5-year OS of 99%, 97%, and 83%, and 1-, 3-, and 5-year RFS of 96%, 60%, and 40%, which compared favorably with historical controls. In a multivariable analysis, increasing tumor size, small bowel location, KIT exon 9 mutation, high mitotic rate, and older age were independent risk factors for a poor RFS.²⁵ It is important to note that the benefit of adjuvant imatinib waned after discontinuation of therapy, creating a rationale to study adjuvant imatinib for longer periods of time.

As a result of the promising phase 2 data, ACOSOG opened a phase 3 randomized trial (Z9001) comparing 1 year of adjuvant imatinib to placebo among patients with surgically resected GISTs that were > 3 cm in size and that stained positive for CD117 on pathology. The trial accrued 713 patients and was stopped early at a planned interim analysis, which revealed a 1-year RFS of 98% for imatinib versus 83% for placebo (hazard ratio [HR], 0.35; P < 0.001). The 1-year OS did not differ between the 2 arms (92.2% vs 99.7%; HR, 0.66; P = 0.47).²⁷ When comparing the 2 arms, imatinib was associated with a higher RFS among patients with a KIT exon 11 deletion, but not among patients with other KIT mutation types, PDGFRA mutations, or who were KIT/PDGFRA wildtype.²⁸ Imatinib was granted approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of high-risk GISTs based on the results of the ACOSOG Z9001 trial.

The EORTC 62024 study was a randomized placebo-controlled trial assessing the benefit of 2 years of adjuvant imatinib.²⁹ Patients had to be considered intermediate or high risk per the 2002 NIH consensus classification to be eligible. The trial enrolled 918 patients. The 5-year OS rate, the original primary endpoint, did not differ between the 2 groups (100% vs 99%). The 3-year and 5-year RFS rates, secondary endpoints, were significantly longer among patients treated with imatinib (84% vs 66% and 69% vs 63%, respectively). Again, it was noted that the benefit of imatinib waned over time after treatment discontinuation.

The Scandinavian Sarcoma Group (SSG XVIII) trial was a prospective randomized phase 3 trial that compared 3 years versus 1 year of adjuvant imatinib.³⁰ Patients had to be enrolled within 12 weeks of the postoperative period and had to have GISTs that were CD117-positive and with a high estimated risk of recurrence, per the modified NIH consensus criteria (size > 10 cm, > 10 mitoses per 50 HPF, diameter > 5 cm with mitotic count > 5, or tumor rupture before or at surgery). Three years of adjuvant imatinib was associated with a 54% reduction in the hazard for recurrence at 5 years (65.6% vs 47.9%; HR, 0.46; P < 0.001) and a 55% reduction in the hazard for death at 5 years (OS 92% vs 81.7%; HR, 0.45; P = 0.02). Based on the results of this study, the FDA granted approval for the use of 3 years of adjuvant imatinib in patients with high-risk resected GISTs.

The observation that a longer duration of adjuvant imatinib was associated with superior RFS and OS led to studies to further explore longer durations of adjuvant imatinib. The PERSIST-5 (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib) was a multicenter, single-arm, phase 2 prospective study of adjuvant imatinib with a primary endpoint of RFS after 5 years.³¹ Patients had to have an intermediate or high risk of recurrence, which included GISTs at any site > 2 cm with > 5 mitoses per 50 HPF or nongastric GISTs that were ≥ 5 cm. With 91 patients enrolled, the estimated 5-year RFS was 90% and the OS was 95%. Of note, about half of the patients stopped treatment early due to a variety of reasons, including patient choice or adverse events. Importantly, there were no recurrences in patients with imatinib-sensitive mutations while on therapy. We know that in patients at high risk of relapse, adjuvant imatinib delays recurrence and improves survival, but whether any patients are cured, or their survival curves are just shifted to the right, is unknown. Only longer follow-up of existing studies, and the results of newer trials utilizing longer durations of adjuvant treatment, will help to determine the real value of adjuvant therapy for GIST patients.³² Based on this study, it would be reasonable to discuss a longer duration of imatinib with patients deemed to be at very high risk of recurrence and who are tolerating therapy well. We are awaiting the data from the randomized phase 3 Scandinavian Sarcoma Group XII trial comparing 5 years versus 3 years of adjuvant imatinib therapy, and from the French ImadGIST trial of adjuvant imatinib for 3 versus 6 years. A summary of the aforementioned key adjuvant trials is shown in the Table.

When imatinib is commenced, careful monitoring for treatment toxicities and drug interactions should ensue in order to improve compliance. Dose density should be maintained if possible, as retrospective studies suggest suboptimal plasma levels are associated with a worse outcome.³³

When should neoadjuvant imatinib be considered?

Neoadjuvant Imatinib

Neoadjuvant imatinib should be considered for patients requiring total gastrectomy, esophagectomy, or abdominoperineal resection of the rectum in order to reduce tumor size, limit subsequent surgical morbidity, mitigate tumor bleeding and rupture, and aid with organ preservation. Patients with rectal GISTs that may otherwise warrant an abdominoperineal resection should be offered a trial of imatinib in the neoadjuvant setting. There is no evidence for the use of any other TKI aside from imatinib in the neoadjuvant or adjuvant setting. With neoadjuvant imatinib, it is difficult to accurately assess the mitotic rate in the resected tumor specimen.

The RTOG 0132/ACRIN 6665 trial was a prospective phase 2 study evaluating the efficacy of imatinib 600 mg daily in the perioperative setting.³⁴ The trial enrolled 50 patients, 30 with primary GISTs (group A) and 22 with recurrent metastatic GISTs (group B). Based on data from the metastatic setting revealing a time to treatment response of about 2.5 months, patients were treated with 8 to 12 weeks of preoperative imatinib followed by 2 years of adjuvant imatinib. Imatinib was stopped 24 hours preoperatively and resumed as soon as possible postoperatively. In group A, 7% of patients achieved a partial response (PR), 83% achieved stable disease, and 2-year progression-free survival (PFS) and OS were 83% and 93%, respectively. In group B, 4.5% of patients achieved a PR, 91% achieved stable disease, and 4.5% experienced progressive disease in the preoperative period; the 2-year PFS and OS were 77% and 91%, respectively. The results of this trial demonstrated the feasibility of using perioperative imatinib with minimal effects on surgical outcomes and set the rationale to use neoadjuvant imatinib in select patients with borderline resectable or rectal GISTs. Another EORTC pooled analysis from 10 sarcoma centers revealed that after a median of 10 months of neoadjuvant imatinib, 83.2% of patients achieved an R0 resection and only 1% progressed during treatment.³⁵ After a median follow-up of 46 months, the 5-year disease-free survival and OS were 65% and 87%, respectively.

Mutational testing should be performed beforehand to ensure the tumor is imatinib-sensitive. If a KIT exon 9 mutation is identified, then 400 mg twice daily should be considered (given the benefit seen with 800 mg imatinib for advanced GIST patients), although there are no studies to confirm this practice. Neoadjuvant imatinib is recommended for a total of 6 to 12 months to ensure maximal tumor debulking, but with very close monitoring and surgical input for disease resistance and growth.¹⁴ Imatinib should be stopped 1 to 2 days preoperatively and resumed once the patient has recovered from surgery for a total of 3 years (pre-/postoperatively combined). Neoadjuvant therapy has been shown to be safe and effective, but there have been no randomized trials to assess survival.

What is appropriate surveillance for resected GISTs?

Surveillance

There have been no randomized studies to guide the management of surveillance after surgical resection and adjuvant therapy. There is no known optimal follow-up schedule, but several have been proposed.^13,36 Among high-risk patients, it is suggested to image every 3 to 6 months during adjuvant therapy, followed by every 3 months for 2 years after discontinuing therapy, then every 6 months for another 3 years and annually thereafter for an additional 5 years. High-risk patients usually relapse within 1 to 3 years after finishing adjuvant therapy, while low-risk patients can relapse later given that their disease can be slower growing. It has been recommended that low-risk patients undergo imaging every 6 months for 5 years, with follow-up individualized thereafter. Very-low-risk patients may not require more than annual imaging. Because most relapses occur within the peritoneum or liver, imaging should encompass the abdomen and pelvis. Surveillance imaging usually consists of CT scans of the abdomen and pelvis. MRI scans can be utilized for patients at lower risk or who are out several years in order to avoid excess radiation exposure. MRI is also specifically helpful for rectal and esophageal lesions. Chest CT or chest radiograph and bone scan are not routinely required for follow-up.

Case Conclusion

The patient receives adjuvant imatinib and experiences grade 2 myalgias, periorbital edema, and macrocytic anemia, which result in imatinib discontinuation after 3 years of treatment. He is seen every 3 to 6 months and a contrast CT abdomen and pelvis is obtained every 6 months for 5 years. During this 5-year follow-up period, he does not have any clinical or radiographic evidence of disease recurrence.

Further follow-up of this patient is presented in the second article in this 2-part review of management of GISTs.

Key Points

• GISTs are the most common mesenchymal neoplasms of the GI tract and can occasionally occur in extragastrointestinal locations as well.
• GISTs encompass a heterogeneous family of tumor subsets with different natural histories, mutations, and TKI responsiveness.
• Surgery is the mainstay of treatment for localized GISTs, with cure rates greater than 50%.
• For very small (< 2 cm) esophagogastric GISTs, endoscopic ultrasound evaluation and follow-up is recommended.
• For tumors ≥ 2 cm, biopsy and excision is the standard approach.
• For localized GISTs, complete surgical resection (R0) is standard treatment, with no lymphadenectomy for clinically negative lymph nodes.
• Mutational analysis should be considered standard of practice. It can be helpful for confirming the diagnosis and can be predictive and prognostic in determining specific TKI therapy and dose.
• Adjuvant imatinib at a dose of 400 mg for 3 years is standard of care for GISTs that are at high risk of relapse and are imatinib-sensitive, and it is the only TKI approved for adjuvant therapy. Patients with PDGFRA D842V, NF1, BRAF or SDH-deficient GISTs should not receive adjuvant imatinib therapy.
• Neoadjuvant therapy can be utilized for sites where extensive resection would lead to significant morbidity. It should be given for 6 to 12 months, but patients need to be monitored closely for tumor growth.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract and arise from the interstitial cells of Cajal of the myenteric plexus. These tumors are rare, with about 1 case per 100,000 persons diagnosed in the United States annually, but may be incidentally discovered in up to 1 in 5 autopsy specimens of older adults.^1,2 Epidemiologic risk factors include increasing age, with a peak incidence between age 60 and 65 years, male gender, black race, and non-Hispanic white ethnicity. Germline predisposition can also increase the risk of developing GISTs; molecular drivers of GIST include gain-of-function mutations in the KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) gene, which both encode structurally similar tyrosine kinase receptors; germline mutations of succinate dehydrogenase (SDH) subunit genes; and mutations associated with neurofibromatosis type 1.

GISTs most commonly involve the stomach, followed by the small intestine, but can arise anywhere within the GI tract (esophagus, colon, rectum, and anus). They can also develop outside the GI tract, arising from the mesentery, omentum, and retroperitoneum. The majority of cases are localized or locoregional, whereas about 20% are metastatic at presentation.¹ GISTs can occur in children, adolescents, and young adults. Pediatric GISTs represent a distinct subset marked by female predominance and gastric origin, are often multifocal, can sometimes have lymph node involvement, and typically lack mutations in the KIT and PDGFRA genes.

This review is the first of 2 articles focusing on the diagnosis and management of GISTs. Here, we review the evaluation and diagnosis of GISTs along with management of localized disease. Management of advanced disease is reviewed in a separate article.

Case Presentation

A 64-year-old African American man with progressive iron deficiency and abdominal discomfort undergoes upper and lower endoscopy and is found to have a bulging mass within his abdominal cavity. He undergoes a computed tomography (CT) evaluation of the chest, abdomen, and pelvis with contrast, which reveals the presence of a 10-cm gastric mass, with no other lesions identified. He undergoes surgical resection of the mass and presents for review of his pathology and to discuss his treatment plan.

What histopathologic features are consistent with GIST?

What factors are used for risk stratification and to predict likelihood of recurrence?

Clinical Presentation and Diagnosis

Most patients present with symptoms of overt or occult GI bleeding or abdominal discomfort, but a significant proportion of GISTs are discovered incidentally. Lymph node involvement is not typical, except for GISTs occurring in children and/or with rare syndromes. Most syndromic GISTs are multifocal and multicentric. After surgical resection, GISTs usually recur or metastasize within the abdominal cavity, including the omentum, peritoneum, or liver. These tumors rarely spread to the lungs, brain, or bones; when tumor spread does occur, it tends to be in heavily pre-treated patients with advanced disease who have been on multiple lines of therapy for a long duration of time.

The diagnosis usually can be made by histopathology. Specimens can be obtained by endoscopic ultrasound (EUS)– or CT-guided methods, the latter of which carries a very small risk of contamination from percutaneous biopsy. In terms of morphology, GISTs can be spindle cell, epithelioid, or mixed neoplasms. Epithelioid tumors are more commonly seen in the stomach and are often PDGFRA-mutated or SDH-deficient. The differential diagnosis includes other soft-tissue GI wall tumors such as leiomyosarcomas/leiomyomas, germ cell tumors, lymphomas, fibromatosis, and neuroendocrine and neurogenic tumors. A unique feature of GISTs that differentiates them from leiomyomas is near universal expression of CD117 by immunohistochemistry (IHC); this characteristic has allowed pathologists and providers to accurately distinguish true GISTs from other GI mesenchymal tumors.³ Recently, DOG1 (discovered on GIST1) immunoreactivity has been found to be helpful in identifying patients with CD117-negative GISTs. Initially identified through gene expression analysis of GISTs, DOG1 IHC can identify the common mutant c-Kit-driven CD117-positive GISTs as well as the rare CD117-negative GISTs, which are often driven by mutated PDGFRA.⁴ Importantly, IHC for KIT and DOG1 are not surrogates for mutational status, nor are they predictive of tyrosine kinase inhibitor (TKI) sensitivity. If IHC of a tumor specimen is CD117- and DOG1-negative, the specimen can be sent for KIT and PDGFRA mutational analysis to confirm the diagnosis. If analysis reveals that these genes are wild-type, then IHC staining for SDH B (SDHB) should follow to assess for an SDH-deficient GIST (negative staining).

Risk Stratification for Recurrence

The clinical behavior of GISTs can be variable. Some are indolent, while others behave more aggressively, with a greater malignant potential and a higher propensity to recur and metastasize. Clinical and pathologic features can provide important prognostic information that allows providers to risk-stratify patients. Various institutions have assessed prognostic variables for GISTs. In 2001, the National Institutes of Health (NIH) held a GIST workshop that proposed an approach to estimating metastatic risk based on tumor size and mitotic index (NIH or Fletcher criteria).⁵ Joensuu et al later proposed a modification of the NIH risk classification to include tumor location and tumor rupture (modified NIH criteria or Joensuu criteria).^6-8 Similarly, the Armed Forces Institute of Pathology (AFIP) identified tumor site as a prognostic factor, with gastric GISTs having the best prognosis (AFIP-Miettinen criteria).^9-11 Tabular schemes were designed which stratified patients into discrete groups with ranges for mitotic rate and tumor size. Nomograms for ease of use were then constructed utilizing a bimodal mitotic rate and included tumor site and size.¹² Finally, contour maps were developed, which have the advantage of evaluating mitotic rate and tumor size as continuous nonlinear variables and also include tumor site and rupture (associated with a high risk of peritoneal metastasis) separately, further improving risk assessment. These contour maps have been validated against pooled data from 10 series (2560 patients).¹³ High-risk features identified from these studies include tumor location, size, mitotic rate and tumor rupture and are now used for deciding on the use of adjuvant imatinib and as requirements to enter clinical trials assessing adjuvant therapy for resected GISTs.

Case Continued

The patient’s operative and pathology reports indicate that the tumor is a spindle cell neoplasm of the stomach that is positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. Resection margins are negative. There are 10 mitoses per 50 high-power fields (HPF). Per the operative report, there was no intraoperative or intraperitoneal tumor rupture. Thus, while his GIST was gastric, which generally has a more favorable prognosis, the tumor harbors high-risk features based on its size and mitotic index.

What further testing should be requested?

Molecular Alterations

It is recommended that a mutational analysis be performed as part of the diagnostic work-up of all GISTs.¹⁴ Mutational analysis can provide prognostic and predictive information for sensitivity to imatinib and should be considered standard of care. It may also be useful for confirming a GIST diagnosis, or, if negative, lead to further evaluation with an IHC stain for SDHB. The c-Kit receptor is a member of the tyrosine kinase family and, through direct interactions with stem cell factor (SCF), can upregulate the PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK-STAT pathways, resulting in transcription and translation of genes that enhance cell growth and survival.¹⁵ The cell of origin of GISTs, the interstitial cells of Cajal, are dependent on the SCF–c-Kit interaction for development.¹⁶ Likewise, the large majority of GISTs (about 70%) are driven by upregulation and constitutive activation of c-Kit, which is normally autoinhibited. About 80% of KIT mutations involve exon 11; these GISTs are most often associated with a gastric location and are associated with a favorable recurrence-free survival (RFS) rate with surgery alone.¹⁷KIT exon 9 mutations are much less common, encompassing only about 10% of GIST KIT mutations, and GISTs with these mutations are more likely to arise from the small bowel.¹⁷

About 8% of GISTs harbor gain-of-function PDGFRA driver mutations rendering constitutively active PDGFRA.¹⁸PDGFRA mutations are mutually exclusive from KIT mutations, and PDGFRA-mutated tumors most often occur in the stomach. PDGFRA mutations generally are associated with a lower mitotic rate and gastric location. Identification of the PDGFRA D842V mutation on exon 18, which is the most common, is important, as it is associated with imatinib resistance, and these patients should not be offered imatinib.¹⁹

Several other mutations associated with GISTs outside of the KIT and PDGFRA spectrum have been identified. About 10% of GISTs are wildtype for KIT and PDGFRA, and not all KIT/PDGFRA-wildtype GISTs are imatinib-sensitive and/or respond to other TKIs.¹⁸ These tumors may harbor aberrations in SDH and NF1, or less commonly, BRAF V600E, FGFR, and NTRK.^20,21 SDH subunits B, C and D play a role in the Krebs cycle and electron transport chain. Germline mutations in these SDH subunits can result in the Carney-Stratakis syndrome characterized by the dyad of multifocal GISTs and multicentric paragangliomas.²² This syndrome is most likely to manifest in the pediatric or young adult population. In contradistinction is the Carney triad, which is associated with acquired loss of function of the SDHC gene due to promoter hypermethylation. This syndrome classically occurs in young women and is characterized by an indolent-behaving triad of multicentric GISTs, non-adrenal paragangliomas, and pulmonary chondromas.²³ Like PDGFRA D842V–mutated GISTs, SDH-deficient and NF1-associated GISTs are considered imatinib resistant, and these patients should not be offered imatinib therapy.¹⁴

Case Continued

The patient’s GIST is found to harbor a KIT exon 11 single codon deletion. He appears anxious and asks to have everything done to prevent his GIST from coming back and to improve his lifespan.

Management

A multidisciplinary team approach to the management of all GISTs is essential and includes input from radiology, gastroenterology, pathology, medical and surgical oncology, nuclear medicine, and nursing.

Surgical Resection

Small esophagogastric and duodenal GISTs ≤ 2 cm can be asymptomatic and managed with serial endoscopic surveillance, typically every 6 to 12 months, with biopsies if the tumors increase in size. GISTs larger than 2 cm require surgical resection, with resection of the full pseudocapsule and an R0 resection, if possible, since larger GISTs carry a higher risk of growth and recurrence. If an R0 resection would lead to significant morbidity or functional sequelae, an R1 may suffice. Rectal GISTs are an exception, where microscopic margins have been shown to be associated with an increased risk of local failure.²⁴ It is important to explore the abdomen thoroughly for peritoneal, rectovaginal, and vesicular implants and metastasis to the liver. A formal lymph node dissection is not necessary because lymph nodes are rarely involved and should only be removed when clinically suspicious. Tumor rupture must be avoided. A laparoscopic approach should only be considered for smaller tumors, since there is a risk of tumor rupture with larger tumors.¹⁴

When is adjuvant imatinib indicated?

Adjuvant Imatinib

Among patients with local or locally advanced GISTs, the risk of death from recurrence with surgery alone can be high, with a historical 5-year overall survival (OS) of about 35%.²⁵ As a result, multiple studies have assessed the benefit of adjuvant imatinib, which is now considered standard of care for patients with imatinib-sensitive, high-risk GISTs. In addition to inhibiting BCR-ABL, imatinib mesylate inhibits multiple other receptor tyrosine kinases, including PDGFR, SCF and c-Kit. As a result, imatinib has demonstrated in vitro inhibition of cell proliferation and apoptosis and clinical activity against GISTs expressing CD117.²⁶ Importantly, adjuvant imatinib should only be offered to patients with imatinib-sensitive mutations, such as KIT exon 11 and KIT exon 9 mutations. Adjuvant imatinib should not be offered to patients with imatinib-insensitive mutations such as PDGFR 842V, NF1, or BRAF-related or SDH-deficient GISTs.

The ACOSOG Z9000 was the first study of adjuvant imatinib in patients with resected GISTs.²⁵ This was a single-arm, phase 2 study involving 106 patients with surgically resected GISTs deemed high-risk for recurrence, defined as size > 10 cm, tumor rupture, or up to 4 peritoneal implants. Patients were treated with imatinib 400 mg daily for 1 year. The primary and secondary endpoints were OS and RFS, respectively. Long-term follow-up of this study demonstrated 1-, 3-, and 5-year OS of 99%, 97%, and 83%, and 1-, 3-, and 5-year RFS of 96%, 60%, and 40%, which compared favorably with historical controls. In a multivariable analysis, increasing tumor size, small bowel location, KIT exon 9 mutation, high mitotic rate, and older age were independent risk factors for a poor RFS.²⁵ It is important to note that the benefit of adjuvant imatinib waned after discontinuation of therapy, creating a rationale to study adjuvant imatinib for longer periods of time.

As a result of the promising phase 2 data, ACOSOG opened a phase 3 randomized trial (Z9001) comparing 1 year of adjuvant imatinib to placebo among patients with surgically resected GISTs that were > 3 cm in size and that stained positive for CD117 on pathology. The trial accrued 713 patients and was stopped early at a planned interim analysis, which revealed a 1-year RFS of 98% for imatinib versus 83% for placebo (hazard ratio [HR], 0.35; P < 0.001). The 1-year OS did not differ between the 2 arms (92.2% vs 99.7%; HR, 0.66; P = 0.47).²⁷ When comparing the 2 arms, imatinib was associated with a higher RFS among patients with a KIT exon 11 deletion, but not among patients with other KIT mutation types, PDGFRA mutations, or who were KIT/PDGFRA wildtype.²⁸ Imatinib was granted approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of high-risk GISTs based on the results of the ACOSOG Z9001 trial.

The EORTC 62024 study was a randomized placebo-controlled trial assessing the benefit of 2 years of adjuvant imatinib.²⁹ Patients had to be considered intermediate or high risk per the 2002 NIH consensus classification to be eligible. The trial enrolled 918 patients. The 5-year OS rate, the original primary endpoint, did not differ between the 2 groups (100% vs 99%). The 3-year and 5-year RFS rates, secondary endpoints, were significantly longer among patients treated with imatinib (84% vs 66% and 69% vs 63%, respectively). Again, it was noted that the benefit of imatinib waned over time after treatment discontinuation.

The Scandinavian Sarcoma Group (SSG XVIII) trial was a prospective randomized phase 3 trial that compared 3 years versus 1 year of adjuvant imatinib.³⁰ Patients had to be enrolled within 12 weeks of the postoperative period and had to have GISTs that were CD117-positive and with a high estimated risk of recurrence, per the modified NIH consensus criteria (size > 10 cm, > 10 mitoses per 50 HPF, diameter > 5 cm with mitotic count > 5, or tumor rupture before or at surgery). Three years of adjuvant imatinib was associated with a 54% reduction in the hazard for recurrence at 5 years (65.6% vs 47.9%; HR, 0.46; P < 0.001) and a 55% reduction in the hazard for death at 5 years (OS 92% vs 81.7%; HR, 0.45; P = 0.02). Based on the results of this study, the FDA granted approval for the use of 3 years of adjuvant imatinib in patients with high-risk resected GISTs.

The observation that a longer duration of adjuvant imatinib was associated with superior RFS and OS led to studies to further explore longer durations of adjuvant imatinib. The PERSIST-5 (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib) was a multicenter, single-arm, phase 2 prospective study of adjuvant imatinib with a primary endpoint of RFS after 5 years.³¹ Patients had to have an intermediate or high risk of recurrence, which included GISTs at any site > 2 cm with > 5 mitoses per 50 HPF or nongastric GISTs that were ≥ 5 cm. With 91 patients enrolled, the estimated 5-year RFS was 90% and the OS was 95%. Of note, about half of the patients stopped treatment early due to a variety of reasons, including patient choice or adverse events. Importantly, there were no recurrences in patients with imatinib-sensitive mutations while on therapy. We know that in patients at high risk of relapse, adjuvant imatinib delays recurrence and improves survival, but whether any patients are cured, or their survival curves are just shifted to the right, is unknown. Only longer follow-up of existing studies, and the results of newer trials utilizing longer durations of adjuvant treatment, will help to determine the real value of adjuvant therapy for GIST patients.³² Based on this study, it would be reasonable to discuss a longer duration of imatinib with patients deemed to be at very high risk of recurrence and who are tolerating therapy well. We are awaiting the data from the randomized phase 3 Scandinavian Sarcoma Group XII trial comparing 5 years versus 3 years of adjuvant imatinib therapy, and from the French ImadGIST trial of adjuvant imatinib for 3 versus 6 years. A summary of the aforementioned key adjuvant trials is shown in the Table.

When imatinib is commenced, careful monitoring for treatment toxicities and drug interactions should ensue in order to improve compliance. Dose density should be maintained if possible, as retrospective studies suggest suboptimal plasma levels are associated with a worse outcome.³³

When should neoadjuvant imatinib be considered?

Neoadjuvant Imatinib

Neoadjuvant imatinib should be considered for patients requiring total gastrectomy, esophagectomy, or abdominoperineal resection of the rectum in order to reduce tumor size, limit subsequent surgical morbidity, mitigate tumor bleeding and rupture, and aid with organ preservation. Patients with rectal GISTs that may otherwise warrant an abdominoperineal resection should be offered a trial of imatinib in the neoadjuvant setting. There is no evidence for the use of any other TKI aside from imatinib in the neoadjuvant or adjuvant setting. With neoadjuvant imatinib, it is difficult to accurately assess the mitotic rate in the resected tumor specimen.

The RTOG 0132/ACRIN 6665 trial was a prospective phase 2 study evaluating the efficacy of imatinib 600 mg daily in the perioperative setting.³⁴ The trial enrolled 50 patients, 30 with primary GISTs (group A) and 22 with recurrent metastatic GISTs (group B). Based on data from the metastatic setting revealing a time to treatment response of about 2.5 months, patients were treated with 8 to 12 weeks of preoperative imatinib followed by 2 years of adjuvant imatinib. Imatinib was stopped 24 hours preoperatively and resumed as soon as possible postoperatively. In group A, 7% of patients achieved a partial response (PR), 83% achieved stable disease, and 2-year progression-free survival (PFS) and OS were 83% and 93%, respectively. In group B, 4.5% of patients achieved a PR, 91% achieved stable disease, and 4.5% experienced progressive disease in the preoperative period; the 2-year PFS and OS were 77% and 91%, respectively. The results of this trial demonstrated the feasibility of using perioperative imatinib with minimal effects on surgical outcomes and set the rationale to use neoadjuvant imatinib in select patients with borderline resectable or rectal GISTs. Another EORTC pooled analysis from 10 sarcoma centers revealed that after a median of 10 months of neoadjuvant imatinib, 83.2% of patients achieved an R0 resection and only 1% progressed during treatment.³⁵ After a median follow-up of 46 months, the 5-year disease-free survival and OS were 65% and 87%, respectively.

Mutational testing should be performed beforehand to ensure the tumor is imatinib-sensitive. If a KIT exon 9 mutation is identified, then 400 mg twice daily should be considered (given the benefit seen with 800 mg imatinib for advanced GIST patients), although there are no studies to confirm this practice. Neoadjuvant imatinib is recommended for a total of 6 to 12 months to ensure maximal tumor debulking, but with very close monitoring and surgical input for disease resistance and growth.¹⁴ Imatinib should be stopped 1 to 2 days preoperatively and resumed once the patient has recovered from surgery for a total of 3 years (pre-/postoperatively combined). Neoadjuvant therapy has been shown to be safe and effective, but there have been no randomized trials to assess survival.

What is appropriate surveillance for resected GISTs?

Surveillance

There have been no randomized studies to guide the management of surveillance after surgical resection and adjuvant therapy. There is no known optimal follow-up schedule, but several have been proposed.^13,36 Among high-risk patients, it is suggested to image every 3 to 6 months during adjuvant therapy, followed by every 3 months for 2 years after discontinuing therapy, then every 6 months for another 3 years and annually thereafter for an additional 5 years. High-risk patients usually relapse within 1 to 3 years after finishing adjuvant therapy, while low-risk patients can relapse later given that their disease can be slower growing. It has been recommended that low-risk patients undergo imaging every 6 months for 5 years, with follow-up individualized thereafter. Very-low-risk patients may not require more than annual imaging. Because most relapses occur within the peritoneum or liver, imaging should encompass the abdomen and pelvis. Surveillance imaging usually consists of CT scans of the abdomen and pelvis. MRI scans can be utilized for patients at lower risk or who are out several years in order to avoid excess radiation exposure. MRI is also specifically helpful for rectal and esophageal lesions. Chest CT or chest radiograph and bone scan are not routinely required for follow-up.

Case Conclusion

The patient receives adjuvant imatinib and experiences grade 2 myalgias, periorbital edema, and macrocytic anemia, which result in imatinib discontinuation after 3 years of treatment. He is seen every 3 to 6 months and a contrast CT abdomen and pelvis is obtained every 6 months for 5 years. During this 5-year follow-up period, he does not have any clinical or radiographic evidence of disease recurrence.

Further follow-up of this patient is presented in the second article in this 2-part review of management of GISTs.

Key Points

• GISTs are the most common mesenchymal neoplasms of the GI tract and can occasionally occur in extragastrointestinal locations as well.
• GISTs encompass a heterogeneous family of tumor subsets with different natural histories, mutations, and TKI responsiveness.
• Surgery is the mainstay of treatment for localized GISTs, with cure rates greater than 50%.
• For very small (< 2 cm) esophagogastric GISTs, endoscopic ultrasound evaluation and follow-up is recommended.
• For tumors ≥ 2 cm, biopsy and excision is the standard approach.
• For localized GISTs, complete surgical resection (R0) is standard treatment, with no lymphadenectomy for clinically negative lymph nodes.
• Mutational analysis should be considered standard of practice. It can be helpful for confirming the diagnosis and can be predictive and prognostic in determining specific TKI therapy and dose.
• Adjuvant imatinib at a dose of 400 mg for 3 years is standard of care for GISTs that are at high risk of relapse and are imatinib-sensitive, and it is the only TKI approved for adjuvant therapy. Patients with PDGFRA D842V, NF1, BRAF or SDH-deficient GISTs should not receive adjuvant imatinib therapy.
• Neoadjuvant therapy can be utilized for sites where extensive resection would lead to significant morbidity. It should be given for 6 to 12 months, but patients need to be monitored closely for tumor growth.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract and arise from the interstitial cells of Cajal of the myenteric plexus. These tumors are rare, with about 1 case per 100,000 persons diagnosed in the United States annually, but may be incidentally discovered in up to 1 in 5 autopsy specimens of older adults.^1,2 Epidemiologic risk factors include increasing age, with a peak incidence between age 60 and 65 years, male gender, black race, and non-Hispanic white ethnicity. Germline predisposition can also increase the risk of developing GISTs; molecular drivers of GIST include gain-of-function mutations in the KIT proto-oncogene and platelet-derived growth factor receptor α (PDGFRA) gene, which both encode structurally similar tyrosine kinase receptors; germline mutations of succinate dehydrogenase (SDH) subunit genes; and mutations associated with neurofibromatosis type 1.

GISTs most commonly involve the stomach, followed by the small intestine, but can arise anywhere within the GI tract (esophagus, colon, rectum, and anus). They can also develop outside the GI tract, arising from the mesentery, omentum, and retroperitoneum. The majority of cases are localized or locoregional, whereas about 20% are metastatic at presentation.¹ GISTs can occur in children, adolescents, and young adults. Pediatric GISTs represent a distinct subset marked by female predominance and gastric origin, are often multifocal, can sometimes have lymph node involvement, and typically lack mutations in the KIT and PDGFRA genes.

This review is the first of 2 articles focusing on the diagnosis and management of GISTs. Here, we review the evaluation and diagnosis of GISTs along with management of localized disease. Management of advanced disease is reviewed in a separate article.

Case Presentation

A 64-year-old African American man with progressive iron deficiency and abdominal discomfort undergoes upper and lower endoscopy and is found to have a bulging mass within his abdominal cavity. He undergoes a computed tomography (CT) evaluation of the chest, abdomen, and pelvis with contrast, which reveals the presence of a 10-cm gastric mass, with no other lesions identified. He undergoes surgical resection of the mass and presents for review of his pathology and to discuss his treatment plan.

What histopathologic features are consistent with GIST?

What factors are used for risk stratification and to predict likelihood of recurrence?

Clinical Presentation and Diagnosis

Most patients present with symptoms of overt or occult GI bleeding or abdominal discomfort, but a significant proportion of GISTs are discovered incidentally. Lymph node involvement is not typical, except for GISTs occurring in children and/or with rare syndromes. Most syndromic GISTs are multifocal and multicentric. After surgical resection, GISTs usually recur or metastasize within the abdominal cavity, including the omentum, peritoneum, or liver. These tumors rarely spread to the lungs, brain, or bones; when tumor spread does occur, it tends to be in heavily pre-treated patients with advanced disease who have been on multiple lines of therapy for a long duration of time.

The diagnosis usually can be made by histopathology. Specimens can be obtained by endoscopic ultrasound (EUS)– or CT-guided methods, the latter of which carries a very small risk of contamination from percutaneous biopsy. In terms of morphology, GISTs can be spindle cell, epithelioid, or mixed neoplasms. Epithelioid tumors are more commonly seen in the stomach and are often PDGFRA-mutated or SDH-deficient. The differential diagnosis includes other soft-tissue GI wall tumors such as leiomyosarcomas/leiomyomas, germ cell tumors, lymphomas, fibromatosis, and neuroendocrine and neurogenic tumors. A unique feature of GISTs that differentiates them from leiomyomas is near universal expression of CD117 by immunohistochemistry (IHC); this characteristic has allowed pathologists and providers to accurately distinguish true GISTs from other GI mesenchymal tumors.³ Recently, DOG1 (discovered on GIST1) immunoreactivity has been found to be helpful in identifying patients with CD117-negative GISTs. Initially identified through gene expression analysis of GISTs, DOG1 IHC can identify the common mutant c-Kit-driven CD117-positive GISTs as well as the rare CD117-negative GISTs, which are often driven by mutated PDGFRA.⁴ Importantly, IHC for KIT and DOG1 are not surrogates for mutational status, nor are they predictive of tyrosine kinase inhibitor (TKI) sensitivity. If IHC of a tumor specimen is CD117- and DOG1-negative, the specimen can be sent for KIT and PDGFRA mutational analysis to confirm the diagnosis. If analysis reveals that these genes are wild-type, then IHC staining for SDH B (SDHB) should follow to assess for an SDH-deficient GIST (negative staining).

Risk Stratification for Recurrence

The clinical behavior of GISTs can be variable. Some are indolent, while others behave more aggressively, with a greater malignant potential and a higher propensity to recur and metastasize. Clinical and pathologic features can provide important prognostic information that allows providers to risk-stratify patients. Various institutions have assessed prognostic variables for GISTs. In 2001, the National Institutes of Health (NIH) held a GIST workshop that proposed an approach to estimating metastatic risk based on tumor size and mitotic index (NIH or Fletcher criteria).⁵ Joensuu et al later proposed a modification of the NIH risk classification to include tumor location and tumor rupture (modified NIH criteria or Joensuu criteria).^6-8 Similarly, the Armed Forces Institute of Pathology (AFIP) identified tumor site as a prognostic factor, with gastric GISTs having the best prognosis (AFIP-Miettinen criteria).^9-11 Tabular schemes were designed which stratified patients into discrete groups with ranges for mitotic rate and tumor size. Nomograms for ease of use were then constructed utilizing a bimodal mitotic rate and included tumor site and size.¹² Finally, contour maps were developed, which have the advantage of evaluating mitotic rate and tumor size as continuous nonlinear variables and also include tumor site and rupture (associated with a high risk of peritoneal metastasis) separately, further improving risk assessment. These contour maps have been validated against pooled data from 10 series (2560 patients).¹³ High-risk features identified from these studies include tumor location, size, mitotic rate and tumor rupture and are now used for deciding on the use of adjuvant imatinib and as requirements to enter clinical trials assessing adjuvant therapy for resected GISTs.

Case Continued

The patient’s operative and pathology reports indicate that the tumor is a spindle cell neoplasm of the stomach that is positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. Resection margins are negative. There are 10 mitoses per 50 high-power fields (HPF). Per the operative report, there was no intraoperative or intraperitoneal tumor rupture. Thus, while his GIST was gastric, which generally has a more favorable prognosis, the tumor harbors high-risk features based on its size and mitotic index.

What further testing should be requested?

Molecular Alterations

It is recommended that a mutational analysis be performed as part of the diagnostic work-up of all GISTs.¹⁴ Mutational analysis can provide prognostic and predictive information for sensitivity to imatinib and should be considered standard of care. It may also be useful for confirming a GIST diagnosis, or, if negative, lead to further evaluation with an IHC stain for SDHB. The c-Kit receptor is a member of the tyrosine kinase family and, through direct interactions with stem cell factor (SCF), can upregulate the PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, and JAK-STAT pathways, resulting in transcription and translation of genes that enhance cell growth and survival.¹⁵ The cell of origin of GISTs, the interstitial cells of Cajal, are dependent on the SCF–c-Kit interaction for development.¹⁶ Likewise, the large majority of GISTs (about 70%) are driven by upregulation and constitutive activation of c-Kit, which is normally autoinhibited. About 80% of KIT mutations involve exon 11; these GISTs are most often associated with a gastric location and are associated with a favorable recurrence-free survival (RFS) rate with surgery alone.¹⁷KIT exon 9 mutations are much less common, encompassing only about 10% of GIST KIT mutations, and GISTs with these mutations are more likely to arise from the small bowel.¹⁷

About 8% of GISTs harbor gain-of-function PDGFRA driver mutations rendering constitutively active PDGFRA.¹⁸PDGFRA mutations are mutually exclusive from KIT mutations, and PDGFRA-mutated tumors most often occur in the stomach. PDGFRA mutations generally are associated with a lower mitotic rate and gastric location. Identification of the PDGFRA D842V mutation on exon 18, which is the most common, is important, as it is associated with imatinib resistance, and these patients should not be offered imatinib.¹⁹

Several other mutations associated with GISTs outside of the KIT and PDGFRA spectrum have been identified. About 10% of GISTs are wildtype for KIT and PDGFRA, and not all KIT/PDGFRA-wildtype GISTs are imatinib-sensitive and/or respond to other TKIs.¹⁸ These tumors may harbor aberrations in SDH and NF1, or less commonly, BRAF V600E, FGFR, and NTRK.^20,21 SDH subunits B, C and D play a role in the Krebs cycle and electron transport chain. Germline mutations in these SDH subunits can result in the Carney-Stratakis syndrome characterized by the dyad of multifocal GISTs and multicentric paragangliomas.²² This syndrome is most likely to manifest in the pediatric or young adult population. In contradistinction is the Carney triad, which is associated with acquired loss of function of the SDHC gene due to promoter hypermethylation. This syndrome classically occurs in young women and is characterized by an indolent-behaving triad of multicentric GISTs, non-adrenal paragangliomas, and pulmonary chondromas.²³ Like PDGFRA D842V–mutated GISTs, SDH-deficient and NF1-associated GISTs are considered imatinib resistant, and these patients should not be offered imatinib therapy.¹⁴

Case Continued

The patient’s GIST is found to harbor a KIT exon 11 single codon deletion. He appears anxious and asks to have everything done to prevent his GIST from coming back and to improve his lifespan.

Management

A multidisciplinary team approach to the management of all GISTs is essential and includes input from radiology, gastroenterology, pathology, medical and surgical oncology, nuclear medicine, and nursing.

Surgical Resection

Small esophagogastric and duodenal GISTs ≤ 2 cm can be asymptomatic and managed with serial endoscopic surveillance, typically every 6 to 12 months, with biopsies if the tumors increase in size. GISTs larger than 2 cm require surgical resection, with resection of the full pseudocapsule and an R0 resection, if possible, since larger GISTs carry a higher risk of growth and recurrence. If an R0 resection would lead to significant morbidity or functional sequelae, an R1 may suffice. Rectal GISTs are an exception, where microscopic margins have been shown to be associated with an increased risk of local failure.²⁴ It is important to explore the abdomen thoroughly for peritoneal, rectovaginal, and vesicular implants and metastasis to the liver. A formal lymph node dissection is not necessary because lymph nodes are rarely involved and should only be removed when clinically suspicious. Tumor rupture must be avoided. A laparoscopic approach should only be considered for smaller tumors, since there is a risk of tumor rupture with larger tumors.¹⁴

When is adjuvant imatinib indicated?

Adjuvant Imatinib

Among patients with local or locally advanced GISTs, the risk of death from recurrence with surgery alone can be high, with a historical 5-year overall survival (OS) of about 35%.²⁵ As a result, multiple studies have assessed the benefit of adjuvant imatinib, which is now considered standard of care for patients with imatinib-sensitive, high-risk GISTs. In addition to inhibiting BCR-ABL, imatinib mesylate inhibits multiple other receptor tyrosine kinases, including PDGFR, SCF and c-Kit. As a result, imatinib has demonstrated in vitro inhibition of cell proliferation and apoptosis and clinical activity against GISTs expressing CD117.²⁶ Importantly, adjuvant imatinib should only be offered to patients with imatinib-sensitive mutations, such as KIT exon 11 and KIT exon 9 mutations. Adjuvant imatinib should not be offered to patients with imatinib-insensitive mutations such as PDGFR 842V, NF1, or BRAF-related or SDH-deficient GISTs.

The ACOSOG Z9000 was the first study of adjuvant imatinib in patients with resected GISTs.²⁵ This was a single-arm, phase 2 study involving 106 patients with surgically resected GISTs deemed high-risk for recurrence, defined as size > 10 cm, tumor rupture, or up to 4 peritoneal implants. Patients were treated with imatinib 400 mg daily for 1 year. The primary and secondary endpoints were OS and RFS, respectively. Long-term follow-up of this study demonstrated 1-, 3-, and 5-year OS of 99%, 97%, and 83%, and 1-, 3-, and 5-year RFS of 96%, 60%, and 40%, which compared favorably with historical controls. In a multivariable analysis, increasing tumor size, small bowel location, KIT exon 9 mutation, high mitotic rate, and older age were independent risk factors for a poor RFS.²⁵ It is important to note that the benefit of adjuvant imatinib waned after discontinuation of therapy, creating a rationale to study adjuvant imatinib for longer periods of time.

As a result of the promising phase 2 data, ACOSOG opened a phase 3 randomized trial (Z9001) comparing 1 year of adjuvant imatinib to placebo among patients with surgically resected GISTs that were > 3 cm in size and that stained positive for CD117 on pathology. The trial accrued 713 patients and was stopped early at a planned interim analysis, which revealed a 1-year RFS of 98% for imatinib versus 83% for placebo (hazard ratio [HR], 0.35; P < 0.001). The 1-year OS did not differ between the 2 arms (92.2% vs 99.7%; HR, 0.66; P = 0.47).²⁷ When comparing the 2 arms, imatinib was associated with a higher RFS among patients with a KIT exon 11 deletion, but not among patients with other KIT mutation types, PDGFRA mutations, or who were KIT/PDGFRA wildtype.²⁸ Imatinib was granted approval by the US Food and Drug Administration (FDA) for the adjuvant treatment of high-risk GISTs based on the results of the ACOSOG Z9001 trial.

The EORTC 62024 study was a randomized placebo-controlled trial assessing the benefit of 2 years of adjuvant imatinib.²⁹ Patients had to be considered intermediate or high risk per the 2002 NIH consensus classification to be eligible. The trial enrolled 918 patients. The 5-year OS rate, the original primary endpoint, did not differ between the 2 groups (100% vs 99%). The 3-year and 5-year RFS rates, secondary endpoints, were significantly longer among patients treated with imatinib (84% vs 66% and 69% vs 63%, respectively). Again, it was noted that the benefit of imatinib waned over time after treatment discontinuation.

The Scandinavian Sarcoma Group (SSG XVIII) trial was a prospective randomized phase 3 trial that compared 3 years versus 1 year of adjuvant imatinib.³⁰ Patients had to be enrolled within 12 weeks of the postoperative period and had to have GISTs that were CD117-positive and with a high estimated risk of recurrence, per the modified NIH consensus criteria (size > 10 cm, > 10 mitoses per 50 HPF, diameter > 5 cm with mitotic count > 5, or tumor rupture before or at surgery). Three years of adjuvant imatinib was associated with a 54% reduction in the hazard for recurrence at 5 years (65.6% vs 47.9%; HR, 0.46; P < 0.001) and a 55% reduction in the hazard for death at 5 years (OS 92% vs 81.7%; HR, 0.45; P = 0.02). Based on the results of this study, the FDA granted approval for the use of 3 years of adjuvant imatinib in patients with high-risk resected GISTs.

The observation that a longer duration of adjuvant imatinib was associated with superior RFS and OS led to studies to further explore longer durations of adjuvant imatinib. The PERSIST-5 (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors With 5 Years of Adjuvant Imatinib) was a multicenter, single-arm, phase 2 prospective study of adjuvant imatinib with a primary endpoint of RFS after 5 years.³¹ Patients had to have an intermediate or high risk of recurrence, which included GISTs at any site > 2 cm with > 5 mitoses per 50 HPF or nongastric GISTs that were ≥ 5 cm. With 91 patients enrolled, the estimated 5-year RFS was 90% and the OS was 95%. Of note, about half of the patients stopped treatment early due to a variety of reasons, including patient choice or adverse events. Importantly, there were no recurrences in patients with imatinib-sensitive mutations while on therapy. We know that in patients at high risk of relapse, adjuvant imatinib delays recurrence and improves survival, but whether any patients are cured, or their survival curves are just shifted to the right, is unknown. Only longer follow-up of existing studies, and the results of newer trials utilizing longer durations of adjuvant treatment, will help to determine the real value of adjuvant therapy for GIST patients.³² Based on this study, it would be reasonable to discuss a longer duration of imatinib with patients deemed to be at very high risk of recurrence and who are tolerating therapy well. We are awaiting the data from the randomized phase 3 Scandinavian Sarcoma Group XII trial comparing 5 years versus 3 years of adjuvant imatinib therapy, and from the French ImadGIST trial of adjuvant imatinib for 3 versus 6 years. A summary of the aforementioned key adjuvant trials is shown in the Table.

When imatinib is commenced, careful monitoring for treatment toxicities and drug interactions should ensue in order to improve compliance. Dose density should be maintained if possible, as retrospective studies suggest suboptimal plasma levels are associated with a worse outcome.³³

When should neoadjuvant imatinib be considered?

Neoadjuvant Imatinib

Neoadjuvant imatinib should be considered for patients requiring total gastrectomy, esophagectomy, or abdominoperineal resection of the rectum in order to reduce tumor size, limit subsequent surgical morbidity, mitigate tumor bleeding and rupture, and aid with organ preservation. Patients with rectal GISTs that may otherwise warrant an abdominoperineal resection should be offered a trial of imatinib in the neoadjuvant setting. There is no evidence for the use of any other TKI aside from imatinib in the neoadjuvant or adjuvant setting. With neoadjuvant imatinib, it is difficult to accurately assess the mitotic rate in the resected tumor specimen.

The RTOG 0132/ACRIN 6665 trial was a prospective phase 2 study evaluating the efficacy of imatinib 600 mg daily in the perioperative setting.³⁴ The trial enrolled 50 patients, 30 with primary GISTs (group A) and 22 with recurrent metastatic GISTs (group B). Based on data from the metastatic setting revealing a time to treatment response of about 2.5 months, patients were treated with 8 to 12 weeks of preoperative imatinib followed by 2 years of adjuvant imatinib. Imatinib was stopped 24 hours preoperatively and resumed as soon as possible postoperatively. In group A, 7% of patients achieved a partial response (PR), 83% achieved stable disease, and 2-year progression-free survival (PFS) and OS were 83% and 93%, respectively. In group B, 4.5% of patients achieved a PR, 91% achieved stable disease, and 4.5% experienced progressive disease in the preoperative period; the 2-year PFS and OS were 77% and 91%, respectively. The results of this trial demonstrated the feasibility of using perioperative imatinib with minimal effects on surgical outcomes and set the rationale to use neoadjuvant imatinib in select patients with borderline resectable or rectal GISTs. Another EORTC pooled analysis from 10 sarcoma centers revealed that after a median of 10 months of neoadjuvant imatinib, 83.2% of patients achieved an R0 resection and only 1% progressed during treatment.³⁵ After a median follow-up of 46 months, the 5-year disease-free survival and OS were 65% and 87%, respectively.

Mutational testing should be performed beforehand to ensure the tumor is imatinib-sensitive. If a KIT exon 9 mutation is identified, then 400 mg twice daily should be considered (given the benefit seen with 800 mg imatinib for advanced GIST patients), although there are no studies to confirm this practice. Neoadjuvant imatinib is recommended for a total of 6 to 12 months to ensure maximal tumor debulking, but with very close monitoring and surgical input for disease resistance and growth.¹⁴ Imatinib should be stopped 1 to 2 days preoperatively and resumed once the patient has recovered from surgery for a total of 3 years (pre-/postoperatively combined). Neoadjuvant therapy has been shown to be safe and effective, but there have been no randomized trials to assess survival.

What is appropriate surveillance for resected GISTs?

Surveillance

There have been no randomized studies to guide the management of surveillance after surgical resection and adjuvant therapy. There is no known optimal follow-up schedule, but several have been proposed.^13,36 Among high-risk patients, it is suggested to image every 3 to 6 months during adjuvant therapy, followed by every 3 months for 2 years after discontinuing therapy, then every 6 months for another 3 years and annually thereafter for an additional 5 years. High-risk patients usually relapse within 1 to 3 years after finishing adjuvant therapy, while low-risk patients can relapse later given that their disease can be slower growing. It has been recommended that low-risk patients undergo imaging every 6 months for 5 years, with follow-up individualized thereafter. Very-low-risk patients may not require more than annual imaging. Because most relapses occur within the peritoneum or liver, imaging should encompass the abdomen and pelvis. Surveillance imaging usually consists of CT scans of the abdomen and pelvis. MRI scans can be utilized for patients at lower risk or who are out several years in order to avoid excess radiation exposure. MRI is also specifically helpful for rectal and esophageal lesions. Chest CT or chest radiograph and bone scan are not routinely required for follow-up.

Case Conclusion

The patient receives adjuvant imatinib and experiences grade 2 myalgias, periorbital edema, and macrocytic anemia, which result in imatinib discontinuation after 3 years of treatment. He is seen every 3 to 6 months and a contrast CT abdomen and pelvis is obtained every 6 months for 5 years. During this 5-year follow-up period, he does not have any clinical or radiographic evidence of disease recurrence.

Further follow-up of this patient is presented in the second article in this 2-part review of management of GISTs.

Key Points

• GISTs are the most common mesenchymal neoplasms of the GI tract and can occasionally occur in extragastrointestinal locations as well.
• GISTs encompass a heterogeneous family of tumor subsets with different natural histories, mutations, and TKI responsiveness.
• Surgery is the mainstay of treatment for localized GISTs, with cure rates greater than 50%.
• For very small (< 2 cm) esophagogastric GISTs, endoscopic ultrasound evaluation and follow-up is recommended.
• For tumors ≥ 2 cm, biopsy and excision is the standard approach.
• For localized GISTs, complete surgical resection (R0) is standard treatment, with no lymphadenectomy for clinically negative lymph nodes.
• Mutational analysis should be considered standard of practice. It can be helpful for confirming the diagnosis and can be predictive and prognostic in determining specific TKI therapy and dose.
• Adjuvant imatinib at a dose of 400 mg for 3 years is standard of care for GISTs that are at high risk of relapse and are imatinib-sensitive, and it is the only TKI approved for adjuvant therapy. Patients with PDGFRA D842V, NF1, BRAF or SDH-deficient GISTs should not receive adjuvant imatinib therapy.
• Neoadjuvant therapy can be utilized for sites where extensive resection would lead to significant morbidity. It should be given for 6 to 12 months, but patients need to be monitored closely for tumor growth.

PHILADELPHIA – Among patients with episodic migraine, 4.5 years of preventive treatment with erenumab is effective, safe, and well tolerated, according to interim data from an open-label extension study. “Erenumab was well tolerated and safe, with no safety signals detected over this period,” said Messoud Ashina, MD, PhD, professor of neurology at the University of Copenhagen. Dr. Ashina presented the interim data from a 5-year, open-label extension study of erenumab at the annual meeting of the American Headache Society.

Erenumab is a monoclonal antibody that targets and blocks the calcitonin gene-related peptide (CGRP) receptor. In May 2018, the Food and Drug Administration approved erenumab for the preventive treatment of migraine in adults. The treatment, marketed as Aimovig, is administered once monthly by self-injection.

During the open-label study, patients initially received 70 mg of erenumab monthly. After approximately 2 years, patients switched to 140 mg of erenumab monthly. The researchers’ interim efficacy analysis included all patients on 140 mg of erenumab with data about monthly migraine days after more than 4 years of treatment. The safety analysis included all patients who enrolled in the open-label treatment period and received at least one dose of erenumab.

Of 250 patients who increased the erenumab dose from 70 mg to 140 mg, a total of 221 (88%) completed the open-label treatment period or remained on 140 mg after more than 4 years. Patients’ average number of monthly migraine days at study baseline was 8.7, and the average change from baseline to the most recent month in the interim analysis was –5.8.

During the most recent month of assessment, 77% of patients had at least a 50% reduction in monthly migraine days from baseline, 56% had at least a 75% reduction, and 33% had a 100% reduction.

Mean change from baseline in acute migraine‐specific medication treatment days was –4.6, from a baseline of 6.1.

Among the 383 patients who entered the open-label treatment period and received at least one dose of erenumab (mean age, 41.3; 79% female), the median erenumab exposure was 58.5 months. The exposure‐adjusted incidence of adverse events per 100 patient‐years was 124.9, and the three most frequent adverse events (per 100 patient-years) were nasopharyngitis (10.9), upper respiratory tract infection (6.8), and influenza (4.7). The exposure‐adjusted incidence rate per 100 patient‐years for constipation was 1.3 (9/383) for 70-mg erenumab and 2.6 (15/250) for 140-mg erenumab.

“The exposure‐adjusted incidence rate per 100 patient‐years of serious adverse events was 3.8, similar to the rate observed for erenumab and placebo during the placebo‐controlled periods of studies,” the researchers said.

The study was sponsored by Amgen, and several study authors are employees of Amgen or Novartis, the companies that market erenumab. Dr. Ashina is a consultant for Amgen, Novartis, and other companies.

[email protected]

SOURCE: Ashina M et al. AHS 2019, Abstract IOR10.

PHILADELPHIA – Among patients with episodic migraine, 4.5 years of preventive treatment with erenumab is effective, safe, and well tolerated, according to interim data from an open-label extension study. “Erenumab was well tolerated and safe, with no safety signals detected over this period,” said Messoud Ashina, MD, PhD, professor of neurology at the University of Copenhagen. Dr. Ashina presented the interim data from a 5-year, open-label extension study of erenumab at the annual meeting of the American Headache Society.

Erenumab is a monoclonal antibody that targets and blocks the calcitonin gene-related peptide (CGRP) receptor. In May 2018, the Food and Drug Administration approved erenumab for the preventive treatment of migraine in adults. The treatment, marketed as Aimovig, is administered once monthly by self-injection.

During the open-label study, patients initially received 70 mg of erenumab monthly. After approximately 2 years, patients switched to 140 mg of erenumab monthly. The researchers’ interim efficacy analysis included all patients on 140 mg of erenumab with data about monthly migraine days after more than 4 years of treatment. The safety analysis included all patients who enrolled in the open-label treatment period and received at least one dose of erenumab.

Of 250 patients who increased the erenumab dose from 70 mg to 140 mg, a total of 221 (88%) completed the open-label treatment period or remained on 140 mg after more than 4 years. Patients’ average number of monthly migraine days at study baseline was 8.7, and the average change from baseline to the most recent month in the interim analysis was –5.8.

During the most recent month of assessment, 77% of patients had at least a 50% reduction in monthly migraine days from baseline, 56% had at least a 75% reduction, and 33% had a 100% reduction.

Mean change from baseline in acute migraine‐specific medication treatment days was –4.6, from a baseline of 6.1.

Among the 383 patients who entered the open-label treatment period and received at least one dose of erenumab (mean age, 41.3; 79% female), the median erenumab exposure was 58.5 months. The exposure‐adjusted incidence of adverse events per 100 patient‐years was 124.9, and the three most frequent adverse events (per 100 patient-years) were nasopharyngitis (10.9), upper respiratory tract infection (6.8), and influenza (4.7). The exposure‐adjusted incidence rate per 100 patient‐years for constipation was 1.3 (9/383) for 70-mg erenumab and 2.6 (15/250) for 140-mg erenumab.

“The exposure‐adjusted incidence rate per 100 patient‐years of serious adverse events was 3.8, similar to the rate observed for erenumab and placebo during the placebo‐controlled periods of studies,” the researchers said.

The study was sponsored by Amgen, and several study authors are employees of Amgen or Novartis, the companies that market erenumab. Dr. Ashina is a consultant for Amgen, Novartis, and other companies.

[email protected]

SOURCE: Ashina M et al. AHS 2019, Abstract IOR10.

PHILADELPHIA – Among patients with episodic migraine, 4.5 years of preventive treatment with erenumab is effective, safe, and well tolerated, according to interim data from an open-label extension study. “Erenumab was well tolerated and safe, with no safety signals detected over this period,” said Messoud Ashina, MD, PhD, professor of neurology at the University of Copenhagen. Dr. Ashina presented the interim data from a 5-year, open-label extension study of erenumab at the annual meeting of the American Headache Society.

Erenumab is a monoclonal antibody that targets and blocks the calcitonin gene-related peptide (CGRP) receptor. In May 2018, the Food and Drug Administration approved erenumab for the preventive treatment of migraine in adults. The treatment, marketed as Aimovig, is administered once monthly by self-injection.

During the open-label study, patients initially received 70 mg of erenumab monthly. After approximately 2 years, patients switched to 140 mg of erenumab monthly. The researchers’ interim efficacy analysis included all patients on 140 mg of erenumab with data about monthly migraine days after more than 4 years of treatment. The safety analysis included all patients who enrolled in the open-label treatment period and received at least one dose of erenumab.

Of 250 patients who increased the erenumab dose from 70 mg to 140 mg, a total of 221 (88%) completed the open-label treatment period or remained on 140 mg after more than 4 years. Patients’ average number of monthly migraine days at study baseline was 8.7, and the average change from baseline to the most recent month in the interim analysis was –5.8.

During the most recent month of assessment, 77% of patients had at least a 50% reduction in monthly migraine days from baseline, 56% had at least a 75% reduction, and 33% had a 100% reduction.

Mean change from baseline in acute migraine‐specific medication treatment days was –4.6, from a baseline of 6.1.

Among the 383 patients who entered the open-label treatment period and received at least one dose of erenumab (mean age, 41.3; 79% female), the median erenumab exposure was 58.5 months. The exposure‐adjusted incidence of adverse events per 100 patient‐years was 124.9, and the three most frequent adverse events (per 100 patient-years) were nasopharyngitis (10.9), upper respiratory tract infection (6.8), and influenza (4.7). The exposure‐adjusted incidence rate per 100 patient‐years for constipation was 1.3 (9/383) for 70-mg erenumab and 2.6 (15/250) for 140-mg erenumab.

“The exposure‐adjusted incidence rate per 100 patient‐years of serious adverse events was 3.8, similar to the rate observed for erenumab and placebo during the placebo‐controlled periods of studies,” the researchers said.

The study was sponsored by Amgen, and several study authors are employees of Amgen or Novartis, the companies that market erenumab. Dr. Ashina is a consultant for Amgen, Novartis, and other companies.

[email protected]

SOURCE: Ashina M et al. AHS 2019, Abstract IOR10.

Cryopreserving semen is a feasible option for preserving the fertility of adolescents and young adults who were assigned male at birth and are beginning or have already begun gender-affirming treatment as transgender women, according to results of a small retrospective cohort study.

The lack of data on this topic, however, makes it difficult to determine how long an individual must be off gender-affirming therapy before spermatogenesis resumes, if it resumes, and what the long-term effects of gender-affirming therapy are.

“This information is critical to address as part of a multidisciplinary fertility discussion with youth and their guardians so that an informed decision can be made regarding fertility preservation use,” wrote Emily P. Barnard, DO, of UPMC Magee-Womens Hospital in Pittsburgh and her associates.

The researchers retrospectively collected data on transgender patients who sought fertility preservation between 2015 and 2018.

The 11 white transgender women (sex assigned male at birth) who followed up on adolescent medicine or pediatric endocrinology referrals for fertility preservation received their consultations between ages 16 and 24, with 19 years having been the median age at which they occurred. Gender dysphoria onset happened at a median age of 12 for the patients, who were evaluated for it at a median age of 17.

All but one patient submitted at least one semen sample, and eight ultimately cryopreserved their semen.

The eight samples from gender-affirming therapy–naive patients had abnormal morphology, with the median morphology having been 6% versus the normal range of greater than 13.0%. Otherwise, the samples collected were normal, but the authors noted that established semen analysis parameters don’t exist for adolescents and young adults.

All eight patients who had their semen cryopreserved, began gonadotropin-releasing hormone (GnRH) agonist therapy after cryopreservation, and four of those patients concurrently began taking estradiol.

One patient had already been taking intramuscular leuprolide acetate every 6 months and discontinued it to attempt fertility preservation. Spermatogenesis returned after 5 months of azoospermia, albeit with abnormal morphology (9%).

Another patient had been taking spironolactone and estradiol for 26 months before ceasing therapy to attempt fertility preservation. She remained azoospermic 4 months after stopping therapy and then moved forward with an orchiectomy.

“For many transgender patients, the potential need to discontinue GnRH agonist or gender-affirming therapy to allow for resumption of spermatogenesis may be a significant barrier to pursuing fertility preservation because cessation of therapy may result in exacerbation of gender dysphoria and progression of undesired male secondary sex characteristics,” the researchers wrote. “For individuals for whom this risk is not acceptable or if azoospermia is noted on semen analysis, there are several alternate options, including electroejaculation, testicular sperm extraction, and testicular tissue cryopreservation,” they continued. Electroejaculation with a transrectal probe is an option particularly for those who cannot masturbate or feel uncomfortable doing so, the authors explained.

For those who have not previously received gender-affirming therapy, the fertility preservation “process can be completed quickly, with collections occurring every 2 to 3 days to preserve several samples before initiating GnRH agonist or gender-affirming therapy,” they concluded.

SOURCE: Barnard EP et al. Pediatrics. 2019 Aug 5. doi: 10.1542/peds.2018-3943.

Cryopreserving semen is a feasible option for preserving the fertility of adolescents and young adults who were assigned male at birth and are beginning or have already begun gender-affirming treatment as transgender women, according to results of a small retrospective cohort study.

The lack of data on this topic, however, makes it difficult to determine how long an individual must be off gender-affirming therapy before spermatogenesis resumes, if it resumes, and what the long-term effects of gender-affirming therapy are.

“This information is critical to address as part of a multidisciplinary fertility discussion with youth and their guardians so that an informed decision can be made regarding fertility preservation use,” wrote Emily P. Barnard, DO, of UPMC Magee-Womens Hospital in Pittsburgh and her associates.

The researchers retrospectively collected data on transgender patients who sought fertility preservation between 2015 and 2018.

The 11 white transgender women (sex assigned male at birth) who followed up on adolescent medicine or pediatric endocrinology referrals for fertility preservation received their consultations between ages 16 and 24, with 19 years having been the median age at which they occurred. Gender dysphoria onset happened at a median age of 12 for the patients, who were evaluated for it at a median age of 17.

All but one patient submitted at least one semen sample, and eight ultimately cryopreserved their semen.

The eight samples from gender-affirming therapy–naive patients had abnormal morphology, with the median morphology having been 6% versus the normal range of greater than 13.0%. Otherwise, the samples collected were normal, but the authors noted that established semen analysis parameters don’t exist for adolescents and young adults.

All eight patients who had their semen cryopreserved, began gonadotropin-releasing hormone (GnRH) agonist therapy after cryopreservation, and four of those patients concurrently began taking estradiol.

One patient had already been taking intramuscular leuprolide acetate every 6 months and discontinued it to attempt fertility preservation. Spermatogenesis returned after 5 months of azoospermia, albeit with abnormal morphology (9%).

Another patient had been taking spironolactone and estradiol for 26 months before ceasing therapy to attempt fertility preservation. She remained azoospermic 4 months after stopping therapy and then moved forward with an orchiectomy.

“For many transgender patients, the potential need to discontinue GnRH agonist or gender-affirming therapy to allow for resumption of spermatogenesis may be a significant barrier to pursuing fertility preservation because cessation of therapy may result in exacerbation of gender dysphoria and progression of undesired male secondary sex characteristics,” the researchers wrote. “For individuals for whom this risk is not acceptable or if azoospermia is noted on semen analysis, there are several alternate options, including electroejaculation, testicular sperm extraction, and testicular tissue cryopreservation,” they continued. Electroejaculation with a transrectal probe is an option particularly for those who cannot masturbate or feel uncomfortable doing so, the authors explained.

For those who have not previously received gender-affirming therapy, the fertility preservation “process can be completed quickly, with collections occurring every 2 to 3 days to preserve several samples before initiating GnRH agonist or gender-affirming therapy,” they concluded.

SOURCE: Barnard EP et al. Pediatrics. 2019 Aug 5. doi: 10.1542/peds.2018-3943.

Cryopreserving semen is a feasible option for preserving the fertility of adolescents and young adults who were assigned male at birth and are beginning or have already begun gender-affirming treatment as transgender women, according to results of a small retrospective cohort study.

The lack of data on this topic, however, makes it difficult to determine how long an individual must be off gender-affirming therapy before spermatogenesis resumes, if it resumes, and what the long-term effects of gender-affirming therapy are.

“This information is critical to address as part of a multidisciplinary fertility discussion with youth and their guardians so that an informed decision can be made regarding fertility preservation use,” wrote Emily P. Barnard, DO, of UPMC Magee-Womens Hospital in Pittsburgh and her associates.

The researchers retrospectively collected data on transgender patients who sought fertility preservation between 2015 and 2018.

The 11 white transgender women (sex assigned male at birth) who followed up on adolescent medicine or pediatric endocrinology referrals for fertility preservation received their consultations between ages 16 and 24, with 19 years having been the median age at which they occurred. Gender dysphoria onset happened at a median age of 12 for the patients, who were evaluated for it at a median age of 17.

All but one patient submitted at least one semen sample, and eight ultimately cryopreserved their semen.

The eight samples from gender-affirming therapy–naive patients had abnormal morphology, with the median morphology having been 6% versus the normal range of greater than 13.0%. Otherwise, the samples collected were normal, but the authors noted that established semen analysis parameters don’t exist for adolescents and young adults.

All eight patients who had their semen cryopreserved, began gonadotropin-releasing hormone (GnRH) agonist therapy after cryopreservation, and four of those patients concurrently began taking estradiol.

One patient had already been taking intramuscular leuprolide acetate every 6 months and discontinued it to attempt fertility preservation. Spermatogenesis returned after 5 months of azoospermia, albeit with abnormal morphology (9%).

Another patient had been taking spironolactone and estradiol for 26 months before ceasing therapy to attempt fertility preservation. She remained azoospermic 4 months after stopping therapy and then moved forward with an orchiectomy.

“For many transgender patients, the potential need to discontinue GnRH agonist or gender-affirming therapy to allow for resumption of spermatogenesis may be a significant barrier to pursuing fertility preservation because cessation of therapy may result in exacerbation of gender dysphoria and progression of undesired male secondary sex characteristics,” the researchers wrote. “For individuals for whom this risk is not acceptable or if azoospermia is noted on semen analysis, there are several alternate options, including electroejaculation, testicular sperm extraction, and testicular tissue cryopreservation,” they continued. Electroejaculation with a transrectal probe is an option particularly for those who cannot masturbate or feel uncomfortable doing so, the authors explained.

For those who have not previously received gender-affirming therapy, the fertility preservation “process can be completed quickly, with collections occurring every 2 to 3 days to preserve several samples before initiating GnRH agonist or gender-affirming therapy,” they concluded.

SOURCE: Barnard EP et al. Pediatrics. 2019 Aug 5. doi: 10.1542/peds.2018-3943.

Shared decision making around low-dose computed tomography screening for lung cancer should include risk and benefit information for baseline conditions such as chronic obstructive pulmonary disease (COPD), research suggests.

picsfive/Fotolia.com

Jonathan M. Iaccarino, MD, of the pulmonary center at the Boston University, and coauthors reported the results of a secondary analysis of patient-level outcomes from 75,138 low-dose CT (LDCT) scans in 26,453 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016).

Currently, LDCT screening is recommended annually for high-risk smokers aged 55-80 years. The National Lung Screening Trial showed that this screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in this group. The guidelines stress the importance of shared decision making, with discussion of the risks and benefits of screening.

Dr. Iaccarino and colleagues point out that decision aids for shared decision making need to include important baseline characteristics, such as the presence of COPD, as these can complicate the risk and benefit analysis.

In this study, they found that 14.2% of LDCT scans performed led to a subsequent diagnostic study and 1.5% resulted in an invasive procedure. In addition, 0.3% of scans resulted in a procedure-related complication, and in 89 cases (0.1%), this procedure-related complication was serious.

At the patient level, nearly one-third (30.5%) received a diagnostic study, 4.2% underwent an invasive procedure – 41% of whom ultimately were found not to have lung cancer – 0.9% had a procedure-related complication, and 0.3% had a serious procedure related complication. Furthermore, among those who experienced a serious complication, 12.5% were found not to have lung cancer.

“Our study analyzes cumulative outcomes at the level of the individual patient over the three years of LDCT screening during the NLST, showing higher rates of diagnostic procedures, invasive procedures, complications and serious complications than apparent when data is presented at the level of the individual test,” the authors wrote.

The 4,632 participants with COPD were significantly more likely to undergo diagnostic studies (36.2%), have an invasive procedure (6%), experience a procedure-related complication (1.5%) and experience a serious procedure-related complication (0.6%) than were participants without COPD. However, they also had a significantly higher incidence of lung cancer diagnosis than did participants without COPD (6.1% vs. 3.6%).

“While most decision aids note the risks of screening may be increased in those with COPD, our study helps quantify these increased risks as well as the increased likelihood of a lung cancer diagnosis, a critical advance given that providing personalized (rather than generic) information results in more accurate risk perception and more informed choices among individuals considering screening,” the authors wrote. “With the significant change in the balance of benefits and risks of screening in patients with COPD, it is critical to adjust the shared decision-making discussions accordingly.”

They also noted that other comorbidities, such as heart disease, vascular disease, and other lung diseases, would likely affect the balance of risk and benefit of LDCT screening, and that there was a need for further exploration of screening in these patients.

Noting the study’s limitations, the authors pointed that their analysis focused on outcomes that were not the primary outcomes of the National Lung Screening trial, and that they relied on self-reported COPD diagnoses.

The study was supported by the American Society of Clinical Oncology, the Charles A. King Trust, and Edith Nourse Rogers Memorial Veterans Hospital. No conflicts of interest were declared.

SOURCE: Iaccarino JM et al. CHEST 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016.

Shared decision making around low-dose computed tomography screening for lung cancer should include risk and benefit information for baseline conditions such as chronic obstructive pulmonary disease (COPD), research suggests.

picsfive/Fotolia.com

Jonathan M. Iaccarino, MD, of the pulmonary center at the Boston University, and coauthors reported the results of a secondary analysis of patient-level outcomes from 75,138 low-dose CT (LDCT) scans in 26,453 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016).

Currently, LDCT screening is recommended annually for high-risk smokers aged 55-80 years. The National Lung Screening Trial showed that this screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in this group. The guidelines stress the importance of shared decision making, with discussion of the risks and benefits of screening.

Dr. Iaccarino and colleagues point out that decision aids for shared decision making need to include important baseline characteristics, such as the presence of COPD, as these can complicate the risk and benefit analysis.

In this study, they found that 14.2% of LDCT scans performed led to a subsequent diagnostic study and 1.5% resulted in an invasive procedure. In addition, 0.3% of scans resulted in a procedure-related complication, and in 89 cases (0.1%), this procedure-related complication was serious.

At the patient level, nearly one-third (30.5%) received a diagnostic study, 4.2% underwent an invasive procedure – 41% of whom ultimately were found not to have lung cancer – 0.9% had a procedure-related complication, and 0.3% had a serious procedure related complication. Furthermore, among those who experienced a serious complication, 12.5% were found not to have lung cancer.

“Our study analyzes cumulative outcomes at the level of the individual patient over the three years of LDCT screening during the NLST, showing higher rates of diagnostic procedures, invasive procedures, complications and serious complications than apparent when data is presented at the level of the individual test,” the authors wrote.

The 4,632 participants with COPD were significantly more likely to undergo diagnostic studies (36.2%), have an invasive procedure (6%), experience a procedure-related complication (1.5%) and experience a serious procedure-related complication (0.6%) than were participants without COPD. However, they also had a significantly higher incidence of lung cancer diagnosis than did participants without COPD (6.1% vs. 3.6%).

“While most decision aids note the risks of screening may be increased in those with COPD, our study helps quantify these increased risks as well as the increased likelihood of a lung cancer diagnosis, a critical advance given that providing personalized (rather than generic) information results in more accurate risk perception and more informed choices among individuals considering screening,” the authors wrote. “With the significant change in the balance of benefits and risks of screening in patients with COPD, it is critical to adjust the shared decision-making discussions accordingly.”

They also noted that other comorbidities, such as heart disease, vascular disease, and other lung diseases, would likely affect the balance of risk and benefit of LDCT screening, and that there was a need for further exploration of screening in these patients.

Noting the study’s limitations, the authors pointed that their analysis focused on outcomes that were not the primary outcomes of the National Lung Screening trial, and that they relied on self-reported COPD diagnoses.

The study was supported by the American Society of Clinical Oncology, the Charles A. King Trust, and Edith Nourse Rogers Memorial Veterans Hospital. No conflicts of interest were declared.

SOURCE: Iaccarino JM et al. CHEST 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016.

Shared decision making around low-dose computed tomography screening for lung cancer should include risk and benefit information for baseline conditions such as chronic obstructive pulmonary disease (COPD), research suggests.

picsfive/Fotolia.com

Jonathan M. Iaccarino, MD, of the pulmonary center at the Boston University, and coauthors reported the results of a secondary analysis of patient-level outcomes from 75,138 low-dose CT (LDCT) scans in 26,453 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016).

Currently, LDCT screening is recommended annually for high-risk smokers aged 55-80 years. The National Lung Screening Trial showed that this screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in this group. The guidelines stress the importance of shared decision making, with discussion of the risks and benefits of screening.

Dr. Iaccarino and colleagues point out that decision aids for shared decision making need to include important baseline characteristics, such as the presence of COPD, as these can complicate the risk and benefit analysis.

In this study, they found that 14.2% of LDCT scans performed led to a subsequent diagnostic study and 1.5% resulted in an invasive procedure. In addition, 0.3% of scans resulted in a procedure-related complication, and in 89 cases (0.1%), this procedure-related complication was serious.

At the patient level, nearly one-third (30.5%) received a diagnostic study, 4.2% underwent an invasive procedure – 41% of whom ultimately were found not to have lung cancer – 0.9% had a procedure-related complication, and 0.3% had a serious procedure related complication. Furthermore, among those who experienced a serious complication, 12.5% were found not to have lung cancer.

“Our study analyzes cumulative outcomes at the level of the individual patient over the three years of LDCT screening during the NLST, showing higher rates of diagnostic procedures, invasive procedures, complications and serious complications than apparent when data is presented at the level of the individual test,” the authors wrote.

The 4,632 participants with COPD were significantly more likely to undergo diagnostic studies (36.2%), have an invasive procedure (6%), experience a procedure-related complication (1.5%) and experience a serious procedure-related complication (0.6%) than were participants without COPD. However, they also had a significantly higher incidence of lung cancer diagnosis than did participants without COPD (6.1% vs. 3.6%).

“While most decision aids note the risks of screening may be increased in those with COPD, our study helps quantify these increased risks as well as the increased likelihood of a lung cancer diagnosis, a critical advance given that providing personalized (rather than generic) information results in more accurate risk perception and more informed choices among individuals considering screening,” the authors wrote. “With the significant change in the balance of benefits and risks of screening in patients with COPD, it is critical to adjust the shared decision-making discussions accordingly.”

They also noted that other comorbidities, such as heart disease, vascular disease, and other lung diseases, would likely affect the balance of risk and benefit of LDCT screening, and that there was a need for further exploration of screening in these patients.

Noting the study’s limitations, the authors pointed that their analysis focused on outcomes that were not the primary outcomes of the National Lung Screening trial, and that they relied on self-reported COPD diagnoses.

The study was supported by the American Society of Clinical Oncology, the Charles A. King Trust, and Edith Nourse Rogers Memorial Veterans Hospital. No conflicts of interest were declared.

SOURCE: Iaccarino JM et al. CHEST 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016.

Most advanced gastrointestinal stromal tumors (GISTs) are due to a recurrence of localized disease, with only a small minority presenting with metastatic disease.¹ Compared with chemotherapy, tyrosine kinase inhibitors (TKIs) have significantly improved the natural history of the disease, with median overall survival (OS) increasing from less than 1 year to about 5 years and approximately 1 in 5 patients achieving long-term survival.² In addition, newer drugs in development and in clinical trials appear promising and have the potential to improve outcomes even further. This article reviews current evidence on options for treating metastatic or recurrent GISTs and GISTs that have progressed following initial therapy. The evaluation and diagnosis of GIST along with management of localized disease are reviewed in a separate article.

Case Presentation

A 64-year-old African American man underwent surgical resection of a 10-cm gastric mass, which pathology reported was positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. There were 10 mitoses per 50 HPF, and there was no intraoperative or intraperitoneal tumor rupture. The patient was treated with adjuvant imatinib, which was discontinued after 3 years due to grade 2 myalgias, periorbital edema, and macrocytic anemia. Surveillance included office visits every 3 to 6 months and a contrast CT abdomen and pelvis every 6 months. For the past 5 years, he has not had any clinical or radiographic evidence of disease recurrence. New imaging reveals multiple liver metastases and peritoneal implants. He feels fatigued and has lost about 10 lb since his last visit. He is 5 years out from his initial diagnosis and 2 years out from last receiving imatinib. His original tumor harbored a KIT exon 11 deletion.

What treatment should you recommend now?

Imatinib for Advanced GISTs

Before the first report of the efficacy of imatinib for metastatic GISTs in 2002, patients with advanced unresectable or metastatic GISTs were routinely treated with doxorubicin-based chemotherapy regimens, which were largely ineffective, with response rates (RRs) of around 5% and a median overall survival (OS) of less than 1 year.^3,4 In 2002 a landmark phase 2 study revealed imatinib’s significant efficacy profile in advanced or metastatic GISTs, resulting in its approval by the US Food and Drug Administration (FDA).⁵ In this study, 147 patients with CD117-positive GISTs were randomly assigned to receive daily imatinib 400 mg or 600 mg for up to 36 months. The RRs were similar between the 2 groups (68.5% vs 67.6%), with a median time to response of 12 weeks and median duration of response of 118 days. Results of this study were much more favorable when compared to doxorubicin, rendering imatinib the new standard of care for advanced GISTs. A long-term follow-up of this study after a median of 63 months confirmed near identical RRs, progression-free survival (PFS), and median survival of 57 months among the 2 groups.⁶

Imatinib Daily Dosing

Although 400 mg of daily imatinib proved to be efficacious, it was unclear if a dose-response relationship existed for imatinib. An EORTC phase 2 study demonstrated a benefit of using a higher dose of imatinib at 400 mg twice daily, producing a RR of 71% (4% complete , 67% partial) and 1-year PFS of 73%, which appeared favorable compared with once-daily dosing and set the framework for larger phase 3 studies.⁷ Two phase 3 studies compared imatinib 400 mg once daily versus twice daily (until disease progression or unacceptable toxicity) among patients with CD117-positive advanced or metastatic GISTs. These studies were eventually combined into a meta-analysis (metaGIST) to compare RR, PFS and OS between the treatment groups. Both studies allowed cross-over to the 800 mg dose for patients who progressed on 400 mg daily.

The first study, conducted jointly by the EORTC, Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group (EU-AUS),⁸ randomly assigned 946 patients to 400 mg once daily or twice daily. There were no differences in response rates between the groups, but the twice-daily group had a predicted 18% reduction in the hazard for progression compared with the once-daily group (estimated HR, 0.82; P = 0.026), which came at the expense of greater toxicities warranting dose reductions (60%) and treatment interruptions (64%). Cross-over to high-dose imatinib was feasible and safe, producing a partial response in 2%, stable disease in 27%, and a median PFS of 81 days. The second study was an intergroup study conducted jointly by SWOG, CALGB, NCI-C, and ECOG (S0033, US-CDN), with a nearly identical study design as the EU-AUS trial.⁹ The trial enrolled 746 patients. After a median follow up of 4.5 years, the median PFS and OS were not statistically different (18 vs 20 months and 55 vs 51 months, respectively). There were also no differences in response rates. One third of patients initially placed on the once-daily arm who crossed over after progression achieved a treatment response or stable disease.

The combined EU-AUS and US-CDN analysis (metaGIST) included 1640 patients with a median age of 60 years and 58% of whom were men; 818 and 822 patients were assigned to the 400 mg and 800 mg total daily doses, respectively.¹⁰ The median follow-up was 37.5 months. There were no differences in OS (49 vs 48.7 months), median PFS (18.9 vs 23.2 months), or overall response rates (51.4% vs 53.9%). Patients who had crossed over (n = 347) to the 800 mg total daily dose arm had a 7.7-month average PFS while on the higher daily dose. An analysis was performed on 377 patients in the EU-AUS trial assessing the impact of mutational status on clinical outcomes among imatinib-treated patients. KIT exon 9 activating mutations were found to be a significant independent prognostic factor for death when compared with KIT exon 11 mutations. However, the adverse prognostic value of KIT exon 9 mutations was partially overcome with higher doses of imatinib, as those who received 800 mg total had a significantly better PFS, with a 61% relative risk reduction, than those who received 400 mg. Altogether, it was concluded that imatinib 400 mg once daily should be the standard-of-care first-line treatment for advanced or metastatic GISTs, unless a KIT exon 9 mutation is present, in which case imatinib 800 mg should be considered, if 400 mg is well tolerated. In addition, patients treated with frontline imatinib at 400 mg once daily, if tolerated well, should be considered for imatinib 800 mg upon progression of disease.

Despite there being problems with secondary resistance, significant progress has occurred in the treatment of metastatic disease over a short period of time. Prior to 2000, median OS for patients with metastatic GISTs was 9 months. With the introduction of imatinib and other TKIs, the median OS has increased to 5 years, with an estimated 10-year OS rate of approximately 20%.²

Since at this point, imatinib was a well-established standard of care for advanced GISTs, it was questioned whether imatinib therapy could be interrupted. At this time, treatment interruption in a stop-and-go fashion was deemed feasible in other metastatic solid tumors such as colorectal cancer (OPTIMOX1).¹¹ The BFR French trial showed that stopping imatinib therapy in patients who had a response or stable disease after 1, 3, or 5 years was generally followed by relatively rapid tumor progression (approximately 50% of patients within 6 months), even when tumors were previously removed.¹² Therefore, it is recommended that treatment in the metastatic setting should be continued indefinitely, unless there is disease progression. Hence, unlike with colorectal cancer or chronic myelogenous leukemia, as of now there is no role for imatinib interruption in metastatic GISTs.

Case Continued

The patient is started on imatinib 400 mg daily, and overall he tolerates therapy well. Interval CT imaging reveals a treatment response. Two years later, imaging reveals an increase in the tumor size and density with a new nodule present within a preexisting mass. There are no clinical trials in the area.

What defines tumor progression?

Disease Progression

When GISTs are responding to treatment, on imaging the tumors can become more cystic and less dense but with an increase in size. In addition, tumor progression may not always be associated with increased size—increased density of the tumor or a nodule within a mass that may indicate progression. If CT imaging is equivocal for progression, positron emission tomography (PET) can play a role in identifying true progression. It is critically important that tumor size and density are carefully assessed when performing interval imaging. Of note, radiofrequency ablation, cryotherapy, or chemoembolization can be used for symptomatic liver metastases or oligometastatic disease. When evaluating for progression, one needs to ask patients about compliance (ie, maintaining dose intensity related to side effects of therapy as well as the financial burden of treatment—copay toxicity).

What are mechanisms of secondary imatinib resistance?

Imatinib resistance can be subtle in patients with GISTs, manifesting with new nodular, enhancing foci enclosed within a preexisting mass (resistant clonal nodule), or can be clinically or radiographically overt.¹³ Imatinib resistance occurs through multiple mechanisms including acquisition of secondary activating KIT mutations in the intracellular ATP-binding domain (exons 13 and 14) and the activation loop (exons 17 and 18).¹⁴

What are the treatment options for this patient?

Second-line Therapy

Sunitinib malate is a multitargeted TKI that not only targets c-Kit and PDGFRA, but also has anti-angiogenic activity through inhibition of vascular endothelial growth factor receptors (VEGFR). Sunitinib gained FDA approval for the second-line treatment of advanced GISTs based on an international double-blind trial that randomized 312 patients with imatinib-resistant metastatic GISTs in a 2:1 fashion to receive sunitinib 50 mg daily for 4 weeks on and 2 weeks off or placebo.^15,16 The trial was unblinded early at the planned interim analysis, which revealed a marked benefit, producing a 66% reduction in the hazard risk of progression (27.3 vs 6.4 weeks, HR, 0.33; P < 0.001). The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, and hand-foot syndrome. Another open-label phase 2 study assessed a continuous dosing schema of sunitinib 37.5 mg daily, which has been shown to be effective with less toxicity.¹⁷ Among the 60 patients enrolled, the primary endpoint of clinical benefit rate at 24 weeks was reached in 53%, which consisted of 13% partial responses and 40% stable disease. Most toxicities were grade 1 or 2 and easily manageable through standard interventions. This has been recommended as an alternative to the initial scheduled regimen.¹⁸ Part of sunitinib’s success is its activity against GISTs harboring secondary KIT exon 13 and 14 mutations, and possibly its anti-angiogenic activity.¹⁹ Sunitinib is particularly efficacious among GISTs harboring KIT exon 9 mutations.

Patients who have progressed on prior imatinib and sunitinib can receive third-line regorafenib, a multi-TKI that differs chemically from sorafenib by a fluorouracil group (fluoro-sorafenib). FDA approval of regorafenib was based on the phase 3 GRID (GIST Regorafenib In progressive Disease) multicenter international trial.²⁰ This trial randomly assigned 199 patients in a 2:1 fashion to receive regorafenib 160 mg daily for 21 days out of 28-day cycles plus best supportive care (BSC) versus placebo plus BSC. Cross-over was allowed. Regorafenib significantly reduced the hazard risk of progression by 73% compared with placebo (4.8 vs 0.9 months; HR, 0.27; P < 0.001). There was no difference in OS, which may be because of cross-over (median OS, 17.4 months in both arms). As a result, regorafenib is now considered standard third-line treatment for patients with metastatic GISTs. It has a less favorable toxicity profile than imatinib, with hand-foot syndrome, transaminitis, hypertension and fatigue being the most common treatment toxicities. In order to avoid noncompliance, it is recommended to start at 80 mg and carefully titrate upwards to the 160 mg dose.

A list of landmark studies for advanced GISTs is provided in Table 1.

A summary of FDA-approved drugs for treating GISTs is provided in Table 2.

Clinical Trials

Clinical trial enrollment should be considered for all patients with advanced or unresectable GISTs throughout their treatment continuum. Owing to significant advances in genomic profiling through next-generation sequencing, multiple driver mutations have recently been identified, and targeted therapies are being explored in clinical trials.²¹ For example, the neurotrophic receptor tyrosine kinase (NTRK) gene appears to be mutated in a small number of advanced GISTs, and these can respond to the highly selective TRK inhibitor larotrectinib.²² Additionally, ongoing studies are assessing immunotherapies for sporadic GISTs and treatment for familial GISTs (Table 3). Some notable studies include those assessing the efficacy of agents that target KIT and PDGFR secondary mutations, including avapritinib (BLU-285) and DCC-2618, MEK inhibitors, and the multi-kinase inhibitor crenolanib for GISTs harboring the imatinib-resistant PDGFRA D842V mutation. There are also studies utilizing checkpoint inhibitors alone or in combination with imatinib.

Case Conclusion

Given the patient’s progression on imatinib, he is started on second-line sunitinib malate. He experiences grade 1 fatigue and hand-foot syndrome, which are managed supportively. After he has been on sunitinib for approximately 8 months, his disease progresses. He subsequently undergoes genomic profiling of his tumor and starts BLU-285 on a clinical trial.

Key Points

• For advanced and metastatic disease, TKIs have substantially improved the prognosis of KIT mutated GISTs, with 3 FDA-approved drugs: imatinib, sunitinib, and regorafenib. Imatinib 400 mg is the standard-of-care frontline therapy for locally advanced, unresectable, or metastatic imatinib-sensitive GISTs. If a patient has a KIT exon 9 mutation and 400 mg is well-tolerated, increasing to 800 mg is recommended. Imatinib should be continued indefinitely unless there is intolerance, a specific patient request for interruption, or progression of disease.
• When there is progression of disease in a patient with a sensitive mutation on 400 mg of imatinib, the dose can be increased to 800 mg.
• For patients who are imatinib-intolerant or have progression, standard second line is sunitinib.
• For patients who further progress or are sunitinib-intolerant, regorafenib is the standard third-line treatment.
• There needs to be close attention to side effects, drug and food interactions, and patient copay costs in order to maintain patient compliance while on TKI therapy.
• There are still major limitations in the systemic treatment of GISTs marked by their inherent genetic heterogeneity and secondary resistance. Continued translational and clinical research is needed in order to improve treatment for patients who develop secondary resistance or who have less common primary resistant mutations. Patients are encouraged to participate in clinical trials of new therapies.

Summary

GISTs are the most common mesenchymal tumors of the GI tract. They comprise an expanding landscape of tumors that are heterogenous in terms of natural history, mutations, and response to systemic treatments. The mainstay of treatment for localized GISTs is surgical resection followed by at least 3-years of adjuvant imatinib for patients with high-risk features who are imatinib-sensitive. Patients with GISTs harboring resistance mutations such as PDGFRA D842V or with SDH-deficient or NF1-associated GISTs should not receive adjuvant imatinib. Patients with more advanced GISTs and/or in difficult to resect sites harboring a sensitive mutation can be considered for neoadjuvant imatinib. Those with metastatic GISTs can receive first-, second-, and third-line imatinib, sunitinib, or regorafenib, respectively. Clinical trial enrollment should be encouraged for patients whose GISTs harbor primary imatinib-resistant mutations, and those with advanced or unresectable GISTs with secondary resistance.

Most advanced gastrointestinal stromal tumors (GISTs) are due to a recurrence of localized disease, with only a small minority presenting with metastatic disease.¹ Compared with chemotherapy, tyrosine kinase inhibitors (TKIs) have significantly improved the natural history of the disease, with median overall survival (OS) increasing from less than 1 year to about 5 years and approximately 1 in 5 patients achieving long-term survival.² In addition, newer drugs in development and in clinical trials appear promising and have the potential to improve outcomes even further. This article reviews current evidence on options for treating metastatic or recurrent GISTs and GISTs that have progressed following initial therapy. The evaluation and diagnosis of GIST along with management of localized disease are reviewed in a separate article.

Case Presentation

A 64-year-old African American man underwent surgical resection of a 10-cm gastric mass, which pathology reported was positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. There were 10 mitoses per 50 HPF, and there was no intraoperative or intraperitoneal tumor rupture. The patient was treated with adjuvant imatinib, which was discontinued after 3 years due to grade 2 myalgias, periorbital edema, and macrocytic anemia. Surveillance included office visits every 3 to 6 months and a contrast CT abdomen and pelvis every 6 months. For the past 5 years, he has not had any clinical or radiographic evidence of disease recurrence. New imaging reveals multiple liver metastases and peritoneal implants. He feels fatigued and has lost about 10 lb since his last visit. He is 5 years out from his initial diagnosis and 2 years out from last receiving imatinib. His original tumor harbored a KIT exon 11 deletion.

What treatment should you recommend now?

Imatinib for Advanced GISTs

Before the first report of the efficacy of imatinib for metastatic GISTs in 2002, patients with advanced unresectable or metastatic GISTs were routinely treated with doxorubicin-based chemotherapy regimens, which were largely ineffective, with response rates (RRs) of around 5% and a median overall survival (OS) of less than 1 year.^3,4 In 2002 a landmark phase 2 study revealed imatinib’s significant efficacy profile in advanced or metastatic GISTs, resulting in its approval by the US Food and Drug Administration (FDA).⁵ In this study, 147 patients with CD117-positive GISTs were randomly assigned to receive daily imatinib 400 mg or 600 mg for up to 36 months. The RRs were similar between the 2 groups (68.5% vs 67.6%), with a median time to response of 12 weeks and median duration of response of 118 days. Results of this study were much more favorable when compared to doxorubicin, rendering imatinib the new standard of care for advanced GISTs. A long-term follow-up of this study after a median of 63 months confirmed near identical RRs, progression-free survival (PFS), and median survival of 57 months among the 2 groups.⁶

Imatinib Daily Dosing

Although 400 mg of daily imatinib proved to be efficacious, it was unclear if a dose-response relationship existed for imatinib. An EORTC phase 2 study demonstrated a benefit of using a higher dose of imatinib at 400 mg twice daily, producing a RR of 71% (4% complete , 67% partial) and 1-year PFS of 73%, which appeared favorable compared with once-daily dosing and set the framework for larger phase 3 studies.⁷ Two phase 3 studies compared imatinib 400 mg once daily versus twice daily (until disease progression or unacceptable toxicity) among patients with CD117-positive advanced or metastatic GISTs. These studies were eventually combined into a meta-analysis (metaGIST) to compare RR, PFS and OS between the treatment groups. Both studies allowed cross-over to the 800 mg dose for patients who progressed on 400 mg daily.

The first study, conducted jointly by the EORTC, Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group (EU-AUS),⁸ randomly assigned 946 patients to 400 mg once daily or twice daily. There were no differences in response rates between the groups, but the twice-daily group had a predicted 18% reduction in the hazard for progression compared with the once-daily group (estimated HR, 0.82; P = 0.026), which came at the expense of greater toxicities warranting dose reductions (60%) and treatment interruptions (64%). Cross-over to high-dose imatinib was feasible and safe, producing a partial response in 2%, stable disease in 27%, and a median PFS of 81 days. The second study was an intergroup study conducted jointly by SWOG, CALGB, NCI-C, and ECOG (S0033, US-CDN), with a nearly identical study design as the EU-AUS trial.⁹ The trial enrolled 746 patients. After a median follow up of 4.5 years, the median PFS and OS were not statistically different (18 vs 20 months and 55 vs 51 months, respectively). There were also no differences in response rates. One third of patients initially placed on the once-daily arm who crossed over after progression achieved a treatment response or stable disease.

The combined EU-AUS and US-CDN analysis (metaGIST) included 1640 patients with a median age of 60 years and 58% of whom were men; 818 and 822 patients were assigned to the 400 mg and 800 mg total daily doses, respectively.¹⁰ The median follow-up was 37.5 months. There were no differences in OS (49 vs 48.7 months), median PFS (18.9 vs 23.2 months), or overall response rates (51.4% vs 53.9%). Patients who had crossed over (n = 347) to the 800 mg total daily dose arm had a 7.7-month average PFS while on the higher daily dose. An analysis was performed on 377 patients in the EU-AUS trial assessing the impact of mutational status on clinical outcomes among imatinib-treated patients. KIT exon 9 activating mutations were found to be a significant independent prognostic factor for death when compared with KIT exon 11 mutations. However, the adverse prognostic value of KIT exon 9 mutations was partially overcome with higher doses of imatinib, as those who received 800 mg total had a significantly better PFS, with a 61% relative risk reduction, than those who received 400 mg. Altogether, it was concluded that imatinib 400 mg once daily should be the standard-of-care first-line treatment for advanced or metastatic GISTs, unless a KIT exon 9 mutation is present, in which case imatinib 800 mg should be considered, if 400 mg is well tolerated. In addition, patients treated with frontline imatinib at 400 mg once daily, if tolerated well, should be considered for imatinib 800 mg upon progression of disease.

Despite there being problems with secondary resistance, significant progress has occurred in the treatment of metastatic disease over a short period of time. Prior to 2000, median OS for patients with metastatic GISTs was 9 months. With the introduction of imatinib and other TKIs, the median OS has increased to 5 years, with an estimated 10-year OS rate of approximately 20%.²

Since at this point, imatinib was a well-established standard of care for advanced GISTs, it was questioned whether imatinib therapy could be interrupted. At this time, treatment interruption in a stop-and-go fashion was deemed feasible in other metastatic solid tumors such as colorectal cancer (OPTIMOX1).¹¹ The BFR French trial showed that stopping imatinib therapy in patients who had a response or stable disease after 1, 3, or 5 years was generally followed by relatively rapid tumor progression (approximately 50% of patients within 6 months), even when tumors were previously removed.¹² Therefore, it is recommended that treatment in the metastatic setting should be continued indefinitely, unless there is disease progression. Hence, unlike with colorectal cancer or chronic myelogenous leukemia, as of now there is no role for imatinib interruption in metastatic GISTs.

Case Continued

The patient is started on imatinib 400 mg daily, and overall he tolerates therapy well. Interval CT imaging reveals a treatment response. Two years later, imaging reveals an increase in the tumor size and density with a new nodule present within a preexisting mass. There are no clinical trials in the area.

What defines tumor progression?

Disease Progression

When GISTs are responding to treatment, on imaging the tumors can become more cystic and less dense but with an increase in size. In addition, tumor progression may not always be associated with increased size—increased density of the tumor or a nodule within a mass that may indicate progression. If CT imaging is equivocal for progression, positron emission tomography (PET) can play a role in identifying true progression. It is critically important that tumor size and density are carefully assessed when performing interval imaging. Of note, radiofrequency ablation, cryotherapy, or chemoembolization can be used for symptomatic liver metastases or oligometastatic disease. When evaluating for progression, one needs to ask patients about compliance (ie, maintaining dose intensity related to side effects of therapy as well as the financial burden of treatment—copay toxicity).

What are mechanisms of secondary imatinib resistance?

Imatinib resistance can be subtle in patients with GISTs, manifesting with new nodular, enhancing foci enclosed within a preexisting mass (resistant clonal nodule), or can be clinically or radiographically overt.¹³ Imatinib resistance occurs through multiple mechanisms including acquisition of secondary activating KIT mutations in the intracellular ATP-binding domain (exons 13 and 14) and the activation loop (exons 17 and 18).¹⁴

What are the treatment options for this patient?

Second-line Therapy

Sunitinib malate is a multitargeted TKI that not only targets c-Kit and PDGFRA, but also has anti-angiogenic activity through inhibition of vascular endothelial growth factor receptors (VEGFR). Sunitinib gained FDA approval for the second-line treatment of advanced GISTs based on an international double-blind trial that randomized 312 patients with imatinib-resistant metastatic GISTs in a 2:1 fashion to receive sunitinib 50 mg daily for 4 weeks on and 2 weeks off or placebo.^15,16 The trial was unblinded early at the planned interim analysis, which revealed a marked benefit, producing a 66% reduction in the hazard risk of progression (27.3 vs 6.4 weeks, HR, 0.33; P < 0.001). The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, and hand-foot syndrome. Another open-label phase 2 study assessed a continuous dosing schema of sunitinib 37.5 mg daily, which has been shown to be effective with less toxicity.¹⁷ Among the 60 patients enrolled, the primary endpoint of clinical benefit rate at 24 weeks was reached in 53%, which consisted of 13% partial responses and 40% stable disease. Most toxicities were grade 1 or 2 and easily manageable through standard interventions. This has been recommended as an alternative to the initial scheduled regimen.¹⁸ Part of sunitinib’s success is its activity against GISTs harboring secondary KIT exon 13 and 14 mutations, and possibly its anti-angiogenic activity.¹⁹ Sunitinib is particularly efficacious among GISTs harboring KIT exon 9 mutations.

Patients who have progressed on prior imatinib and sunitinib can receive third-line regorafenib, a multi-TKI that differs chemically from sorafenib by a fluorouracil group (fluoro-sorafenib). FDA approval of regorafenib was based on the phase 3 GRID (GIST Regorafenib In progressive Disease) multicenter international trial.²⁰ This trial randomly assigned 199 patients in a 2:1 fashion to receive regorafenib 160 mg daily for 21 days out of 28-day cycles plus best supportive care (BSC) versus placebo plus BSC. Cross-over was allowed. Regorafenib significantly reduced the hazard risk of progression by 73% compared with placebo (4.8 vs 0.9 months; HR, 0.27; P < 0.001). There was no difference in OS, which may be because of cross-over (median OS, 17.4 months in both arms). As a result, regorafenib is now considered standard third-line treatment for patients with metastatic GISTs. It has a less favorable toxicity profile than imatinib, with hand-foot syndrome, transaminitis, hypertension and fatigue being the most common treatment toxicities. In order to avoid noncompliance, it is recommended to start at 80 mg and carefully titrate upwards to the 160 mg dose.

A list of landmark studies for advanced GISTs is provided in Table 1.

A summary of FDA-approved drugs for treating GISTs is provided in Table 2.

Clinical Trials

Clinical trial enrollment should be considered for all patients with advanced or unresectable GISTs throughout their treatment continuum. Owing to significant advances in genomic profiling through next-generation sequencing, multiple driver mutations have recently been identified, and targeted therapies are being explored in clinical trials.²¹ For example, the neurotrophic receptor tyrosine kinase (NTRK) gene appears to be mutated in a small number of advanced GISTs, and these can respond to the highly selective TRK inhibitor larotrectinib.²² Additionally, ongoing studies are assessing immunotherapies for sporadic GISTs and treatment for familial GISTs (Table 3). Some notable studies include those assessing the efficacy of agents that target KIT and PDGFR secondary mutations, including avapritinib (BLU-285) and DCC-2618, MEK inhibitors, and the multi-kinase inhibitor crenolanib for GISTs harboring the imatinib-resistant PDGFRA D842V mutation. There are also studies utilizing checkpoint inhibitors alone or in combination with imatinib.

Case Conclusion

Given the patient’s progression on imatinib, he is started on second-line sunitinib malate. He experiences grade 1 fatigue and hand-foot syndrome, which are managed supportively. After he has been on sunitinib for approximately 8 months, his disease progresses. He subsequently undergoes genomic profiling of his tumor and starts BLU-285 on a clinical trial.

Key Points

• For advanced and metastatic disease, TKIs have substantially improved the prognosis of KIT mutated GISTs, with 3 FDA-approved drugs: imatinib, sunitinib, and regorafenib. Imatinib 400 mg is the standard-of-care frontline therapy for locally advanced, unresectable, or metastatic imatinib-sensitive GISTs. If a patient has a KIT exon 9 mutation and 400 mg is well-tolerated, increasing to 800 mg is recommended. Imatinib should be continued indefinitely unless there is intolerance, a specific patient request for interruption, or progression of disease.
• When there is progression of disease in a patient with a sensitive mutation on 400 mg of imatinib, the dose can be increased to 800 mg.
• For patients who are imatinib-intolerant or have progression, standard second line is sunitinib.
• For patients who further progress or are sunitinib-intolerant, regorafenib is the standard third-line treatment.
• There needs to be close attention to side effects, drug and food interactions, and patient copay costs in order to maintain patient compliance while on TKI therapy.
• There are still major limitations in the systemic treatment of GISTs marked by their inherent genetic heterogeneity and secondary resistance. Continued translational and clinical research is needed in order to improve treatment for patients who develop secondary resistance or who have less common primary resistant mutations. Patients are encouraged to participate in clinical trials of new therapies.

Summary

GISTs are the most common mesenchymal tumors of the GI tract. They comprise an expanding landscape of tumors that are heterogenous in terms of natural history, mutations, and response to systemic treatments. The mainstay of treatment for localized GISTs is surgical resection followed by at least 3-years of adjuvant imatinib for patients with high-risk features who are imatinib-sensitive. Patients with GISTs harboring resistance mutations such as PDGFRA D842V or with SDH-deficient or NF1-associated GISTs should not receive adjuvant imatinib. Patients with more advanced GISTs and/or in difficult to resect sites harboring a sensitive mutation can be considered for neoadjuvant imatinib. Those with metastatic GISTs can receive first-, second-, and third-line imatinib, sunitinib, or regorafenib, respectively. Clinical trial enrollment should be encouraged for patients whose GISTs harbor primary imatinib-resistant mutations, and those with advanced or unresectable GISTs with secondary resistance.

Most advanced gastrointestinal stromal tumors (GISTs) are due to a recurrence of localized disease, with only a small minority presenting with metastatic disease.¹ Compared with chemotherapy, tyrosine kinase inhibitors (TKIs) have significantly improved the natural history of the disease, with median overall survival (OS) increasing from less than 1 year to about 5 years and approximately 1 in 5 patients achieving long-term survival.² In addition, newer drugs in development and in clinical trials appear promising and have the potential to improve outcomes even further. This article reviews current evidence on options for treating metastatic or recurrent GISTs and GISTs that have progressed following initial therapy. The evaluation and diagnosis of GIST along with management of localized disease are reviewed in a separate article.

Case Presentation

A 64-year-old African American man underwent surgical resection of a 10-cm gastric mass, which pathology reported was positive for CD117, DOG1, and CD34 and negative for smooth muscle actin and S-100, consistent with a diagnosis of GIST. There were 10 mitoses per 50 HPF, and there was no intraoperative or intraperitoneal tumor rupture. The patient was treated with adjuvant imatinib, which was discontinued after 3 years due to grade 2 myalgias, periorbital edema, and macrocytic anemia. Surveillance included office visits every 3 to 6 months and a contrast CT abdomen and pelvis every 6 months. For the past 5 years, he has not had any clinical or radiographic evidence of disease recurrence. New imaging reveals multiple liver metastases and peritoneal implants. He feels fatigued and has lost about 10 lb since his last visit. He is 5 years out from his initial diagnosis and 2 years out from last receiving imatinib. His original tumor harbored a KIT exon 11 deletion.

What treatment should you recommend now?

Imatinib for Advanced GISTs

Before the first report of the efficacy of imatinib for metastatic GISTs in 2002, patients with advanced unresectable or metastatic GISTs were routinely treated with doxorubicin-based chemotherapy regimens, which were largely ineffective, with response rates (RRs) of around 5% and a median overall survival (OS) of less than 1 year.^3,4 In 2002 a landmark phase 2 study revealed imatinib’s significant efficacy profile in advanced or metastatic GISTs, resulting in its approval by the US Food and Drug Administration (FDA).⁵ In this study, 147 patients with CD117-positive GISTs were randomly assigned to receive daily imatinib 400 mg or 600 mg for up to 36 months. The RRs were similar between the 2 groups (68.5% vs 67.6%), with a median time to response of 12 weeks and median duration of response of 118 days. Results of this study were much more favorable when compared to doxorubicin, rendering imatinib the new standard of care for advanced GISTs. A long-term follow-up of this study after a median of 63 months confirmed near identical RRs, progression-free survival (PFS), and median survival of 57 months among the 2 groups.⁶

Imatinib Daily Dosing

Although 400 mg of daily imatinib proved to be efficacious, it was unclear if a dose-response relationship existed for imatinib. An EORTC phase 2 study demonstrated a benefit of using a higher dose of imatinib at 400 mg twice daily, producing a RR of 71% (4% complete , 67% partial) and 1-year PFS of 73%, which appeared favorable compared with once-daily dosing and set the framework for larger phase 3 studies.⁷ Two phase 3 studies compared imatinib 400 mg once daily versus twice daily (until disease progression or unacceptable toxicity) among patients with CD117-positive advanced or metastatic GISTs. These studies were eventually combined into a meta-analysis (metaGIST) to compare RR, PFS and OS between the treatment groups. Both studies allowed cross-over to the 800 mg dose for patients who progressed on 400 mg daily.

The first study, conducted jointly by the EORTC, Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group (EU-AUS),⁸ randomly assigned 946 patients to 400 mg once daily or twice daily. There were no differences in response rates between the groups, but the twice-daily group had a predicted 18% reduction in the hazard for progression compared with the once-daily group (estimated HR, 0.82; P = 0.026), which came at the expense of greater toxicities warranting dose reductions (60%) and treatment interruptions (64%). Cross-over to high-dose imatinib was feasible and safe, producing a partial response in 2%, stable disease in 27%, and a median PFS of 81 days. The second study was an intergroup study conducted jointly by SWOG, CALGB, NCI-C, and ECOG (S0033, US-CDN), with a nearly identical study design as the EU-AUS trial.⁹ The trial enrolled 746 patients. After a median follow up of 4.5 years, the median PFS and OS were not statistically different (18 vs 20 months and 55 vs 51 months, respectively). There were also no differences in response rates. One third of patients initially placed on the once-daily arm who crossed over after progression achieved a treatment response or stable disease.

The combined EU-AUS and US-CDN analysis (metaGIST) included 1640 patients with a median age of 60 years and 58% of whom were men; 818 and 822 patients were assigned to the 400 mg and 800 mg total daily doses, respectively.¹⁰ The median follow-up was 37.5 months. There were no differences in OS (49 vs 48.7 months), median PFS (18.9 vs 23.2 months), or overall response rates (51.4% vs 53.9%). Patients who had crossed over (n = 347) to the 800 mg total daily dose arm had a 7.7-month average PFS while on the higher daily dose. An analysis was performed on 377 patients in the EU-AUS trial assessing the impact of mutational status on clinical outcomes among imatinib-treated patients. KIT exon 9 activating mutations were found to be a significant independent prognostic factor for death when compared with KIT exon 11 mutations. However, the adverse prognostic value of KIT exon 9 mutations was partially overcome with higher doses of imatinib, as those who received 800 mg total had a significantly better PFS, with a 61% relative risk reduction, than those who received 400 mg. Altogether, it was concluded that imatinib 400 mg once daily should be the standard-of-care first-line treatment for advanced or metastatic GISTs, unless a KIT exon 9 mutation is present, in which case imatinib 800 mg should be considered, if 400 mg is well tolerated. In addition, patients treated with frontline imatinib at 400 mg once daily, if tolerated well, should be considered for imatinib 800 mg upon progression of disease.

Despite there being problems with secondary resistance, significant progress has occurred in the treatment of metastatic disease over a short period of time. Prior to 2000, median OS for patients with metastatic GISTs was 9 months. With the introduction of imatinib and other TKIs, the median OS has increased to 5 years, with an estimated 10-year OS rate of approximately 20%.²

Since at this point, imatinib was a well-established standard of care for advanced GISTs, it was questioned whether imatinib therapy could be interrupted. At this time, treatment interruption in a stop-and-go fashion was deemed feasible in other metastatic solid tumors such as colorectal cancer (OPTIMOX1).¹¹ The BFR French trial showed that stopping imatinib therapy in patients who had a response or stable disease after 1, 3, or 5 years was generally followed by relatively rapid tumor progression (approximately 50% of patients within 6 months), even when tumors were previously removed.¹² Therefore, it is recommended that treatment in the metastatic setting should be continued indefinitely, unless there is disease progression. Hence, unlike with colorectal cancer or chronic myelogenous leukemia, as of now there is no role for imatinib interruption in metastatic GISTs.

Case Continued

The patient is started on imatinib 400 mg daily, and overall he tolerates therapy well. Interval CT imaging reveals a treatment response. Two years later, imaging reveals an increase in the tumor size and density with a new nodule present within a preexisting mass. There are no clinical trials in the area.

What defines tumor progression?

Disease Progression

When GISTs are responding to treatment, on imaging the tumors can become more cystic and less dense but with an increase in size. In addition, tumor progression may not always be associated with increased size—increased density of the tumor or a nodule within a mass that may indicate progression. If CT imaging is equivocal for progression, positron emission tomography (PET) can play a role in identifying true progression. It is critically important that tumor size and density are carefully assessed when performing interval imaging. Of note, radiofrequency ablation, cryotherapy, or chemoembolization can be used for symptomatic liver metastases or oligometastatic disease. When evaluating for progression, one needs to ask patients about compliance (ie, maintaining dose intensity related to side effects of therapy as well as the financial burden of treatment—copay toxicity).

What are mechanisms of secondary imatinib resistance?

Imatinib resistance can be subtle in patients with GISTs, manifesting with new nodular, enhancing foci enclosed within a preexisting mass (resistant clonal nodule), or can be clinically or radiographically overt.¹³ Imatinib resistance occurs through multiple mechanisms including acquisition of secondary activating KIT mutations in the intracellular ATP-binding domain (exons 13 and 14) and the activation loop (exons 17 and 18).¹⁴

What are the treatment options for this patient?

Second-line Therapy

Sunitinib malate is a multitargeted TKI that not only targets c-Kit and PDGFRA, but also has anti-angiogenic activity through inhibition of vascular endothelial growth factor receptors (VEGFR). Sunitinib gained FDA approval for the second-line treatment of advanced GISTs based on an international double-blind trial that randomized 312 patients with imatinib-resistant metastatic GISTs in a 2:1 fashion to receive sunitinib 50 mg daily for 4 weeks on and 2 weeks off or placebo.^15,16 The trial was unblinded early at the planned interim analysis, which revealed a marked benefit, producing a 66% reduction in the hazard risk of progression (27.3 vs 6.4 weeks, HR, 0.33; P < 0.001). The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, and hand-foot syndrome. Another open-label phase 2 study assessed a continuous dosing schema of sunitinib 37.5 mg daily, which has been shown to be effective with less toxicity.¹⁷ Among the 60 patients enrolled, the primary endpoint of clinical benefit rate at 24 weeks was reached in 53%, which consisted of 13% partial responses and 40% stable disease. Most toxicities were grade 1 or 2 and easily manageable through standard interventions. This has been recommended as an alternative to the initial scheduled regimen.¹⁸ Part of sunitinib’s success is its activity against GISTs harboring secondary KIT exon 13 and 14 mutations, and possibly its anti-angiogenic activity.¹⁹ Sunitinib is particularly efficacious among GISTs harboring KIT exon 9 mutations.

Patients who have progressed on prior imatinib and sunitinib can receive third-line regorafenib, a multi-TKI that differs chemically from sorafenib by a fluorouracil group (fluoro-sorafenib). FDA approval of regorafenib was based on the phase 3 GRID (GIST Regorafenib In progressive Disease) multicenter international trial.²⁰ This trial randomly assigned 199 patients in a 2:1 fashion to receive regorafenib 160 mg daily for 21 days out of 28-day cycles plus best supportive care (BSC) versus placebo plus BSC. Cross-over was allowed. Regorafenib significantly reduced the hazard risk of progression by 73% compared with placebo (4.8 vs 0.9 months; HR, 0.27; P < 0.001). There was no difference in OS, which may be because of cross-over (median OS, 17.4 months in both arms). As a result, regorafenib is now considered standard third-line treatment for patients with metastatic GISTs. It has a less favorable toxicity profile than imatinib, with hand-foot syndrome, transaminitis, hypertension and fatigue being the most common treatment toxicities. In order to avoid noncompliance, it is recommended to start at 80 mg and carefully titrate upwards to the 160 mg dose.

A list of landmark studies for advanced GISTs is provided in Table 1.

A summary of FDA-approved drugs for treating GISTs is provided in Table 2.

Clinical Trials

Clinical trial enrollment should be considered for all patients with advanced or unresectable GISTs throughout their treatment continuum. Owing to significant advances in genomic profiling through next-generation sequencing, multiple driver mutations have recently been identified, and targeted therapies are being explored in clinical trials.²¹ For example, the neurotrophic receptor tyrosine kinase (NTRK) gene appears to be mutated in a small number of advanced GISTs, and these can respond to the highly selective TRK inhibitor larotrectinib.²² Additionally, ongoing studies are assessing immunotherapies for sporadic GISTs and treatment for familial GISTs (Table 3). Some notable studies include those assessing the efficacy of agents that target KIT and PDGFR secondary mutations, including avapritinib (BLU-285) and DCC-2618, MEK inhibitors, and the multi-kinase inhibitor crenolanib for GISTs harboring the imatinib-resistant PDGFRA D842V mutation. There are also studies utilizing checkpoint inhibitors alone or in combination with imatinib.

Case Conclusion

Given the patient’s progression on imatinib, he is started on second-line sunitinib malate. He experiences grade 1 fatigue and hand-foot syndrome, which are managed supportively. After he has been on sunitinib for approximately 8 months, his disease progresses. He subsequently undergoes genomic profiling of his tumor and starts BLU-285 on a clinical trial.

Key Points

• For advanced and metastatic disease, TKIs have substantially improved the prognosis of KIT mutated GISTs, with 3 FDA-approved drugs: imatinib, sunitinib, and regorafenib. Imatinib 400 mg is the standard-of-care frontline therapy for locally advanced, unresectable, or metastatic imatinib-sensitive GISTs. If a patient has a KIT exon 9 mutation and 400 mg is well-tolerated, increasing to 800 mg is recommended. Imatinib should be continued indefinitely unless there is intolerance, a specific patient request for interruption, or progression of disease.
• When there is progression of disease in a patient with a sensitive mutation on 400 mg of imatinib, the dose can be increased to 800 mg.
• For patients who are imatinib-intolerant or have progression, standard second line is sunitinib.
• For patients who further progress or are sunitinib-intolerant, regorafenib is the standard third-line treatment.
• There needs to be close attention to side effects, drug and food interactions, and patient copay costs in order to maintain patient compliance while on TKI therapy.
• There are still major limitations in the systemic treatment of GISTs marked by their inherent genetic heterogeneity and secondary resistance. Continued translational and clinical research is needed in order to improve treatment for patients who develop secondary resistance or who have less common primary resistant mutations. Patients are encouraged to participate in clinical trials of new therapies.

Summary

GISTs are the most common mesenchymal tumors of the GI tract. They comprise an expanding landscape of tumors that are heterogenous in terms of natural history, mutations, and response to systemic treatments. The mainstay of treatment for localized GISTs is surgical resection followed by at least 3-years of adjuvant imatinib for patients with high-risk features who are imatinib-sensitive. Patients with GISTs harboring resistance mutations such as PDGFRA D842V or with SDH-deficient or NF1-associated GISTs should not receive adjuvant imatinib. Patients with more advanced GISTs and/or in difficult to resect sites harboring a sensitive mutation can be considered for neoadjuvant imatinib. Those with metastatic GISTs can receive first-, second-, and third-line imatinib, sunitinib, or regorafenib, respectively. Clinical trial enrollment should be encouraged for patients whose GISTs harbor primary imatinib-resistant mutations, and those with advanced or unresectable GISTs with secondary resistance.

Abbott Laboratories has issued a recall of all Ellipse Implantable Cardioverter Defibrillators manufactured between April 5, 2019, and May 29, 2019, because of exposed aluminum wires within the device, potentially preventing defibrillation.

The Ellipse Implantable Cardioverter Defibrillators, formerly manufactured by St. Jude Medical (now a wholly-owned subsidiary of Abbott), provide pacing for patients with bradycardia and electric shock or pacing for patients with tachycardia. The device is implanted under the skin in the upper chest area with leads running into the heart.

The recall has been issued because electrical failures have occurred; Abbott has determined that these failures are caused by a faulty manufacturing process that left some aluminum wires in the leads partially exposed. Wires without proper insulation are likely to short, leaving the device without the ability to provide high voltage therapy.

Abbott is aware of no related reports of electrical failure in any of the devices that have already been implanted, the Food and Drug Administration announced, and no reports of patient harm, adverse events, or death have occurred. All affected devices that were implanted have either been replaced or are scheduled to be replaced, the agency said.

[email protected]

Abbott Laboratories has issued a recall of all Ellipse Implantable Cardioverter Defibrillators manufactured between April 5, 2019, and May 29, 2019, because of exposed aluminum wires within the device, potentially preventing defibrillation.

The Ellipse Implantable Cardioverter Defibrillators, formerly manufactured by St. Jude Medical (now a wholly-owned subsidiary of Abbott), provide pacing for patients with bradycardia and electric shock or pacing for patients with tachycardia. The device is implanted under the skin in the upper chest area with leads running into the heart.

The recall has been issued because electrical failures have occurred; Abbott has determined that these failures are caused by a faulty manufacturing process that left some aluminum wires in the leads partially exposed. Wires without proper insulation are likely to short, leaving the device without the ability to provide high voltage therapy.

Abbott is aware of no related reports of electrical failure in any of the devices that have already been implanted, the Food and Drug Administration announced, and no reports of patient harm, adverse events, or death have occurred. All affected devices that were implanted have either been replaced or are scheduled to be replaced, the agency said.

[email protected]

Abbott Laboratories has issued a recall of all Ellipse Implantable Cardioverter Defibrillators manufactured between April 5, 2019, and May 29, 2019, because of exposed aluminum wires within the device, potentially preventing defibrillation.

The Ellipse Implantable Cardioverter Defibrillators, formerly manufactured by St. Jude Medical (now a wholly-owned subsidiary of Abbott), provide pacing for patients with bradycardia and electric shock or pacing for patients with tachycardia. The device is implanted under the skin in the upper chest area with leads running into the heart.

The recall has been issued because electrical failures have occurred; Abbott has determined that these failures are caused by a faulty manufacturing process that left some aluminum wires in the leads partially exposed. Wires without proper insulation are likely to short, leaving the device without the ability to provide high voltage therapy.

Abbott is aware of no related reports of electrical failure in any of the devices that have already been implanted, the Food and Drug Administration announced, and no reports of patient harm, adverse events, or death have occurred. All affected devices that were implanted have either been replaced or are scheduled to be replaced, the agency said.

[email protected]

Physicians who receive professional coaching are less emotionally exhausted and less vulnerable to burnout, according to the results of a pilot study.

dragana991/iStock/Getty Images Plus

“This intervention adds to the growing literature of evidence-based approaches to promote physician well-being and should be considered a complementary strategy to be deployed in combination with other organizational approaches to improve system-level drivers of work-related stressors,” wrote Liselotte N. Dyrbye, MD, of the Mayo Clinic in Rochester, Minn., and coauthors in JAMA Internal Medicine.

Dr. Dyrbye and colleagues conducted a randomized pilot study of 88 Mayo Clinic physicians in the departments of medicine, family medicine, and pediatrics. Half (n = 44) received 3.5 hours of sessions facilitated by a professional coach. The other half (n = 44) served as controls. Participants’ well-being – in regard to burnout, quality of life, resilience, job satisfaction, engagement, and meaning at work – was surveyed at baseline and the study’s completion.

Physicians in the coaching group participated in a 1-hour initial telephone session, designed to establish a relationship between the physician and coach, as well as to assess needs, set goals, identify values, and create an action plan. During follow-up sessions, coaches would check in, help plan and set goals, and suggest strategies/changes to incorporate into daily life. Physicians were permitted to ask for support on any issue, but also were expected to see as many patients as their colleagues outside of the study.

After 6 months, physicians in the coaching group saw a significant decrease in emotional exhaustion by a mean of 5.2 points, compared with an increase of 1.5 points in the control group. At 5 months, absolute rates of high emotional exhaustion decreased by 19.5% in the coaching group and increased by 9.8% in the control group and absolute rates of overall burnout decreased by 17.1% in the coaching group and increased by 4.9% in the control group. Quality of life and resilience scores also improved, though there were no notable differences between groups in measures of job satisfaction, engagement, and meaning at work.

The authors noted their study’s limitations, which included a modest sample size and a volunteer group of participants.

In addition, the lower percentage of men in the study – 48 of 88 participants were women – may be a result of factors that deserve further investigation. Finally, burnout rates among volunteers were higher than those among other physicians, suggesting that “the study appealed to those in greatest need of the intervention.”

The study was funded by the Mayo Clinic department of medicine’s Program on Physician Well-Being and the Physician Foundation. Two of the authors – Dr. Dyrbye and Tait D. Shanafelt, MD, of Stanford (Calif.) University – reported being the coinventors of, and receiving royalties for, the Physician Well-Being Index, Medical Student Well-Being Index, Nurse Well-Being Index, and the Well-Being Index.

SOURCE: Dyrbye LN et al. JAMA Intern Med. 2019 Aug 5. doi: 10.1001/jamainternmed.2019.2425.

Physicians who receive professional coaching are less emotionally exhausted and less vulnerable to burnout, according to the results of a pilot study.

dragana991/iStock/Getty Images Plus

“This intervention adds to the growing literature of evidence-based approaches to promote physician well-being and should be considered a complementary strategy to be deployed in combination with other organizational approaches to improve system-level drivers of work-related stressors,” wrote Liselotte N. Dyrbye, MD, of the Mayo Clinic in Rochester, Minn., and coauthors in JAMA Internal Medicine.

Dr. Dyrbye and colleagues conducted a randomized pilot study of 88 Mayo Clinic physicians in the departments of medicine, family medicine, and pediatrics. Half (n = 44) received 3.5 hours of sessions facilitated by a professional coach. The other half (n = 44) served as controls. Participants’ well-being – in regard to burnout, quality of life, resilience, job satisfaction, engagement, and meaning at work – was surveyed at baseline and the study’s completion.

Physicians in the coaching group participated in a 1-hour initial telephone session, designed to establish a relationship between the physician and coach, as well as to assess needs, set goals, identify values, and create an action plan. During follow-up sessions, coaches would check in, help plan and set goals, and suggest strategies/changes to incorporate into daily life. Physicians were permitted to ask for support on any issue, but also were expected to see as many patients as their colleagues outside of the study.

After 6 months, physicians in the coaching group saw a significant decrease in emotional exhaustion by a mean of 5.2 points, compared with an increase of 1.5 points in the control group. At 5 months, absolute rates of high emotional exhaustion decreased by 19.5% in the coaching group and increased by 9.8% in the control group and absolute rates of overall burnout decreased by 17.1% in the coaching group and increased by 4.9% in the control group. Quality of life and resilience scores also improved, though there were no notable differences between groups in measures of job satisfaction, engagement, and meaning at work.

The authors noted their study’s limitations, which included a modest sample size and a volunteer group of participants.

In addition, the lower percentage of men in the study – 48 of 88 participants were women – may be a result of factors that deserve further investigation. Finally, burnout rates among volunteers were higher than those among other physicians, suggesting that “the study appealed to those in greatest need of the intervention.”

The study was funded by the Mayo Clinic department of medicine’s Program on Physician Well-Being and the Physician Foundation. Two of the authors – Dr. Dyrbye and Tait D. Shanafelt, MD, of Stanford (Calif.) University – reported being the coinventors of, and receiving royalties for, the Physician Well-Being Index, Medical Student Well-Being Index, Nurse Well-Being Index, and the Well-Being Index.

SOURCE: Dyrbye LN et al. JAMA Intern Med. 2019 Aug 5. doi: 10.1001/jamainternmed.2019.2425.

Physicians who receive professional coaching are less emotionally exhausted and less vulnerable to burnout, according to the results of a pilot study.

dragana991/iStock/Getty Images Plus

“This intervention adds to the growing literature of evidence-based approaches to promote physician well-being and should be considered a complementary strategy to be deployed in combination with other organizational approaches to improve system-level drivers of work-related stressors,” wrote Liselotte N. Dyrbye, MD, of the Mayo Clinic in Rochester, Minn., and coauthors in JAMA Internal Medicine.

Dr. Dyrbye and colleagues conducted a randomized pilot study of 88 Mayo Clinic physicians in the departments of medicine, family medicine, and pediatrics. Half (n = 44) received 3.5 hours of sessions facilitated by a professional coach. The other half (n = 44) served as controls. Participants’ well-being – in regard to burnout, quality of life, resilience, job satisfaction, engagement, and meaning at work – was surveyed at baseline and the study’s completion.

Physicians in the coaching group participated in a 1-hour initial telephone session, designed to establish a relationship between the physician and coach, as well as to assess needs, set goals, identify values, and create an action plan. During follow-up sessions, coaches would check in, help plan and set goals, and suggest strategies/changes to incorporate into daily life. Physicians were permitted to ask for support on any issue, but also were expected to see as many patients as their colleagues outside of the study.

After 6 months, physicians in the coaching group saw a significant decrease in emotional exhaustion by a mean of 5.2 points, compared with an increase of 1.5 points in the control group. At 5 months, absolute rates of high emotional exhaustion decreased by 19.5% in the coaching group and increased by 9.8% in the control group and absolute rates of overall burnout decreased by 17.1% in the coaching group and increased by 4.9% in the control group. Quality of life and resilience scores also improved, though there were no notable differences between groups in measures of job satisfaction, engagement, and meaning at work.

The authors noted their study’s limitations, which included a modest sample size and a volunteer group of participants.

In addition, the lower percentage of men in the study – 48 of 88 participants were women – may be a result of factors that deserve further investigation. Finally, burnout rates among volunteers were higher than those among other physicians, suggesting that “the study appealed to those in greatest need of the intervention.”

The study was funded by the Mayo Clinic department of medicine’s Program on Physician Well-Being and the Physician Foundation. Two of the authors – Dr. Dyrbye and Tait D. Shanafelt, MD, of Stanford (Calif.) University – reported being the coinventors of, and receiving royalties for, the Physician Well-Being Index, Medical Student Well-Being Index, Nurse Well-Being Index, and the Well-Being Index.

SOURCE: Dyrbye LN et al. JAMA Intern Med. 2019 Aug 5. doi: 10.1001/jamainternmed.2019.2425.

BANGKOK – Since founding the Epilepsy Unit at Glasgow’s Western Infirmary 37 years ago, Martin J. Brodie, MD, has seen many changes in the field, including the introduction of more than a dozen new antiepileptic drugs (AEDs) in the past 2 decades.

Bruce Jancin/MDedge News

And based upon this vast clinical experience coupled with his leadership of landmark studies, he has a message for his physician colleagues and their epilepsy patients. And it’s not pretty.

“Has the probability of achieving seizure freedom increased significantly in the last 3 decades? Regrettably, the answer is no,” he declared at the International Epilepsy Congress.

“Over all these years, in terms of seizure freedom there has been no real difference in outcome. There’s really quite a long way to go before we can say that we are doing all that well for people,” he said at the congress sponsored by the International League Against Epilepsy.

In the year 2000, he and his coinvestigators published a prospective, longitudinal, observational cohort study of 470 newly diagnosed patients with epilepsy treated at the Western Infirmary during 1982-1997, all with a minimum of 2 years’ follow-up. Sixty-one percent achieved complete freedom from seizures for at least 1 year on monotherapy, and another 3% did so on polytherapy, for a total rate of 64% (N Engl J Med. 2000 Feb 3;342[5]:314-19).

But these were patients who by and large were treated with older AEDs such as carbamazepine, which has since fallen by the wayside because of toxicities. Scottish neurologists now generally turn to lamotrigine (Lamictal), levetiracetam (Spritam), and other, newer AEDs. So Dr. Brodie and his coworkers recently published a follow-up study, this one featuring 30 years of longitudinal follow-up of 1,795 patients newly treated for epilepsy with AEDs, new and old, during 1982-2012. The investigators demonstrated that the seizure-free survival curves over time were virtually superimposable. In the larger, more recent study, remission was achieved in 55% of patients with AED monotherapy and in another 9% with polytherapy, for a total rate of 64%, identical to the rate in the 2000 study, and as was the case in the earlier study, 36% of patients remained uncontrolled (JAMA Neurol. 2018 Mar 1;75[3]:279-86).


“Overall, the way this population behaves, there’s no difference in efficacy and no difference in tolerability whether you’re using old drugs used properly or new drugs used properly,” said Dr. Brodie, professor of neurology at the University of Glasgow (Scotland).

It’s noteworthy that Sir William R. Gowers, the Londoner who has been called the greatest neurologist of all time, reported a 70% seizure-free rate in 1881, while Dr. Brodie and workers achieved a 64% rate in their 30-year study. “It’s interesting that the numbers are so bad, really, I suppose,” Dr. Brodie commented.

How about outcomes in pediatric epilepsy?

Dr. Brodie and coworkers recently published a 30-year prospective cohort study of 332 adolescent epilepsy patients newly diagnosed and treated at the Western Infirmary during 1982-2012. At the end of the study, 67% were seizure-free for at least the past year, a feat accomplished via monotherapy in 83% of cases. The seizure-free rate was 72% in those with generalized epilepsy, significantly better than the 60% figure in those with focal epilepsy. The efficacy rate was 74% with newer AED monotherapy and similar at 77% with monotherapy older drugs. Adverse event rates ranged from a low of 12% with lamotrigine to 56% with topiramate (Topamax), according to the findings published in Epilepsia (2019 Jun;60[6]:1083-90).

Roughly similar outcomes have been reported from Norway in a study of 600 children with epilepsy, median age 7 years, with a median follow-up of 5.8 years that is considerably shorter than that in the Glasgow pediatric study. Overall, 59% of the Norwegian children remained seizure free for at least 1 year, 30% developed drug-resistant epilepsy, and 11% followed an intermediate remitting/relapsing course (Pediatrics. 2018 Jun. doi: 10.1542/peds.2017-4016).
 

Why the decades of flat pharmacologic outcomes?

The consistently suboptimal seizure-free outcomes obtained over the past 30 years shouldn’t really be surprising, according to Dr. Brodie.

“Although we think we have lots of mechanisms of action and lots of differences between the drugs, they’re arguably all antiseizure drugs and not antiepilepsy drugs. We don’t treat the whale; we treat the spout. We don’t treat what we cannot see; we treat what we can see, which is the seizures, but we’re not influencing the long-term outcome,” the neurologist explained.
 

The compelling case for early epilepsy surgery

Epilepsy surgery remains underutilized, according to Dr. Brodie and other experts.

The International League Against Epilepsy defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately chosen and used AED schedules. Dr. Brodie’s work was influential in creating that definition because his data demonstrated the sharply diminishing returns of additional drug trials.

“When do we consider epilepsy surgery? Arguably, the earlier, the better. After two drugs have failed appropriately, I don’t think anybody in this room would argue about that, although people in some of the other rooms might,” he said at the congress.

Influential in his thinking on this score were the impressive results of an early study, the first-ever randomized trial of surgery for epilepsy. In 80 patients with a 21-year history of drug-refractory temporal lobe epilepsy who were randomized to surgery or 1 year of AED therapy, at 1 year of follow-up blinded epileptologists rated 58% of surgically treated patients as free from seizures that impair awareness of self and surroundings, compared with just 8% in the AED group (N Engl J Med. 2001 Aug 2;345[5]:311-8).

“That’s a big outcome, and I’m very keen to ensure that my data continue to drive the push for early surgery,” according to the neurologist.

A Cochrane review of 177 studies totaling more than 16,000 patients concluded that 65% of epilepsy patients had good outcomes following surgery. Prognostic factors associated with better surgical outcomes included complete surgical resection of the epileptogenic focus, the presence of mesial temporal sclerosis, concordance of MRI and EEG findings, and an absence of cortical dysplasia (Cochrane Database Syst Rev. 2019;6:CD010541. doi: 10.1002/14651858.CD010541.pub3).

In addition, a systematic review and meta-analysis by Canadian investigators found that 72% of adults with lesional epilepsy identified by MRI or histopathology were seizure-free after surgery, compared with 36% of those with nonlesional epilepsy. The disparity in outcomes was similar in pediatric epilepsy patients, with seizure freedom after surgery in 74% of those with lesional disease versus 45% with nonlesional epilepsy (Epilepsy Res. 2010 May;89[2-3]:310-8).
 

Whither are neurostimulatory device therapies headed?

Dr. Brodie was quick to admit that as a pharmacologic researcher, device modalities including vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation are outside his area of expertise. But he’s been following developments in the field with interest.

“These device therapies have shown efficacy in short-term randomized trials, but very few patients attain long-term seizure freedom. I think these are largely palliative techniques. I gave up on these techniques a long time ago because I felt it was a very costly way of reducing seizures by a relatively small margin, and really we need to go a little bit further than that. But I know there’s a lot of work going on at the moment,” he said.

Dr. Brodie reported serving on the scientific advisory boards of more than a half dozen pharmaceutical companies.

[email protected]

BANGKOK – Since founding the Epilepsy Unit at Glasgow’s Western Infirmary 37 years ago, Martin J. Brodie, MD, has seen many changes in the field, including the introduction of more than a dozen new antiepileptic drugs (AEDs) in the past 2 decades.

Bruce Jancin/MDedge News

And based upon this vast clinical experience coupled with his leadership of landmark studies, he has a message for his physician colleagues and their epilepsy patients. And it’s not pretty.

“Has the probability of achieving seizure freedom increased significantly in the last 3 decades? Regrettably, the answer is no,” he declared at the International Epilepsy Congress.

“Over all these years, in terms of seizure freedom there has been no real difference in outcome. There’s really quite a long way to go before we can say that we are doing all that well for people,” he said at the congress sponsored by the International League Against Epilepsy.

In the year 2000, he and his coinvestigators published a prospective, longitudinal, observational cohort study of 470 newly diagnosed patients with epilepsy treated at the Western Infirmary during 1982-1997, all with a minimum of 2 years’ follow-up. Sixty-one percent achieved complete freedom from seizures for at least 1 year on monotherapy, and another 3% did so on polytherapy, for a total rate of 64% (N Engl J Med. 2000 Feb 3;342[5]:314-19).

But these were patients who by and large were treated with older AEDs such as carbamazepine, which has since fallen by the wayside because of toxicities. Scottish neurologists now generally turn to lamotrigine (Lamictal), levetiracetam (Spritam), and other, newer AEDs. So Dr. Brodie and his coworkers recently published a follow-up study, this one featuring 30 years of longitudinal follow-up of 1,795 patients newly treated for epilepsy with AEDs, new and old, during 1982-2012. The investigators demonstrated that the seizure-free survival curves over time were virtually superimposable. In the larger, more recent study, remission was achieved in 55% of patients with AED monotherapy and in another 9% with polytherapy, for a total rate of 64%, identical to the rate in the 2000 study, and as was the case in the earlier study, 36% of patients remained uncontrolled (JAMA Neurol. 2018 Mar 1;75[3]:279-86).


“Overall, the way this population behaves, there’s no difference in efficacy and no difference in tolerability whether you’re using old drugs used properly or new drugs used properly,” said Dr. Brodie, professor of neurology at the University of Glasgow (Scotland).

It’s noteworthy that Sir William R. Gowers, the Londoner who has been called the greatest neurologist of all time, reported a 70% seizure-free rate in 1881, while Dr. Brodie and workers achieved a 64% rate in their 30-year study. “It’s interesting that the numbers are so bad, really, I suppose,” Dr. Brodie commented.

How about outcomes in pediatric epilepsy?

Dr. Brodie and coworkers recently published a 30-year prospective cohort study of 332 adolescent epilepsy patients newly diagnosed and treated at the Western Infirmary during 1982-2012. At the end of the study, 67% were seizure-free for at least the past year, a feat accomplished via monotherapy in 83% of cases. The seizure-free rate was 72% in those with generalized epilepsy, significantly better than the 60% figure in those with focal epilepsy. The efficacy rate was 74% with newer AED monotherapy and similar at 77% with monotherapy older drugs. Adverse event rates ranged from a low of 12% with lamotrigine to 56% with topiramate (Topamax), according to the findings published in Epilepsia (2019 Jun;60[6]:1083-90).

Roughly similar outcomes have been reported from Norway in a study of 600 children with epilepsy, median age 7 years, with a median follow-up of 5.8 years that is considerably shorter than that in the Glasgow pediatric study. Overall, 59% of the Norwegian children remained seizure free for at least 1 year, 30% developed drug-resistant epilepsy, and 11% followed an intermediate remitting/relapsing course (Pediatrics. 2018 Jun. doi: 10.1542/peds.2017-4016).
 

Why the decades of flat pharmacologic outcomes?

The consistently suboptimal seizure-free outcomes obtained over the past 30 years shouldn’t really be surprising, according to Dr. Brodie.

“Although we think we have lots of mechanisms of action and lots of differences between the drugs, they’re arguably all antiseizure drugs and not antiepilepsy drugs. We don’t treat the whale; we treat the spout. We don’t treat what we cannot see; we treat what we can see, which is the seizures, but we’re not influencing the long-term outcome,” the neurologist explained.
 

The compelling case for early epilepsy surgery

Epilepsy surgery remains underutilized, according to Dr. Brodie and other experts.

The International League Against Epilepsy defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately chosen and used AED schedules. Dr. Brodie’s work was influential in creating that definition because his data demonstrated the sharply diminishing returns of additional drug trials.

“When do we consider epilepsy surgery? Arguably, the earlier, the better. After two drugs have failed appropriately, I don’t think anybody in this room would argue about that, although people in some of the other rooms might,” he said at the congress.

Influential in his thinking on this score were the impressive results of an early study, the first-ever randomized trial of surgery for epilepsy. In 80 patients with a 21-year history of drug-refractory temporal lobe epilepsy who were randomized to surgery or 1 year of AED therapy, at 1 year of follow-up blinded epileptologists rated 58% of surgically treated patients as free from seizures that impair awareness of self and surroundings, compared with just 8% in the AED group (N Engl J Med. 2001 Aug 2;345[5]:311-8).

“That’s a big outcome, and I’m very keen to ensure that my data continue to drive the push for early surgery,” according to the neurologist.

A Cochrane review of 177 studies totaling more than 16,000 patients concluded that 65% of epilepsy patients had good outcomes following surgery. Prognostic factors associated with better surgical outcomes included complete surgical resection of the epileptogenic focus, the presence of mesial temporal sclerosis, concordance of MRI and EEG findings, and an absence of cortical dysplasia (Cochrane Database Syst Rev. 2019;6:CD010541. doi: 10.1002/14651858.CD010541.pub3).

In addition, a systematic review and meta-analysis by Canadian investigators found that 72% of adults with lesional epilepsy identified by MRI or histopathology were seizure-free after surgery, compared with 36% of those with nonlesional epilepsy. The disparity in outcomes was similar in pediatric epilepsy patients, with seizure freedom after surgery in 74% of those with lesional disease versus 45% with nonlesional epilepsy (Epilepsy Res. 2010 May;89[2-3]:310-8).
 

Whither are neurostimulatory device therapies headed?

Dr. Brodie was quick to admit that as a pharmacologic researcher, device modalities including vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation are outside his area of expertise. But he’s been following developments in the field with interest.

“These device therapies have shown efficacy in short-term randomized trials, but very few patients attain long-term seizure freedom. I think these are largely palliative techniques. I gave up on these techniques a long time ago because I felt it was a very costly way of reducing seizures by a relatively small margin, and really we need to go a little bit further than that. But I know there’s a lot of work going on at the moment,” he said.

Dr. Brodie reported serving on the scientific advisory boards of more than a half dozen pharmaceutical companies.

[email protected]

BANGKOK – Since founding the Epilepsy Unit at Glasgow’s Western Infirmary 37 years ago, Martin J. Brodie, MD, has seen many changes in the field, including the introduction of more than a dozen new antiepileptic drugs (AEDs) in the past 2 decades.

Bruce Jancin/MDedge News

And based upon this vast clinical experience coupled with his leadership of landmark studies, he has a message for his physician colleagues and their epilepsy patients. And it’s not pretty.

“Has the probability of achieving seizure freedom increased significantly in the last 3 decades? Regrettably, the answer is no,” he declared at the International Epilepsy Congress.

“Over all these years, in terms of seizure freedom there has been no real difference in outcome. There’s really quite a long way to go before we can say that we are doing all that well for people,” he said at the congress sponsored by the International League Against Epilepsy.

In the year 2000, he and his coinvestigators published a prospective, longitudinal, observational cohort study of 470 newly diagnosed patients with epilepsy treated at the Western Infirmary during 1982-1997, all with a minimum of 2 years’ follow-up. Sixty-one percent achieved complete freedom from seizures for at least 1 year on monotherapy, and another 3% did so on polytherapy, for a total rate of 64% (N Engl J Med. 2000 Feb 3;342[5]:314-19).

But these were patients who by and large were treated with older AEDs such as carbamazepine, which has since fallen by the wayside because of toxicities. Scottish neurologists now generally turn to lamotrigine (Lamictal), levetiracetam (Spritam), and other, newer AEDs. So Dr. Brodie and his coworkers recently published a follow-up study, this one featuring 30 years of longitudinal follow-up of 1,795 patients newly treated for epilepsy with AEDs, new and old, during 1982-2012. The investigators demonstrated that the seizure-free survival curves over time were virtually superimposable. In the larger, more recent study, remission was achieved in 55% of patients with AED monotherapy and in another 9% with polytherapy, for a total rate of 64%, identical to the rate in the 2000 study, and as was the case in the earlier study, 36% of patients remained uncontrolled (JAMA Neurol. 2018 Mar 1;75[3]:279-86).


“Overall, the way this population behaves, there’s no difference in efficacy and no difference in tolerability whether you’re using old drugs used properly or new drugs used properly,” said Dr. Brodie, professor of neurology at the University of Glasgow (Scotland).

It’s noteworthy that Sir William R. Gowers, the Londoner who has been called the greatest neurologist of all time, reported a 70% seizure-free rate in 1881, while Dr. Brodie and workers achieved a 64% rate in their 30-year study. “It’s interesting that the numbers are so bad, really, I suppose,” Dr. Brodie commented.

How about outcomes in pediatric epilepsy?

Dr. Brodie and coworkers recently published a 30-year prospective cohort study of 332 adolescent epilepsy patients newly diagnosed and treated at the Western Infirmary during 1982-2012. At the end of the study, 67% were seizure-free for at least the past year, a feat accomplished via monotherapy in 83% of cases. The seizure-free rate was 72% in those with generalized epilepsy, significantly better than the 60% figure in those with focal epilepsy. The efficacy rate was 74% with newer AED monotherapy and similar at 77% with monotherapy older drugs. Adverse event rates ranged from a low of 12% with lamotrigine to 56% with topiramate (Topamax), according to the findings published in Epilepsia (2019 Jun;60[6]:1083-90).

Roughly similar outcomes have been reported from Norway in a study of 600 children with epilepsy, median age 7 years, with a median follow-up of 5.8 years that is considerably shorter than that in the Glasgow pediatric study. Overall, 59% of the Norwegian children remained seizure free for at least 1 year, 30% developed drug-resistant epilepsy, and 11% followed an intermediate remitting/relapsing course (Pediatrics. 2018 Jun. doi: 10.1542/peds.2017-4016).
 

Why the decades of flat pharmacologic outcomes?

The consistently suboptimal seizure-free outcomes obtained over the past 30 years shouldn’t really be surprising, according to Dr. Brodie.

“Although we think we have lots of mechanisms of action and lots of differences between the drugs, they’re arguably all antiseizure drugs and not antiepilepsy drugs. We don’t treat the whale; we treat the spout. We don’t treat what we cannot see; we treat what we can see, which is the seizures, but we’re not influencing the long-term outcome,” the neurologist explained.
 

The compelling case for early epilepsy surgery

Epilepsy surgery remains underutilized, according to Dr. Brodie and other experts.

The International League Against Epilepsy defines drug-resistant epilepsy as failure to achieve sustained seizure freedom after adequate trials of two tolerated and appropriately chosen and used AED schedules. Dr. Brodie’s work was influential in creating that definition because his data demonstrated the sharply diminishing returns of additional drug trials.

“When do we consider epilepsy surgery? Arguably, the earlier, the better. After two drugs have failed appropriately, I don’t think anybody in this room would argue about that, although people in some of the other rooms might,” he said at the congress.

Influential in his thinking on this score were the impressive results of an early study, the first-ever randomized trial of surgery for epilepsy. In 80 patients with a 21-year history of drug-refractory temporal lobe epilepsy who were randomized to surgery or 1 year of AED therapy, at 1 year of follow-up blinded epileptologists rated 58% of surgically treated patients as free from seizures that impair awareness of self and surroundings, compared with just 8% in the AED group (N Engl J Med. 2001 Aug 2;345[5]:311-8).

“That’s a big outcome, and I’m very keen to ensure that my data continue to drive the push for early surgery,” according to the neurologist.

A Cochrane review of 177 studies totaling more than 16,000 patients concluded that 65% of epilepsy patients had good outcomes following surgery. Prognostic factors associated with better surgical outcomes included complete surgical resection of the epileptogenic focus, the presence of mesial temporal sclerosis, concordance of MRI and EEG findings, and an absence of cortical dysplasia (Cochrane Database Syst Rev. 2019;6:CD010541. doi: 10.1002/14651858.CD010541.pub3).

In addition, a systematic review and meta-analysis by Canadian investigators found that 72% of adults with lesional epilepsy identified by MRI or histopathology were seizure-free after surgery, compared with 36% of those with nonlesional epilepsy. The disparity in outcomes was similar in pediatric epilepsy patients, with seizure freedom after surgery in 74% of those with lesional disease versus 45% with nonlesional epilepsy (Epilepsy Res. 2010 May;89[2-3]:310-8).
 

Whither are neurostimulatory device therapies headed?

Dr. Brodie was quick to admit that as a pharmacologic researcher, device modalities including vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation are outside his area of expertise. But he’s been following developments in the field with interest.

“These device therapies have shown efficacy in short-term randomized trials, but very few patients attain long-term seizure freedom. I think these are largely palliative techniques. I gave up on these techniques a long time ago because I felt it was a very costly way of reducing seizures by a relatively small margin, and really we need to go a little bit further than that. But I know there’s a lot of work going on at the moment,” he said.

Dr. Brodie reported serving on the scientific advisory boards of more than a half dozen pharmaceutical companies.

[email protected]

A 60-year-old man visits your clinic 30 days after he was hospitalized for acute coronary syndrome (ACS) due to ST-elevation myocardial infarction (STEMI). The patient underwent percutaneous coronary intervention (PCI) with placement of a stent and received aspirin and a loading dose of ticagrelor for antiplatelet therapy. He was discharged on dual antiplatelet therapy (DAPT) consisting of daily aspirin and ticagrelor. He asks about the risk for bleeding associated with these medications. Should you recommend any changes?

Platelet inhibition during and after ACS to prevent recurrent ischemic events is a cornerstone of treatment for patients after a myocardial infarction (MI).² Current American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend that patients with coronary artery disease who recently had an MI continue DAPT with aspirin and a P2Y12 blocker (clopidogrel, ticlopidine, ticagrelor, prasugrel, or cangrelor) for 12 months following ACS to reduce recurrent ischemia.^2-4

Studies have shown that using the newer P2Y12 inhibitors (prasugrel and ticagrelor) after PCI leads to a significant reduction in recurrent ischemic events, compared with clopidogrel.^5-7 These data prompted a guideline change recommending the use of the newer agents over clopidogrel for 12 months following PCI.² Follow-up studies show strong evidence for the use of the newer P2Y12 agents in the first month following PCI, but they also demonstrate an increased bleeding risk in the maintenance phase (from 30 days to 12 months post-PCI).^6,7 This increased risk is the basis for the study by Cuisset et al, which examined switching from a newer P2Y12 agent to clopidogrel after the initial 30-day period following PCI.

STUDY SUMMARY

Switched DAPT is superior

This open-label RCT (N = 646) evaluated changing DAPT from aspirin plus a newer P2Y12 blocker (prasugrel or ticagrelor) to a combination of aspirin and clopidogrel after the first month of DAPT post-ACS.¹ Prior to PCI, patients received a loading dose of ticagrelor (180 mg) or prasugrel (60 mg). Subsequently, all patients took aspirin (75 mg/d) and either prasugrel (10 mg/d) or ticagrelor (90 mg bid) for 1 month. After 30 days, participants who had no adverse events were randomly assigned in a 1:1 ratio to continue the aspirin and newer P2Y12 blocker regimen or switch to aspirin and clopidogrel (75 mg/d). In the following year, researchers examined the composite outcome of cardiovascular death, urgent revascularization, stroke, and major bleeding (defined by a Bleeding Academic Research Consortium [BARC] classification ≥ Type 2 at 1-year post-ACS).

Of the participants (average age, 60), 40% had a STEMI and 60% had a non-STEMI. Overall, 43% of patients were prescribed ticagrelor and 57% prasugrel. At 1 year, 86% of the switched-DAPT group and 75% of the unchanged-DAPT group were still taking their medication. The composite outcome at 1-year follow-up was lower in the switched group compared with the unchanged group (13.4% vs 26.3%; hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.34-0.68; number needed to treat [NNT], 8).

Bleeding events (ranging from minimal to fatal) were lower in the switched group (9.3% vs 23.5%; HR, 0.39; 95% CI, 0.27-0.57; NNT, 7) and events identified as BARC ≥ Type 2 (defined as needing medical treatment) were also lower in this group (4% vs 14.9%; HR, 0.30, 95% CI, 0.18-0.50; NNT, 9). There were no significant differences in reported recurrent cardiovascular ischemic events (9.3% vs 11.5%; HR, 0.80, 95% CI, 0.50-1.29).

WHAT’S NEW

Less bleeding, no increase in ischemic events

Cardiology guidelines recommend the newer P2Y12 blockers as part of DAPT after ACS, but this trial showed switching to clopidogrel for DAPT after 30 days of treatment lowers bleeding events with no difference in recurrent ischemic events.^2-4

Continue to: CAVEATS

Less-than-ideal study methods

In this open-label and unblinded study, the investigators adjudicating critical events were blinded to the treatment allocation. However, patients could self-report minor bleeding and medication discontinuation for which no consultation was sought. In addition, the investigators used opaque envelopes—a less-than-ideal method—to conceal allocation at enrollment.

CHALLENGES TO IMPLEMENTATION

PCP may not change cardiologist’s ­prescription

Implementing this practice is facilitated by the comparatively lower cost of clopidogrel versus the newer P2Y12 blockers. However, after ACS and PCI treatment, cardiologists usually initiate antiplatelet therapy and may continue to manage patients after discharge. The primary care provider (PCP) may not be responsible for the DAPT switch initially; furthermore, ordering a switch may require coordination if the PCP is hesitant to change the cardiologist’s prescription. Lastly, guidelines currently recommend using the newer P2Y12 blockers for 12 months.² CR

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[3]:162,164).

A 60-year-old man visits your clinic 30 days after he was hospitalized for acute coronary syndrome (ACS) due to ST-elevation myocardial infarction (STEMI). The patient underwent percutaneous coronary intervention (PCI) with placement of a stent and received aspirin and a loading dose of ticagrelor for antiplatelet therapy. He was discharged on dual antiplatelet therapy (DAPT) consisting of daily aspirin and ticagrelor. He asks about the risk for bleeding associated with these medications. Should you recommend any changes?

Platelet inhibition during and after ACS to prevent recurrent ischemic events is a cornerstone of treatment for patients after a myocardial infarction (MI).² Current American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend that patients with coronary artery disease who recently had an MI continue DAPT with aspirin and a P2Y12 blocker (clopidogrel, ticlopidine, ticagrelor, prasugrel, or cangrelor) for 12 months following ACS to reduce recurrent ischemia.^2-4

Studies have shown that using the newer P2Y12 inhibitors (prasugrel and ticagrelor) after PCI leads to a significant reduction in recurrent ischemic events, compared with clopidogrel.^5-7 These data prompted a guideline change recommending the use of the newer agents over clopidogrel for 12 months following PCI.² Follow-up studies show strong evidence for the use of the newer P2Y12 agents in the first month following PCI, but they also demonstrate an increased bleeding risk in the maintenance phase (from 30 days to 12 months post-PCI).^6,7 This increased risk is the basis for the study by Cuisset et al, which examined switching from a newer P2Y12 agent to clopidogrel after the initial 30-day period following PCI.

STUDY SUMMARY

Switched DAPT is superior

This open-label RCT (N = 646) evaluated changing DAPT from aspirin plus a newer P2Y12 blocker (prasugrel or ticagrelor) to a combination of aspirin and clopidogrel after the first month of DAPT post-ACS.¹ Prior to PCI, patients received a loading dose of ticagrelor (180 mg) or prasugrel (60 mg). Subsequently, all patients took aspirin (75 mg/d) and either prasugrel (10 mg/d) or ticagrelor (90 mg bid) for 1 month. After 30 days, participants who had no adverse events were randomly assigned in a 1:1 ratio to continue the aspirin and newer P2Y12 blocker regimen or switch to aspirin and clopidogrel (75 mg/d). In the following year, researchers examined the composite outcome of cardiovascular death, urgent revascularization, stroke, and major bleeding (defined by a Bleeding Academic Research Consortium [BARC] classification ≥ Type 2 at 1-year post-ACS).

Of the participants (average age, 60), 40% had a STEMI and 60% had a non-STEMI. Overall, 43% of patients were prescribed ticagrelor and 57% prasugrel. At 1 year, 86% of the switched-DAPT group and 75% of the unchanged-DAPT group were still taking their medication. The composite outcome at 1-year follow-up was lower in the switched group compared with the unchanged group (13.4% vs 26.3%; hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.34-0.68; number needed to treat [NNT], 8).

Bleeding events (ranging from minimal to fatal) were lower in the switched group (9.3% vs 23.5%; HR, 0.39; 95% CI, 0.27-0.57; NNT, 7) and events identified as BARC ≥ Type 2 (defined as needing medical treatment) were also lower in this group (4% vs 14.9%; HR, 0.30, 95% CI, 0.18-0.50; NNT, 9). There were no significant differences in reported recurrent cardiovascular ischemic events (9.3% vs 11.5%; HR, 0.80, 95% CI, 0.50-1.29).

WHAT’S NEW

Less bleeding, no increase in ischemic events

Cardiology guidelines recommend the newer P2Y12 blockers as part of DAPT after ACS, but this trial showed switching to clopidogrel for DAPT after 30 days of treatment lowers bleeding events with no difference in recurrent ischemic events.^2-4

Continue to: CAVEATS

Less-than-ideal study methods

In this open-label and unblinded study, the investigators adjudicating critical events were blinded to the treatment allocation. However, patients could self-report minor bleeding and medication discontinuation for which no consultation was sought. In addition, the investigators used opaque envelopes—a less-than-ideal method—to conceal allocation at enrollment.

CHALLENGES TO IMPLEMENTATION

PCP may not change cardiologist’s ­prescription

Implementing this practice is facilitated by the comparatively lower cost of clopidogrel versus the newer P2Y12 blockers. However, after ACS and PCI treatment, cardiologists usually initiate antiplatelet therapy and may continue to manage patients after discharge. The primary care provider (PCP) may not be responsible for the DAPT switch initially; furthermore, ordering a switch may require coordination if the PCP is hesitant to change the cardiologist’s prescription. Lastly, guidelines currently recommend using the newer P2Y12 blockers for 12 months.² CR

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[3]:162,164).

A 60-year-old man visits your clinic 30 days after he was hospitalized for acute coronary syndrome (ACS) due to ST-elevation myocardial infarction (STEMI). The patient underwent percutaneous coronary intervention (PCI) with placement of a stent and received aspirin and a loading dose of ticagrelor for antiplatelet therapy. He was discharged on dual antiplatelet therapy (DAPT) consisting of daily aspirin and ticagrelor. He asks about the risk for bleeding associated with these medications. Should you recommend any changes?

Platelet inhibition during and after ACS to prevent recurrent ischemic events is a cornerstone of treatment for patients after a myocardial infarction (MI).² Current American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend that patients with coronary artery disease who recently had an MI continue DAPT with aspirin and a P2Y12 blocker (clopidogrel, ticlopidine, ticagrelor, prasugrel, or cangrelor) for 12 months following ACS to reduce recurrent ischemia.^2-4

Studies have shown that using the newer P2Y12 inhibitors (prasugrel and ticagrelor) after PCI leads to a significant reduction in recurrent ischemic events, compared with clopidogrel.^5-7 These data prompted a guideline change recommending the use of the newer agents over clopidogrel for 12 months following PCI.² Follow-up studies show strong evidence for the use of the newer P2Y12 agents in the first month following PCI, but they also demonstrate an increased bleeding risk in the maintenance phase (from 30 days to 12 months post-PCI).^6,7 This increased risk is the basis for the study by Cuisset et al, which examined switching from a newer P2Y12 agent to clopidogrel after the initial 30-day period following PCI.

STUDY SUMMARY

Switched DAPT is superior

This open-label RCT (N = 646) evaluated changing DAPT from aspirin plus a newer P2Y12 blocker (prasugrel or ticagrelor) to a combination of aspirin and clopidogrel after the first month of DAPT post-ACS.¹ Prior to PCI, patients received a loading dose of ticagrelor (180 mg) or prasugrel (60 mg). Subsequently, all patients took aspirin (75 mg/d) and either prasugrel (10 mg/d) or ticagrelor (90 mg bid) for 1 month. After 30 days, participants who had no adverse events were randomly assigned in a 1:1 ratio to continue the aspirin and newer P2Y12 blocker regimen or switch to aspirin and clopidogrel (75 mg/d). In the following year, researchers examined the composite outcome of cardiovascular death, urgent revascularization, stroke, and major bleeding (defined by a Bleeding Academic Research Consortium [BARC] classification ≥ Type 2 at 1-year post-ACS).

Of the participants (average age, 60), 40% had a STEMI and 60% had a non-STEMI. Overall, 43% of patients were prescribed ticagrelor and 57% prasugrel. At 1 year, 86% of the switched-DAPT group and 75% of the unchanged-DAPT group were still taking their medication. The composite outcome at 1-year follow-up was lower in the switched group compared with the unchanged group (13.4% vs 26.3%; hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.34-0.68; number needed to treat [NNT], 8).

Bleeding events (ranging from minimal to fatal) were lower in the switched group (9.3% vs 23.5%; HR, 0.39; 95% CI, 0.27-0.57; NNT, 7) and events identified as BARC ≥ Type 2 (defined as needing medical treatment) were also lower in this group (4% vs 14.9%; HR, 0.30, 95% CI, 0.18-0.50; NNT, 9). There were no significant differences in reported recurrent cardiovascular ischemic events (9.3% vs 11.5%; HR, 0.80, 95% CI, 0.50-1.29).

WHAT’S NEW

Less bleeding, no increase in ischemic events

Cardiology guidelines recommend the newer P2Y12 blockers as part of DAPT after ACS, but this trial showed switching to clopidogrel for DAPT after 30 days of treatment lowers bleeding events with no difference in recurrent ischemic events.^2-4

Continue to: CAVEATS

Less-than-ideal study methods

In this open-label and unblinded study, the investigators adjudicating critical events were blinded to the treatment allocation. However, patients could self-report minor bleeding and medication discontinuation for which no consultation was sought. In addition, the investigators used opaque envelopes—a less-than-ideal method—to conceal allocation at enrollment.

CHALLENGES TO IMPLEMENTATION

PCP may not change cardiologist’s ­prescription

Implementing this practice is facilitated by the comparatively lower cost of clopidogrel versus the newer P2Y12 blockers. However, after ACS and PCI treatment, cardiologists usually initiate antiplatelet therapy and may continue to manage patients after discharge. The primary care provider (PCP) may not be responsible for the DAPT switch initially; furthermore, ordering a switch may require coordination if the PCP is hesitant to change the cardiologist’s prescription. Lastly, guidelines currently recommend using the newer P2Y12 blockers for 12 months.² CR

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[3]:162,164).

Benefits of adding chemotherapy to pelvic radiotherapy in localized high-risk endometrial cancer increase with follow-up, finds an updated analysis of the randomized PORTEC-3 trial.

The relative risk-benefit profile of chemoradiotherapy is uncertain, with some evidence suggesting it varies according to disease histology and stage, noted lead investigator Stephanie de Boer, MD, department of radiation oncology, Leiden (the Netherlands) University Medical Center, and coinvestigators.

PORTEC-3, a multicenter phase 3 trial, enrolled women who had undergone surgery for high-risk endometrial cancer: FIGO 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion, lymphovascular space invasion, or both; stage II or III disease; or stage I to III disease with serous or clear cell histology. In all, 660 women were evenly assigned to external-beam radiotherapy alone (48.6 Gy in 1.8-Gy fractions, on 5 days per week) or radiotherapy and chemotherapy (two cycles of cisplatin given during radiotherapy, followed by four cycles of carboplatin and paclitaxel).

A previous analysis, at a median follow-up of 60.2 months (5.0 years), showed a significant 5-year failure-free survival benefit of chemoradiotherapy over radiotherapy (hazard ratio [HR], 0.71; P = .022) but only a trend toward an overall survival benefit (Lancet Oncol. 2018;19[3]:295-309).

The updated analysis, now at a median follow-up of 72.6 months (6.1 years), was reported in Lancet Oncology and showed that chemoradiotherapy was still significantly superior to radiotherapy alone in terms of 5-year failure-free survival (76.5% vs. 69.1%; adjusted HR, 0.70; P = .016) but was now also significantly superior in terms of 5-year overall survival (81.4% vs. 76.1%; adjusted HR, 0.70; P = .034)

The 5-year probability of distant metastasis was lower with chemoradiotherapy than with radiotherapy alone (21.4% vs. 29.1%; HR, 0.74; P = .047). The two groups did not differ significantly with respect to isolated vaginal recurrence as first site (0.3% in each group) or isolated pelvic recurrence as first site (0.9% in each group).

Only a single patient, in the chemoradiotherapy group, experienced a grade 4 adverse event (ileus or obstruction). The chemoradiotherapy and radiotherapy-only groups were similar on the rate of grade 3 adverse events (8% vs. 5%; P = .24), the most common of which was hypertension. However, the former had a higher rate of grade 2 or worse adverse events (38% vs. 23%; P = .002), such as persistent sensory neuropathy (6% vs. 0%). None of the patients died from treatment-related causes.

“Combined adjuvant chemotherapy and radiotherapy should be discussed and recommended as a new standard of care, especially for women with stage III endometrial cancer or serous cancers, or both,” Dr. de Boer and coinvestigators maintained. “Shared decision making between doctors and their patients remains essential to weigh the costs and benefits for individual patients.

“Molecular analysis has the potential to improve risk stratification and should be used to identify subgroups that can derive the greatest benefit from chemotherapy and to select patients for targeted therapies; molecular studies on tissue samples donated by PORTEC-3 trial participants are ongoing,” they noted.

Dr. de Boer disclosed no competing interests in relation to the study. The study was supported in part by the Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Cancer Australia, the Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

SOURCE: de Boer SM et al. Lancet Oncol. 2019 July 22. doi: 10.1016/S1470-2045(19)30395-X.

Benefits of adding chemotherapy to pelvic radiotherapy in localized high-risk endometrial cancer increase with follow-up, finds an updated analysis of the randomized PORTEC-3 trial.

The relative risk-benefit profile of chemoradiotherapy is uncertain, with some evidence suggesting it varies according to disease histology and stage, noted lead investigator Stephanie de Boer, MD, department of radiation oncology, Leiden (the Netherlands) University Medical Center, and coinvestigators.

PORTEC-3, a multicenter phase 3 trial, enrolled women who had undergone surgery for high-risk endometrial cancer: FIGO 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion, lymphovascular space invasion, or both; stage II or III disease; or stage I to III disease with serous or clear cell histology. In all, 660 women were evenly assigned to external-beam radiotherapy alone (48.6 Gy in 1.8-Gy fractions, on 5 days per week) or radiotherapy and chemotherapy (two cycles of cisplatin given during radiotherapy, followed by four cycles of carboplatin and paclitaxel).

A previous analysis, at a median follow-up of 60.2 months (5.0 years), showed a significant 5-year failure-free survival benefit of chemoradiotherapy over radiotherapy (hazard ratio [HR], 0.71; P = .022) but only a trend toward an overall survival benefit (Lancet Oncol. 2018;19[3]:295-309).

The updated analysis, now at a median follow-up of 72.6 months (6.1 years), was reported in Lancet Oncology and showed that chemoradiotherapy was still significantly superior to radiotherapy alone in terms of 5-year failure-free survival (76.5% vs. 69.1%; adjusted HR, 0.70; P = .016) but was now also significantly superior in terms of 5-year overall survival (81.4% vs. 76.1%; adjusted HR, 0.70; P = .034)

The 5-year probability of distant metastasis was lower with chemoradiotherapy than with radiotherapy alone (21.4% vs. 29.1%; HR, 0.74; P = .047). The two groups did not differ significantly with respect to isolated vaginal recurrence as first site (0.3% in each group) or isolated pelvic recurrence as first site (0.9% in each group).

Only a single patient, in the chemoradiotherapy group, experienced a grade 4 adverse event (ileus or obstruction). The chemoradiotherapy and radiotherapy-only groups were similar on the rate of grade 3 adverse events (8% vs. 5%; P = .24), the most common of which was hypertension. However, the former had a higher rate of grade 2 or worse adverse events (38% vs. 23%; P = .002), such as persistent sensory neuropathy (6% vs. 0%). None of the patients died from treatment-related causes.

“Combined adjuvant chemotherapy and radiotherapy should be discussed and recommended as a new standard of care, especially for women with stage III endometrial cancer or serous cancers, or both,” Dr. de Boer and coinvestigators maintained. “Shared decision making between doctors and their patients remains essential to weigh the costs and benefits for individual patients.

“Molecular analysis has the potential to improve risk stratification and should be used to identify subgroups that can derive the greatest benefit from chemotherapy and to select patients for targeted therapies; molecular studies on tissue samples donated by PORTEC-3 trial participants are ongoing,” they noted.

Dr. de Boer disclosed no competing interests in relation to the study. The study was supported in part by the Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Cancer Australia, the Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

SOURCE: de Boer SM et al. Lancet Oncol. 2019 July 22. doi: 10.1016/S1470-2045(19)30395-X.

Benefits of adding chemotherapy to pelvic radiotherapy in localized high-risk endometrial cancer increase with follow-up, finds an updated analysis of the randomized PORTEC-3 trial.

The relative risk-benefit profile of chemoradiotherapy is uncertain, with some evidence suggesting it varies according to disease histology and stage, noted lead investigator Stephanie de Boer, MD, department of radiation oncology, Leiden (the Netherlands) University Medical Center, and coinvestigators.

PORTEC-3, a multicenter phase 3 trial, enrolled women who had undergone surgery for high-risk endometrial cancer: FIGO 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion, lymphovascular space invasion, or both; stage II or III disease; or stage I to III disease with serous or clear cell histology. In all, 660 women were evenly assigned to external-beam radiotherapy alone (48.6 Gy in 1.8-Gy fractions, on 5 days per week) or radiotherapy and chemotherapy (two cycles of cisplatin given during radiotherapy, followed by four cycles of carboplatin and paclitaxel).

A previous analysis, at a median follow-up of 60.2 months (5.0 years), showed a significant 5-year failure-free survival benefit of chemoradiotherapy over radiotherapy (hazard ratio [HR], 0.71; P = .022) but only a trend toward an overall survival benefit (Lancet Oncol. 2018;19[3]:295-309).

The updated analysis, now at a median follow-up of 72.6 months (6.1 years), was reported in Lancet Oncology and showed that chemoradiotherapy was still significantly superior to radiotherapy alone in terms of 5-year failure-free survival (76.5% vs. 69.1%; adjusted HR, 0.70; P = .016) but was now also significantly superior in terms of 5-year overall survival (81.4% vs. 76.1%; adjusted HR, 0.70; P = .034)

The 5-year probability of distant metastasis was lower with chemoradiotherapy than with radiotherapy alone (21.4% vs. 29.1%; HR, 0.74; P = .047). The two groups did not differ significantly with respect to isolated vaginal recurrence as first site (0.3% in each group) or isolated pelvic recurrence as first site (0.9% in each group).

Only a single patient, in the chemoradiotherapy group, experienced a grade 4 adverse event (ileus or obstruction). The chemoradiotherapy and radiotherapy-only groups were similar on the rate of grade 3 adverse events (8% vs. 5%; P = .24), the most common of which was hypertension. However, the former had a higher rate of grade 2 or worse adverse events (38% vs. 23%; P = .002), such as persistent sensory neuropathy (6% vs. 0%). None of the patients died from treatment-related causes.

“Combined adjuvant chemotherapy and radiotherapy should be discussed and recommended as a new standard of care, especially for women with stage III endometrial cancer or serous cancers, or both,” Dr. de Boer and coinvestigators maintained. “Shared decision making between doctors and their patients remains essential to weigh the costs and benefits for individual patients.

“Molecular analysis has the potential to improve risk stratification and should be used to identify subgroups that can derive the greatest benefit from chemotherapy and to select patients for targeted therapies; molecular studies on tissue samples donated by PORTEC-3 trial participants are ongoing,” they noted.

Dr. de Boer disclosed no competing interests in relation to the study. The study was supported in part by the Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Cancer Australia, the Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

SOURCE: de Boer SM et al. Lancet Oncol. 2019 July 22. doi: 10.1016/S1470-2045(19)30395-X.