What are the next steps in the management of this patient?
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.