Resectable Primary Gastrointestinal Stromal Tumors
General principles for the surgical therapy of gastrointestinal stromal tumors (GIST) include the following:
- All GIST 2 cm or larger in size are typically resected; the management of incidentally encountered GIST smaller than 2 cm in size remains controversial. There is no evidence that patients should undergo re-excision in cases in which there is complete resection of all macroscopic disease but microscopically margins are positive; watchful waiting and adjuvant imatinib may be appropriate for these patients.[1,2] In general, gastric GIST 5 cm or smaller in size may be removed by laparoscopic wedge resection. Because GIST rarely involve the locoregional lymph nodes, extensive lymph node resection or resection is rarely indicated. These tumors may have fragile pseudocapsules, so care must be taken to avoid rupturing the pseudocapsule during surgery, which could result in peritoneal dissemination.
- Therapy with postoperative adjuvant imatinib for GIST patients with completely resected localized disease is under investigation. This is a very heterogeneous population in terms of risk of relapse and death after surgical resection (see Table 1). Depending on mitotic count, tumor size, and tumor site, the risk of relapse after complete gross resection may be considerable. Results from two trials suggest that adjuvant imatinib reduces recurrence after complete resection of localized, primary GIST.[3,4] However, it is not clear whether improvements in recurrence with adjuvant therapy will translate into improved survival. In addition, the optimal duration of adjuvant imatinib is unknown.
In a single-arm, open-label, phase II multicenter study (ACOSOG-Z9000), patients underwent complete gross resection of KIT-expressing primary GIST that were at high risk of recurrence (tumor size >10 cm, tumor rupture, or <5 peritoneal metastases) and received a daily dose of imatinib for 1 year. One hundred and seven patients with gastric (50%) and intestinal (42%) GIST and a median tumor size of 13 cm were evaluable with a median follow-up of 4 years. The 1-, 2- and 3-year rates for overall survival (OS) were 99%, 97%, and 97%, respectively, while the 1-, 2- and 3-year recurrence-free survival (RFS) rates were 94%, 73%, and 61%, respectively.[Level of evidence: 3iiiDiii]
In one randomized, double-blinded phase III trial (ACOSOG-Z9001), 713 patients who had undergone complete gross resection of a primary GIST measuring at least 3 cm and expressing KIT had been treated with 1 year of imatinib (400 mg daily) or placebo. The original primary endpoint of the trial was OS. However, when the overall death rate from GIST was shown to be low because of the efficacy of imatinib for advanced or recurrent disease, the investigators changed the endpoint to RFS. The trial was subsequently stopped early because of an interim analysis, which showed that patients who had been assigned to the imatinib arm experienced a 1-year RFS of 98%, whereas those assigned to the placebo arm had a 1-year RFS of 83% (overall HR = 0.35; 95% confidence interval (CI), 0.22–0.53; P < .0001). Since quality of life (QoL) was not measured in the study, it was not clear whether delayed RFS translated into improved patient QoL. No difference in OS was observed between the two arms, possibly because of the fairly short follow-up time and the crossover design of the study.[Level of evidence: 1iDii] In the course of the trial, at 48 months, there had been 5 deaths of the original 359 patients in the imatinib arm (about 1%) and 8 deaths of the original 354 patients in the placebo arm (about 2%) ( P = .47). It is possible that imatinib was simply delaying recurrences that could have been treated equally well at relapse in those patients who had a recurrence of their tumors. In fact, the RFS curves appeared to converge after about 30 months of follow-up. The question of whether RFS will translate into improved OS may be answered by an ongoing Intergroup trial (EORTC-62024) in which patients are randomly assigned to 2 years of adjuvant imatinib versus observation, with OS as the primary endpoint.
Given the current uncertainties about the overall impact of adjuvant imatinib, shared decision making with the patient is important. Since the cost of administration of imatinib for a year or more may be high, knowledge about what the patient may have to pay out of pocket may help inform the discussion.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with gastrointestinal stromal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007. [PUBMED Abstract]
- Otani Y, Furukawa T, Yoshida M, et al.: Operative indications for relatively small (2-5 cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 139 (4): 484-92, 2006. [PUBMED Abstract]
- Dematteo RP, Ballman KV, Antonescu CR, et al.: Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 373 (9669): 1097-104, 2009. [PUBMED Abstract]
- DeMatteo RP, Owzar K, Antonescu CR, et al.: Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: the U.S. Intergroup phase II trial ACOSOG Z9000. [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-8, 2008.
- Kelley RK, Venook AP: Nonadherence to imatinib during an economic downturn. N Engl J Med 363 (6): 596-8, 2010. [PUBMED Abstract]