Perioperative Tyrosine Kinase Inhibitors for GIST: Standard . . . or an Idea That Needs Further Investigation?

Excellent safety, efficacy, and tolerability profiles have resulted in the rapid integration of oral tyrosine kinase inhibitors into most facets of the treatment of gastrointestinal stromal tumors (GIST). With these agents having firmly established themselves in the treatment of advanced unresectable disease, there is now a growing body of literature concerning their use in the perioperative setting. Three distinct GIST management scenarios currently exist that require close collaboration between surgeon and medical oncologist: adjuvant therapy, neoadjuvant therapy, and development of drug resistance.

Key Questions

The most studied of perioperative treatment strategies are in patients with a primary GIST who have undergone complete resection. As discussed in the accompanying article by dos Santos Fernandes and colleagues, clinical trials led by the American College of Surgeons Oncology Group (ACOSOG) have demonstrated adjuvant imatinib (Gleevec) administered for up to 1 year to be safe and effective in decreasing risk of recurrence in patients, with the greatest benefit in those with tumors larger than 10 cm.[1]

Perhaps the most important question arising from these studies is what the duration of imatinib therapy administration should be. This may be answered by ongoing European studies that are evaluating adjuvant therapy for up to 3 years. Indeed, some have speculated that for high-risk patients, therapy may need to be lifelong. Such an approach may well be feasible given the tolerability of imatinib; however, more information on long-term side effects is still required.

It also is incumbent upon us to demonstrate that such an approach is not jeopardizing the management of recurrent and metastatic disease. To date, no data suggest that adjuvant imatinib cures patients, and its use in the advanced disease setting results in a median progression-free survival of 18 to 24 months, with only 5% achieving a complete response.[2,3] Is it possible that “lifelong therapy” would suppress disease until it develops imatinib resistance? And if so, are we helping patients by this approach, given the limited efficacy of second-line sunitinib (Sutent) therapy, with a median progression-free survival of 6 months,[4] and no other approved therapy available?

Risk stratification, we believe, will be key to identifying patients who will benefit from adjuvant imatinib. Data from the phase III trials from ACOSOG and the European Organisation for Research and Treatment of Cancer (EORTC) should aid us in our understanding of the benefits and limitations of adjuvant imatinib therapy in recurrence-free and overall survival. In addition to the standard prognosticators (size, mitotic rate, and tumor location), tumor genotyping to determine mutation status will likely soon be incorporated into most treatment planning, given the evidence for improved progression-free survival in patients with tumors containing exon 9 mutations treated with high-dose imatinib.[5]

Neoadjuvant Treatment

Recognition that imatinib therapy was associated with high response rates, often resulting in tumor shrinkage in patients with advanced disease, led to early investigation of its use in the neoadjuvant setting. The Radiation Therapy Oncology Group (RTOG) and American College of Radiology Imaging Network (ACRIN) cosponsored a prospective phase II study evaluating safety, efficacy, and radiographic imaging characteristics associated with neoadjuvant imatinib administered to patients who presented with either operable recurrent, metastatic, or primary GIST with high-risk characteristics.[6] Following 8 to 12 weeks of preoperative treatment, imatinib was discontinued within 24 hours of surgery and then re-administered in the adjuvant setting for an additional 2 years. This study demonstrated that the approach was feasible and not associated with notable perioperative complications.

We agree with dos Santos Fernandes and coauthors that despite the interesting results of this RTOG/ACRIN study, neoadjuvant strategies, especially for primary tumors, have yet to gain acceptance as the standard of care. These approaches may still be considered by experienced multidisciplinary teams, whereby an objective response could result in organ preservation or improve the likelihood that minimally invasive surgical techniques can be used.

At our own institution, we utilize a neoadjuvant strategy only in patients who present with enough identifiable high-risk characteristics to warrant future adjuvant imatinib administration (size > 5 cm, mitotic index > 5/50 high-power fields, anatomic location resulting in a potentially morbid resection), and then only for as long as the induction therapy results in a continued decrease in tumor size as evaluated by computed tomography. Once “maximal radiographic response” is achieved, imatinib therapy is discontinued and patients undergo immediate surgery. Patients whose tumors shrink to < 5 cm are typically addressed by laparoscopic resection at our institution.

Assessment Alternatives

The RTOG/ACRIN study demonstrated the limitations of the Response Evaluation Criteria in Solid Tumors (RECIST) to rapidly assess GIST responses to the new tyrosine kinase inhibitors, compared with 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET), which appears very sensitive in detecting early responses. However, expense and lesser availability of FDG-PET continue to generate great interest in new tomographic modalities that could yield similar results. The Choi criteria offer one means of assessing tumor response by considering not only size, but also changes in tumor density.[7]

Extrapolation of neoadjuvant therapy principles also leads to the consideration of how to address the development of drug resistance in patients being treated with imatinib. Several retrospective studies have observed wide disparities in surgical outcomes for focal vs diffuse disease progression during imatinib administration.[8-10] We concur that resection of metastatic progressive disease appears to benefit only patients with focal progression (ie, limited discrete solitary lesions), and it has little to offer to those who experience generalized disease progression while receiving imatinib or other tyrosine kinase inhibitor therapy.

Conclusions

While it is difficult to apply the traditional oncologic terms benign and malignant to GIST, risk stratification can identify patients who may potentially benefit from perioperative imatinib administration. Continued aggressive accrual to clinical trials will help us transform these various perioperative treatment strategies into standard practice for experienced multidisciplinary teams treating patients with this unique disease.

Financial Disclosure:Dr. von Mehren is on an advisory board for and has received research support from Novartis.

Acknowledgment:This manuscript was supported in part by NIH grant (CA106588).

References:

1. DeMatteo R, Owzar K, Maki R, et al: Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup phase III trial ACOSOG Z9001 (abstract 10079). J Clin Oncol 25(suppl 18), 2007.
2. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004.
3. Blanke CD, Rankin C, von Mehren M, et al: Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the KIT receptor tyrosine kinase: S0033. J ClinOncol 26:620-625, 2008.
4. Demetri GD, van Oosterom AT, Garrett CR, et al: Efficacy and safety of sunitinib in advanced gastrointestinal stromal tumors after failure of imatinib: A randomized controlled trial. Lancet 368:1329-1338, 2006.
5. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42:1093-1103, 2006.
6. Choi H, Charnsangavej C, Faria SC, et al: Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25:1753-1759, 2007.
7. Eisenberg BL, Harris J, Blanke CD, et al: Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors (GIST)-early results of RTOG 0132. J Surg Oncol Oct 21, 2008 (epub ahead of print).
8. Raut CP, Posner M, Desai J, et al: Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24:2325-2331, 2006.
9. Rutkowski P, Nowecki Z, Nyckowski P, et al: Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 93:304-311, 2006.
10. Gronchi A, Fior M, Miselli F, et al: Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg 245:341-346, 2007.