Systemic Therapy
Imatinib - Progression
Patients who undergo complete resection of primary GIST face a 50% recurrence rate after 5 years, and median time to progression for advanced GIST treated with Glivec is 2 years.1 Vigilant surveillance by radiologists to monitor recurrence or progressive disease is therefore essential. The 50% recurrence rate after 5 years with complete resection of primary GIST and the 2-year median time to progression in the US/Finland trial for advanced GIST patients treated with Glivec emphasize the need for imaging
surveillance of all GIST patients.
Specific guidelines for monitoring have not been established. In a consensus conference, experts in the field of GIST management recommended that for intermediate- and high-risk tumors, CT scanning every 3 to 4 months for 3 years, every 6 months through year 5, and then every year thereafter would be a reasonable follow-up approach.2 For low- or very-low-risk GISTs, systematic follow-up with CT scanning every 6 months for 5 years was felt to be acceptable. The conferees noted that there is no evidence at the present time indicating whether these are the optimal time intervals and whether follow-up with CT is beneficial in these patients.
Recurrence may occur at the site of resection, in the peritoneum, or as metastasis to the liver. Spurious new lesions can be artifacts of portal-venous-phase images of enhanced CT in which hypervascular GIST hepatic metastases become imperceptible against the surrounding hepatic parenchyma and reappear when they become hypoattenuating in response to Glivec® therapy.3,4
If evidence of progression appears on follow-up imaging, 3 progressive steps should be followed: confirmation of the findings; assessment of patient dosing compliance; and measurement of Glivec blood levels to ensure that pharmacokinetic factors are not responsible for loss of response.3,4
Nodule within a mass: unique pattern of progression
Protocols that assess response to therapy based on tumor size typically measure 1 dimension (RECIST)6 or 2 dimensions (Southwest Oncology Group [SWOG] criteria)7 or calculate volume with computer-assisted modeling.8 During Glivec therapy, however, GIST progression frequently appears as one or more new, small, intratumoral nodules that are resistant to Glivec. Overall tumor density, size, or configuration of the responding lesion does not change.9-11 In 2004, Desai et al reported on 89 patients treated with Glivec who were followed for a median of 39 months. In 22 of 42 patients with progressive disease (SWOG criteria), a unique “nodule within a mass” pattern, defined as a new, enhancing nodular focus enclosed within a preexisting hypoenhancing or nonenhancing tumor mass previously responsive to Glivec, was evident. In 17 of these 22 patients, the resistant clones were the first sign of progression. Development of nodules was unrelated to starting dose. Comparative tissue biopsies at baseline and at the appearance of progressing nodules were available for 9 patients. Genotypic analyses of KIT and PDGFRA demonstrated new activating mutations in 7 (78%) of 9 patients.9
Awareness of this unique pattern of progression is essential for experts analyzing radiologic images in Glivec®-treated GIST. RECIST criteria for progression, which do not recognize nodular development without tumor enlargement as progression, do not provide an adequate standard in this situation.11
Tumor flare
The cytostatic activity of Glivec arrests tumor proliferation and metabolism; therefore, populations of metabolically quiescent tumor cells can rapidly reactivate when this kinase-targeted inhibitory drug is withdrawn. Reactivation, visualized by PET imaging, is referred to as a “tumor flare.”5,12,13 From a clinical perspective, these results emphasize that in patients initially responding to Glivec and subsequently undergoing limited progression, the withdrawal of Glivec can reactivate GIST cells previously kept in check by continuous kinase-directed inhibition. Glivec therapy should therefore be continued in patients who have evidence of ongoing benefit and who tolerate the drug well.2,5
References:
1. Blanke CD, Joensuu H, Demetri GD, et al. Outcome of advanced gastrointestinal stromal tumor (GIST) patients treated with imatinib mesylate: four-year follow-up of a phase II randomized trial [abstract]. Presented at: 2006 Gastrointestinal Cancers Symposium; January 26-28, 2006; San Francisco, Calif. Abstract 7.
2. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST
Consensus Conference of 20-21 March 2004, under the auspices of European Society for Medical Oncology. Ann Oncol. 2005;16:566-578.
3. Demetri G, Benjamin R, Blanke CD, et al. NCCN Task Force report: optimal management of patients with gastrointestinal stromal tumor (GIST)—expansion and update of NCCN Clinical Practice Guidelines. J Natl Compr Canc Netw. 2004;2(suppl 1):S1-S26.
4. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51-58.
5. Reichardt P. Optimising therapy for GIST patients. Eur J Cancer. 2006;4(suppl 1):19-26.
6. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216.
7. Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs. 1992;10:239-253
8. Prasad SR, Jhaveri KS, Saini S, et al. CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques initial observations. Radiology. 2002;225:416-419.
9. Desai J, Shankar S, Heinrich MC, et al. Clonal evolution of resistance to imatinib (IM) in patients (pts) with gastrointestinal stromal tumor (GIST): molecular and radiologic evaluation of new lesions [abstract]. Proc Am Soc Clin Oncol. 2004;23:197. Abstract 3010.
10. Chen LL, Sabripour M, Andtbacka RH, et al. Imatinib resistance in gastrointestinal stromal tumors. Curr Oncol Rep. 2005;7:293-299.
11. Shankar S, vanSonnenberg E, Desai J, et al. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology. 2005;235:892-898.
12. Van Den Abbeele AD, Badawi RD, Manola J, et al. Effects of cessation of imatinib mesylate (IM) therapy in patients (pts) with IM-refractory gastrointestinal stromal tumors (GIST) as visualized by FDG-PET scanning [abstract]. Proc Am Soc Clin Oncol. 2004;23:198. Abstract 3012.
13. Van Oosterom AT, Dumez H, Desai J, et al. Combination signal transduction inhibition: a phase I/II trial of the oral mTOR-inhibitor everolimus (E, RAD001) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM [abstract]. Proc Am Soc Clin Oncol. 2004;23:195. Abstract 3002.