Evaluation of Self-Reported Progression and Correlation of Imatinib Dose to Survival in Patients with Metastatic Gastrointestinal Stromal Tumors: An Open Cohort Study
Self-reported progression was evaluated as a predictor of survival in patients with metastatic gastrointestinal stromal tumor (GIST).
This is a follow-up of an open cohort study of Life Raft Group (LRG) members with a diagnosis of KIT-positive metastatic GIST receiving imatinib from May 2000–December 2007 reporting their subjective response to therapy by completion of an internet-based questionnaire. Subjects received ≥ 1 year of imatinib and reported an initial positive response. Members reporting stable disease or progression were excluded. Self-reported progression-free survival (srPFS) was compared with overall survival (OS) and analyzed by starting and last reported dose.
One hundred sixty-nine subjects reported a mean starting dose of 527.8±177.9 mg/d at a mean age of 53.8±11.6 years at initial diagnosis. Of those reporting progression, 66% died versus 11% of those not reporting progression (P < 0.0001). When analyzed by last reported dose, a median srPFS benefit of 27.3 months was observed for the >400 mg/d group (P = 0.0017). Sixty-two percent of subjects who initiated therapy at >400 mg/d reported a dose reduction. When analyzed by last reported dose, a significant benefit in OS (P = 0.0229) and srPFS (P = 0.0069) was observed for subjects taking 600 over 400 mg/d.
srPFS strongly correlated with OS. Significant advantages were observed when last reported dose was considered, as was higher daily dose. These observations suggest that careful escalation to intermediate daily doses should be investigated further for its potential to reduce the incidence and severity of adverse events, but also as a strategy against developing secondary resistance to imatinib.
- Mucciarini, C, Rossi, G, Bertolini, F, Valli, R, Cirilli, C, Rashid, I, Marcheselli, L, Luppi, G, Federico, M (2007) Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. BMC Cancer 7: pp. 230 CrossRef
- Goettsch, WG, Bos, SD, Breekveldt-Postma, N, Casparie, M, Herings, RM, Hogendoorn, PC (2005) Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer 41: pp. 2868-2872 CrossRef
- Reddy, P, Boci, K, Charbonneau, C (2007) The epidemiologic, health-related quality of life, and economic burden of gastrointestinal stromal tumours. J Clin Pharm Ther 32: pp. 557-565 CrossRef
- Hirota, S, Isozaki, K, Moriyama, Y, Hashimoto, K, Nishida, T, Ishiguro, S, Kawano, K, Hanada, M, Kurata, A, Takeda, M (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279: pp. 577-580 CrossRef
- Kitamura, Y, Hirota, S, Nishida, T (2003) Gastrointestinal stromal tumors (GIST): a model for molecule-based diagnosis and treatment of solid tumors. Cancer Sci 94: pp. 315-320 CrossRef
- Heinrich, MC, Corless, CL, Duensing, A, McGreevey, L, Chen, CJ, Joseph, N, Singer, S, Griffith, DJ, Haley, A, Town, A (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299: pp. 708-710 CrossRef
- Fletcher, JA, Rubin, BP (2007) KIT mutations in GIST. Curr Opin Genet Dev 17: pp. 3-7 CrossRef
- Burkill, GJ, Badran, M, Al-Muderis, O, Meirion Thomas, J, Judson, IR, Fisher, C, Moskovic, EC (2003) Malignant gastrointestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread. Radiology 226: pp. 527-532 CrossRef
- Dematteo, RP, Heinrich, MC, El-Rifai, WM, Demetri, G (2002) Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 33: pp. 466-477 CrossRef
- Gold, JS, Zwan, SM, Gonen, M, Maki, RG, Singer, S, Brennan, MF, Antonescu, CR, Matteo, RP (2007) Outcome of metastatic GIST in the era before tyrosine kinase inhibitors. Ann Surg Oncol 14: pp. 134-142 CrossRef
- Druker, BJ, Tamura, S, Buchdunger, E, Ohno, S, Segal, GM, Fanning, S, Zimmermann, J, Lydon, NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2: pp. 561-566 CrossRef
- Buchdunger, E, Cioffi, CL, Law, N, Stover, D, Ohno-Jones, S, Druker, BJ, Lydon, NB (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295: pp. 139-145
- Mol, CD, Dougan, DR, Schneider, TR, Skene, RJ, Kraus, ML, Scheibe, DN, Snell, GP, Zou, H, Sang, BC, Wilson, KP (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem 279: pp. 31655-31663 CrossRef
- Joensuu, H, Roberts, PJ, Sarlomo-Rikala, M, Andersson, LC, Tervahartiala, P, Tuveson, D, Silberman, S, Capdeville, R, Dimitrijevic, S, Druker, B, Demetri, GD (2001) Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 344: pp. 1052-1056 CrossRef
- Cassier, PA, Dufresne, A, Arifi, S, El Sayadi, H, Labidi, I, Ray-Coquard, I, Tabone, S, Meeus, P, Ranchere, D, Sunyach, MP (2008) Imatinib mesilate for the treatment of gastrointestinal stromal tumour. Expert Opin Pharmacother 9: pp. 1211-1222 CrossRef
- Schnadig, ID, Blanke, CD (2006) Gastrointestinal stromal tumors: imatinib and beyond. Curr Treat Options in Oncol 7: pp. 427-437 CrossRef
- Siehl, J, Thiel, E (2007) C-kit, GIST, and imatinib. Recent Results Cancer Res 176: pp. 145-151 CrossRef
- Guilhot, F (2004) Indications for imatinib mesylate therapy and clinical management. Oncologist 9: pp. 271-281 CrossRef
- Hoeben, A, Schoffski, P, Debiec-Rychter, M (2008) Clinical implications of mutational analysis in gastrointestinal stromal tumours. Br J Cancer 98: pp. 684-688 CrossRef
- Carter, TA, Wodicka, LM, Shah, NP, Velasco, AM, Fabian, MA, Treiber, DK, Milanov, ZV, Atteridge, CE, Biggs, WH, Edeen, PT (2005) Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 102: pp. 11011-11016 CrossRef
- Heinrich, MC, Corless, CL, Demetri, GD, Blanke, CD, Mehren, M, Joensuu, H, McGreevey, LS, Chen, CJ, Abbeele, AD, Druker, BJ (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21: pp. 4342-4349 CrossRef
- Glabbeke, M, Verweij, J, Casali, PG, Cesne, A, Hohenberger, P, Ray-Coquard, I, Schlemmer, M, Oosterom, AT, Goldstein, D, Sciot, R (2005) Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European organisation for research and treatment of cancer–Italian sarcoma group–Australasian gastrointestinal trials group study. J Clin Oncol 23: pp. 5795-5804 CrossRef
- Desai, J, Shankar, S, Heinrich, MC, Fletcher, JA, Fletcher, CD, Manola, J, Morgan, JA, Corless, CL, George, S, Tuncali, K (2007) Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 13: pp. 5398-5405 CrossRef
- Oosterom, AT, Judson, I, Verweij, J, Stroobants, S, Donato di Paola, E, Dimitrijevic, S, Martens, M, Webb, A, Sciot, R, Glabbeke, M (2001) Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358: pp. 1421-1423 CrossRef
- Blanke, CD, Demetri, GD, Mehren, M, Heinrich, MC, Eisenberg, B, Fletcher, JA, Corless, CL, Fletcher, CD, Roberts, PJ, Heinz, D (2008) Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26: pp. 620-625 CrossRef
- Blanke, CD, Rankin, C, Demetri, GD, Ryan, CW, Mehren, M, Benjamin, RS, Raymond, AK, Bramwell, VH, Baker, LH, Maki, RG (2008) 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 Clin Oncol 26: pp. 626-632 CrossRef
- Verweij, J, Casali, PG, Zalcberg, J, LeCesne, A, Reichardt, P, Blay, JY, Issels, R, Oosterom, A, Hogendoorn, PC, Glabbeke, M (2004) Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364: pp. 1127-1134 CrossRef
- Feng, W., Henk, H., Thomas, S., Baladi, J., Hatfield, A., Goldberg, G.A., Cortes J. (2006). Compliance and persistency with imatinib. Journal of Clinical Oncology (ASCO Annual Meeting), 24:6038.
- Van Glabbeke MM, Owzar K, Rankin C, Simes J, Crowley J, GIST Meta-analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): a meta-analysis based on 1,640 patients (pts). Journal of Clinical Oncology (2007 ASCO Annual Meeting ), 2007. p. 10004.
- Patel, S, Zalcberg, JR (2008) Optimizing the dose of imatinib for treatment of gastrointestinal stromal tumours: lessons from the phase 3 trials. Eur J Cancer 44: pp. 501-509 CrossRef
- Demetri, GD, Benjamin, RS, Blanke, CD, Blay, JY, Casali, P, Choi, H, Corless, CL, Debiec-Rychter, M, DeMatteo, RP, Ettinger, DS (2007) 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: pp. S1-29
- Barckett P, Call J, Josephy PD, Scherzer NJ, Singleton R. Disease progression in patients with metastatic gastrointestinal stromal tumor (GIST) receiving Gleevec (imatinib): the effect of drug dosage. In: Connective Tissue Oncology Society 10th Annual Meeting, 2004. p. 227.
- Delbaldo, C, Chatelut, E, Re, M, Deroussent, A, Seronie-Vivien, S, Jambu, A, Berthaud, P, Cesne, A, Blay, JY, Vassal, G (2006) Pharmacokinetic–pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Cancer Res 12: pp. 6073-6078 CrossRef
- Widmer, N, Decosterd, LA, Csajka, C, Leyvraz, S, Duchosal, MA, Rosselet, A, Rochat, B, Eap, CB, Henry, H, Biollaz, J, Buclin, T (2006) Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol 62: pp. 97-112 CrossRef
- Demetri GD, Wang Y, Wehrle E, Blanke C, Joensuu H, von Mehren M. Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST). In: Gastrointestinal Cancers Symposium, 2008. p. 3.
- Judson, I, Ma, P, Peng, B, Verweij, J, Racine, A, Paola, ED, Glabbeke, M, Dimitrijevic, S, Scurr, M, Dumez, H, Oosterom, A (2005) Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 55: pp. 379-386 CrossRef
- Burger, H, Nooter, K (2004) Pharmacokinetic resistance to imatinib mesylate: role of the ABC drug pumps ABCG2 (BCRP) and ABCB1 (MDR1) in the oral bioavailability of imatinib. Cell Cycle 3: pp. 1502-1505
- Debiec-Rychter, M, Sciot, R, Cesne, A, Schlemmer, M, Hohenberger, P, Oosterom, AT, Blay, JY, Leyvraz, S, Stul, M, Casali, PG (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42: pp. 1093-1103 CrossRef
- Evaluation of Self-Reported Progression and Correlation of Imatinib Dose to Survival in Patients with Metastatic Gastrointestinal Stromal Tumors: An Open Cohort Study
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Journal of Gastrointestinal Cancer
Volume 41, Issue 1 , pp 60-70
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- gastrointestinal stromal tumor
- self-reported progression-free survival
- overall survival
- open cohort study
- Industry Sectors
- Author Affiliations
- 1. The Life Raft Group, 40 Galesi Dr, Wayne, NJ, 07470, USA
- 2. Department of Cellular and Molecular Biology, University of Guelph, Guelph, ON, Canada, N1G 2W1
- 3. 14071 Brant Point Circle, Ft Myers, FL, 33919, USA