Abstract
Purpose
Combination chemotherapy results in a significant survival advantage in patients with advanced gastric cancer compared to best supportive care. Nevertheless, the prognosis remains poor with a median survival of 8–10 months. Topoisomerase-I inhibitors such as irinotecan have activity in advanced gastric cancer. Pegamotecan may offer significant advantages over other topoisomerase-I inhibitors due to its prolonged circulating half-life, tolerability and passive tumour accumulation.
Patients and methods
This was a non-randomised, multi-centre, two-step Fleming design phase II study. Eligible patients with locally advanced (inoperable) or metastatic gastric or gastro-oesophageal adenocarcinoma, with measurable disease, ECOG performance status ≤2, with adequate haematological, renal and hepatic function, who had received ≤1 prior chemotherapy regimen for advanced disease, were treated with 7,000 mg/m2 of pegamotecan as a 1-h infusion every 21 days until disease progression or unacceptable toxicity. The primary efficacy measure was the objective response rate.
Results
Five of the 35 patients recruited into this study had a partial response (14.3%), with a median time to progression of 11.9 weeks (95% CI: 6.6, 13.1), and median overall survival of 38.1 weeks (95% CI: 29.0, 47.3). Grade 3/4 toxicities included neutropenia in 6 (17.1%) patients, thrombocytopenia in 4 (11.4%), fatigue in 8 (22.9%), nausea in 6 (17%), vomiting in 6 (17%) and anorexia in 4 (11.4%) patients. There were no episodes of febrile neutropenia and no toxic deaths.
Conclusions
Pegamotecan has activity in this patient population and was generally well-tolerated. The favourable rate of haematological toxicities and diarrhoea compared with irinotecan in similar studies suggests that pegamotecan could be combined with other active agents in further studies in this disease.
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References
Kelley JR, Duggan JM (2003) Gastric cancer epidemiology and risk factors. J Clin Epidemiol 56:1–9
Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287–1289
Murad AM, Santiago FF, Petroianu A et al (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72:37–41
Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587–591
Glimelius B, Ekstrom K, Hoffman K et al (1997) Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8:163–168
Findlay M, Cunningham D, Norman A et al (1994) A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF). Ann Oncol 5:609–616
Webb A, Cunningham D, Scarffe JH et al (1997) Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261–267
Wohrer SS, Raderer M, Hejna M (2004) Palliative chemotherapy for advanced gastric cancer. Ann Oncol 15:1585–1595
Van Cutsem E, Moiseyenko VM, Tjulandin S et al (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991–4997
Futatsuki K, Wakui A, Nakao I et al (1994) Late phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer. CPT-11 Gastrointestinal Cancer Study Group. Gan To Kagaku Ryoho 21:1033–1038
Enzinger PC, Ilson DH (2000) Irinotecan in esophageal cancer. Oncology 14:26–30
Benedetti JK, Burris HA 3rd, Balcerzak SP, Macdonald JS (1997) Phase II trial of topotecan in advanced gastric cancer: a Southwest Oncology Group Study. Invest New Drugs 15:261–264
Saltz LB, Schwartz GK, Ilson DH et al (1997) A phase II study of topotecan administered five times daily in patients with advanced gastric cancer. Am J Clin Oncol 20:621–625
Greenwald RB, Conover CD, Choe YH (2000) Poly(ethylene glycol) conjugated drugs and prodrugs: a comprehensive review. Crit Rev Ther Drug Carrier Syst 17:101–161
Lee S, Greenwald RB, McGuire J et al (2001) Drug delivery systems employing 1, 6-elimination: releasable poly(ethylene glycol) conjugates of proteins. Bioconjug Chem 12:163–169
Conover CD, Pendri A, Lee C et al (1997) Camptothecin delivery systems: the antitumor activity of a camptothecin-20-0-polyethylene glycol ester transport form. Anticancer Res 17:3361–3368
Conover CD, Greenwald RB, Pendri A et al (1998) Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker. Cancer Chemother Pharmacol 42:407–414
Rowinsky EK, Rizzo J, Ochoa L et al (2003) A phase I and pharmacokinetic study of pegylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies. J Clin Oncol 21:148–157
Fleming TR (1982) One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151
Therasse P, Arbuck SG, Eisenhauer EA et al (2000) 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 92:205–216
Kaplan E, Meier P (1958) Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
Oken MM, Creech RH, Tormey DC et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655
Cella DF, Tulsky DS, Gray G et al (1993) The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11:570–579
Aktipis S (1986) DNA: the replication process and repair. In: Devleri TM (ed) Textbook of biochemistry with clinical correlations. Wiley, New York, p 625
Wall ME, Wani MC, Cook CE et al (1966) Plant antitumor agents 1: the isolation and structure of camptothecin, a novel alkaloidal leukaemia and tumor inhibitor for Camptotheca accuminata. J Am Chem Soc 88:3888–3890
Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873–14878
Hsiang YH, Liu LF (1988) Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726
Gottlieb JA, Guarino AM, Call JB et al (1970) Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep 54:461–470
Creaven PJ, Allen LM (1973) Renal clearance of camptothecin (NSC-100880): effect of urine volume. Cancer Chemother Rep 57:175–184
Garcia-Carbonero R, Supko JG (2002) Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 8:641–661
Pizzolato JF, Saltz LB (2003) The camptothecins. Lancet 361:2235–2242
Enzinger PC, Kulke MH, Clark JW et al (2005) A phase II trial of irinotecan in patients with previously untreated advanced esophageal and gastric adenocarcinoma. Dig Dis Sci 50:2218–2223
Kohne CH, Catane R, Klein B et al (2003) Irinotecan is active in chemonaive patients with metastatic gastric cancer: a phase II multicentric trial. Br J Cancer 89:997–1001
Ajani JA, Takimoto C, Becerra CR et al (2005) A phase II clinical and pharmacokinetic study of intravenous exatecan mesylate (DX-8951f) in patients with untreated metastatic gastric cancer. Invest New Drugs 23:479–484
Kindler HL, Avadhani A, Wade-Oliver K et al (2004) 9-Aminocamptothecin (9-AC) given as a 120-hour continuous infusion in patients with advanced adenocarcinomas of the stomach and gastroesophageal junction: a phase II trial of the University of Chicago phase II consortium. Invest New Drugs 22:323–327
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The authors are grateful to all the staff at the study centres who contributed to this study.
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Scott, L.C., Yao, J.C., Benson, A.B. et al. A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma. Cancer Chemother Pharmacol 63, 363–370 (2009). https://doi.org/10.1007/s00280-008-0746-2
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DOI: https://doi.org/10.1007/s00280-008-0746-2