Phase II trial of irinotecan in patients with metastatic colorectal carcinoma.

Pitot, Henry C.; Wender, Donald B.; O’Connell, Michael J.; Schroeder, Georgene; Goldberg, Richard M.; Rubin, Joseph; Mailliard, James A.; Knost, James A.; Ghosh, Chirantan; Kirschling, Ron J.; Levitt, Ralph; Windschitl, Harold E.

doi:10.1200/jco.1997.15.8.2910

Cited by 247 publications

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“…Phase II trials have demonstrated objective response rates of 16 -27% in pretreated patients, with stabilisation of disease in a further 40 -60% of patients (Rougier et al, 1997;Van Cutsem et al, 1999). Median overall survival rates of up to 10 months are achievable when irinotecan is used in relapsed/refractory colorectal cancer (Shimada et al, 1993;Rothenberg et al, 1996Rothenberg et al, , 1999Pitot et al, 1997;Rougier et al, 1997;Van Cutsem et al, 1999). Two European phase III trials investigating the efficacy and safety of irinotecan, following 5-FU failure in advanced colorectal cancer, have demonstrated significant improvements in survival compared with best supportive care and 5-FU (Cunningham et al, 1998;Rougier et al, 1998).…”

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Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

et al. 2005

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Although irinotecan 350 mg m À2 is a standard option for relapsed/refractory advanced colorectal cancer, there is some evidence that suggests that a higher dose may be more effective, with acceptable tolerability, following 5-fluorouracil (5-FU). This study assessed the optimal dosing strategy for irinotecan, along with treatment efficacy and safety. A total of 164 patients with metastatic colorectal cancer progressing after failure on 5-FU or raltitrexed received either 350 mg m À2 irinotecan (Group A; n ¼ 36) or 250, 350 or 500 mg m À2 , according to individual patient tolerance (Group B; n ¼ 62) or based on risk factor optimisation (Group C; n ¼ 66). There were no complete responses. There was a trend towards a higher overall response rate in Group B (13%) than in Groups A (8%) and C (9%). Tumour control growth rate was high in all three groups: 58% in group A, 60% in Group B and 50% in Group C. A total of 34% of patients in Group B and 9% in Group C were able to receive a dose of 500 mg m À2 . Median duration of response and time to progression were significantly longer in Groups A and B compared with Group C. No significant between-group differences for any adverse events were seen, although there was a small trend towards better tolerability in Group B. Individual dose escalation based on patient tolerance may allow more patients to receive a higher irinotecan dose without causing additional toxicity and can be an appropriate patient management strategy. 1999). Median overall survival rates of up to 10 months are achievable when irinotecan is used in relapsed/refractory colorectal cancer (Shimada et al, 1993; Rothenberg et al, 1996 Rothenberg et al, , 1999Pitot et al, 1997;Rougier et al, 1997;Van Cutsem et al, 1999). Two European phase III trials investigating the efficacy and safety of irinotecan, following 5-FU failure in advanced colorectal cancer, have demonstrated significant improvements in survival compared with best supportive care and 5-FU (Cunningham et al, 1998;Rougier et al, 1998). The main adverse events accompanying treatment with irinotecan in these trials were diarrhoea, neutropenia, fatigue, nausea and vomiting.Although 350 mg m À2 as an intravenous infusion every 3 weeks is the standard recommended dosage of irinotecan, pharmacokinetic parameters of irinotecan-lactone and the active metabolite SN-38-lactone vary between individuals (Xie et al, 2002). This may be attributed to differences in the levels of the enzymes that metabolise irinotecan, notably carboxylesterase for SN-38. Furthermore, the variable interindividual patient exposure to SN-38 has been identified as an important determinant of toxicity .At the same time, there is convincing evidence of a doseresponse relationship, and therefore a rationale for increasing doses when possible. In a phase I trial by Abigerges et al (1995), there were two recommended doses: 350 mg m À2 without highdose loperamide and 600 mg m À2 with high-dose loperamide. With the exception of one responder treated at 260 mg m À2 , all objective responses...

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Optimisation of irinotecan dose in the treatment of patients with metastatic colorectal cancer after 5-FU failure: results from a multinational, randomised phase II study

et al. 2005

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“…Treatment compliance for this regimen was good, with median relative DIs delivered for L-OHP, LV and 5-FU of 92%, 92% and 94%, respectively. In the preoxaliplatin era, CPT-11 was shown to be an active agent in patients with rapidly progressing colorectal cancer (Rothenberg et al, 1996), in patients refractory to 5-FU (Rougier et al, 1998) and in patients who had progressed during or shortly after 5-FU-based chemotherapy (Pitot et al, 1997). In Rothenberg's study, however, 23% of patients developed grade 4 diarrhoea and the other studies reported a high-toxicity profile with several hospital deaths attributable to multiple gastrointestinal toxicities, together with unexpected thromboembolic events (Rothenberg et al, 2001).…”

Section: Months)mentioning

confidence: 99%

Multicentre phase II study of bifractionated CPT-11 with bimonthly leucovorin and 5-fluorouracil in patients with metastatic colorectal cancer pretreated with FOLFOX

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et al. 2004

Br J Cancer

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This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m 2 administered over 90 min, followed by LV, 200 mg m 2 administered over 2 h plus 5-FU 400 mg m 2 as a bolus and 600 mg m 2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3 -4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.

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“…In clinical studies CPT-11 has demonstrated single-agent activity in advanced CRC with response rates of 20-25%. 56 In combination with 5FU, CPT-11 has produced response rates of 49% for advanced CRC. 57 Furthermore, CPT-11 has demonstrated significant activity in tumours that are refractory to 5FU.…”

Section: Cpt-11 (Irinotecan)mentioning

confidence: 99%