Bulletin du cancer
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Randomized Controlled Trial Multicenter Study Clinical Trial
[Comparative trial of oral granisetron and intravenous ondansetron in patients receiving chemotherapy for breast cancer. Study Group of Granisetron].
This multicentric randomized trial compared two strategies in the prevention of acute and delayed nausea and vomiting induced by moderately emetogenic chemotherapy in patients with breast cancer. The antiemetic efficacy and side effects of oral granisetron, followed by metoclopramide, were compared to those of intravenous (IV) ondansetron followed by oral ondansetron. 198 chemonaive patients with breast cancer, treated with a moderately emetogenic chemotherapy, were randomly assigned to receive either oral granisetron 1 mg twice a day on day 1, followed by metoclopramide, 60 mg on day 2 and 3, or ondansetron, 8 mg IV on day 1, followed by ondansetron 8 mg tablet twice a day on day 2 and 3. Both treatments have shown similar control of acute emesis: complete response was achieved in 71% of granisetron group and 66% of ondansetron, and total response in respectively 49% and 53%. ⋯ Furthermore, during the overall study period (day 1 to 5), the percentage of complete responses in the group receiving oral granisetron followed by oral metoclopramide was significantly higher than in the group receiving ondansetron (53% versus 37%; p = 0.022). In conclusion, oral granisetron has shown similar efficacy as IV ondansetron in the prevention of acute emesis induced by moderately emetogenic chemotherapy. Oral granisetron followed by metoclopramide seems more efficient than IV plus oral ondansetron in the prevention of delayed emesis.
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The randomised trial is the best context for the assessment of any new molecule in oncology. The authors emphasize the methodological aspects of randomised trials and suggest strategies to be adopted in phase III trials, based on the newly orthodox concept of evidence-based medicine, while underscoring the need for context specific adaptations to increase relevance and specificity of sought endpoints, including other means of controlling adequately the clinical experiment without randomization (patient as his own control models). The authors also suggest certain strategic changes. For example, restrictive but relevant eligibility criteria may help decrease the number of patients needed without compromising statistical power as well as other strategies aimed at proving the efficacy of a new molecule without carrying out large trials, which are too long and costly.
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Treatments of advanced colorectal cancer progressing after a 5FU based chemotherapy have not been extensively studied. However, 5FU in continuous infusion, L-OHP alone or in combination with 5FU and CPT11 have proved their efficacy in terms of tumor growth control and symptomatic effect. Irinotecan only has been evaluated prospectively in phase III studies. ⋯ Both treatments were equally well tolerated. These two randomized studies have proved the efficacy of irinotecan as second line chemotherapy for colorectal cancers progressing under 5FU. Combination of irinotecan to 5FU and/or L-OHP have now to be evaluated in this situation.
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Irinotecan (CPT11), a topoisomerase I inhibitor, is a new cytotoxic agent with a broad spectrum of clinical activity. Two main schedules have been studied and produce similar activity and side-effects: the "european" one--350 mg/m2 every 21 days-, and the "japanese-north american" one where CPT11 is given at a weekly dose of 100-120 mg/m2 for 4 consecutive weeks followed by a 2 week rest period. Activity was initially characterized in advanced colorectal cancers; response rates, disease free-survival and overall survival were 11%, 7-10 months and 8-11 months in patients failing fluoropyrimidine based chemotherapy--statistically improved as compared to best supportive care and infusional fluorouracil-, and 20-30% in patients not previously treated. ⋯ Irinotecan can be combined to fluoropyrimidines, raltitrexed, cisplatin, carboplatin and oxaliplatin, to gemcitabine, etoposide, vinorelbine and taxanes with flexible schedules (weekly, every 2 weeks, every 21 days. Most of these combinations have an additive or supra additive activity. Its mechanism of action, the spectrum of activity and the acceptable risk-benefit ratio point to irinorecan as a major advance in the field of cytotoxic anticancer therapy.
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Review
[Irinotecan: various administration schedules, study of drug combinations, phase I experience].
Irinotecan (CPT11) is a synthetic camptothecin-derived DNA topoisomerase I inhibitor. Based on phase I clinical trials, several schedules have been recommended for phase I studies including 350 mg/m2 every 3 weeks in Europe, 125 mg/m2 for 4 weeks every 6 weeks in the USA, and 100 mg/m2 weekly or delayed until recovery in case of grade > 2 toxicity in Japan. The principal dose-limiting toxicities in those schedules are neutropenia and delayed diarrhea. ⋯ Those variations may be related to modifications in the hepatic metabolism of the drug that may occur in patients with hepatic dysfunction and/or in patients with concomitant medications. The understanding of the individual metabolism of the drug would help to determine individual dose adaptation. Based on synergistic preclinical interaction with several drugs, combinations of irinotecan with other cytotoxic drugs such as thymidylate synthethase inhibitors and platinum salts are currently investigated in phase I-II studies.