High-dose intravenously (i.v) vitamin C in cancer patients is controversial. Numerous studies carried out on cancer cell lines and animal models demonstrated that millimolar vitamin C concentrations inhibit tumor cells viability, especially in association with chemotherapy. In cancer patients, high-dose i.v vitamin C in monotherapy does not show any anti-cancer activity. Clinical trials assessing high-dose i.v vitamin C concomitantly with chemotherapy do not conclude to reliable evidence for tumor control or overall survival benefit. Randomized double-blind trials are warranted.

The international phase IIIb study, ATHENA assessed the combination of bevacizumab/taxane-based chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer (mBC) in real-life setting. Among the 365 patients included in France, median overall survival (OS) is 28.4 months (CI95% 24.8-33.0), with a median time from treatment start to end of study of 36,5 months (25,1-45,4). Exploratory analyses in three sub-groups show that the median OS in long responder patients (not progressing for at least one year; n = 116) is not reached. In responder patients (n = 308), median OS is 33.0 months (CI95% 28.6-37.4) and 12.4 months (CI95% 11.2-17.4) in non-responders (n = 41). In patients with mBC expressing hormone receptors (HR+), treated with first-line hormone therapy before inclusion (n = 87) median OS in is 23.2 months (CI95% 19.6-28.6), and 35.3 months (CI95% 32.2-not reached); P = 0.004 in patients treated first with chemotherapy + bevacizumab (n = 179). The safety analysis in the various sub-groups of grade 3-5 adverse events of particular interest to bevacizumab of this study was comparable to the safety data of randomized phase III studies.

To compare chemoradiation with systemic chemotherapy to chemotherapy alone in locally advanced pancreatic cancer.

There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors.

Ovarian cancer is the most frequent cause of death due to gynecologic malignancy in both the United States and in Europe. A phase III investigation compared second line treatment Caelyx with topotecan in patients with advanced epithelial ovarian carcinoma who failed a first-line platinum-containing regimen. A total of 474 patients were enrolled Although no significant advantage of Caelyx over topotecan with regards to overall survival and progression was found, there were fewer adverse events in the Caelyx arm and Caelyx had significantly better quality of life profile. We conducted a cost minimization analysis of both treatment arms. Costs were estimated from the viewpoint of the hospital, over the duration of the study period (12 weeks). The frequency of adverse events was derived from the trial's CRF, the treatment patterns of adverse events was estimated for each type of adverse event and each grade for a given type of adverse event. Costs included that of the drug and management of adverse events. Because of uncertainty on actual time spent in French hospitals, administration costs were not valued. Adverse events valued in the analysis were: stomatitis/ pharyngitis, PPE, nausea/vomiting diarrhea, anemia, thrombocytopenia, neutropenia, sepsis, fever. Drug costs and costs of blood products were valued using the purchase price by the hospital, costs of tests and hospital days were estimated from the hospital's accounting system. The drug cost per patient was 8,735 euros for Caelyx and 6,196 euros for topotecan, the cost of adverse events were 528 and 3,632 euros for Caelyx and topotecan respectively, due to the high rate of adverse events in patient treated with topotecan. The total costs were 9,279 and 9,938 for Caefyx and topotecan respectively.

The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases.

The objective of the study was to estimate the cost of first line chemotherapy in metastatic colorectal cancer treated in the Gustave-Roussy Institute. Patients were randomized in the study FFCD 9601 with four schedules of treatment: Tomudex(R), 5FU weekly, LV5FU2 with low dose of folinic acid and LV5FU2 with high dose of folinic acid.

To compare by a prospective study in low risk polycythemia vera (PV) patients alone two drugs: hydroxyurea and pipobroman. Toxicity, efficiency, and leukemogenic potential were studied.

This multicentric double-blind, dose-ranging study was to compare efficacy and safety of two oral doses of granisetron solution in the prevention of chemotherapy-induced emesis in children with malignant diseases : 294 children, aged 1 to 16, treated with a moderately or highly emetogenic chemotherapy were randomly assigned to receive oral granisetron either 20 microg/kg (n = 143) or 40 microg/kg (n = 151) before and 6 to 12 hours after the start of chemotherapy. Fifty-one percent of patients treated with 20 microg/kg bd of oral granisetron solution achieved a complete response (no vomiting, no worse than mild nausea, no rescue therapy and no withdrawal during the specified period) and 59% achieved a major response (no more than one episode of vomiting, no worse than mild nausea, no rescue therapy and no withdrawal during the specified period). There was no difference between the two oral doses of granisetron. Treatment was rated as good or very good by investigators in 70% of cases. In conclusion, oral granisetron suspension either at 20 microg/kg bd or at 40 microg/kg bd showed good efficacy and safety in the prevention of chemotherapy-induced emesis in children with malignant diseases. Oral granisetron solution can be used as prophylaxis of emesis in children receiving moderately or highly emetogenic chemotherapy.

In the treatment of anal canal carcinoma, since the work of Nigro, the 5-fluorouracil-mitomycin C regimen is considered standard when applied concomitantly with radiotherapy. Surgery is used mainly to salvage the failures after irradiation. Two randomized European trials (EORTC, UKCCCR) have shown that the 5-fluorouracil-mitomycin C combination improves local control but not overall survival. The RTOG-ECOG trial has shown that mitomycin C improves local control when compared to 5-fluorouracil alone. This chemotherapy is responsible for a toxic death in 2% of cases. The 5-fluorouracil-cisplatin regimen will possibly represent an alternative to the 5-fluorouracil-mitomycin C. Ongoing trials will help to answer this question.

NEED FOR NEW CHEMOTHERAPY AGENTS: Metastasic breast cancer is an excellent model for studying anticancer agents: chemotherapy or hormonotherapy or compounds modifying the organism's response. If no adjuvant treatment is given after locoregional treatment of breast cancer, metastasis will develop within 10 years in 30% of the patients free of initial nodal invasion and within 5 years in 50% of the patients with initial nodal invasion. ADJUVANT TREATMENTS: Hormonotherapy and chemotherapy reduce mortality due to breast cancer by 10%. New adjuvant agents have been recently introduced. Taxans (docetaxel, paclitaxel) are the most active molecules since antracyclines. New aromataase inhibitors include letrozole and anastrozole. Their efficacy has been demonstrated in phase II and phase III trials, allowing their experimentation as adjuvant treatments.

This multicentre randomized single-blind parallel group study compared the efficacy of oral ondansetron plus methylprednisolone (OND+MPS) with conventional antiemetic strategies (TH) over 4 consecutive courses in moderately emetogenic chemotherapy. This study was conducted in naive patients receiving a minimum of 3 cytotoxics including adriamycin (> or = 35 mg/m2) and cyclophosphamide (> or = 500 mg/m2) plus an other alkylating agent. Of the 364 patients included in the study, 70% had a breast cancer and 30% a lymphoma. Patients were divided into two groups. On day 1, one group of patients received OND (8 mg, po) 2 hours before chemotherapy, followed by a slow intravenous injection of MPS (120 mg) 30 minutes before chemotherapy. Eight hours after the start of chemotherapy, patients received OND (8 mg, po) and MPS (16 mg, po). On days 2-4, patients received OND (8 mg, po) and MPS (16 mg, po) twice daily. The second group of patients received conventional antiemetic treatment (benzamide plus corticosteroids with or without benzodiazepins). The primary efficacy parameter was defined as complete control of emesis (0 emetic episodes) over 4 consecutive courses of chemotherapy. In the OND+MPS group, 63% of patients experienced complete control of emesis versus 33% in the TH group (p < 0.001). The secondary parameters (percentage of days with no emetic episodes, control of emetic episodes, grade of nausea at each course, patient preference and quality of life evaluation) were always significantly better in the OND+MPS treated group. The percentage of days without any emetic episode over the 4 courses of chemotherapy was 91% in the OND+MPS group and 75% in the TH group (p < 0.001). Ninety-two percent of patients from OND+MPS group preferred to continue their treatment versus 76% in the TH group (p < 0.001). Concerning the quality of life assessed by FLIC and FLIE questionnaires, the analysis showed a significant difference at the end of the treatment in favor of OND+MPS (p = 0.037 and 0.0075 respectively). This study showed the interest in using the combination OND+MPS right from the first course of moderately emetogenic chemotherapy.

Ifosfamide is one of the most efficient antimitotic in soft tissue sarcoma. To try to find a possible dose-effect, 10 patients with advanced pretraited relapsed soft tissue sarcoma received 15 g/m2/cycle ifosfamide in continuous infusion during 5 days. A pharmacokinetic study was done for 2 patients. All patients received growth factors, ondansetron and 8 clonazepam. Renal toxicity was evaluated after the first and the second cycle. Twenty two cycles were delivered to patients who have been already treated with ifosfamid (10 patients with 15 g/m2 to 54 g/m2, median 27 g/m2) or cis platinum (2 patients). No major renal or neurologic toxicity was observed; only subclinical modifications of urinary enzymes excretion were found. Two patients had visual hallucinations at the end of a cycle and just in the 2 following days; another presented a neuropathy of inferior limbs. Hematological toxicity was very limited. Pharmacokinetic study did not show induction mechanism at this dosage and with this type of administration. So ifosfamide 3 g/m2 during 5 days is feasible. The few level of complications observed is perhaps linked to the daily dose of 3 g/m2 instead of 4 g/m2 or more used in the other studies.

Originally developed against the effects of ionizing radiations, amifostine is an organic thiophosphate compound shown able to selectively protect normal tissues against cytotoxic agents in cellular and animal models, without protecting tumor tissues. Amifostine is a prodrug which is dephosphorylated into its active metabolite, a free thiol derivative, by membrane alkaline phosphatase of the target issue. This unique metabolism supports its cellular selectivity and its preferential uptake by normal tissues. In phase II clinical trials, a decreased toxicity has been demonstrated in patients given alkylating agents; however, reduction of the response has not been observed. On the basis of these results, a prospective, randomized, phase III study has been conducted in patients with ovarian carcinoma receiving a combination of cisplatinum and cyclophosphamide. A significant decrease in hematologic, renal and neurologic toxicity was observed in the amifostine-treated patients compared with the control group, and response rates did not significantly differ between the two groups. Insufficient or emerging data are only available for other applications, including either in vitro manipulation of hematopoietic grafts or in vivo treatment of non-Hodgkin's lymphoma, head and neck carcinoma, non-small cell lung cancer and radioprotection. No data are yet available in regard to the potential protective effects of amifostine against mutagenicity and cancerogenicity of both chemo- and radiotherapy.

Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy.

The anti-emetic action of alizapride was compared to that of metoclopramide in a strict double-blind study of 57 cases files derived from 21 patients treated with anti-mitotic chemotherapy. For each treatment, each patient received two ampoules before and after the chemotherapy. Each ampoule contained either 50 mg of alizapride or 10 mg of metoclopramide. There were 24 good or excellent results and 4 nil results with alizapride and 16 good or excellent results and 13 nil results with metoclopramide. The superiority of alizapride over metoclopramide was therefore established with statistical significance (0.05 greater than p greater than 0.02).

In order to prevent vomiting induced by anti-cancer chemotherapy, the efficiency of domperidone has been compared to metoclopramide in a randomised trial. No difference has been observed between both emetic treatments.