A Taamma

Institut de Cancérologie Gustave Roussy, Île-de-France, France

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Publications (23)140.43 Total impact

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    ABSTRACT: To determine maximum tolerated dose (MTD), recommended dose, safety and pharmacokinetics of irofulven combined with cisplatin in advanced solid tumor patients. Cisplatin and irofulven were given sequentially i.v. over 30 min on day 1 and 15 every 4 weeks. Four dose levels (DL) were explored: irofulven (mg/kg)/cisplatin (mg/m2): DL1: 0.3/30; DL2: 0.4/30; DL3: 0.4/40; DL4: 0.5/40. Dose-limiting toxicity (DLT) included dosing omission and delay > 1 week. MTD was the DL with DLT in 2/2 or > or = 2/6 patients during cycle 1-2. Between March 2002 and April 2003, 33 patients were treated. DLT occurred in 1/6 patients in DL1 (hypomagnesemia, hypocalcemia); 1/6 in DL2 (thrombocytopenia); 2 heavily pretreated patients out of 6 patients in DL3 (neutropenic infection, thrombocytopenia, stomatitis); 2/3 in DL4 (asthenia, blurred vision). Three DLT occurred in 12 additional patients treated at DL2. No toxic deaths occurred; grade 4 toxicity and grade 3 non-hematological toxicity were infrequent. Six patients reported grade 1-2 visual events. Antitumor activity was observed over a broad spectrum of tumor types in all DLs: 1 partial response in bulky sarcoma (DL1); 1 clinical response in endometrial carcinoma (DL1); 2 partial responses not confirmed due to discontinuation (ovarian DL2, renal DL4); 8 stabilizations > 3 months; PSA response: 3/9 prostate cancer patients. Irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions. Irofulven with cisplatin was adequately tolerated and substantial evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and cisplatin 30 mg/m2.
    Investigational New Drugs 08/2006; 24(4):311-9. · 3.50 Impact Factor
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    ABSTRACT: Yondelis (trabectedin, ET-743) is a novel marine-derived anticancer compound found in the ascidian Ecteinascidia turbinata. It is currently under phase II/III development in breast cancer, hormone refractory prostate cancer, sarcomas and ovarian cancer. Activity in breast cancer experimental models has been reported, and preliminary evidence of activity in this setting during the phase I programme has also been observed. The present study assessed the activity and feasibility of trabectedin in women with advanced breast cancer previously treated with conventional therapies. Patients with advanced disease previously treated with at least one but not more than two regimens that included taxanes or anthracyclines as palliative therapy were eligible. Trabectedin 1.5 mg m(-2) was administered as a 24-h continuous infusion every 3 weeks. Patients were kept on therapy until disease progression, unacceptable toxicity or patient refusal. Twenty-seven patients were included between April 1999 and September 2000. Their median age was 54 years (range: 36-67) and 63% of them had two metastatic sites. Twenty-two patients were performance status 1. All patients had previously received anthracyclines, and 23 out of 27 patients had received taxanes. Of 21 patients with measurable disease, three confirmed partial responses, one unconfirmed partial response and two minor responses (49 and 32% tumour shrinkage) were observed; six patients had stable disease. Median survival was 10 months (95% confidence interval: 4.88-15.18). Transient and noncumulative transaminitis was observed in most of the patients. The pharmacokinetic profile of trabectedin in this patient's population is in line with the overall data available with this schedule. The policy of dose adjustments based on the intercycle peaks of bilirubin and alkaline phosphatase appears to have a positive impact in the therapeutic index of trabectedin. Trabectedin can induce response and tumour control in previously treated advanced breast cancer, with manageable toxicity, thus warranting further development as a single agent or in combination regimens.
    British Journal of Cancer 07/2006; 94(11):1610-4. · 5.08 Impact Factor
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    ABSTRACT: A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients. Patients received ET-743 1,500 microg/m(2) (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies). Results Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease (> or = 6 months). Three patients were rendered tumor free after surgery. Median progression-free survival was 1.9 months (range, 0.69 to 17.90 months); 24% of patients were progression free at 6 months. Median survival was 12.8 months, with 30% of patients alive at 2 years. Four patients withdrew because of treatment-related toxicity. Two treatment-related deaths occurred (renal failure and febrile neutropenia, and rhabdomyolysis and decompensated cirrhosis, respectively) that were probably related to protocol eligibility violations. Reversible grade 3 to 4 AST or ALT occurred in 50% of patients and grade 3 to 4 neutropenia occurred in 61% of patients, with six episodes of febrile neutropenia. Nausea, vomiting, and asthenia were prevalent but mild and manageable. With a 4% overall response rate (95% CI, 0.5 to 12.8) and an 11% rate of third-party-verified tumor regression (overall response rate + minor response), ET-743 has a 24% 6-month disease progression control rate, confirming evidence of antitumoral activity and a manageable safety profile in patients experiencing disease progression with pretreated soft tissue sarcoma.
    Journal of Clinical Oncology 03/2004; 22(5):890-9. · 18.04 Impact Factor
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    ABSTRACT: To evaluate the efficacy and safety of an oxaliplatin, fluorouracil (5-FU), and folinic acid (FA) combination in patients with metastatic or advanced gastric cancer (M/AGC). Of the 54 eligible patients with measurable or assessable M/AGC, 53 received oxaliplatin 100 mg/m(2) and FA 400 mg/m(2) (2-hour intravenous infusion) followed by 5-FU bolus 400 mg/m(2) (10-minute infusion) and then 5-FU 3,000 mg/m(2) (46-hour continuous infusion) every 14 days. Patients (69% male, 31% female) had a median age of 61 years (range, 31 to 75 years), 89% had a performance status of 0 or 1, 70% had newly diagnosed disease, and 87% had metastatic disease. All had histologically confirmed adenocarcinoma. With a median of three involved organs, disease sites included the lymph nodes (67%), stomach (65%), and liver (61%). A median of 10 cycles per patient and 468 complete cycles were administered. Best responses in the 49 assessable patients were two complete responses and 20 partial responses, giving an overall best response rate of 44.9%. Eight patients underwent complementary treatment with curative intent (six with surgery and two with chemoradiotherapy). Median follow-up, time to progression, and overall survival were 18.6 months, 6.2 months, and 8.6 months, respectively. Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and anemia occurred in 38%, 19%, 4%, and 11% of patients, respectively, and febrile neutropenia occurred in six patients (one episode each). Grade 3 peripheral neuropathy occurred in 21% of patients (oxaliplatin-specific scale). Seven patients withdrew because of treatment-related toxicity. This oxaliplatin/5-FU/FA regimen shows good efficacy and an acceptable safety profile in M/AGC patients, and may prove to be a suitable alternative regimen in this indication.
    Journal of Clinical Oncology 01/2003; 20(23):4543-8. · 18.04 Impact Factor
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    ABSTRACT: Ecteinascidin 743 (ET-743) is a novel, marine-derived anticancer agent currently under clinical development for the treatment of solid tumors. The aim of this study was to develop and validate limited sampling strategies for the prediction of ET-743 clearance in phase II studies, using two techniques: the stepwise linear regression approach and the Bayesian estimation approach. Data from a phase I dose-finding study were used with ET-743 administered as a 24-h infusion. Plasma concentration time data from 34 patients treated with 1200. 1500 or 1800 microg/m2 ET-743 were randomly divided into an index data set, used for the development of the strategies, and a validation data set. With the linear regression approach, clearance (obtained by non-compartmental analysis) was correlated with the ratios of dose to the observed concentrations. For the Bayesian approach a three-compartment population pharmacokinetic model was developed; optimal time-points were selected using the D-optimality algorithm. The strategies were compared by assessment of their predictive performance of CL in the validation data set. The linear regression method yielded a single-point sampling schedule with no significant bias and acceptable precision (-0.03% and 21%, respectively). With the Bayesian approach, a three-sample strategy was selected which resulted in less-accurate, but unbiased, predictions (bias 13%, precision 34%). Optimal sampling strategies were developed and validated for estimation of ET-743 clearance. Although the linear regression approach showed slightly better predictive performance, the Bayesian approach is preferred for the current phase II studies as it is more robust and flexible and allows the description of the full pharmacokinetic profile.
    Cancer Chemotherapy and Pharmacology 01/2002; 48(6):459-66. · 2.80 Impact Factor
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    ABSTRACT: To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program. Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 microg/m(2) (six patients), 1,500 microg/m(2) (the recommended dose, 22 patients), or 1,800 microg/m(2) (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks. Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing's sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months. ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.
    Journal of Clinical Oncology 04/2001; 19(5):1248-55. · 18.04 Impact Factor
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    ABSTRACT: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 microg/m(2). The MTD was defined as 1,800 microg/m(2) (DL 9), and the phase II RD was 1,500 microg/m(2) (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 microg/m(2)) in 94% and 25% of cycles, respectively. At the RD (1,500 microg/m(2)), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting > or = 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood. The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 microg/m(2), with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.
    Journal of Clinical Oncology 04/2001; 19(5):1256-65. · 18.04 Impact Factor
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    ABSTRACT: To determine the feasibility of the paclitaxel, oxaliplatin, cisplatin combination in advanced ovarian cancer (AOC), 15 patients with AOC (8 chemonaive, and 7 second-line, disease-free interval > or = 12 months) received paclitaxel 135 mg/m2 at day 1, with oxaliplatin 100 mg/m2 and cisplatin 75 mg/m2 at day 2, every 3 weeks for 6 cycles. Pretreated patients received prophylactic granulocyte colony-stimulating factor (5 microg/kg/d, days 6-13). Seventy cycles were administered; median 5 (range: 2-6 cycles) in chemonaive, and 4 (range: 2-6) in pretreated patients. There were grades III to IV neutropenia in 77%, febrile neutropenia in 24%, and grades III to IV thrombocytopenia in 4% of the cycles. Besides neutropenia, cumulative neurosensory toxicity was also limiting although reversible, with National Cancer Institute Common Toxicity Criteria grades II to III observed in 13 patients. Three of the pretreated patients had complete responses (43%), three had partial responses, and one had disease stabilization. Six of the 8 chemonaive patients had complete responses (75%), 1 had disease stabilization, and 1 had disease progression. The median follow-up is 17 months (range: 9-20 months) in chemonaive and 41 months (range: 13-58 months) in pretreated patients, and time to progression has been consistently more than 12 months, with 6 patients (5 chemonaive) still progression free (range: 15+ to 22+ months). This active combination shows acceptable hematologic toxicity, and reversible cumulative neurosensory toxicity. Further clinical exploration of the present combination appears warranted.
    American Journal of Clinical Oncology 01/2001; 23(6):569-74. · 2.55 Impact Factor
  • European Journal of Cancer - EUR J CANCER. 01/2001; 37.
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    ABSTRACT: Ecteinascidin (ET) 743 is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies revealed activity of ET-743 against different tumor types. A Phase I clinical trial was designed with ET-743 to identify the maximum tolerated dose and dose-limiting toxicities (DLTs). Furthermore, the pharmacokinetics of ET-743 and relationships with pharmacodynamics were evaluated. Adult patients with solid, resistant tumors received ET-743 as a 24-h i.v. infusion every 21 days. Blood samples were obtained during the first treatment course and in several consecutive courses. Noncompartmental pharmacokinetic analysis was performed. Relationships between pharmacokinetics and hepatic and hematological toxicities were explored. Fifty-two patients were treated at nine dose levels (50-1800 microg/m2). The DLTs, neutropenia and thrombocytopenia, were experienced at 1800 microg/m2. Twenty-five patients were treated at the recommended Phase II dose of 1500 microg/m2. At this dose, the mean value +/- SD for total body clearance was 59 +/- 31 liters/h, and the mean t(1/2) was 89 +/- 41 h. Pharmacokinetics were linear over the dose range tested. Prior exposure to ET-743 did not alter the pharmacokinetics in subsequent courses. The percentage of decrease in WBC count and absolute neutrophil count was correlated to the area under the plasma concentration versus time curve (AUC). Hepatic toxicity, defined as rise in alanine aminotransferase and aspartate aminotransferase, increased with dose and AUC but was reversible and not dose limiting. In conclusion, ET-743 administered as a 24-h i.v. infusion at a dose of 1500 microg/m2 is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.
    Clinical Cancer Research 01/2001; 6(12):4725-32. · 7.84 Impact Factor
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    ABSTRACT: Epidermoid carcinoma of the head and neck accounts for 10% of all cancers. At diagnosis, 60% of patients have a locally advanced disease, leading to high mortality and major functional handicaps. Chemotherapy has been shown to be active in patients presenting metastatic and/or locoregional recurrence, with 20 to 30% response rates, although no clearly established survival benefit has been demonstrated. Combining chemotherapy with surgery and/or radiotherapy has become possible with the development of new drugs and has recently led to major changes in management protocols for locally advanced epidermoid carcinoma of the head and neck. Therapeutic gain has been focalized on improving locoregional control, decreasing metastatic spread, and on the concept of an organ conservation strategy with schedules including chemotherapy as an inducing, concomitant, or alternating treatment with radiotherapy. Although many agents have demonstrated their efficacy, the role of chemotherapy in epidermoid carcinoma of the head and neck is not totally defined. The aim of treatment in metastatic and/or locoregional recurrent disease is palliative care. Regimens associating cisplatinum give a high response rate in patients previously untreated, without any real benefit in terms of survival. An evaluation of the activity of new agents with novel modes of action is currently under way. In locally advanced disease, concomitant chemotherapy with radiotherapy seems to give a minimal but real benefit as evidenced in the different meta-analyses recently published.
    Annales d Otolaryngologie et de Chirurgie Cervico-Faciale 01/2001; 117(6):390-402.
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    ABSTRACT: To review incidence and analyze profile of long-term complete responders among patients with undifferentiated carcinoma of nasopharyngeal type (UCNT) treated at a single institution. We present a cohort of 20 long-term unmaintained complete responders to chemotherapy for metastatic UCNT treated at the Institut Gustave Roussy between April 1978 and November 1996. A patient was considered a long-term survivor if he or she was disease-free for more than 36 months without treatment after obtaining a complete response by chemotherapy. Patient characteristics were as follows: sex, 17 men and three women; median age, 28 years (range, 9 to 62 years); median World Health Organization performance status, 1; and initial tumor-node-metastasis stage (International Union Against Cancer-American Joint Committee on Cancer, 1987) of T3 to T4, 60%, and of N2b to N3, 75%. Epstein-Barr virus serology was characteristic in 19 patients. Of 16 pretreated patients, 11 were pretreated by radiotherapy alone and five by chemotherapy and radiotherapy. Thirteen patients had metastatic relapses of locally controlled UCNT. Tumor sites were bone in 15 patients, lung in four, and liver (biopsy-proven) in two. Chemotherapy included the following: cisplatin, bleomycin, and fluorouracil in five patients; bleomycin, epirubicin, and cisplatin in seven patients; fluorouracil, mitomycin, epirubicin, and cisplatin in four patients; and fluorouracil, bleomycin, epirubicin, and cisplatin in one patient. Three patients were treated with platinum-based regimens before 1985. Patients received a median of six cycles (range, three to 13). Thirteen patients with bone metastases received consolidating radiotherapy. As of June 1999, 14 of 20 patients were still alive with no evidence of disease after treatment (disease-free survival time, 82+ to 190+ months), three patients died of other causes while in complete response at 61, 109, and 208 months after treatment, and three patients died of disease at 42, 89, and 115 months after treatment. Long-term complete responses were obtained in both bone and visceral disease. Our data support a curative role for chemotherapy in metastatic UCNT and are a major incentive to continue research for better combinations to increase the percentage of patients with metastatic UCNT who attain complete responses and long-term survival.
    Journal of Clinical Oncology 04/2000; 18(6):1324-30. · 18.04 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the toxicity and efficacy of the combination of 5-fluorouracil, bleomycin, epirubicin, and cisplatin (FBEC) in the treatment of patients with undifferentiated carcinoma of nasopharyngeal type (UCNT). The study included patients with metastatic or recurrent disease (Group A) and previously untreated patients with locally advanced nonmetastatic disease (T >/= 3 or any T, N >/= 2, M0, according to 1987 criteria of the International Union Against Cancer and the American Joint Committee on Cancer (Group B). From January 1992 to November 1996, 49 patients with histologically proven UCNT were treated with intravenous (i.v.) 5-fluorouracil (700 mg/m(2)/day by continuous infusion for 4 days), epirubicin (70 mg/m(2) i.v. on Day 1), Bleomycin (10 mg i.v. bolus on Day 1 followed by 12 mg/m(2)/day by continuous infusion for 4 days), and cisplatin (100 mg/m(2) on Day 5); this regimen was repeated every 21 days. Six cycles were given to Group A (26 patients), with bleomycin omitted during the last 3 cycles. In Group B (23 patients), only 3 cycles were given, followed by conventional radiotherapy (70 gray for 7 weeks). Of the 26 patients entered in Group A, 23 were evaluable for response. Nine complete responses (CRs) and 9 partial responses (PRs) were assessed, for a 78% objective response rate (ORR) (95% CI: 56-92). Three patients are alive with no evidence of disease after 43, 61, and 73 months, respectively. These patients achieved a CR with chemotherapy followed by consolidating radiotherapy to their target lesions. In Group B, the ORR was 91.5%, with 5 CRs (22%) and 16 PRs (69.5%) assessed in the 23 patients. Three months after the end of radiotherapy, the ORR was 87% (20 patients). After a median follow-up of 51 months (range, 24-67 months), 15 patients (65%) are alive without evidence of disease. Forty percent of cycles (51% in Group A, 25% in Group B) resulted in Grade 4 neutropenia, with fever and/or sepsis in 9.5%. Mucositis was seen in 42% of pretreated patients. There were 3 treatment-related deaths (2 from complications of infection and 1 bleomycin fibrosis at a total dose of 160 mg/m(2)), all of them in Group A. The FBEC regimen has good activity, with durable responses in patients with locally advanced, metastatic, or recurrent UCNT. This regimen is safe for patients with locally advanced disease, but close follow-up and supportive measures are needed when it is used to treat those with metastatic or recurrent disease.
    Cancer 11/1999; 86(7):1101-8. · 5.20 Impact Factor
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    ABSTRACT: This phase-II study was conducted to investigate the potential benefit from the addition of mitomycin to a conventional anthracycline-cisplatin- and 5-fluorouracil-based chemotherapy for recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type (UCNT). Between July 1989 and December 1991, 44 consecutive patients (M/F 36/8; median age: 45, range 20-72; performance status (PS) 0: 20 patients, PS 1: 14 patients, PS 2: 10 patients) with recurrent or metastatic UCNT were entered in this study after complete clinical, biological, and radiological pre-therapeutic work-ups. Chemotherapy (FMEP regimen) consisted of 800 mg/m2/day 5-fluorouracil in continuous infusion from day 1 to day 4 combined with 70 mg/m2 epirubicin, 10 mg/m2 mitomycin, and 100 mg/m2 cisplatin on day 1, every four weeks for six cycles. Mitomycin was delivered in cycles 1, 3, and 5 only. Eleven patients had isolated loco-regional recurrences, 12 patients had local recurrences associated with distant metastasis, and 21 patients had metastasis only. Toxicity and response were evaluated according to WHO criteria. Grade 3-4 neutropenia was observed in 122 of 212 evaluable cycles (57%) and 39 of 44 patients (89%); febrile neutropenia occurred in 16 patients (36%) and 24 cycles (11.3%). Grade 3-4 thrombocytopenia was observed in 27 patients (61%) and 45 cycles (21%), including 27 of 45 cycles (60%) with mitomycin. Grade 3 anemia was noted in 18 patients (40%) and 23 cycles (11%), including 18 of 23 cycles (78%) with mitomycin. Grade 3-4 mucositis occurred in 25 cycles (11%) and 14 patients (32%), mainly in those previously treated with radiation therapy in the head and neck area. There were four treatment-related deaths (9%); three of them neutropenia-related, and one of cardiac toxicity. Forty-four patients were evaluable for response: There were 23 of 44 objective responses (52%), including six complete responses (13%), and 17 partial responses (38%). Additional radiotherapy was given to 13 patients after documentation of response: Nasopharyngeal tumor + cervical nodes (eight patients) and/or on bone metastasis sites (five patients); mediastinal lymph nodes (one patient). At a median follow-up of 87 months (range 71-100), five patients are alive and in continuous complete remission. The median survival time was 14 months and the median time to progression nine months. The regimen under study is active in recurrent/metastatic UCNT, but associated with excessive toxicity.
    Annals of Oncology 05/1999; 10(4):421-5. · 7.38 Impact Factor
  • European Journal of Cancer - EUR J CANCER. 01/1999; 35.
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    ABSTRACT: Of the new generation platinum compounds that have been evaluated, those with the 1,2-diaminocyclohexane carrier ligand-including oxaliplatin--have been focused upon in recent years. Molecular biology studies and the National Cancer Institute in vitro cytotoxic screening showed that diaminocyclohexane platinums such as oxaliplatin belong to a distinct cytotoxic family, differing from cisplatin and carboplatin, with specific intracellular target(s), mechanism(s) of action and/or mechanism(s) of resistance. In phase I trials, the dose-limiting toxicity of oxaliplatin was characterized by transient acute dysesthesias and cumulative distal neurotoxicity, which was reversible within a few months after treatment discontinuation. Moreover, oxaliplatin did not display any, auditory, renal and hematologic dose-limiting toxicity at the recommended dose of 130 mg/m2 q three weeks or 85 mg/m2 q two weeks given as a two-hour i.v. infusion. Clinical phase II experiences on the antitumoral activity of oxaliplatin have been conducted in hundreds of patients with advanced colorectal cancers (ACRC). Single agent activity reported as objective response rate in ACRC patients is 10% and 20% overall in ACRC patients with 5-fluorouracil (5-FU) pretreated/refractory and previously untreated ACRC, respectively. Synergistic cytotoxic effects in preclinical studies with thymidylate synthase inhibitors, cisplatin/carboplatin and topoisomerase I inhibitors, and the absence of hematologic dose-limiting toxicity have made oxaliplatin an attractive compound for combinations. Phase II trials combining oxaliplatin with 5-FU and folinic acid ACRC patients previously treated/refractory to 5-FU showed overall response rates ranging from 21% to 58%, and survivals ranging from 12 to 17 months. In patients with previously untreated ACRC, combinations of oxaliplatin with 5-FU and folinic acid showed response rates ranging from 34% to 67% and median survivals ranging from 15 to 19 months. Two randomized trials totaling 620 previously untreated patients with ACRC, comparing 5-FU and folinic acid to the same regimen with oxaliplatin, have shown a 34% overall response rate in the oxaliplatin group versus 12% in the 5-FU/folinic acid group for the first trial; and 51.2% vs. 22.6% in the second one. These statistically significant differences were confirmed in time to progression advantage for the oxaliplatin arm (8.7 vs. 6.1 months, and 8.7 vs. 6.1 months, respectively). A small but consistent number of histological complete responses have been reported in patients with advanced colorectal cancer treated with the combination of oxaliplatin with 5-FU/folinic acid, and secondary metastasectomy is increasingly done by oncologists familiar with the combination. Based on preclinical and clinical reports showing additive or synergistic effects between oxaliplatin and several anticancer drugs including cisplatin, irinotecan, topotecan, and paclitaxel, clinical trials of combinations with other compounds have been performed or are still ongoing in tumor types in which oxaliplatin alone showed antitumoral activity such as ovarian, non-small-cell lung, breast cancer and non-Hodgkin lymphoma. Its single agent and combination therapy data in ovarian cancer confirm its non-cross resistance with cisplatin/carboplatin. While the role of oxaliplatin in medical oncology is yet to be fully defined, it appears to be an important new anticancer agent.
    Annals of Oncology 11/1998; 9(10):1053-71. · 7.38 Impact Factor
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    ABSTRACT: Our objective was to determine the maximum tolerated dose (MTD) of paclitaxel when given as a 7 day continuous i.v. infusion, repeated every 3 weeks, and to evaluate the toxicity and the efficacy of such a schedule of administration as a salvage treatment in ovarian cancer patients pretreated and refractory to 3 or 24 h paclitaxel. Thirteen women were enrolled in this phase I trial. Four dose levels ranging from 105 to 157.5 mg/m2/cycle were explored. Two of four patients experienced dose-limiting febrile neutropenia at the dose of 157.5 mg/m2. No objective response was observed, although three patients experienced disease stabilization (five to six cycles), with regression of disease symptoms, two of them having sustained 50% or greater decrease in CA 125. We conclude that the MTD in this population was paclitaxel 140 mg/m2/7 days. Schedule-dependent mechanisms of resistance to paclitaxel could not be demonstrated in this clinical setting of heavily pretreated ovarian cancer patients.
    Anti-Cancer Drugs 10/1997; 8(8):763-6. · 2.23 Impact Factor
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    ABSTRACT: Low-dose protracted continuous infusion (CI) 5-fluorouracil (5-FU), as proposed by Lokich et al, has been reported to be active and well tolerated in colorectal and breast cancers. We initiated a phase II trial with CI 5-FU in heavily pretreated undifferentiated carcinoma of the nasopharyngeal type (UCNT) patients in February 1989. Twenty-one UCNT patients with recurrent and/or metastatic disease were treated with CI 5-FU (300 mg/m2) for 6 consecutive weeks. Treatment was to be continued until disease progression. Toxicity was mild. Diarrhea and mucositis (WHO grade 2 or greater) were seen in 4 (20%) and 6 patients (30%), respectively. Myelosuppression was infrequent, with only one patient with bone marrow invasion, experiencing grade 3 leukopenia. Two complete and 3 partial responses were obtained in 20 evaluable patients (ORR:25%). The median time to progression was 4 months (range 2-14); The median survival for the whole population was 10 months (avg 2-41). This appears to be a useful palliative treatment for heavily pretreated UCNT patients.
    Head & Neck 02/1997; 19(1):41-7. · 2.83 Impact Factor
  • European Journal of Cancer - EUR J CANCER. 01/1997; 33.
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    ABSTRACT: Background Low-dose protracted continuous infusion (CI) 5-fluorouracil (5-FU), as proposed by Lokich et al, has been reported to be active and well tolerated in colorectal and breast cancers. We initiated a phase II trial with CI 5-FU in heavily pretreated undifferentiated carcinoma of the nasopharyngeal type (UCNT) patients in February 1989.Methods Twenty-one UCNT patients with recurrent and/or metastatic disease were treated with CI 5-FU (300 mg/m2) for 6 consecutive weeks. Treatment was to be continued until disease progression.ResultsToxicity was mild. Diarrhea and mucositis (WHO grade 2 or greater) were seen in 4 (20%) and 6 patients (30%), respectively. Myelosuppression was infrequent, with only one patient with bone marrow invasion, experiencing grade 3 leukopenia. Two complete and 3 partial responses were obtained in 20 evaluable patients (ORR:25%). The median time to progression was 4 months (range 2–14); the median survival for the whole population was 10 months (avg 2–41).Conclusion This appears to be a useful palliative treatment for heavily pretreated UCNT patients. © 1997 John Wiley & Sons, Inc. Head Neck 19: 41–47, 1997.
    Head & Neck 01/1997; 19(1):41-47. · 2.83 Impact Factor