Monder Mahjoubi

Irinotecan Combined With Bolus Fluorouracil, Continuous Infusion Fluorouracil, and High-Dose Leucovorin Every Two Weeks (LV5FU2 Regimen): A Clinical Dose-Finding and Pharmacokinetic Study in Patients With Pretreated Metastatic Colorectal Cancer

PURPOSE To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT-11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC). PATIENTS AND METHODS All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m(2)). LV5FU2 was started 1 hour after the end of the biweekly CPT-11 infusion and was also administered on day 2. RESULTS Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m(2), and a dose level of 300 mg/m(2) was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m(2). Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months. CONCLUSION The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT-11 at 180 to 200 mg/m(2) in combination with LV5FU2 has been selected as the recommended dose for further studies.

Efficacy of combined 5-fluorouracil and cisplatinum in advanced gastric carcinomas. A phase II trial with prognostic factor analysis

Combined chemotherapy has demonstrated a degree of efficacy in gastric carcinoma. As 5-fluorouracil (5FU) and cisplatinum are two of the most active drugs, we have tested the efficacy of combined 5FU and cisplatinum in a prospective phase II trial. Cycles were administered every 4 weeks and consisted of 5FU 1000 mg/m2/day 5 days continuous intravenous (i.v.) infusion and cisplatinum 100 mg/m2 on day 2. Cycles were repeated according to tolerance and efficacy. 87 patients entered the study, 57 with metastatic or recurrent tumour (M) and 30 with locally advanced gastric cancer (LAGC). The response rate for the 83 evaluable patients was 43% [95% confidence interval (CI) 30-56%]. There were four complete responses (5%), 32 partial responses (39%), 34 cases of stable disease and 13 cases of progressive disease. Responses were more frequent in patients with a good performance status (P = 0.02), with their primary located in the cardia (P = 0.003), with a non-linitis plastica tumour form (P = 0.003) or a tumour containing less than 50% of independent cells (P = 0.016). Median survival was 9 months for the total population. It was better in patients with a good performance status (P = 0.01), and those who did not have linitis plastica (P = 0.005). Toxicity was acceptable, although grade 3-4 neutropenia was reported in 22% of the cycles, mucositis in 14% and 3 patients died of septic complications. The combination of 5FU and cisplatinum is effective in terms of tumour response in advanced gastric cancer and warrants testing with the other active regimens.

Neoadjuvant chemotherapy in locally advanced gastric carcinoma-A phase II trial with combined continuous intravenous 5-fluorouracil and bolus cisplatinum.

Locally advanced gastric adenocarcinomas (LAGC) have a poor prognosis, particularly when tumours are bulky, located in the cardia or in the event of locoregional lymph node involvement. Patients bearing these tumours were entered in a phase II trial of neoadjuvant chemotherapy, combining continuous intravenous 5-fluorouracil (5FU) (1000 mg/m2 for 5 days) and cisplatinum (CDDP) (100 mg/m2 on day 2) repeated every 4 weeks, for one to six cycles according to response and tolerance. 30 patients have been entered, 26 after clinical evaluation (CAT scan and upper gastrointestinal endoscopy) and 4 with unresectable tumours at prior laparotomy. Median age was 60 years, 15/30 patients had a tumour of the cardia, 15/30 had enlarged lymph nodes and 7/30 had linitis plastica (diffuse type). A mean number of three cycles was administered (range 1-6). 27 of the 30 patients were evaluable for response. One patient achieved a complete response (CR) and 14 a partial response (56%; 95% confidence interval 38-74%). No patient had tumour progression, and only 1/6 with linitis plastica responded. 28 patients underwent surgery, and 23 had a macroscopically complete resection (77% of the 30 entered patients); RO resections were performed in 60% of the cases, mainly after an objective response (13/15 versus 4/12 in nonresponders). No pathological CR were seen. Grade 4 neutropenia was observed in eight cycles (5 patients), with five septic complications and one death due to toxicity. Four postoperative complications were observed: 2 cases of severe pneumonia and 2 subphrenic abscesses. One postoperative death, due to intravascular disseminated coagulation, was observed at day 30. Median survival was 16 months and the 1-, 2- and 3-year survival was 67, 42 and 38%, respectively. Patients with linitis plastica had a significantly shorter survival (P < 0.002). We conclude that neodjuvant chemotherapy is feasible in LAGC, although randomised trials are warranted to demonstrate its efficacy on survival and resection rates.

Phase I Study of Retelliptine Dihydrochloride (SR 95325 B) Using a Single Two-Hour Intravenous Infusion Schedule

Retelliptine dihydrochloride (SR 95325 B, NSC D-626717-W) is an ellipticine derivative having a very high level of antitumor activity in resistant murine solid tumor models. We studied in a Phase I trial escalating doses of retelliptine using a single 2-hour IV infusion schedule. Data from other Phase I studies allowed a starting dose of 80 mg/m2 and a rapid dose escalation. Included were 15 patients (M/F = 13/2) with a median age of 55 (range: 17–72). There were 22 courses delivered at the following dose levels: 80, 180, 700, 900, 1,200, and 1,500 mg/m2. Primary tumor types were kidney (6 patients), colon (3 patients), pancreas (2 patients), and others (4 patients).Mild dose-related visual troubles (blurring, accommodation troubles, oculomotor paresis) occurred in 9/11 patients starting from 700 mg/m2. Asymptomatic EKG anomalies, including significant prolongation of PR and QRS intervals occurred at 1500 mg/m2 (in 3/3 patients) marking the maximum tolerated dose. Both visual and EKG anomalies were spontaneously reversible few minutes to few hours after the end of infusion. Other possible drug-related toxicity occurred sporadically such as somnolence, bronchospasm, dry mouth, and vomiting (2 patients each). There were no significant laboratory anomalies. Neither drug-related deaths nor objective complete or partial responses were observed. The recommended dose for Phase II trial using the 2-hour intravenous infusion schedule is 1,200 mg/m2.

Phase II Trial of Ifosfamide in the Treatment of Metastatic Hormone-Refractory Patients with Prostatic Cancer

Cyclophosphamide has been considered one of the reference drugs of chemotherapy in randomized trials in hormone-refractory prostate cancer by the National Prostatic Cancer Project (NPCP). Ifosfamide, another oxazaphosphorine agent, and an analog of cyclophosphamide, appears to be more active and less toxic in a broad spectrum of tumors. Fifteen patients with metastatic hormone-refractory prostate cancer were treated with continuous infusion of ifosfamide 2 g/m2 per day for 2 days, together with the uroepithelial protective agent Mesna 2.4 g/m2 per day for 2 days, both to be repeated every 3 weeks. All patients have failed on previous hormonal therapy and 7 patients had received previous chemotherapy. The median age was 66 years. Fourteen patients were evaluable; none of whom achieved an objective response. Four patients were stabilized and 10 had disease progression while on chemotherapy. Major toxicity included 2 reversible encephalopathy, 3 grade I reversible renal toxicity, and 1 hemorrhagic cystitis. We concluded that ifosfamide given in this schedule in this group of patients is not an active agent in prostate cancer.

High failure rate of carboplatin-etoposide combination in good risk non-seminomatous germ cell tumours

24 patients with good risk non-seminomatous germ cell tumours (GR-NSGCT) were enrolled in a phase II trial combining carboplatin (C) and etoposide (E). Carboplatin was given at a fixed dose of 450 mg/m2 at d2, and E 120 mg/m2, dl-3, every 4 weeks x 4 cycles (cy). Myelosuppression was the major toxicity with neutropenia grade 4 in 18 cy (19%) and grade 3 in 26 cy (27%). Thrombocytopenia grade 3 and 4 occurred in 7 and 1 cy, respectively. Responses included: 20 complete responses (CR) (83%) with 16 clinical CR and 4 pathological CR; 3 additional patients had complete surgical removal of residual disease (SRRD) with viable tumour (surgical CR); 1 patient progressed during C+E therapy. 5 of the 16 clinical CR relapsed, and all the 3 surgical CR progressed despite post-operative salvage chemotherapy. Adverse events occurred in 9 patients (37.5%; 95% C.I., 19-59%). After a median follow-up of 24 m (range 14 to 38) 4 patients had died [3 progressive disease (PD), 1 suicide while in CR], 3 were alive with PD, and 17 had no evidence of disease. No significant correlation between area under the curve values of carboplatin, overall treatment failure and the platelet nadirs was observed. We conclude that the efficacy of the C+E regimen as given in our protocol is inferior to the standard cisplatin-containing regimens. The low dose-density (D/I) of carboplatin could be responsible for the high failure rate.

Phase II trial of LY 186641 in advanced renal cancer

SummaryLY 186641 is a diarylsulfonylurea with a broad spectrum antitumor activity against both murine and human solid tumors. We report here the results of a phase II trial of LY 186641 in advanced renal cell adenocarcinoma.The drug was administered orally, once daily for 2 weeks, every 21 days at a 700 mg/m2/d dose. Sixteen patients were enrolled in this phase II trial; 12 males, 4 females, with a median age of 58 years. All patients had progressive measurable metastatic disease. The primary tumor was surgically removed in all but one patient. Three patients were previously treated by biologic response modifiers (BRMs). A total of 72 courses were administered. The most common side effects were methemoglobulinemia (MetHgb) and anemia which occurred in 13 and 10 patients respectively. The MetHgb did not exceed 15%, and only 3 patients required blood transfusion for grade 3 (2 patients) and grade 4 (1 patient) anemia. Reversible hepatotoxicity was observed in 3 patients.There were one pathological complete response, seven stable disease and 8 progressive disease.

Phase II trial of pirarubicin in the treatment of advanced bladder cancer.

SummaryDoxorubicin is one of the standard drugs in the chemotherapy of advanced urothelial tumors. Pirarubicin, a new anthracycline, turned out to be equally active and less toxic than its parent compound in preclinical studies. Twenty one patients with either metastatic or inoperable locally advanced bladder carcinoma were treated with intravenous infusion of pirarubicin: 25 mg/m2/day for 3 days every 4 weeks in the first 15 patients and 20 mg/m2/day for 3 days every 3 weeks in the others. Fifteen patients were not pretreated and 6 received prior chemotherapy (5 patients with doxorubicin containing regimen). Twenty patients were evaluable for response; there were 2 partial response, 8 stable disease and 10 progressive disease. All pretreated patients progressed. Hematological toxicity was moderate, however there was one toxic death with grade 4 neutropenia which occured in a heavily pretreated patient receiving a dose of 25 mg/m2/day for 3 days. There was no clinical cardiac toxicity. Single agent Pirarubicin displays an objective response rate of 10% (95% of CI 0 to 23%) which reaches 14% (95% CI 0 to 29%) when non pretreated patients are analyzed separately. This rate is in the range of doxorubicin activity.