Leucovorin and Fluorouracil With or Without Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer.

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m2/d) followed by a 5FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P = .0003) and better response rate (50.7% v 22.3%; P = .0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P = .12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41.7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P = .004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.

Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer.

PURPOSE: In a previous study of treatment for advanced colorectal cancer, the LV5FU2 regimen, comprising leucovorin (LV) plus bolus and infusional fluorouracil (5FU) every 2 weeks, was superior to the standard North Central Cancer Treatment Group/Mayo Clinic 5-day bolus 5FU/LV regimen. This phase III study investigated the effect of combining oxaliplatin with LV5FU2, with progression-free survival as the primary end point. PATIENTS AND METHODS: Four hundred twenty previously untreated patients with measurable disease were randomized to receive a 2-hour infusion of LV (200 mg/m(2)/d) followed by a 5FU bolus (400 mg/m(2)/d) and 22-hour infusion (600 mg/m(2)/d) for 2 consecutive days every 2 weeks, either alone or together with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1. RESULTS: Patients allocated to oxaliplatin plus LV5FU2 had significantly longer progression-free survival (median, 9.0 v 6.2 months; P =.0003) and better response rate (50.7% v 22.3%; P =.0001) when compared with the control arm. The improvement in overall survival did not reach significance (median, 16.2 v 14.7 months; P =. 12). LV5FU2 plus oxaliplatin gave higher frequencies of National Cancer Institute common toxicity criteria grade 3/4 neutropenia (41. 7% v 5.3% of patients), grade 3/4 diarrhea (11.9% v 5.3%), and grade 3 neurosensory toxicity (18.2% v 0%), but this did not result in impairment of quality of life (QoL). Survival without disease progression or deterioration in global health status was longer in patients allocated to oxaliplatin treatment (P =.004). CONCLUSION: The LV5FU2-oxaliplatin combination seems beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged progression-free survival with acceptable tolerability and maintenance of QoL.

Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer.

Oxaliplatin has shown in vivo cytotoxic activity against colorectal cell lines. Preliminary studies suggest potentiation of fluorouracil (5-FU). To assess this issue, we performed a phase II study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. The regimen (FOLFOX2) consisted of oxaliplatin 100 mg/m2 as a 2-h infusion on day 1; leucovorin 500 mg/m2 as a 2-h infusion, followed by 5-FU 24-h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. The initial 5-FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 46 patients were treated, all with disease progression on leucovorin and 5-FU therapy for metastatic disease, or relapse less than 6 months after the end of adjuvant therapy. One complete response (CR) and 20 partial responses (PRs) were observed for an overall response rate of 46%. 22 patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU as the one used in the FOLFOX2 regimen, and among them, 10 had PRs (45%). From the start of FOLFOX2, median progression-free survival was 7 months and median survival 17 months. WHO toxicity > or = grade 3 per patient was: peripheral neuropathy 9%, nausea 4%, diarrhoea 9%, mucositis 13%, neutropenia 39%, thrombocytopenia 11%, alopecia 9%, and allergy 2%. Overall, 21 patients (46%) experienced grade 3-4 toxicity. This combination of leucovorin, 5-FU and oxaliplatin achieves a high response rate in pretreated patients with CRC resistant to leucovorin and 5-FU. Limiting toxicities are neutropenia and peripheral neuropathy.

[Oxaliplatin, folinic acid and 5-fluorouracil (folfox) in pretreated patients with metastatic advanced cancer. The GERCOD]. / Oxaliplatine, acide folinique et 5-fluorouracile (folfox) en seconde ligne thérapeutique du cancer colorectal métastasé. Le GERCOD.

Preliminary studies suggest synergy between oxaliplatin and fluorouracil (5-FU). To assess this issue, we performed a study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. Regimen consisted of oxaliplatin day 1, 130 mg/m2 every two cycles (folfox 1) or 100 mg/m2/cycle (folfox 2) or 85 mg/m2/cycle (folfox 3) and leucovorin 500 mg/m2 as a 2-hour infusion, followed by 5-FU 22 h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. One hundred and thirteen patients have been treated. One complete response (CR) and 32 partial responses (PRs) were observed for an overall response rate of 29.2%. Sixty-seven patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU than the one used in the folfox regimens, among them 18 had PRs (26.9%). The best response rate was observed in patients treated with the folfox 2 regimen: 41.7%. From start of folfox, median progression-free survival was 6 months and median survival 13 months. Limiting toxicities were peripheral neuropathy and neutropenia. Fifty-four percent of the patients experienced WHO toxicity > or = grade 3 with the folfox1 regimen, 45% with the folfox2 and 40% with the folfox3. The folfox regimens achieve a high response rate in pretreated patients with CRC. Further studies are needed to determine the best oxaliplatin dose-intensity.

Phase I study of RP 49532A, a new protein-synthesis inhibitor, in patients with advanced refractory solid tumors.

Giroline (RP 49532A) is a new protein-synthesis inhibitor with broad antitumor activity in experimental models. In the present phase I study, Giroline was given by 24-h i.v. infusion every 3 weeks at doses ranging from 3 to 15 mg/m2 to 12 patients with advanced refractory solid tumors. The dose-limiting toxic effects were delayed hypotension and severe asthenia. The maximum tolerated dose (MTD) was 15 mg/m2. Transient nausea and vomiting during infusion were reported at all dose levels. Mild reversible prolongation of prothrombin time and activated partial thromboplastin time was observed in most patients at dose levels above 3 mg/m2. No antitumor activity was observed. The toxicity profile of Giroline precludes further evaluation in cancer patients.

Population pharmacokinetics of docetaxel during phase I studies using nonlinear mixed-effect modeling and nonparametric maximum-likelihood estimation.

Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2 h) at various dose levels (70-115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(Theta1 + Theta02 x AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh-1 m-2) and 37.2 l/h with interpatient coefficients of variations (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML versus 1241 for NONMEM) and in terminal half-lives, notably the mean t1/2 gamma, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss and t1/2 gamma, respectively. However, the NPML-estimated probability density function (pdf) of t1/2 gamma was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.

Docetaxel (Taxotere), a novel taxoid, in the treatment of advanced colorectal carcinoma: an EORTC Early Clinical Trials Group Study.

Docetaxel (Taxotere), a new semisynthetic taxoid, is a potentially important chemotherapeutic agent for the treatment of cancer. Forty patients with bidimensionally measurable advanced adenocarcinoma of the colon were treated with docetaxel 100 mg m-2 every 3 weeks as a 1 h infusion without routine premedication. Thirty-nine patients were eligible: 23 males and 16 females. Median age was 60 years (range 41-75) and WHO performance status 1 (0-2). Prior adjuvant chemotherapy was performed in four patients and prior radiotherapy in nine patients. Bidimensionally measurable disease sites included: liver in 26 patients, lymph nodes and abdominal/peritoneal masses in 13, lung/mediastinal masses in ten and subcutaneous nodes in four. The median number of cycles given was 2 (range 1-15). Thirty-three patients were evaluable for response. One patient (3%) achieved a complete response and two (6%) (95% confidence limits 0-14%) a partial response. Side-effects were similar to those observed in other studies. Docetaxel, given at this dosage and schedule, has minimal activity in the treatment of colorectal carcinoma.

Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group.

BACKGROUND: Docetaxel (Taxotere) is a new cytotoxic agent acting as a promoter of tubulin polymerisation with broad spectrum antitumor activity in preclinical testing. Phase I clinical trials have shown promising activity of docetaxel in patients with breast, ovarian and lung carcinomas. The objective of this open multicentre phase II study was to determine the efficacy and tolerability of this agent in patients with head and neck cancer. PATIENTS AND METHODS: Patients with proven advanced and/or recurrent squamous cell carcinoma of the head and neck without prior chemotherapy for advanced disease were eligible for this trial. Docetaxel was given at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks. Dose reductions were performed according to hematological and non-hematological toxicities. No pre-medication was given to prevent hypersensitivity reactions. RESULTS: Fourty-three patients entered this trial: 39 patients were evaluable for toxicity and 37 patients were evaluable for response. Sixty-five percent of the patients had locoregional disease, 28% had metastatic disease, and 7% had both. Twenty-five percent of the patients had previously received neo-adjuvant cisplatin-based chemotherapy. A total of 166 docetaxel courses were administered. The most frequent side-effects associated with docetaxel were alopecia (90% of the patients), asthenia (69% of the patients) and short lasting neutropenia (grade 3-4 neutropenia in 61% of the courses). Fifty-four percent of the patients experienced skin toxicity, 23% experienced hypersensitivity reaction, and 31% developed peripheral edema. Ten partial and 2 complete responses were observed, yielding a response rate of 32% (95% confidence interval 17%-47%). CONCLUSION: Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck.

Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion.

Taxotere (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl Taxol; RP 56976; NSC 628503) is a semisynthetic analogue of Taxol. It is twice as active in inhibiting tubuline depolymerization and has a better in vivo activity on B16 melanoma, with responses in advanced colon 38 and PO3 adenocarcinoma. Sixty-five patients (49 women, 16 men), with a median age of 57 years, received 248 courses of Taxotere given as a 1-2-h i.v. infusion every 2 or 3 weeks. Ten distinct dose levels from 5 to 115 mg/m2 were studied. Dose-dependent, reversible neutropenia was the limiting toxicity. Delayed and cumulative skin reactions occurred beyond 70 mg/m2. Alopecia was observed in the majority of patients beyond 70 mg/m2. Four partial responses were achieved in patients with ovarian carcinoma, breast carcinoma, small cell lung cancer, and carcinoma with unknown primary. The pharmacokinetics of Taxotere, determined in 23 patients receiving 20 to 115 mg/m2, was linear. At the highest doses, the Taxotere plasma profile was typically triphasic, with a terminal half-life of 13.5 +/- 7.5 (SD) h, a plasma clearance of 21.1 +/- 5.3 liters/h/m2, and a distribution volume of 72 +/- 40 liters/m2. AUC correlated with the percentage decrease of neutrophils in a sigmoid Emax model. The renal excretion of unchanged Taxotere was very low (< 5% of the dose). The recommended dose for phase II trials with this schedule is 100 mg/m2 every 3 weeks.

Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.

N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.

[Comparison between single-dose and hyperfractionated total-body irradiation for the conditioning of allogenic grafts of the bone marrow. A retrospective study of 54 patients with malignant hematologic diseases]. / Comparaison entre irradiation totale en un temps et hyperfractionnée pour le conditionnement des greffes de moëlle allogéniques. Une étude rétrospective de 54 malades atteints d'hemopathies malignes.

The present study is a retrospective analysis of 54 patients with hematological malignancies who were treated by total body irradiation (TBI) and allogenic bone-marrow transplantation from 1982-1986. Patients were not randomly assigned to receive either single dose total body irradiation (STBI) (10 Gy x 1-4 cGy/min-lung dose 8 Gy) or hyperfractionated total body irradiation (HTBI) (1,20 Gy x 11-3 fractions/day-lung dose 9 Gy). Thirty one patients received STBI and 23 a HTBI regimen. Despite the presence of a large proportion of patients with a high risk of leukemic relapse in the HTBI group, the incidence of relapse did not differ significantly in the two groups: STBI (16%), HTBI (21%). Lung and liver toxicity were predominant in the STBI group. Interstitial pneumonitis occurred in 45% of the STBI patients versus 13% in the HTBI group. This difference remains significant when adjusted to the incidence of graft versus host disease (GVHD) in the two groups. Three cases of veino-occlusive disease were observed (10%), but only in the STBI group. Even when differences in age and the frequency of GVHD are considered in the two groups, these findings suggest that HTBI is at least as effective as STBI and that toxicity is reduced with this schedule.

Clinical pharmacology of high-dose etoposide associated with cisplatin. Pharmacokinetic and metabolic studies.

Twelve patients were treated with high-dose etoposide give alone or in combination with cisplatin during a clinical trial. We had previously observed, in some subjects who received a combination of high-dose etoposide (350 mg/m2/day X 5 days) and cisplatin (40 mg/m2/day X 5 days), delayed hematological recovery after autologous bone marrow transplantation. Therefore we investigated the pharmacokinetics of etoposide and did not find any drug interaction with cisplatin. In four of these patients we also monitored etoposide salivary excretion and found saliva to plasma ratios in the range 0.003-0.25. The secretion of etoposide into saliva may be of concern if we consider that peroxidases in salivary glands are able to oxidize the drug leading to free radicals. In vitro experiments showed that sulfhydryl compounds are able to inhibit the formation of the etoposide radical. Furthermore, we were able to detect the presence of a new biotransformation product of etoposide in plasma samples of some patients. Fast atom bombardment liquid chromatography-mass spectrometry allowed us to identify this metabolite as the etoposide aglycone. The presence of this derivative in plasma 48 h after the last injection prompted us to delay autologous bone marrow transplantation to 72 h after the end of treatment, since the aglycone is cytotoxic and able to induce DNA strand breaks mediated by topoisomerase II.