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.

High-dose chemotherapy with etoposide, cyclophosphamide and escalating dose of carboplatin followed by autologous bone marrow transplantation in cancer patients. A pilot study.

25 patients with poor-prognosis malignancies were treated with a combination of fixed-dose etoposide (1750 mg/m2), cyclophosphamide (6400 mg/m2) and escalating doses of carboplatin (from 800 to 1600 mg/m2) followed by autologous bone marrow transplantation (ABMT). The median duration of granulocytopenia (< 500/mm3) and thrombocytopenia (< 20,000/mm3) was 23 days and 20.5 days, respectively. The main non-haematological toxicity was gastro-intestinal, with moderate to severe diarrhoea in 15 patients. No significant renal toxicity was observed. 2 patients died early due to toxicity. The overall response rate was 58% including 42% having complete responses. 4 of the 25 patients are alive with no evidence of disease at 22, 27, 40 and 43 months after ABMT. The encouraging antitumoral activity of this regimen makes it a good candidate for intensified chemotherapy in patients with various malignancies. Toxicity is acceptable and may be reduced in the near future with the widespread use of haematopoietic growth factors.

Phase II randomized study of paclitaxel versus mitomycin in advanced breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to be an effective agent in the treatment of metastatic breast carcinoma. This multicenter randomized study compared paclitaxel 175 mg/m2 given as a 3-hour infusion every 3 weeks with mitomycin 12 mg/m2 given as an intravenous infusion every 6 weeks. Eighty-one patients have been randomized, and preliminary results of a planned analysis of the first 36 evaluable patients per arm are reported. Pretreatment characteristics were well balanced between the two groups. All patients previously have received chemotherapy for metastatic disease, and half had both adjuvant therapy and chemotherapy for metastatic disease. All but one patient previously had received anthracyclines. Of the first 81 randomized patients, 72 were evaluable for response and toxicity (four never treated, five concomitant hormonotherapy). Partial responses were seen in 17% of patients in the paclitaxel arm and 6% in the mitomycin arm (P = .14). Crossover to paclitaxel therapy following progression on mitomycin achieved an objective response rate of 24% (five of 21 patients). Responses to paclitaxel therapy lasted for a median duration of 9.1 months (range, 6.2 to 12+ months). Median time to progression was significantly longer in the paclitaxel arm (3.5 months v 1.6 months; P = .026). The quality-of-life-adjusted analysis confirmed the advantage of paclitaxel therapy, even when the delay of disease progression was adjusted for important adverse events. Adverse events, most importantly neutropenia and neuropathy, were more frequently observed in the paclitaxel arm. However, patients remained on paclitaxel therapy for many more courses than did those treated in the mitomycin arm. In conclusion, paclitaxel 175 mg/m2 given as a 3-hour intravenous infusion has been demonstrated to be an active agent in the treatment of chemotherapy-refractory advanced breast cancer, even after therapy with mitomycin has failed.

Carboplatin plus paclitaxel in the first-line treatment of advanced ovarian cancer: preliminary results of a phase I study.

This phase I trial was designed to determine the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given as a 3-hour infusion in combination with carboplatin (400 mg/m2) as first-line chemotherapy for stage IIIC/IV ovarian adenocarcinoma. After premedication, paclitaxel was infused over 3 hours, followed by carboplatin infused over 30 minutes on day 1 of a 28-day cycle (group 1, with 28 patients accrued and 150 evaluable cycles) or on day 1 of a 21-day cycle (group 2, with 16 patients accrued and 55 evaluable cycles). Dose-limiting toxicities assessed after the first course included grade 4 neutropenia lasting longer than 7 days, febrile grade 4 neutropenia requiring intravenous antibiotics, grade 4 thrombocytopenia, mucositis greater than grade 2 for more than 7 days, grade > or = 3 nonhematologic toxicity (excluding alopecia, vomiting, and muscular pain), no hematologic recovery on day 42 (for group 1) or on day 35 (for group 2), neurotoxicity above grade 2, and persistence of nonhematologic toxicity (excluding alopecia, nausea/vomiting, and musculoskeletal pain) grade > or = 2 at scheduled re-treatment. If any of the events occurred during the first cycle in three or more of six patients, maximum tolerated dose was considered to have been reached. The hematologic toxicity associated with the two treatment schedules was mainly neutropenia, but it was of short duration. Very few dose reductions or dose delays were necessary. Until now, the six planned courses have been administered without colony-stimulating factors. No toxic death has occurred. Grade 2 or 3 peripheral neuropathy has occurred in 12% of patients, mainly with high doses of paclitaxel. At this time, the maximum tolerated dose has not been reached at paclitaxel 275 mg/m2 every 4 weeks or 225 mg/m2 every 3 weeks, and enrollment continues.

Phase I study of paclitaxel and epirubicin in patients with metastatic breast cancer: a preliminary report on safety.

Attempting to develop a new active, convenient regimen, we initiated a phase I study of paclitaxel (Taxol; Bristol-Myers squibb Company, Princeton, NJ) combined with epirubicin (Farmitalia Carlo Erba, Milan, Italy) in patients with metastatic breast cancer. In addition to standard eligibility criteria, patients with chemotherapy-naive metastasis and at least one measurable lesion had to have left ventricular ejection fractions of at least 50%; the metastatic relapse had to have occurred more than 6 months after adjuvant treatment. Anthracycline-pretreated patients could not have received cumulative doses of more than 300 mg/m2 doxorubicin, 450 mg/m2 epirubicin, or 70 mg/m2 mitoxantrone. An intravenous bolus dose of epirubicin was followed by a 3-hour paclitaxel infusion, with courses repeated every 3 weeks. To date, seven dose levels have been investigated and 31 patients have been treated, 19 of whom had already received anthracyclines. Grades 3 and 4 neutropenia occurred in 37% and 19% of 123 courses, respectively, with five episodes of febrile neutropenia. Grade 2 or 3 neurotoxicity has been observed in 42% of patients and cardiac toxicity in four patients (13%), all of whom had already received anthracyclines. One patient experienced transient myocardial ischemia, one had an asymptomatic decrease in ejection fraction, and two patients had clinical heart failure that required treatment. Dose-limiting toxicity was reached at dose level 5 (paclitaxel 200 mg/m2 plus epirubicin 60 mg/m2), with two of three patients experiencing febrile neutropenia. Reducing the epirubicin dose to 50 mg/m2, however, allowed the paclitaxel dose to be escalated to 250 mg/m2. At this dose level, only one of six patients experienced febrile neutropenia. At a preliminary response evaluation (dose levels 1 to 6), 11 patients (44%) had partial responses, 12 patients (48%) had stable disease, and disease progressed in two patients. We conclude that the combination paclitaxel/epirubicin is safe for patients with metastatic breast cancer and, at this early evaluation, shows promising antitumor activity. Additional patients will be treated at dose level 5 to confirm whether dose-limiting toxicity occurs at this step. Indeed, we took into consideration that dose-limiting toxicity observed at this particular dose level in two of three patients might be due to hazard, since paclitaxel dose escalation up to 250 mg/m2 was further possible in association with 50 mg/m2 epirubicin.

Phase I study of paclitaxel (Taxol) plus vinorelbine (Navelbine) in patients with untreated stage IIIb and IV non-small cell lung cancer.

A dose escalation study of paclitaxel in combination with vinorelbine was conducted in 21 patients with previously untreated stage IIIb or IV non-small cell lung cancer (NSCLC). All three patients treated with the initial dose of paclitaxel 135 mg/m(2) administered as a 1-h intravenous infusion and vinorelbine 25 mg/m(2) experienced dose-limiting toxicity (febrile neutropenia). After modification of the dosing schedule, the MTD of paclitaxel was found to be 115 mg/m(2) when combined with vinorelbine 20 mg/m(2) on day 1, followed by vinorelbine 20 mg/m(2) on day 5. Partial responses were achieved in 24% of patients, with a median duration of response of 126 days (range from 84 to 484 days) and a 1-year survival rate of 42%. In conclusion, haematologic toxicity (febrile neutropenia/neutropenia) severely restricts the dosing schedule of combined paclitaxel and vinorelbine, and possibly limits anti-tumour efficacy.

300 mg/m2 carboplatin (Cb), adriamycin (A) cyclophosphamide (C) (CACb-300) combination in advanced ovarian carcinoma: a feasibility study.

Carboplatin (Cb) is an active drug in ovarian carcinoma that has fewer visceral side effects than cisplatin (CDDP) but higher myelotoxicity, which makes it difficult to combine at efficient doses with other myelotoxic drugs. In a preliminary study in advanced ovarian carcinoma, Rosso et al. showed the maximum tolerated dose of Cb given in combination with cyclophosphamide (C) and adriamycin (A) to be 200 mg/m2. Since the efficacy of Cb may be dose-dependent, as is that of CDDP, we started a feasibility study of a CACb-300 regimen, that is, using Cb at 300 mg/m2 with lower C and A doses. Our data shows that the CACb-300 combination can safely be given in previously untreated patients for at least six 28-day cycles.

Impact of UFT on tumoral TS and DPD levels in colorectal cancer.

This was an open lable, pilot translational clinical pharmacology study of a brief (7 day) course of UFT, 300 mg/m2/day, in combination with leucovorin, 90 mg/day, in six patients with newly diagnosed advanced colorectal cancer. The primary objectives of the study were to examine the impact of this treatment course on the UFT targets which are thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). The rate of tumoral TS inhibition after the 7-day UFT treatment sequence varied from 5% up to 31%. UFT treatment induced a constant and variable decrease in tumor DPD activity ranging from 13% to 60%. UFT treatment induced a constant increase in uracil concentrations both in plasma and tumors. FT, 5-FU and the metabolite fluoro-beta-alanine (FBAL) were found in plasma and tumors at variable concentrations; the highest drug concentrations were those of FBAL in plasma. The present translational clinical study provides data related to the in vivo pharmacological effects of UFT with a description of its impact on cellular targets.

High dose chemotherapy including vepeside, cyclophosphamide and carboplatin with autologous bone marrow transplantation in one case of chemoresistant testicular cancer.

Non seminomatous germ cell testicular tumors (NSGCTT) is a very chemosensitive cancer; vepeside, cyclophosphamide or ifosfamide and cisplatin are the most effective drugs. Carboplatin is also active with a lack of nephrotoxicity, but there is probably a cross-resistance to cisplatin. High dose chemotherapy with autologous bone marrow transplantation is able to cure poor prognosis testicular cancers in first partial remission or in sensitive relapse. We report one case of non seminomatous testicular cancer which was progressive after chemotherapy with cisplatin and vepeside or teniposide, and which is in prolonged complete remission after conventional chemotherapy (vepeside, ifosfamide, carboplatin) and high dose chemotherapy (carboplatin, vepeside, cyclophosphamide) with autologous bone marrow transplantation.

[Is there a place for chemotherapy in the initial treatment of cervical cancer? Review of the literature]. / La chimiothérapie a-t-elle une place lors du traitement initial des cancers du col utérin? Revue de la littérature.

Despite their high efficiency in treating cancer of the uterine cervix, surgery and radiotherapy can not cure (local and/or metastatic disease) a certain number of patients with initially adverse risk factors, mostly local or regionally advanced cervical carcinoma (stage III-IVA) or early stage (IB-II) disease with bulky primary lesion or involved regional nodes. Since the 1980s, many investigators have tried to determine whether or not there is any benefit in introducing chemotherapy earlier in the therapeutic plan for these patients: either initially before surgery or radiotherapy (neoadjuvant), or during radiotherapy (concurrent), or after local treatment (adjuvant). In this review we seek to sum up the published data available and to determine if at present there is a place for chemotherapy in the initial treatment of cervical cancer.

[Palliative chemotherapy of epidermoid carcinoma of the upper respiratory and digestive tracts with a combination of carboplatin and 5-fluorouracil]. / Chimiothérapie palliative des carcinomes épidermoïdes des voies aéro-digestives supérieures par une association de carboplatine et de 5 fluoro-uracile.

One hundred and thirteen patients with advanced squamous cell cancer of the head and neck were entered into a multicenter trial. Median age was 54 yr (range: 33-74 yr). Median Karnofsky index was 70 (60-100). Thirty-five patients had had prior induction chemotherapy. The first schedule was carboplatin 300 mg/m2, dl and fluoro-uracil 1000 mg/m2/d administered in continuous IV infusion for 96 h every 4 weeks (group 1). The second schedule was carboplatin 350 mg/m2, dl and fluoro-uracil administered at the same dose every 3 weeks (group II). Median number of cycles was 3 (range: 1-16). Seven patients were not eligible. The response rate was 26% (95% confidence limits: 18-34). Nine patients had a complete response. The median duration of response was 6 months (2-16+). The response rates in the 2 groups were not statistically different (21 and 31%) but disease progression was more frequent in group I (61%) than in group II patients (25%). Six early deaths occurred, without sign of drug toxicity. Grade 2 hematological toxicity between or before any cycle was more frequent in group II patients, in particular for leucopenia (13 vs 42%, P less than 0.05). One death was related to granulopenia. Grade 2 or 3 gastric toxicity was observed in 43 patients. No other major toxicity was observed. In our study, combination therapy with carboplatin and fluoro-uracil was found to be moderately active but myelotoxic.

[Taxol (paclitaxel), first molecule of a new class of cytotoxic agents: taxanes]. / Taxol (paclitaxel), première molécule d'une nouvelle classe d'agents cytotoxiques: les taxanes.

Taxol is the first of the taxanes, a new class of cytotoxic agents whose cellular target is the microtubules network. Taxol induces the polymerisation of the alpha and beta sub-units of the tubulin. This mechanism of action which is different from the vinca-alkaloids explains the main cytotoxic activity of paclitaxel through the formation of abnormal and stable bundles of microtubules. Severe hypersensitivity reactions which were seen in early phase I studies are prevented by an oral corticosteroids and H1 and H2 blockers premedication. Profound neutropenia is frequent but of short duration explaining that infectious manifestations are rare and neutropenia not cumulative. Thrombopenia and anemia are rare. Neurotoxicity is dose related but severe peripheral neuropathy is rare. Conduction abnormalities are mainly asymptomatic bradycardias. In second line ovarian cancer and breast metastatic cancer a noticeable level of activity has been observed, and in lung and head and neck cancer Taxol has proved to be effective.

[Study of high doses of carboplatin as a first choice in the therapy of advanced ovarian cancers]. / Etude du carboplatine administré à forte dose en première ligne thérapeutique dans les cancers de l'ovaire évolués.

Thirty female patients with ovarian cancer of poor prognosis were included in a chemotherapy trial using high dose IV carboplatin--800 mg/m2 every 5 weeks. The subjects had three to six cycles prior to second laparotomy. Twenty-eight patients were assessable. There was no neurological, auditory or renal toxicity. Limiting toxicity was haematological, the mean neutrophil count was less than 650 mm3 and the mean platelet count less than 30,000/mm3. No death occurred from toxicity. The clinical response rate was 67%, and the surgical response rate 53.5%, with 15% complete histological responses. Survival at 18 months is 36%. A trial concerning 36 patients treated with an association of carboplatin at the same dose combined with cyclophosphamide has just been completed and the results are being analyzed.

Cutaneous toxicity of autologous bone marrow transplantation in nonseminomatous germ cell tumors.

High doses of carboplatin or cisplatin combined with cyclophosphamide and etoposide followed by autologous bone marrow transplantation (ABMT) rescue have been used in the treatment of testicular tumors that have had a bad prognosis. Unusual cutaneous complications, evoking radiation-induced dermatitis, have been seen in two of eight patients with the same regimen. This new type of toxicity seems to be related to high-dose combination chemotherapies. Good results in the treatment of patients with testicular tumors on relapse who continue to respond to chemotherapy lead to the extension of this type of schedule and cutaneous toxicity will probably develop.

Synergistic antitumoral activity of combined UFT, folinic acid and oxaliplatin against human colorectal HT29 cell xenografts in athymic nude mice.

This study was designed to assess the inhibition of tumor growth by oxaliplatin combined with UFT and folinic acid (FA). Growth inhibition was studied in nude mice transplanted with human colorectal HT29 tumor cell xenografts and treated for 28 days with oral UFT (20 mg/kg/day) and FA (4 mg/kg/day), i.p. oxaliplatin (10 mg/kg on day 1) or a combination of oxaliplatin, UFT and FA, or else not treated (controls). Tumor surface area and weight were recorded twice a week, and mice were sacrificed at day 28. Two separate experiments were performed for each group of 25 mice. At day 28, mean tumor weights (g) were 2.89+/-0.22 (controls), 2.03+/-0.14 (oxaliplatin), 2.02+/-0.21 (UFT/FA) and 1.23+/-0.17 (oxaliplatin+UFT/FA). For the three treatment groups, tumor weight decreases were 30.1% (p<0.05), 29.9% (p<0.05) and 57.5% (p<0.001), respectively. Combined treatment (UFT/FA+oxaliplatin) reduced tumor weight by 39% compared to oxaliplatin alone (p<0.05) or UFT/FA (p<0.05). These results demonstrate the synergistic effect of the combination of oxaliplatin, UFT and FA in this HT29 cell xenograft model, and warrant further investigations in patients with metastatic colorectal cancer.

A phase II study of the combination of carboplatin and ifosfamide in previously untreated metastatic small cell lung carcinoma.

This Phase II study evaluated the combination of two active agents in small cell lung carcinoma (SCLC): carboplatin and ifosfamide. Thirty previously untreated patients (27 men and 3 women) with a median age of 59 years were included in this study. Twelve patients had one metastatic site and 18 had two or more metastatic sites. The median performance status was 80%. The chemotherapy (CT) regimen administered during the course of this study consisted of carboplatin (300 mg/m2) and ifosfamide (4 g/m2) plus mesna every 4 weeks. All 30 patients were evaluable: 1 achieved a complete remission (CR) and 18 achieved a partial remission (PR) (objective response rate, 63%). The median response time was 3 months and the median survival time was 8 months (range, 1 to 25+ months). Bone marrow toxicity was Grade III in three patients and Grade IV in four patients. The carboplatin and ifosfamide combination was well tolerated. No cross-resistance with the doxorubicin and etoposide regimen was established because 4 of 11 patients responded to this combination (+/- cisplatin) after failing to respond to the ifosfamide and carboplatin regimen. The ifosfamide and carboplatin combination may be considered for inclusion in non-cross-resistant alternating CT schedules.

Escalating high-dose carboplatin and autologous bone marrow transplantation in solid tumors.

Twenty-seven patients with poor-prognosis malignancies were treated with a combination (CARBOPEC) of fixed-dose etoposide (1,750 mg/m2), cyclophosphamide (6,400 mg/m2), and escalating doses of carboplatin (from 800 to 1,600 mg/m2) followed by autologous bone marrow transplantation (ABMT). All patients had previously received platinum derivatives. The diagnoses were as follows: germ cell tumors (GCTs; n = 15); ovarian carcinomas (n = 8); rhabdomyosarcomas (n = 3), and Hodgkin's disease (n = 1). All 27 patients were fully evaluated for toxicity. The median duration of granulocytopenia (leukocytes < 0.5 x 10(9)/l) and thrombocytopenia (platelets < 20 x 10(9)/l) was 23 and 20 days, respectively. Hematologic growth factors were used in 3 cases. The main nonhematologic toxicity was gastrointestinal, with moderate to severe diarrhea in 18 patients. No significant renal toxicity was observed. The overall response rate to this high-dose chemotherapy was 55%, with a complete response (CR) rate of 45% (9 patients). The median duration of CR was 9 months. Five of the 27 patients are alive with no evidence of disease (NED) at 5, 22, 27, 40, and 43 months after ABMT. Four of the 11 patients with refractory GCTs have NED at 5, 22, 27, and 40 months, together with 1 of the 3 responders (43 months). Our study shows the encouraging antitumor activity of this regimen. Similar chemotherapy schedules have also been used with high response rates in GCT, ovarian cancer, breast cancer, and soft tissue sarcoma in children. The CARBOPEC protocol seems to be a good candidate for therapy intensification in patients with various malignancies. A European trial for salvage therapy in GCT will be activated in the near future. Moreover, results should improve with the widespread use of hematopoietic growth factors and optimization of carboplatin administration that takes pharmacokinetic parameters into account.

Phase II trial of intraperitoneal carboplatin in ovarian carcinoma patients with macroscopic residual disease at second-look laparotomy. A multicentre study of the French Fédération Nationale des Centres de Lutte Contre le Cancer.

BACKGROUND: Because of its antitumour activity and its pharmacological advantage when administered by the intraperitoneal route, carboplatin was studied in a phase II multicentric trial. The aim of the study was to determine the response rate and the toxicity of carboplatin administered intraperitoneally and to determine if pathological complete response could be attained in women with macroscopic residual ovarian cancer at second-look laparotomy after intravenous cisplatin chemotherapy. PATIENTS AND METHODS: Twenty-nine patients with macroscopical residual disease after intravenous cisplatin-based chemotherapy at second-look laparotomy, were treated at that time with 300 mg/m2 of carboplatin administered in the abdominal cavity every four weeks for six cycles. In instances of negative findings at physical and CT scan examination, laparotomy evaluation was performed and the catheter was removed. The dose of carboplatin was increased or decreased according to hematological toxicity. RESULTS: Efficacy is evaluable in 25 pts: 2 pts had pathological complete responses and 1 pt had microscopic disease (12% response rate of evaluable patients). Toxicity is evaluable for 135 cycles in 29 patients. No grade 4 hematological toxicity was observed, 2 pts had grade 3 leukopenia and 3 pts had grade 3 thrombocytopenia; grade 3 vomiting was observed in 11% of cycles. No peritoneal complication was observed; catheter dysfunction occurred after the first cycle in one patient who refused a surgical procedure to remove the catheter and to pursue treatment. CONCLUSION: Intraperitoneal carboplatin demonstrates efficacy in patients with macroscopical residual disease at second-look laparotomy after first-line cisplatin chemotherapy. The recommended dose for further studies is 300 mg/m2 administered every 4 weeks. A low response rate does not favour a randomised study.