Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design.

PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m(2) on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m(2) on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P =.10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P =.47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P =.08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug's tolerability.

Gemcitabine and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results.

OBJECTIVES: To evaluate the pharmacokinetic parameters, efficacy and toxicity of a combination of gemcitabine (GEM) and vinorelbine (VNB) in recurrent heavily pre-treated squamous cell head and neck carcinoma. MATERIALS AND METHODS: Twenty-four patients previously treated with concomitant chemo-radiotherapy (n = 13), surgery plus radiotherapy (n = 10) and surgery + concomitant chemo-radiotherapy (n = 1) were enrolled; 7 patients had received one or more courses of palliative chemotherapy. Twenty patients had a local-regional recurrence and 4 patients had metastases. The doses were 1200 mg/m2 for GEM and 30 mg/m2 for VNB on days 1 and 8 every 21 days; a maximum of 6 cycles was allowed. Pharmacokinetic investigations were performed on 9 patients receiving GEM and VNB. As a PK control, a second group of 5 patients was given GEM as single agent, at the same doses and with the same i.v. infusion length. RESULTS: Twenty-four patients received a total of 135 cycles (median per patient, 5). Neutropenia was the most frequent side-effect (92% of patients; grade 3-4 in 50%). The overall response rate was 25% which included 1 of 24 complete responses (4%) and 4 of 24 partial responses (21%). Responses were observed only in patients with good prognostic characteristics. The median response duration was 5.5 months (2-16 months) and the overall median survival was 9 months (range, 2-25+). Vinorelbine serum levels showed no evidence of any pharmacokinetic interaction with GEM; most of all, no rebound in VNB disposition can be produced by GEM pre-administration. CONCLUSION: The GEM-VNB combination has a palliative role in patients with favourable characteristics; the results seem no better than those observed with VNB alone. Moreover, this drug association does not alter the pharmacokinetic profile of both drugs, also compared to GEM monotherapy.

Postoperative adjuvant chemoradiotherapy in older patients with head and neck cancer.

BACKGROUND: In head and neck cancer, the locoregional failure of patients with positive margins, vascular or perineural invasion, and extracapsular spread is high and results in poor survival. OBJECTIVE: To assess the effect of adjuvant chemoradiotherapy in improving treatment outcomes among older patients with head and neck cancer. METHODS: Forty patients undergoing radical surgery (median age, 73.5 years [range, 70-78 years]) were enrolled (35 men and 5 women; Eastern Cooperative Oncology Group performance status, grade 0-2). Disease sites included the oral cavity (10 patients), oropharynx (12 patients), hypopharynx (8 patients), and larynx (10 patients); pathological TNM classifications included T1 N2 (8 patients), T2 N1-2 (12 patients), T3 N0-2 (8 patients), and T4 N0-2 (12 patients), with the following poor prognostic factors: positive margins (6 patients), vascular invasion (14 patients), neural invasion (16 patients), and extracapsular spread (26 patients). All patients were treated with carboplatin (30 mg/m2 on days 1-5 of weeks 1, 3, and 5) concomitant with radiotherapy (54.0 Gy to all risk volumes plus 10.0 Gy to high-risk volumes; 5 daily fractions of 1.8 Gy each per week). RESULTS: No grade 4 toxicity was observed. Grade 3 toxicity included mucositis (10 patients), neutropenia (6 patients), dermatitis (2 patients), and thrombocytopenia (1 patient). The radiotherapy dose administered was 52.0 Gy to all risk volumes plus 10.0 Gy to high-risk volumes. Thirty-two patients (80%) received 3 cycles, 6 (15%) received 2 cycles, and 2 (5%) received 1 cycle. Three-year survival was as follows: disease-free survival, 58%; overall survival, 64%; and local control, 79%. CONCLUSIONS: Adjuvant chemoradiotherapy may be successful in fit older patients. The results of adjuvant chemoradiotherapy were better than those observed in a comparable group treated with radiotherapy alone and were similar to those observed in a younger group with the same poor prognostic factors treated with adjuvant carboplatin plus radiotherapy.

Docetaxel and vinorelbine: an effective regimen in recurrent squamous cell esophageal carcinoma.

Vinorelbine and docetaxel are two effective drugs in esophageal cancer; our purpose was to evaluate efficacy and toxicity of a combination of these drugs in recurrent squamous cell esophageal cancer. Twenty patients previously treated with concomitant chemoradiotherapy (n = 14), surgery alone (n = 2), surgery plus radiotherapy (n = 2), or concomitant chemoradiotherapy + surgey (n = 2) were enrolled. Thirteen patients had a local-regional recurrence, two patients had metastases, and five patients had both. The doses were 80 mg/m(2) for docetaxel and 20 mg/m(2) for vinorelbine on d 1 every 21 d for a maximum of six cycles. Twenty patients received a total of 106 cycles (median per patient, 5). Neutropenia was the most frequent and severe side effect (grade 4 in 80%; grade 3 in 20%). The overall response rate was 60%, which included 3 of 20 complete responses (15%) and 9 of 20 partial responses (45%). Median response duration was 7 mo (2-50+). Overall median survival was 10.5 mo (range, 2-55+). A dysphagia improvement was observed in 81% of patients. In conclusion, the data from this phase II study indicate that this combination is effective in recurrent heavily pretreated patients with a short-lasting manageable toxicity.

Carboplatin plus taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma.

BACKGROUND: Recurrent undifferentiated nasopharyngeal carcinoma is a chemosensitive disease. Few third-line treatments have been reported. METHODS: Twelve patients (9 males, 3 females; median age 50 years, range, 20-62) with recurrent undifferentiated nasopharyngeal carcinoma were treated with carboplatin AUC 5.5 + paclitaxel (175 mg/m2, 3-hr infusion) on day 1 every 3 weeks. All patients had been previously treated for recurrent disease with a first-line cisplatin-based chemotherapy and a second-line therapy with low-dose continuous infusion 5-fluorouracil. RESULTS: Overall, 54 courses were given (median, 5; range, 2-6). Three patients (25%) obtained a partial response lasting 6, 10 and 26+ months, 1 (8.3%) a minimal response lasting 6 months, and 3 (25%) no change with a median duration of 5 months. The median survival time was 14 months for patients who had a partial or minimal response or no change, and 5 months for nonresponders. Median overall survival was 9.5 months (3-30+). The treatment was well tolerated, and toxicity was manageable. CONCLUSIONS: The combination has a good palliative role as third-line chemotherapy in recurrent undifferentiated nasopharyngeal cancer.

Pharmacokinetic study of oxaliplatin iv chronomodulated infusion combined with 5-fluorouracil iv continuous infusion in the treatment of advanced colorectal cancer.

We investigated the pharmacokinetics (PK), preliminary clinical results and toxicity of chronomodulated oxaliplatin (OHP) plus 5-fluorouracil (5-FU) without folinic acid (FA) in 13 patients with metastatic colorectal cancer. 5-FU (200 mg/m2/day as 14-day continuous iv infusion for six cycles) plus OHP at increasing doses (25-30-35 mg/m2/day, as 12 h chronomodulated iv infusion on days 1-2-3-4, every 14 days for six cycles) were administered to reach maximum tolerated dose (MTD). At MTD (30 mg/m2/day), a PK study of 5-FU and OHP (in total and ultrafiltered-UF plasma) was performed. 5-FU plasma levels were fairly stable, below that reported in similar studies and closely related to the lack of the most typical 5-FU toxicities. OHP Cmax occurred 7 h after infusion start; a progressive accumulation of free Pt and ultrafiltered Pt (UF-OHP) through cycles 1-6 was noted. A marked difference between total plasma and UF Pt was seen in the elimination phase. OHP plasma clearance decrease was related to Vz (volume of distribution of late elimination phase), whereas in UF-OHP was due to a change in Ke or t1/2. In conclusion, the association of 5-FU with chronomodulated OHP do not seem to influence PK parameters of either drugs. Toxicity was modest/acceptable and clinical efficacy good: preliminary data showed a threshold neurotoxicity at total plasma Pt concentrations >1500 ng/ml and UF plasma Pt concentrations >150 ng/ml.

Clinical data and pharmacokinetics of a docetaxel-vinorelbine combination in anthracycline resistant/ relapsed metastatic breast cancer.

The aim of this study was to evaluate the pharmacokinetic parameters, efficacy and toxicity of a docetaxel and vinorelbine combination in metastatic breast cancer patients previously treated with anthracycline. A population of 40 patients was analyzed; 30 patients (75%) had visceral metastases as the dominant site of disease, including 20 patients (50%) with liver metastases. Three or more organs were involved in 43% of patients. All patients had received prior anthracycline therapy. Five patients (12%) had primary resistant disease, 10 patients (25%) secondary resistant disease and 25 patients (63%) had progressive metastatic breast cancer after first-line chemotherapy. Docetaxel and vinorelbine were given at 80 mg/m2 and 20 mg/m2 i.v., respectively, on day 1 every 3 weeks. After a median of 5 cycles, it was found that 5 patients had a complete remission (13%), 19 a partial remission (48%), 9 had stable disease (22%) and 7 had progressive disease (17%). Response rates in patients with visceral and liver metastases were 57% and 50%, respectively. After a median follow-up of 24 months (13-36), median time to progression was 8.5 months and median overall survival 17 months. Grade 4 neutropenia was observed in 78% of courses (febrile neutropenia in 9%). Possible pharmacokinetic interactions were studied in 23 patients by administering docetaxel immediately followed by vinorelbine (protocol A) or vinorelbine followed by docetaxel (protocol B). Patients in protocol B had significantly higher vinorelbine plasma levels and more pronounced neutropenia. Docetaxel plus vinorelbine is an effective combination in anthracycline resistant/relapsed metastatic breast cancer. The administration sequence docetaxel --> vinorelbine is safer than the reverse order.

Docetaxel, carboplatin and concomitant radiotherapy for unresectable squamous cell carcinoma of the head and neck: pharmacokinetic and clinical data of a phase I-II study.

Concomitant chemoradiotherapy is the most effective treatment of unresectable head and neck cancer. Docetaxel and carboplatin are two active drugs that potentiate radiotherapy. Thirty patients (median age = 56 years; median Eastern Cooperative Oncology Group performance status = 1) received radiotherapy (70 Gy, 2 Gy/d, 5 d/wk) concurrent with carboplatin AUC 0.3 to 0.5 on day 1-5, weeks 1, 3, 5, 7, and docetaxel 15 to 25 mg/m2 on day 4 of weeks 2, 4, and 6. Site of unresectable squamous cell carcinoma was as follows: oropharynx, 41%; hypopharynx, 27%; oral cavity, 16%; and larynx, 16%. Stage was III in 13% and IV in 87%. In 11 patients, pharmacokinetic parameters were evaluated. Acute G4 toxicity was as follows: neutropenia, 20%; mucositis, 33%. We had the following acute G3 toxicities: mucositis, 40%; neutropenia, 37%; dermatitis, 23%; and anemia, 13%. The maximum tolerated dosage was area under the curve 0.5 for carboplatin and 20 mg/m2 for docetaxel. Median radiotherapy dose was 69 Gy, and 175 out of 210 courses (83%) were administered. At the end of the treatment, we had 20 complete responses (CR) (67%), 9 partial responses (30%), and 1 no change (3%). After radial neck dissection, 2 patients achieved a CR (overall CR = 73%). After a median follow-up of 2.5 years, we had a 3-year local progression-free survival of 85%, failure-free survival of 69%, and overall survival of 60%. A significant increase of Cmax of carboplatin concentration was noted at the beginning of weeks 3, 5, and 7. Total plasma platinum raises during each course of 5 days of carboplatin without reaching a steady state. Carboplatin, docetaxel, and concomitant conventional radiotherapy is a feasible and effective treatment of unresectable head and neck cancer. The concurrent administration of two drugs does not alter pharmacokinetic drug behavior compared with single-agent data.

Docetaxel and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results.

The purpose of this study was to evaluate pharmacokinetic parameters, efficacy, and toxicity of a combination of docetaxel (DTX) and vinorelbine (VNB) in recurrent heavily pretreated squamous cell head and neck cancer. Twenty-nine patients previously treated with concomitant chemoradiotherapy (n = 14), surgery plus radiotherapy (n = 13), surgery+concomitant chemoradiotherapy (n = 1) and radiotherapy alone (n = 1) were enrolled; 9 patients had received 1 or more courses of palliative chemotherapy. Twenty-one patients had a local-regional recurrence, and 8 patients had metastases. The doses were 80 mg/m2 for DTX and 20 mg/m2 for VNB on day 1 every 21 days for a maximum of 6 cycles. Pharmacokinetic evaluations were performed on 24 patients; in a group of 12 patients, VNB administration immediately followed DTX infusion (schedule A), and in 12 patients VNB administration was immediately followed by DTX infusion (schedule B). Twenty-nine patients received a total of 137 cycles (median per patient, 5). Neutropenia was the most frequent and severe side effect (grade IV in 79%; grade III in 21%). Grade IV (7%) and III (14%) infections were observed in the first 12 patients; ciprofloxacin prophylaxis in the following 17 patients reduced the severe toxicity to 0%. The overall response rate was 49%, which included 3 of 29 complete responses (10%) and 11 of 29 partial responses (38%). Median complete and partial response durations were 20+ and 5.5 months, respectively. Overall median survival was 10 months (range, 2-30+). The mean values of area under the curve, mean residence time (MRT), and C(max) of VNB were significantly lower for schedule A than for schedule B. The mean values of VNB clearance were significantly higher for schedule A than for schedule B. Neutrophil count at the nadir was much lower for patients receiving schedule B. The DTX-VNB combination is effective in heavily pretreated patients with a short-lasting manageable toxicity. Pharmacokinetic evaluations suggested that the sequence DTX --> VNB is safer than the sequence VNB --> DTX.