Fulvia Pedani

Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies

Some previous studies have shown that vinorelbine (VNB) is active in recurrent salivary gland tumors.

Cytoreductive Surgery and Intraperitoneal Chemohyperthermia for Recurrent Peritoneal Carcinomatosis from Ovarian Cancer

Aggressive surgical cytoreduction has been shown to have a positive impact on survival of patients with ovarian cancer. After first-line chemotherapy, 47% of patients relapse within 5 years, and median survival after second line chemotherapy is 10—15 months. Adding intraperitoneal chemohyperthermia (IPCH) to surgical cytoreduction could further control ceolomic spread of disease. The aim of this study was to determine morbidity and mortality, regional relapse-free survival and, preliminarily, overall survival after combining cytoreductive surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian epithelial cancer relapsed after prior chemotherapy. Thirty women affected with such a relapse were included. Patients underwent extensive cytoreductive surgery including tumor resections and peritonectomy, followed by intraoperative IPCH with cisplatin. Complete surgical cytoreduction down to nodules less than 2.5 mm (CC0—CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). We registered one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Kaplan-Meier estimates of median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively. Patients with CC0—CC1 had locoregional relapse-free and overall survival rates of 24.4 and 37.8 months, whereas the remainder had survival rates of 4.1 and 11.0 months. We concluded that cytoreductive surgery combined with IPCH is feasible with acceptable morbidity and mortality and seems to promise good results in selected patients affected with peritoneal carcinomatosis from ovarian cancer.

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 continous 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 pallitive role as third-line chemotherapy in recurrent undifferentiated nasopharyngeal cancer.

Concomitant chemoradiotherapy followed by adjuvant chemotherapy in parotid gland undifferentiated carcinoma.

Aims and background Undifferentiated carcinoma of the parotid gland is a poor-prognosis lesion. Results in unresectable lesions, treated with radiotherapy alone, are very disappointing. Methods Six patients with T3-4 N0-1 inoperable lesions were treated with conventional radiotherapy (64-70 Gy, 2 Gy per fraction 5 times a week) and concomitant cisplatin (100 mg/m2, days 1, 22 and 43). Four weeks after radiotherapy, adjuvant chemotherapy (cisplatin, 80 mg/m2, day 1, + VP16, 100 mg/m2, days 1, 3 and 5, q = 3 weeks, for 3 cycles) was given. Results A median dose of 66 Gy (range, 64-70 Gy) was delivered, and all patients recived 3 courses of cisplatin during radiotherapy. Five of 6 patients recived all three chemotherapeutic adjuvant courses. Two months after the end of treatment, 3 CR (50%), 2 PR (33%) and 1 NC (16%) was observed. Median CR and PR duration was 26+ and 10 months, respectively. Median overall survival was 18 months. No severe acute or late toxicity was observed. Conclusions Concomitant chemoradiotherapy followed by adjuvant chemotherapy in advanced unresectable undifferentiated parotid carcinoma is feasibile and well tolerated. The high percentage of long-lasting CR is encouraging.

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/m2 for docetaxel and 20 mg/m2 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.

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 Cmax 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.

Gemcitabine and oxaliplatin in patients with metastatic breast cancer resistant to or pretreated with both anthracyclines and taxanes: clinical and pharmacokinetic data.

Objectives:To evaluate the efficacy, the toxicity and the pharmacokinetics of a gemcitabine (GEM) and oxaliplatin (OXA) combination in metastatic breast cancer patients (MBC), previously treated with anthracycline and taxanes. Methods:A total of 40 women were enrolled; 37 patients had visceral metastases as dominant site of disease, including 20 patients with liver metastases and 14 with multiple visceral metastases. Three patients received neo-adjuvant chemotherapy, 13 patients adjuvant chemotherapy alone, 24 patients chemotherapy for MBC alone. Gemcitabine was given at 1000 mg/m2 on days 1, 8 followed by oxaliplatin at 100 mg/m2 iv on day 2 every 2 weeks (GEM-OXA sequence). Possible pharmacokinetic interactions were studied in 10 patients, by administering on cycle 1 gemcitabine d1/oxaliplatin d2 (GEM-OXA) and on cycle 2 oxaliplatin d1/gemcitabine d2 (OXA-GEM). Results:After a median of 8 cycles, 10 partial response (PR) (25%), 16 stable disease (SD) (40%), and 14 progressive disease (PD) (35%) were obtained. The median duration of response was 6 months (3–9) for responding patients and 4.9 months (2–7.5) for patients with stable disease. For PR, SD and PD patients, median survival was 18 (10–23+), 13 (8–18), and 6 months (4–13), respectively. G3-4 neutropenia occurred in 20% of patients (febrile G3 neutropenia in 2.5%), G3-4 thrombocytopenia and anemia in 15% and 7.5%. The most frequent G3-4 nonhematologic toxicity was represented by peripheral neuropathy (20%), always reversible. The GEM-OXA and OXA-GEM schedules showed a similar pharmacokinetic behavior, with no sequence-dependent interaction. Conclusions:The combination gemcitabine plus oxaliplatin has moderate activity in anthracycline and taxanes resistant/relapsed heavily treated patients, mild toxicity and no administration sequence-dependent pharmacokinetic interactions.

Clinical and pharmacokinetic data of a docetaxel-epirubicin combination in metastatic breast cancer

In order to explore activity and pharmacokinetic data of a docetaxel-epirubicin combination we analyzed a population of 60 metastatic breast cancer patients. All the patients had an ECOG performance status < 3; 41 patients (68%) had visceral metastases as dominant site of disease, including 33% with liver metastases. Three or more involved organs were present in 43% of patients; 35% had received prior hormonotherapy; 10% for metastatic disease. Twenty-five patients (42%) had received prior adjuvant chemotherapy; 15% a CAF regimen. Twenty per cent of patients had less than 12 months disease-free interval. Docetaxel and epirubicin were both given at a dose of 75 mg/m2 i.v. d.1 every 3 weeks. After a median of six cycles we had 5 CR (8.3%), 40 PR (66.6%), 7 NC (11.6%), and 8 PD (13.3%). Response rates in patients with visceral and liver metastases were 78% and 55% respectively. Premenopausal status, < 1 year disease free survival and > 3 metastatic sites were associated with a lower response rate. After a median follow-up of 19 months (12–36), median disease-free survival is 11 months and median overall survival has not been reached. Grade 4 neutropenia was observed in 75% of courses but with febrile neutropenia in 6.2% of courses only. Non-hematologic toxicity wasn’t clinically important. A NYHA class III reversible cardiac failure was observed in one patient (1.6%). The pharmacokinetic evaluation in 16 patients has shown that docetaxel transiently interfered with epirubicin plasma level when docetaxel was administered 1 h after epirubicin.

Gemcitabine and oxaliplatin in patients with pancreatic adenocarcinoma: clinical and pharmacokinetic data.

Objectives: This phase 2 study evaluated clinical efficacy, toxicity, and pharmacokinetics of combination gemcitabine (GEM) and oxaliplatin (OXA) in patients with advanced pancreatic adenocarcinoma. Methods: Of 30 eligible patients, 20 had metastatic disease and 10 had nonmetastatic unresectable locally advanced disease. Gemcitabine 1000 mg/m2 as a 10 mg/m2/min intravenous infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour intravenous infusion on day 2 were administered every 2 weeks. Pharmacokinetics were evaluated in 11 patients by administering the 2 drugs in opposing sequences GEM-OXA (GEM day 1, OXA day 2) and OXA-GEM (OXA day 1, GEM day 2). Results: Of 30 patients evaluated, 9 had a partial response, 11 had disease stabilization, and 10 had disease progression. Median progression-free survival and overall survival were 5.5 and 9.5 months, respectively. The 1-year survival was 37% for all patients. This study revealed no significant pharmacokinetic interaction between the 2 drugs in the GEM-OXA or in the OXA-GEM sequence. Conclusions: The combination of GEM and OXA was well tolerated and showed a promising activity in patients with advanced pancreatic adenocarcinoma; no sequence-dependent pharmacokinetic interaction occurred when comparing the GEM-OXA versus the OXA-GEM sequence, with a 24-hour interval.

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.