Anna Maria Gabriele

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.

Clinical and Biological Prognostic Factors in 179 Cases with Sinonasal Carcinoma Treated in the Italian Piedmont Region

Objectives: In spite of aggressive surgery and high-dose radiotherapy, the long-term survival of patients with sinonasal cancer remains disappointing. In this paper, we report data from 179 consecutive cases treated in the Italian Piedmont region between 1996 and 2000 according to a fixed protocol. Methods: Clinical and pathological data and the following biological parameters were analyzed: microvessel density and growth fraction by CD31 and Ki-67 positivity, respectively, and immunohistochemical expression of vascular endothelial growth factor (VEGF). Results: The median follow-up period was 75 months (range 45–108 months). Median overall survival was 26 months; 2- and 5-year overall survival rates were 52 and 36%, respectively. Patients with T1-T2 adenocarcinoma and squamous cell cancers (SCC) had better median survival than those with other lesions (p < 0.05). Patients treated with surgery with or without radiotherapy had better survival (p < 0.01), while chemotherapy had a marginally favorable effect (p = 0.09). The type of surgery and radiotherapy dose had no impact on survival; in contrast, there was a strong association between Ki-67 expression and microvessel density and overall survival (p < 0.05 and p = 0.039, respectively), while VEGF-C was a prognostic factor in SCC patients only (p < 0.05). Conclusions: In sinonasal cancer, tumor stage and histology have a clear impact on survival; surgery with or without radiotherapy represents the main choice of treatment for such tumors. The efficacy of neoadjuvant and concomitant chemoradiotherapy needs to be further investigated. The proliferative index and angiogenesis show a major role in the natural history of this 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.

Induction chemotherapy with cisplatin and epirubicin followed by radiotherapy and concurrent cisplatin in locally advanced nasopharyngeal carcinoma observed in a non-endemic population

BACKGROUND AND PURPOSE Chemoradiotherapy (CRT) represents the main therapy choice in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). The aim of this study was the clinical evaluation of neoadjuvant chemotherapy (NACT) followed by CRT in a non-endemic population affected by advanced NPC. MATERIALS AND METHODS Patients with locoregionally advanced NPC were treated with three cycles of induction chemotherapy (CHT) with cisplatin (100 mg/m(2)) plus epirubicin (90 mg/m(2)), followed by cisplatin (100 mg/m(2)) and concomitant radiotherapy (70 Gy). RESULTS In 40 patients treated with such protocol, after the completion of induction CHT and CRT we observed the objective response rates of 90% and 100%, respectively. Treatment tolerability and toxicity were easily controllable. With a median follow-up time of 54 months, 3- and 5-year disease-free survival was 75% and 65% and 3- and 5-year overall survival was 84% and 77%. Three- and 5-year locoregional control was 82% and 70%, and 5-year distant metastases free survival was 75%. CONCLUSIONS NACT with cisplatin and epirubicin followed by concomitant CRT represents a feasible, efficient treatment for patients with advanced NPC. This regimen ensures an excellent locoregional disease control and overall survival with a low incidence of distant metastases.

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.

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.

Stage III-IV sinonasal and nasal cavity carcinoma treated with three-dimensional conformal radiotherapy

AIMS AND BACKGROUND To report the dosimetric data and clinical outcomes of patients with advanced neoplasm of the paranasal sinuses and nasal cavity, treated by three-dimensional conformal radiotherapy. METHODS Between 2000 and 2005, 31 consecutive patients were treated for locally advanced tumors of paranasal sinuses and nasal cavity. The primary tumor was located as follows: maxillary sinus 15 (48.4%); ethmoid sinus 10 (32.3%); nasal cavity 6 (19.3%). The patients were separated in two groups according to the modality of treatment: group A included 21 patients treated with postoperative three-dimensional conformal radiotherapy with or without chemotherapy; group B included 10 patients treated with radical three-dimensional conformal radiotherapy with or without chemotherapy. The median radiation dose to the planning target volume was 60 Gy (range, 56-63) for patients who underwent complete surgical resection and 68 Gy (range, 64-70) for those who did not have tumor resection or patients with residual disease. RESULTS The median follow-up was 42 months. Five-year local tumor control and overall survival actuarial rates were 74% and 72%, respectively, in the postoperative setting, 20% and 25%, respectively, with the primary radiotherapy. Local recurrence was the most common site of failure. No patient developed radio-induced blindness; 4 patients underwent enucleation as part of radical surgery. Dosimetric data are reported. CONCLUSIONS The local control rate for these tumors remains low. The prognosis depends on localization, tumor stage and treatment modality. Three-dimensional conformal radiotherapy reduces the risk on optical pathways but does not modify outcome.

Radiotherapy alone or with concomitant daily low-dose carboplatin in locally advanced, unresectable head and neck cancer: definitive results of a phase III study with a follow-up period of up to ten years.

Aim and background Radiotherapy is the conventional treatment for locally advanced inoperable head and neck squamous cell carcinoma. However, the poor therapeutic results justify the development of radiochemotherapy combinations. In an attempt to improve local control and survival in patients with stage III and IV unresectable head and neck squamous cell carcinoma and based on the results of our previous dose escalation study, we undertook a prospective multicentric randomized trial. Materials and methods From November 1992 through December 1995, a total of 164 patients were randomized to receive radiotherapy alone (arm I) or combined (arm II) with daily low-dose carboplatin. Results The 3, 5 and 10-year local-regional recurrence-free survival rates were better in arm II(21.7%, 15.1% and 15.1%, respectively) than in arm I (15%, 10.7% and 10.7%), but without statistical significance (P = 0.11). The 3, 5 and 10-year disease-free survival rates showed the same positive trend for arm II (16%, 6.8% and 6.8% vs 9%, 5.5% and 5.5%, in arm I, respectively), again without statistical significance (P = 0.09). Instead, a statistical advantage was found in overall survival rates at 3, 5 and 10-years (28.9%, 9% and 5.5% in arm II and 11.1%, 6.9% and 6.9% in arm I, respectively) (P = 0.02). The 3, 5 and 10-year local-regional recurrence-free survival rates in stage IV disease were statistically better in arm II (21.5%, 15.9% and 15.9%) than in arm I (12.8%, 7.7% and 7.7%, respectively) (P = 0.04). Conclusions Long-term results in both treatment arms of the trial appear less positive than most published series. However, our findings do not exclude that carboplatin may be beneficial, but the benefit in local control must be lower than the 15% assumed to dimension the trial.

Combined chemo-radiotherapy for stage IV undifferentiated nasopharyngeal carcinoma.

Undifferentiated nasopharyngeal carcinoma is a chemosensitive lesion, but its role in the management of local advanced disease is under investigation. Twenty-seven untreated stage IV undifferentiated nasopharyngeal carcinoma patients were treated with radiotherapy (median dose, 66.6 Gy, 1.8 Gy/day) and concomitant cisplatin (100 mg/m2 days 1, 22 and 43). After 4 weeks, patients received, every 4 weeks, 3 cycles with cisplatin (80 mg/m2 day 1) + 5-fluorouracil (1000 mg/m2/day continuous infusion for 96 h). After radiotherapy, we observed 74% complete responses and 26% partial responses; after adjuvant chemotherapy 96% had a complete and 4% a partial response. After a median follow-up of 36 months, 81% of the patients were alive (70% with no evidence of disease). Four-year overall and disease-free survival was 70% and 60%, respectively. Concomitant chemotherapy plus radiotherapy was well tolerated, whereas adjuvant chemotherapy was more toxic. Long-term results were significantly better than those observed with radiotherapy alone.