Phase III study comparing sequential versus alternate administration of cisplatin-etoposide and topotecan as first-line treatment in small cell lung cancer.

AIM: To compare the efficacy and tolerance of sequential versus alternate front-line administration of cisplatin-etoposide (PE) and topotecan (T) in patients with extensive stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients were randomized to receive either 4 cycles PE (cisplatin 80 mg/m(2) i.v. day 1 and etoposide100 mg/m(2)/d i.v. days 1-3 every 21 days) followed by 4 cycles T (1.5 mg/m(2)/d i.v. days 1-5 every 21 days) (arm A, 183 patients) or the same regimens using an alternate sequence (arm B, 181 patients). RESULTS: There was no significant difference in terms of compliance with treatment, overall response rates (51.4% vs. 55.2%; p=0.458), median response duration (4.3 vs. 5.2 months; p=0.780), median time to tumour progression (5.7 vs. 6.4 months; p=0.494), median overall survival (10.9 vs. 9.8 months; p=0.186) and 1-year survival (43.8% vs. 36.5%) between the two arms. The incidence of severe grade 3-4 haematological and grade 2-4 non-haematological (asthenia, mucositis, diarrhoea and neurotoxicity) toxicity was comparable between the two arms. CONCLUSION: The comparison of sequential versus alternate administration of cisplatin-etoposide and topotecan as front-line treatment of patients with extensive stage SCLC revealed no clinically meaningful differences in terms of efficacy and tolerance.

Predictive value of D-dimer plasma levels in response and progressive disease in patients with lung cancer.

Patients with cancer may present with one or more circulatory markers of haemostatic activation which may be associated with tumor growth and cancer cell dissemination. In our clinical practice we observed haemostatic abnormalities with or without thrombotic episodes in cancer patients. The aim of the present study was to detect the D-dimer plasma levels in advanced-stage lung cancer patients before, during and after chemotherapy, and to determine whether there is a correlation with response rate, disease recurrence and survival, in order to estimate the possible predictive value of D-dimer plasma levels. Forty-seven/52 patients were evaluable and analysed; 38 patients had non-small-cell lung cancer (NSCLC) and 9 small-cell lung cancer (SCLC) and all were at an advanced stage or inoperable. Two (4.3%) achieved complete response (CR), 17 (36.2%) partial response (PR), and 16 (34%) had progressive disease (PD). We found that 14/19 (73.7%) patients with CR or PR showed a reduction in D-dimer plasma values and 11/16 (68.8%) with PD showed increased values; also, in patients with recurrent disease (12/13, 92.3%), D-dimer plasma levels were increased. All of the above values were statistically significant. D-Dimer plasma levels decrease or increase after response and progressive disease, respectively, and can act as a predictive factor of the evolution of the disease.

Sequential versus alternating administration of cisplatin/etoposide and topotecan as first-line treatment in extensive-stage small-cell lung cancer: preliminary results of a Phase III Trial of the Hellenic Oncology Research Group.

BACKGROUND: This trial was designed to compare the efficacy and toxicity of sequential versus alternating administration of cisplatin/etoposide and topotecan in patients with previously untreated extensive-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS: Two hundred eighty-four chemotherapy-naive patients were randomized between the sequential therapy arm (n=142; 4 cycles of cisplatin 75 mg/m2 intravenously [I.V.] on day 1 with etoposide 100 mg/m2 per day I.V. on days 1-3 followed by 4 cycles of topotecan 1.5 mg/m2 per day I.V. on days 1-5) and the alternating arm (n=142; same doses of cisplatin/etoposide on cycles 1, 3, 5, and 7 and topotecan on cycles 2, 4, 6, and 8). Treatment cycles for both regimens were administered every 3 weeks. RESULTS: At this preliminary analysis, no statistically significant difference in the overall response rate, duration of response, time to disease progression, or median survival was observed between the 2 arms. A total of 756 cycles of the sequential therapy and 830 cycles of the alternating therapy were administered, with a median numbers of 6 and 7 cycles per patient, respectively. Topotecan was administered in 85 patients on the sequential arm and 132 patients on the alternating arm. Dose reductions for toxicity were similar in both arms. Grade 3/4 toxicities in the sequential and alternating arms, respectively, included neutropenia (51% and 52%; P=NS), anemia (12% and 11%; P=NS), febrile neutropenia (7% and 9%; P=NS), thrombocytopenia (19% and 20%; P=NS), and asthenia (8% and 2%; P=0.02). There were 4 toxicity-related deaths in the sequential arm versus 3 in the alternating arm. CONCLUSION: Our preliminary conclusion is that the sequential and alternating regimens resulted in comparable activity and tolerability in previously untreated patients with extensive-stage SCLC.

Mesothelioma: treatment and survival of a patient population and review of the literature.

BACKGROUND: Our purpose was to evaluate the survival of patients with pleural and intraperitoneal malignant mesothelioma and, particularly, to estimate the efficacy of chemotherapy as well as radiotherapy and surgery. A review of the literature with respect to these parameters is included. PATIENTS AND METHODS: Thirty-five patients with malignant mesothelioma (28 with pleural and 7 with intraperitoneal) were enrolled. Twenty-eight patients underwent chemotherapy, 7/35 radiation and 9/35 surgery (2 with pleural and 7 with abdominal disease). Combination chemotherapy included cisplatin-gemcitabine, cisplatin (or carboplatin) with premetrexed and doxorubicin-cyclophosphamide. RESULTS: In 2/28 patients with pleural mesothelioma the tumor was excised and in 7 with intraperitoneal disease, surgical therapy was palliative and there was survival prolongation. Radiotherapy was only palliative. Chemotherapy produced a very low response: 2/28 (7.14%) patients achieved a partial response. The median survival was 17 months, 4-year survival, 24.4% and 5-year survival, 12.12%. No serious toxicity was observed. CONCLUSION: Malignant mesothelioma of the pleura and intraperitoneum is a slow-growing disease which is indicated by the long survival, despite the failure of chemotherapy, radiation therapy and surgery.

Phase II study of cisplatin-combined schedules as second-line chemotherapy in patients with non-small cell lung cancer.

BACKGROUND: The aim of this study was to evaluate the effectiveness of cisplatin- (CDDP) combined chemotherapy in non-cisplatin pretreated patients with non-small-cell lung cancer (NSCLC). The second cytotoxic drug administered was either etoposide or gemcitabine. First-line treatment was based on paclitaxel combined with either carboplatin or vinorelbine. PATIENTS AND METHODS: Seventy-eight patients with histologically- or cytologically- confirmed NSCLC, having failed front-line treatment, were enrolled. All patients received 80 mg/m2 of cisplatin as second-line treatment, on day 1, repeated every 3 weeks; in 48 patients the second agent was etoposide (120 mg/m2) on days 1, 2 and 3, repeated every 3 weeks and in 30 patients 1 g/m2 of gemcitabine on day 1, repeated every 3 weeks. RESULTS: All patients were evaluable for response and toxicity. No complete responses were observed. Thirteen (16.67%) patients achieved partial response, 42 (53.85%) stable disease and 23 (29.49%) had disease progression. The median duration of response was 4 months (range 2-8+ months), median time to tumor progression (TTP) 5 months (range 2-9 months) and median survival time after starting second-line chemotherapy, 6 months (range 2-9+ months). Toxicity was acceptable: 9 patients presented with nephrotoxicity (11.54%) and 13 (16.67%) with grade 3-4 neutropenia. CONCLUSION: The cisplatin combination as second-line treatment in patients with NSCLC exhibited a notable degree of activity and tumor growth control was evidenced by the 16.67% partial response and 53.85% disease stability.

Response to radiotherapy in brain metastases and survival of patients with non-small cell lung cancer.

The present study involves non-small cell lung (NSCLC) cancer patients with brain metastases, who were treated with radiation therapy, and our aim was to determine response rate and survival. A total of 167 patients were recruited, 155 (125 male, 30 female) of whom were evaluable. Performance status was 0-2 and histology or cytology included 66 (42.58%) adenocarcinomas, 62 (40.00%) undifferentiated and 27 (17.42%) squamous cell carcinomas. The stage of disease at diagnosis was IIIA-B in 92 (59.35%) patients and IV in 63 (40.65%). All patients had whole brain irradiation (3 Gy x 5 days/week for 2 weeks to a total dose of 30 Gy), which was performed by a linear accelerator and a 6-MV photon beam. Objective response was observed in 59/155 (38.06%) patients with 17 (10.97%) complete and 42 (27.09%) partial responses, and median survival of 5 months for all patients [95% confidence interval (CI) 3.9-6.1]. Responders had statistically significant longer survival than non-responders. Although responders represented less than half of our patients with NSCLC and brain metastases, they had significantly longer survival.

A multicenter phase II study of the combination of gemcitabine and docetaxel in previously treated patients with small cell lung cancer.

PURPOSE: To evaluate the efficacy and toxicity of the combination of gemcitabine and docetaxel in pretreated patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Twenty-two pretreated patients (median age 61 years, PS: 0-1 in 77% and 2 in 23%) with limited or extensive stage disease were treated with gemcitabine 1000 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8, every 21 days. Fifteen (68%) of the 22 patients had received two prior regimens and fourteen (64%) were refractory to front-line chemotherapy. RESULTS: All patients were evaluable for efficacy analysis. No complete or partial responses were observed. Disease stabilization was obtained in one (5%) patient. The median survival was 14 weeks and the six-month survival rate was 28%. WHO grade 2 and 3 toxicities were infrequent and easily manageable. CONCLUSION: The combination of gemcitabine and docetaxel was inactive as salvage treatment in this poor prognosis group of patients with SCLC.

Paclitaxel and vinorelbine combination in advanced inoperable adenocarcinoma of the lung: a phase II study.

BACKGROUND: The purpose of this study was to determine the efficacy of paclitaxel (PCT) combined with vinorelbine (VRL) in adenocarcinoma of the lung. PATIENTS AND METHODS: Untreated inoperable patients with metastatic disease were enrolled and underwent front-line treatment with a new combination as follows: a 30-minute infusion of VRL at a dose of 25 mg/m2 followed by a 3-hour infusion of PCT 135 mg/m2. Chemotherapy was repeated every 2 weeks with the intention of administering 9 cycles. RESULTS: Fifty-four out of 58 enrolled patients were assessable; the median age was 63 years (range 48-81). All patients were chemotherapy-naïve and all had histologically- or cytologically- confirmed adenocarcinoma. Twenty-seven patients (50%) responded: 5 with complete response (9.3%) and 22 with partial response (40.7%); 17 patients had stable disease (31.5%) and 10 showed disease progression (18.5%). Median response duration was 6 months (range 2-14.5) and median survival was 10 months (range 2-35+). The main adverse reaction was myelotoxicity in 87% of the patients, of whom only 8 (14.8%) had grade 4 neutropenia which in 4 cases (7.4%) was febrile. No patient required dose reduction, but treatment was postponed by one week in 4 patients a total of nine times. Patients received 98.6% of the planned dose. CONCLUSION: The PCT and VRL combination is an active first-line treatment for lung adenocarcinoma. These two cytotoxic drugs produce acceptable toxicity when repeated every 2 weeks.

Amifostine reduces radiochemotherapy-induced toxicities in patients with locally advanced non-small cell lung cancer.

Radiochemotherapy (RCT) is an effective treatment for locally advanced non-small cell lung cancer, but can be limited by acute and late toxicities (esophagitis, pneumonitis, and myelosuppression). This trial investigated whether pretreatment with amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD), a radioprotector, could reduce the incidence of RCT-induced acute and late toxicities. Between October 1997 and August 1999, 73 patients with previously untreated stage IIIa-IIIb non-small cell lung cancer were randomized to treatment with RCT alone or RCT plus amifostine (300 mg/m(2) daily intravenous infusion). Chemotherapy consisted of either paclitaxel (60 mg/m(2)) or carboplatin (area under the concentration-curve of 2) once weekly during a 5- to 6-week course of conventional radiotherapy given as 2 Gy daily fraction, 5 days a week to a total dose of 55 to 60 Gy. Esophagitis and acute lung toxicity were evaluated during treatment; late lung toxicity was assessed at 3 and 6 months after RCT and was graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria. Esophageal endoscopy was performed the fourth week during RCT and 1 month after the end of RCT. Endoscopic findings of radiation esophagitis were scored from 0 to 3. There was no significant difference between treatment arms in baseline patient characteristics. A total of 68 patients were evaluable for toxicity and efficacy (RCT group, n = 32; RCT plus amifostine, n = 36). The incidence of grade >or= 3 esophagitis during RCT was significantly lower for patients receiving amifostine than for those receiving RCT alone (38.9% v 84.4%; P <.001). The incidence of grade >or= 3 acute pulmonary toxicity was also significantly reduced in amifostine-treated patients (19.4% v 56.3%; P =.002). At 3 months following RCT, patients treated with amifostine had a significantly lower incidence of pneumonitis than those who received RCT alone (P =.009). Endoscopic grade >or= 2 esophagitis was observed in eight of 15 patients in the RCT group and in three of 18 patients in the RCT plus amifostine group (P =.061). No significant differences in response rates were noted between patients receiving RCT with or without amifostine (P =.498). Amifostine is effective in reducing the incidence of both acute and late toxicities associated with RCT in patients with locally advanced non-small cell lung cancer without compromising antitumor efficacy.