Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status: a Minnie Pearl Cancer Research Network Phase II Trial.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) and poor performance status (PS) are often excluded from trials. Gefitinib is a safe oral agent that may benefit these patients. PATIENTS AND METHODS: Seventy-two patients with poor PS and advanced NSCLC were enrolled onto this study of gefitinib 250 mg per day given orally until disease progression, with evaluation at 8 weeks. Eligible patients had no previous chemotherapy, an Eastern Cooperative Oncology Group PS of 2/3, and stage IIIB/IV NSCLC. Quality of life (QOL) and symptom response (SR) scores were calculated using the Functional Assessment of Cancer-Lung questionnaire. Patient characteristics included a median age of 75 years; PS of 2/3; and bronchoalveolar (n=3), adenocarcinoma (n=29), squamous cell (n=21), large-cell (n=11), and unspecified histology (n=6). Mean treatment duration was 4 months (range, 3 days to 18 months), and median duration of follow-up was 12 months. Grade 3/4 toxicities included rash and diarrhea. RESULTS: Among 70 patients assessed for response, there were 3 partial responses (4%), 32 patients with stable disease (46%), and 18 with progressive disease (26%). Median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.3 months, respectively. Six-month and 1-year PFS and OS rates were 35% and 21% and 50% and 24%, respectively. Eighty-two percent and 48% of patients reported improvements or no change in QOL and SR, respectively. CONCLUSION: Gefitinib demonstrates modest efficacy and is well tolerated as initial therapy in advanced NSCLC for patients with poor PS.

A randomized controlled trial of darbepoetin alfa administered as a fixed or weight-based dose using a front-loading schedule in patients with anemia who have nonmyeloid malignancies.

BACKGROUND: The effect of using fixed versus weight-based doses for erythropoietic agents has not been reported previously. To investigate this issue, the authors conducted a randomized Phase II study of darbepoetin alfa administered as either a fixed dose or a weight-based dose using an accelerated correction and maintenance dosing regimen (front-loading). METHODS: During the correction phase, patients with anemia (hemoglobin < 11.0 g/dL) who had nonmyeloid malignancies and who were receiving chemotherapy were given darbepoetin alfa at a fixed dose of 325 microg (n = 122) or at a weight-based dose of 4.5 microg/kg (n = 120) once weekly until they achieved a hemoglobin concentration > or = 12.0 g/dL. Patients then received darbepoetin alfa (325 microg or 4.5 microg/kg) once every 3 weeks for the remainder of the 16-week treatment period (maintenance phase). RESULTS: Darbepoetin alfa resulted in high Kaplan-Meier rates of hematopoietic response (> or = 2 g/dL increase from the baseline level or a hemoglobin level > or = 12 g/dL) in both the fixed-dose group (86%; 95% confidence interval [95% CI], 78- 94%) and the weight-based dose group (84%; 95% CI, 76-92%). The median time to hematopoietic response was 34 days (95% CI, 28-44 days) for the fixed-dose group and 36 days (95% CI, 30-45 days) for the weight-based dose group. Hemoglobin concentrations were maintained at target levels for up to 16 weeks in both groups. Darbepoetin alfa was well tolerated, and no clinically significant differences between fixed doses and weight-based doses were observed. CONCLUSIONS: Darbepoetin alfa was effective when administered as either a fixed dose or a weight-based dose using a front-loading approach to rapidly correct anemia and effectively maintain hemoglobin levels in patients with anemia who had malignant disease.

Combination chemotherapy with gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network.

The purpose of the study was to evaluate the combination of gemcitabine and vinorelbine in the treatment of patients with relapsed or refractory small cell lung cancer. Between March 1998 and February 1999, 30 patients with relapsed or refractory small cell lung cancer who had received treatment with one previous combination chemotherapy regimen entered this multicenter, community-based clinical trial. All patients had received previous platinum/etoposide combination chemotherapy; in addition, 12 patients had received paclitaxel as part of their first-line therapy. All patients received gemcitabine 1000 mg/m2 and vinorelbine 20 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Patients were reevaluated for response after two cycles of therapy; those with objective response or stable disease continued treatment for six courses or until disease progression. Three of 28 evaluable patients (10%) had partial responses to treatment. None of the 17 patients with refractory disease responded, while 3 of 12 patients (25%) with relapsed disease had partial responses. Median survival was 5 months. Treatment was generally well tolerated; myelosuppression was the major toxicity, but only two patients developed febrile neutropenia, and there were no treatment-related deaths. Non-hematologic toxicity was uncommon; alopecia did not occur with this regimen. The activity of gemcitabine and vinorelbine in patients with previously treated small cell lung cancer is modest and is limited to patients with relapsed (versus refractory) disease. In patients with relapsed small cell lung cancer, this regimen provides an additional treatment option, with decreased toxicity when compared to other second-line options. However, novel treatment approaches are necessary before substantial improvements in treating this patient population will be realized.

Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma.

PURPOSE: To evaluate response to single-agent rituximab in patients with indolent non-Hodgkin's lymphoma (NHL) and no previous systemic therapy, and the feasibility, toxicity, and efficacy of maintenance rituximab, administered at 6-month intervals, in patients with objective response or stable disease after first-line rituximab therapy. PATIENTS AND METHODS: Patients with indolent NHL (follicular or small lymphocytic subtypes) previously untreated with systemic therapy received rituximab 375 mg/m(2) intravenously weekly for 4 weeks. Patients were restaged at week 6 for response; those with objective response or stable disease received maintenance rituximab courses (identical dose and schedule) at 6-month intervals. Maintenance was continued for a maximum of four rituximab courses or until progression. Between March 1998 and May 1999, 62 patients were entered onto this trial; minimum follow-up was 24 months. RESULTS: Sixty patients (97%) completed the first 4-week course of rituximab and were assessable for response. All have now completed rituximab therapy; 36 (58%) received four courses at 6-month intervals. The objective response rate at 6 weeks was 47%; 45% of patients had stable disease. With continued maintenance, final response rate increased to 73%, with 37% complete responses. Response was similar in patients with follicular versus small lymphocytic subtypes (76% v 70%, respectively). Median actuarial progression-free survival was 34 months. Two patients experienced grade 3/4 toxicity with the first dose; one patient was removed from treatment. No cumulative or additional toxicities were seen with maintenance courses. CONCLUSION: Rituximab is highly active and extremely well tolerated as first-line single-agent therapy for indolent NHL. First-line treatment with scheduled maintenance at 6-month intervals produces high overall and complete response rates and a longer progression-free survival (34 months) than has been reported with a standard 4-week treatment.

Paclitaxel, carboplatin, and topotecan in the treatment of patients with small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network.

BACKGROUND: The objective of this study was to evaluate the feasibility, toxicity, and efficacy of a novel three-drug regimen containing paclitaxel, carboplatin, and topotecan followed by oral etoposide in the first-line treatment of patients with small cell lung carcinoma. METHODS: One hundred five patients with previously untreated, limited stage or extensive stage small cell lung carcinoma were treated in this multicenter, community-based, Phase II trial. All patients received paclitaxel 135 mg/m(2) by 1-hour intravenous (i.v.) infusion on Day 1, carboplatin at an area under the serum concentration-time curve of 5.0 i.v. on Day 1, and topotecan 0.75 mg/ m(2) i.v. on Days 1-3. The treatment regimen was repeated at 21-day intervals for 4 courses. Patients with limited stage disease also received radiation therapy (45 grays [Gy]; in single daily fractions of 1.8 Gy) beginning concurrently with the third course of chemotherapy. Patients who had an objective response or stable disease after 4 courses of combined paclitaxel, carboplatin, and topotecan then received 3 courses of oral etoposide (50 mg alternating with 100 mg for 10 consecutive days) repeated at 21-day intervals. RESULTS: Treatment with paclitaxel, carboplatin, and topotecan produced response rates of 88% and 93% in patients with extensive stage disease and limited stage disease, respectively. The median survival for patients with extensive stage and limited stage disease was 8.3 months and 17.2 months, respectively. The addition of oral etoposide was feasible, but there was no suggestion that it prolonged remission. This three- drug regimen was associated with acceptable toxicity in patients with a good performance status, although it was tolerated very poorly by patients with an Eastern Cooperative Oncology Group performance status of 2; 5 of 12 patients (42%) had treatment-related deaths. CONCLUSIONS: Although this three-drug regimen was active in the treatment of patients with small cell lung carcinoma, it was more toxic than standard platinum and etoposide regimens and provided no apparent improvement in efficacy. Further investigation of topotecan as a component of first-line therapy should focus on two-drug combination regimens in which the topotecan dose can be optimized. Routine use of three-drug regimens in patients with small cell lung carcinoma should await demonstration of superiority in randomized trials.

Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study.

PURPOSE: To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site. PATIENTS AND METHODS: One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m(2) intravenously (i.v.) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL i.v. on day 1, and paclitaxel 200 mg/m(2) i.v. on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m(2) i.v. for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1. RESULTS: Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively. CONCLUSION: Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.