Paclitaxel and carboplatin adjuvant therapy alone or with radiotherapy for resected nonsmall cell lung carcinoma: a feasibility study of the Minnie Pearl Cancer Research Network.

BACKGROUND: The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer). METHODS: One hundred two patients with resected nonsmall cell lung carcinoma were treated in the postoperative period with 3 courses of paclitaxel 200 mg/m(2) intravenously (i.v.) over 1 hour and carboplatin area under the curve of 6 i.v. every 3 weeks for 3 courses. Patients with Stage IB received no further therapy, and those with higher stages also subsequently received radiotherapy plus concurrent weekly paclitaxel and carboplatin over 6 weeks. The median age was 61 years, with 56 men and 46 women, and the predominant histologic type was adenocarcinoma. Twenty pneumonectomies, 80 lobectomies, and 2 other procedures were performed. Ninety percent of the patients (92 of 102) received all 3 courses of adjuvant paclitaxel and carboplatin (84% received full doses). Seventy-three percent received full doses of radiotherapy and concurrent weekly chemotherapy (49 of 67 patients), and 14 others received greater than 75% of the radiotherapy and concurrent chemotherapy. RESULTS: Toxicity of the chemotherapy was mild with only three hospitalizations for neutropenia and fever and no treatment-related deaths. Severe hypersensitivity occurred in six patients (6%). Concurrent radiation therapy and weekly chemotherapy also was well tolerated with the exception of Grade 3-4 esophagitis observed in 27% (17 of 67 patients). Follow-up was short with a median of 10 months, and 65% of all patients remained progression free. CONCLUSIONS: Three courses of paclitaxel and carboplatin is tolerable, feasible, and can be delivered in most patients in the adjuvant setting. Subsequently, in higher stage patients, concurrent postoperative radiation therapy and weekly paclitaxel and carboplatin is well tolerated and delivered in most patients. Definitive prospective randomized Phase III adjuvant trials are warranted.

Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial.

BACKGROUND: The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of the combination of paclitaxel, carboplatin, and long-term continuous infusion 5-fluorouracil (5-FU) in the treatment of advanced squamous carcinomas of various primary sites. METHODS: Patients were eligible for this trial if they had metastatic squamous carcinoma at any site except the lung. In addition, patients with locally advanced squamous carcinoma of the head and neck were eligible, if they were considered unlikely to be cured with combined modality therapy. Sixty patients entered this trial between February 1995 and March 1999; 12 patients (20%) had received 1 previous chemotherapy regimen, whereas 48 patients (80%) were previously untreated. All patients received the following regimen: paclitaxel 200 mg/m(2), 1-hour intravenous infusion, Days 1 and 22; carboplatin area under the concentration-time curve (AUC) 6.0 intravenously, Days 1 and 22; 5-FU 225 mg/m(2)/day, by 24-hour continuous intravenous infusion, Days 1-35. Treatment courses were repeated at 6-week intervals; responding patients continued treatment for a maximum of 4 courses (24 weeks). RESULTS: Thirty-nine of 60 patients treated (65%) had objective responses to this regimen, with 25% complete responses. Twelve patients (22%) remain progression free from 7 to 63 months (median, 35 months) after completion of therapy. Complete responses were observed in squamous carcinomas from various primary sites including head and neck, esophagus, cervix, vagina, anus, and unknown primary. The most frequent Grade 3/4 toxicities observed with this 3-drug regimen included leukopenia (48%), diarrhea (17%), mucositis (28%), and portacath-related events (13%). CONCLUSIONS: The combination of paclitaxel, carboplatin, and long-term infusional 5-FU is feasible, well tolerated, and highly efficacious in patients with advanced squamous carcinomas of various primary sites. This regimen merits further investigation.

Taxane-based chemotherapy for patients with carcinoma of unknown primary site.

BACKGROUND: The purpose of this study was to determine the long-term follow-up on survival of patients with carcinoma of unknown primary site treated with taxane-based chemotherapy in a multicenter community-based setting. PATIENTS AND METHODS: Patients were treated with three sequential phase II trials between 1995 and 1998 as follows: Study I: paclitaxel 200 mg/m2 intravenously (i.v.) Day 1, carboplatin AUC = 6 i.v. Day 1, and oral etoposide 50 mg daily alternating with 100 mg daily days 1-10 every 3 weeks; Study II: docetaxel 75 mg/m2 i.v. Day 1, cisplatin 75 mg/m2 i.v. Day 1, repeated every 3 weeks; Study III: docetaxel 65 mg/m2 i.v. Day 1, carboplatin AUC 6 i.v. Day 1, repeated every 3 weeks. A total of 144 patients (71 on Study I, 26 on Study II, 47 on Study III) were treated (45% had well differentiated carcinoma, 48% had poorly differentiated carcinomas, and 6% poorly differentiated neuroendocrine tumors). The majority of the patients had multiple sites of metastatic disease. RESULTS: Thirty-six percent of all evaluable patients responded to therapy (27% partial and 9% complete responses). The median survival was 10 months with 1-, 2-, 3-, and 4-year survivals of 42%, 22%, 17%, and 17%, respectively. Follow-up ranges from 11 to 50 months. Women survived significantly longer than men. Thirty-one patients remain alive and 14 are progression-free. The primary toxicity was leukopenia with the carboplatin regimens and nausea and vomiting with the cisplatin regimen. A review of the survival of several large previously reported series of patients was compared to results after taxane-based chemotherapy. A compelling argument is made that chemotherapy is superior to best supportive care alone and that taxane-based chemotherapy is superior to other forms of chemotherapy. However, prospective randomized trials will be necessary to definitively demonstrate the superiority of this treatment compared to other therapies for these patients. CONCLUSION: Taxane-based chemotherapy for patients with carcinoma of unknown primary site appears to be clinically beneficial and is associated with long-term survival for a minority of patients at 2-, 3-, and 4-year follow-up.

Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network.

PURPOSE: To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel and gemcitabine in patients with advanced transitional-cell carcinoma of the urothelial tract. PATIENTS AND METHODS: Fifty-four patients with advanced unresectable urothelial carcinoma entered this multi-centered, community-based, phase II trial between May 1997 and December 1999. All patients were treated with paclitaxel 200 mg/m(2) by 1-hour intravenous (IV) infusion on day 1 and gemcitabine 1,000 mg/m(2) IV on days 1, 8, and 15; courses were repeated every 21 days. Patients who had objective response or stable disease continued treatment for six courses. RESULTS: Twenty-nine of 54 patients (54%; 95% confidence interval, 40% to 67%) had major responses to treatment, including 7% complete responses. With a median follow-up of 24 months, 16 patients (30%) remain alive and nine (17%) are progression-free. The median survival for the entire group was 14.4 months; 1- and 2-year actuarial survival rates were 57% and 25%, respectively. Seven (47%) of 15 patients previously treated with platinum-based chemotherapy responded to paclitaxel/gemcitabine. Grade 3/4 toxicity was primarily hematologic, including leukopenia (46%), thrombocytopenia (13%), and anemia (28%). Ten patients (19%) required hospitalization for neutropenia and fever, and one patient had treatment-related septic death. CONCLUSION: The combination of paclitaxel and gemcitabine is active and well tolerated in the first- or second-line treatment of patients with advanced transitional-cell carcinoma of the urothelial tract. Response rate and duration compare favorably with those produced by other active, first-line regimens. This regimen should be further evaluated in phase II and III studies, as well as in patients with compromised renal function.

Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma. A Minnie Pearl Cancer Research Network Phase II Trial.

BACKGROUND: Weekly administration of docetaxel was found to reduce myelosuppression and other nonhematologic toxicities when compared with administration every 3 weeks. In the current Phase II trial, the authors evaluated the feasibility, toxicity, and efficacy of weekly docetaxel in the treatment of elderly patients with newly diagnosed advanced nonsmall cell lung carcinoma. METHODS: Thirty-nine patients with advanced, previously untreated nonsmall cell lung carcinoma entered this Phase II trial between February 1998 and January 1999. Patients were required either to be age >/= 65 years or to be poor candidates for combination chemotherapy due to coexistent medical illnesses. All patients received docetaxel, 36 mg/m(2), administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Patients were reevaluated after 8 weeks of treatment; responding patients continued weekly docetaxel for a maximum of 32 weeks or until disease progression. RESULTS: Weekly docetaxel was well tolerated by this elderly group of patients with nonsmall cell lung carcinoma. Grade 3 leukopenia was noted in only 3 patients (8%), and no patient developed Grade 4 myelosuppression. Grade 3/4 nonhematologic toxicity also was uncommon; fatigue/asthenia was reported in 4 patients (10%). Seven of 38 evaluable patients (18%) had objective responses to weekly docetaxel whereas an additional 13 patients (34%) had a minor response or stable disease at first reevaluation. The median survival in this group of elderly patients was 5 months, with a 1-year actuarial survival rate of 27%. CONCLUSIONS: The results of the current study show that weekly docetaxel is active and well tolerated in elderly patients with advanced nonsmall cell lung carcinoma and provides an additional treatment option for these patients, who often tolerate combination chemotherapy regimens poorly.

Paclitaxel, carboplatin, and vinorelbine in the treatment of advanced non-small cell lung cancer: a phase II trial of the Minnie Pearl Cancer Research Network.

PURPOSE: To evaluate the feasibility, toxicity, and efficacy of adding vinorelbine to the paclitaxel/carboplatin combination in the treatment of advanced non-small cell lung cancer. PATIENTS AND METHODS: Patients with advanced (stage IIIB/IV) non-small cell lung cancer who had received no previous chemotherapy were treated with the following three-drug regimen: paclitaxel, 200 mg/m2, 1-hour i.v. infusion, day 1; carboplatin, AUC 6.0 i.v., day 1; and vinorelbine, 22.5 mg/m2 i.v. days 1 and either 8 or 15. Treatment was repeated every 21 days. This phase II trial was conducted in a multicenter, community-based setting. RESULTS: Eighty-nine patients were treated with a median of four courses of therapy (range, one to eight). Thirty-one patients (35%) had major responses (two complete, 29 partial), and 36 patients (40%) had a minor response or stable disease. Actuarial median survival was 8.6 months; 1 year survival was 43%. Leukopenia was the major toxicity: 73% of patients had grade 3/4 toxicity, and 32 patients (36%) were hospitalized for neutropenia/fever (11% of total courses administered). Treatment-related death due to infection occurred in four patients (4%). CONCLUSIONS: This three-drug regimen is feasible and efficacious in the treatment of advanced non-small cell lung cancer. The addition of vinorelbine increases the incidence of severe leukopenia substantially when compared with the paclitaxel/carboplatin regimen. However, other toxicities are not markedly increased. Ongoing randomized trials will define the role of this regimen in the treatment of non-small cell lung cancer.

Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma.

Rituximab, a chimeric antibody that targets CD20(+) B cells, produces a 48% response rate in patients with refractory low-grade non-Hodgkin lymphoma. In this phase II trial, patients with low-grade non-Hodgkin lymphoma who had previously received no systemic therapy were treated with rituximab, 375 mg/m(2), administered by IV infusion for 4 consecutive weeks. Patients with objective response or stable disease received repeat 4-week courses of rituximab at 6-month intervals. At the time of initial reevaluation at 6 weeks, 21 of 39 patients (54%) had objective response to treatment, and an additional 14 patients (36%) had stable disease or minor response. Response rates were similar in patients with follicular and small lymphocytic (CLL-type) lymphoma (52% versus 57%, respectively). At present, follow-up is short and only 13 patients have undergone a second course of rituximab treatment. However, 4 additional responses were documented either prior to the second course of rituximab (2 patients) or following the second course (2 patients) and 4 patients improved from partial to complete response. The current response rate is 64%, with 6 complete responses (15%). Treatment with rituximab was well tolerated, with only 1 patient experiencing grade 3/4 infusion-related toxicity. Rituximab is well tolerated and highly active in patients with low-grade non-Hodgkin lymphoma previously untreated with systemic therapy. Although further follow-up is required, the demonstration of minimal toxicity and considerable activity of this new biologic agent represents an important beginning of more specific, less toxic treatment for this important group of cancer patients.

Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin.

PURPOSE: To evaluate the toxicity, response rate and short-term survival associated with the chemotherapy combinations of docetaxel plus cisplatin or carboplatin when used for the treatment of patients with metastatic carcinoma of unknown primary site. PATIENTS AND METHODS: Twenty-six patients were treated with docetaxel 75 mg/m2 i.v. and cisplatin 75 mg/m2 i.v. given every three weeks (study A) and subsequently, 47 patients were treated with docetaxel 65 mg/m2 and carboplatin (AUC dose = 6) every three weeks (study B). Stable or responding patients received a maximum of eight courses of therapy. Patients who were known to be in treatable subset groups were excluded from these trials. The majority of patients had two or more sites of metastasis; about 45% had adenocarcinoma and 50% poorly differentiated carcinoma. RESULTS: In study A, 6 of 23 (26%) assessable patients had a major response to therapy. The median survival was eight months and one-year survival 42%. Seven patients were removed from the study early for grade 3 or 4 nausea and vomiting. In study B, 9 of 40 assessable patients (22%) had a major response to therapy. Median survival was eight months and one-year survival 29%. Toxicity associated with this regimen was predominantly myelosuppression. Comparisons of the two sequential trials showed no differences in response rates or survivals (P = 0.75). CONCLUSIONS: Docetaxel and cisplatin (study A) is an active combination in carcinoma of unknown primary site, but associated with substantial gastrointestinal toxicity. A combination of docetaxel plus carboplatin (study B) is better tolerated and produced a similar response rate, median survival and one-year survival. Comparative phase III trials will be necessary to unequivically prove a survival advantage for any form of therapy in these patients. However, the survival for patients with carcinoma of unknown primary site receiving docetaxel-based chemotherapy is comparable to the survivals for several other groups of advanced cancer patients, such as non-small cell lung cancer, receiving various types of chemotherapy.

Phase II trial evaluating triplet chemotherapy using gemcitabine, paclitaxel, and carboplatin in the treatment of patients with advanced non-small cell lung cancer.

The purpose of this study was to evaluate the combination of gemcitabine, paclitaxel, and carboplatin in patients with advanced non-small cell lung cancer. Previously untreated patients with stage IIIB or IV non-small cell lung cancer were enrolled into this trial. Sixty-nine patients from the phase II portion and eight patients from the phase I portion were treated with gemcitabine 1,000 mg/m2 intravenously on days I and 8, paclitaxel 200 mg/m2 as a 1-hour infusion on day 1, and carboplatin at an area under the curve of 5.0 intravenously on day 1. Treatment courses were repeated every 21 days. The phase II component of the study was completed at 13 community-based practices in the Minnie Pearl Cancer Research Network. Thirty-four of 71 fully evaluable patients had an objective response (48%, two complete and 32 partial responses). Twenty-five patients (35%) were stable and 12 (17%) progressed. The median response duration was 6 months (range, 3 to 14 months) and the median survival was 9.9 months, with 1- and 2-year survival rates of 47% and 21%, respectively. The combination of gemcitabine, paclitaxel, and carboplatin has been shown to be safe and effective; thus, this three-drug regimen will be compared with a standard two-drug regimen, paclitaxel/carboplatin, in a phase III study.

Phase I/II trial of paclitaxel by 1-hour infusion, carboplatin, and gemcitabine in the treatment of patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: The combination of paclitaxel and carboplatin is widely used in the treatment of patients with advanced nonsmall cell lung carcinoma. In this Phase I/II study the authors evaluated the feasibility, toxicity, and efficacy of adding a third active antineoplastic agent, gemcitabine, to the paclitaxel/carboplatin combination for the treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Patients with advanced (AJCC Stage IIIB or IV) nonsmall cell lung carcinoma previously untreated with chemotherapy were eligible for this trial. The maximum tolerated doses, determined in the Phase I trial and subsequently used in the Phase II trial, were: paclitaxel, 200 mg/m2, as a 1-hour infusion on Day 1; carboplatin, at area under the curve dose of 5.0 intravenously (i.v.), on Day 1; and gemcitabine, 1000 mg/m2 i.v., on Days 1 and 8. Treatment courses were repeated every 21 days. The Phase II study was conducted in 13 community-based practices in the Minnie Pearl Cancer Research Network; 77 patients were treated between December 1996 and September 1997. RESULTS: Thirty-four of 77 patients (44%) in the Phase II trial had major responses (partial responses, 32 patients and complete responses, 2 patients). An additional 25 patients (33%) had stable disease or minor response; only 23% of patients progressed or were removed from study at or prior to first reevaluation. The median survival was 9.4 months, with a 45% actuarial 1-year survival rate. Myelosuppression was the most common toxicity, with Grade 3/4 NCI Common Toxicity Criteria leukopenia and thrombocytopenia in 49% and 45% of patients, respectively. However, only 11 patients (14%) required hospitalization for neutropenia/ fever, and none had bleeding complications. Grade 3/4 nonhematologic toxicities included fatigue (41%), arthralgias/myalgias (26%), peripheral neuropathy (8%), nausea/emesis (6%), and hypersensitivity reactions (4%). There was one treatment-related death due to sepsis. CONCLUSIONS: This three-drug regimen is active and has acceptable toxicity in patients with advanced nonsmall cell lung carcinoma. Myelosuppression, particularly thrombocytopenia, is increased in comparison to the paclitaxel/carboplatin regimen. Fatigue also may be increased, but other nonhematologic toxicities are not altered substantially by adding gemcitabine. Although the response rate and median survival are improved modestly compared with our previous experience with paclitaxel/carboplatin, definitive conclusions regarding the efficacy of this regimen await the completion of randomized trials.

Phase I trial of paclitaxel, carboplatin, and topotecan with or without filgrastim (granulocyte-colony stimulating factor) in the treatment of patients with advanced, refractory cancer.

BACKGROUND: Topotecan is a new antineoplastic agent with a broad spectrum of activity. The purpose of this Phase I trial was to define the maximum tolerated dose of topotecan when added to the widely used combination of paclitaxel and carboplatin. METHODS: Patients with advanced cancer that was refractory or resistant to standard treatments were treated with paclitaxel, carboplatin, and topotecan; doses were escalated in sequential cohorts of patients. After definition of the maximum tolerated dose without cytokines, granulocyte-colony stimulating factor (G-CSF) was added and further dose escalation was attempted. RESULTS: The maximum tolerated doses were: paclitaxel, 135 mg/m2, as a 1-hour intravenous (i.v.) infusion on Day 1; carboplatin, area under the curve 5.0, on Day 1; and topotecan, 0.75 mg/m2, i.v. on Days 1, 2, and 3; the regimen was repeated every 21 days. Myelosuppression, particularly thrombocytopenia, was the dose-limiting toxicity with this three-drug combination. Nonhematologic toxicity was uncommon. The addition of G-CSF did not allow substantial dose escalation because thrombocytopenia was uneffected by this agent. Eleven of 25 patients had major responses to this combination, including 8 of 14 patients with previously treated small cell lung carcinoma. CONCLUSIONS: The combination of paclitaxel, carboplatin, and topotecan is feasible, although only relatively low doses of all three drugs can be tolerated due to myelosuppression. This regimen showed a high level of activity in these patients with refractory cancer, and merits further investigation.