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.

Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of docetaxel administered weekly to elderly or poor-performance status patients with advanced breast cancer. PATIENTS AND METHODS: Forty-one patients with advanced breast cancer who were either over the age of 65 or considered to be poor candidates for combination chemotherapy received docetaxel 36 mg/m2 weekly for 6 consecutive weeks, followed by 2 weeks without treatment. The median age of patients in this trial was 74 years, and 73% of patients had one or more visceral sites of metastases. Seventy-five percent of patients received weekly docetaxel as first-line treatment for metastatic breast cancer, and the other 25% received it as second-line treatment. Thirty-six patients were assessable for efficacy, and all patients were assessed for toxicity. RESULTS: A total of 448 doses of weekly docetaxel were administered to 41 patients. Thirteen patients (36%) had objective responses to treatment, and an additional 13 patients (36%) had stable disease or minor response. Median time to progression for responding and stable patients was 7 months (range, 3 to 27 months). Median survival for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Severe neutropenia occurred in only 0.4% of courses, and no other hematologic toxicity was observed. Grade 3/4 fatigue was the most common toxicity, occurring in 20% of patients. CONCLUSION: Weekly docetaxel therapy is active and well tolerated by elderly and/or poor-performance status patients with advanced breast cancer. This treatment can be administered with minimal myelosuppression. Weekly docetaxel provides an additional option for treatment in this difficult subgroup of patients with metastatic breast cancer. Well-tolerated combination regimens containing weekly docetaxel merit evaluation for this patient population.

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, 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.

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.

Gemcitabine and vinorelbine in the second-line treatment of nonsmall cell lung carcinoma patients: a minnie pearl cancer research network phase II trial.

BACKGROUND: Second-line chemotherapy for patients with nonsmall cell lung carcinoma has been ineffective due to the lack of activity of older agents following platinum-based therapy. This Phase II trial evaluated the feasibility, toxicity, and efficacy of two active new agents, gemcitabine and vinorelbine, used in combination as second-line therapy for patients with nonsmall cell lung carcinoma. METHODS: Patients with advanced nonsmall cell lung carcinoma who had progressive disease after previous chemotherapy or combined-modality therapy were eligible for this trial. All patients received vinorelbine 20 mg/m(2) followed by gemcitabine 1000 mg/m(2) on Days 1, 8, and 15 of each 28-day cycle. Patients were reevaluated for a response after two treatment courses: responding patients and those with stable disease received a maximum of six courses. Fifty-five patients were treated between January 1998 and November 1998; 47 patients (85%) had previously received both a taxane and a platinum agent. RESULTS: Objective responses were seen in 9 of 50 evaluable patients (18%), including 8 partial responses and 1 complete response. Twenty-four additional patients (48%) had either minor response or stable disease. The median time to progression for patients with objective response or stable disease was 5 months. The median survival was 6.5 months with an actuarial 1-year survival of 20%. The treatment was well tolerated with uncommon nonhematologic toxicity and no alopecia. Grade 3 neutropenia and thrombocytopenia occurred in 27% and 22% of patients, respectively, but Grade 4 neutropenia was uncommon (occurring in 9% of patients) and only 4 patients required hospitalization for treatment of neutropenia and fever. CONCLUSIONS: The combination of vinorelbine and gemcitabine is active and well tolerated as second-line therapy for patients with advanced nonsmall cell lung carcinoma. This regimen merits further evaluation as a first-line therapy for patients with this disease.

Carcinoma of unknown primary site.

BACKGROUND: The long term survival and toxicity associated with the chemotherapy combination of paclitaxel, carboplatin, and extended-schedule etoposide used for the treatment of patients with metastatic carcinoma of unknown primary site were evaluated. METHODS: Seventy-one patients were treated between March 1995 and November 1996 with paclitaxel, carboplatin, and oral etoposide every 21 days. Stable or responding patients received four to eight courses of therapy. The following histologies were represented: well differentiated adenocarcinoma (34 patients); poorly differentiated adenocarcinoma or poorly differentiated carcinoma (30 patients); poorly differentiated neuroendocrine carcinoma (6 patients); and squamous cell carcinoma (1 patient). RESULTS: Forty-eight percent of assessable patients had major responses to therapy (95% confidence interval, 39%-55%), and 10 patients (15%) had complete responses. There were no response differences among the major histologic types. The median survival for all 71 patients was 11 months, and the 1-year, 2-year, and 3-year survival rates were 48%, 20%, and 14%, respectively. The minimum follow-up period was 34 months (range, 34-50 mos). The regimen was tolerated well with no treatment-related deaths and only 12 hospitalizations for neutropenia and fever. There was no serious long term toxicity. CONCLUSIONS: In this large Phase II trial, the combination of paclitaxel, carboplatin, and oral etoposide produced major responses or stable disease status in nearly 80% of patients who had carcinoma of unknown primary site. The median survival and 1-year, 2-year, and 3-year survival rates were noteworthy. The current study obtained similar or superior results to those seen with chemotherapy for many other groups of patients, such as those who had well defined advanced malignancies, those who were considered to have responsive tumors, and those who had obtained substantial benefits from cytotoxic therapy. Although the regimen reported in the current study can become an attractive option for many patients with carcinoma of unknown primary site, there remains a need for further clinical trials.

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 docetaxel administered by weekly infusion in patients with advanced refractory cancer.

PURPOSE: Docetaxel is a highly active antineoplastic agent; however, grade IV leukopenia occurs in the large majority of patients treated with a dose of 100 mg/m2 every 3 weeks. Recent experience with weekly paclitaxel has demonstrated a bone marrow-sparing effect when a weekly administration schedule is used. We investigated a weekly schedule of docetaxel in an attempt to alter the toxicity profile and improve the therapeutic index. PATIENTS AND METHODS: Thirty-eight patients with advanced, refractory malignancy entered this phase I trial between October 1996 and June 1997. Docetaxel was administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Sequential cohorts of patients were treated at the following dose levels: 20, 25, 30, 36, 43, and 52 mg/m2. Patients were reevaluated after one course (8 weeks); patients with objective response or stable disease continued treatment for a maximum of four courses or until disease progression. RESULTS: Thirty-five patients completed at least one course of therapy. Myelosuppression was not a dose-limiting toxicity (DLT) at any of the doses tested. Only five episodes of grade III leukopenia occurred (14% of patients, 2% of doses), and no grade IV leukopenia was produced. No grade III or IV thrombocytopenia or anemia was observed. Grade III fatigue and asthenia were observed in all three patients treated at 52 mg/m2/wk and in two of 10 at 43 mg/m2/wk. Other grade III toxicity included acral erythema (n = 1), neuropathy (n = 1), peripheral edema (n = 1), and diarrhea (n = 1). The DLTs of this docetaxel schedule are fatigue and asthenia. Although the maximum-tolerated dose by definition of this study was 43 mg/m2/wk, we selected 36 mg/m2/wk for ongoing phase II studies. CONCLUSION: The toxicity profile of docetaxel is markedly altered when the drug is administered by a weekly schedule. Myelosuppression is mild and uncommon. Fatigue and asthenia are the DLTs; other nonhematologic toxicities, which included peripheral edema and neuropathy, are uncommon, and the arthralgia/myalgia syndrome was not observed. Weekly administration of docetaxel may provide a better tolerated, efficacious use of this drug; further investigation of weekly docetaxel as a single agent and in combination regimens is warranted.

Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.

PURPOSE: To evaluate the efficacy and toxicity of a novel chemotherapy combination that includes paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of patients with carcinoma of unknown primary tumor site. PATIENTS AND METHODS: Fifty-five patients with carcinoma of unknown primary tumor site were treated with the following regimen, administered every 21 days: paclitaxel 200 mg/m2 by 1-hour intravenous (I.V.) infusion on day 1, carboplatin at an estimated area under the concentration-time curve (AUC) of 6.0 on day 1, and etoposide 50 mg alternated with 100 mg orally on days 1 through 10. Responding patients received a total of four courses of treatment. The following histologies were included: adenocarcinoma, 30 patients; poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA), 21; poorly differentiated neuroendocrine carcinoma, three; and squamous carcinoma, one. RESULTS: Twenty-five of 53 assessable patients (47%; 95% confidence interval [CI], 33% to 61%) had major objective responses to treatment (seven complete responses). Response rates were similar in patients with adenocarcinoma versus PDC (45% and 48%, respectively). The actuarial median survival time for the entire group was 13.4 months. The regimen was well tolerated, with only seven hospitalizations for treatment of neutropenia and fever (4% of courses) and no treatment-related deaths. CONCLUSION: The combination of paclitaxel, carboplatin, and extended-schedule etoposide is highly active and well tolerated in patients with carcinoma of unknown primary tumor site. Response rates and survival in this multicenter community-based trial compare favorably with all previously studied empiric regimens. In addition, this regimen is substantially less toxic and easier to administer than the cisplatin-based regimens previously used in this setting. If this level of efficacy is confirmed, this treatment should be considered standard first-line therapy in patients with carcinoma of unknown primary tumor site.