Gemcitabine combined with epirubicin in the treatment of patients with locally advanced or metastatic breast cancer: a phase II study

This phase II study of gemcitabine and epirubicin evaluated the activity and toxicity in advanced breast cancer. Female patients with stage IIIB or IV breast cancer received gemcitabine 1000 mg/m2 and then epirubicin 15 mg/m2 on days 1, 8, and 15 of 28-day cycles. Thirty-five patients with stage IV disease, a median age of 59 years (range, 39-73), and a median Karnofsky performance status of 90 (range, 60-100) were enrolled. Fourteen (40.0%) patients received prior chemotherapy (12 adjuvant, 4 metastatic, 2 both). Of 35 evaluable patients, 10 had PR, for an overall RR of 28.6%, and 12 (34.3%) patients had SD. Median time to progression and overall survival were 5.8 months (95% CI, 3.4-9.5 months) and 17.1 months (95% CI, 11.2-19.9 months), respectively. WHO grade 3/4 neutropenia occurred in 51.5% of patients without febrile neutropenia, and grade 3 thrombocytopenia in 29.4% of patients without hemorrhage or platelet transfusions. The most common nonhematologic toxicities were grade 3 alopecia (38.2%) and nausea/vomiting (11.4%). There were no grade 4 nonhematologic toxicities. Gemcitabine plus epirubicin is active and well tolerated in patients with metastatic breast cancer. Future studies should continue to evaluate the impact of various schedules on outcome.     

Activity of single-agent gemcitabine as second-line treatment after previous chemotherapy or radiotherapy in advanced non-small-cell lung cancer

The aim of the study was to evaluate activity, toxicity and health-related quality of life (HRQL) with gemcitabine as second-line treatment after previous chemo- or radiotherapy in non-small-cell lung cancer (NSCLC). Patients with previously treated NSCLC were treated with gemcitabine (1000 mg/m(2)) on days 1, 8 and 15 in a 28-day cycle. Eighty patients were included; median age was 57 years (range 38-77). Prior treatment consisted of platinum-containing chemotherapy in 29 patients and high-dose thoracic radiotherapy in 51 patients. Median number of cycles was three (range 1-6). Granulocytopenia CTC grade 3 and 4 occurred in 9% and thrombocytopenia CTC grade 3 and 4 in 9% of cycles. Non-haematological toxicity was mild. Tumour response was achieved in 13% of the patients (95% CI 7-20), median survival time was 26 weeks and 1-year survival was 22%. Tumour response to second-line gemcitabine could not be predicted from response to first-line therapy, first-line treatment modality or treatment interval. In a subset of 35 patients HRQL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-LC13 questionnaires and showed improvement or control of symptoms and functioning in approximately 30% of patients. We conclude that gemcitabine in second-line treatment has modest anti-tumour activity, is well tolerated, and may control tumour-related symptoms and improve HRQL in a significant minority of patients.     

Phase II study of regimen of gemcitabine and cisplatin in advanced non-small cell lung cancer

BACKGROUND: Cisplatin-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC). Many novel drugs, including gemcitabine, navelbine, paclitaxel and docetaxel have been used in combination with cisplatin. Of these drugs, gemcitabine is reported to have a high response rate and acceptable toxicity. The aim of this study was to evaluate the efficacy and safety of the combination of gemcitabine and cisplatin. METHODS: Thirty-two patients with NSCLC, who met the selection criteria from June 1998 to January 1999, were enrolled. All of them were confirmed by histology and were in an advanced stage, i.e. stage IIIB with pleural effusion or stage IV. Cisplatin at a dose of 80 mg/m2 was given monthly on day 15, in combination with gemcitabine at a dose of 1000 mg/m2 administered on days 1, 8 and 15 of the 28-day cycle. RESULTS: Of the 32 assessable patients, two showed complete remission and 11 achieved partial remission. The overall response was 40.6% (95% CI, 24.8-56.4%). The median time to disease progression was 7.2 months (95% CI, 4.87-9.53 months). The major hematological toxicity was neutropenia. Seven patients (22.9%) developed grade 3 and 4 neutropenia, but none developed febrile neutropenia. One patient (3.1%) had grade 3 thrombocytopenia. One patient (3.1%) developed grade 3 anemia. Nausea and vomiting were seen in 12 patients (37.5%). CONCLUSIONS: The regimen of combined gemcitabine with cisplatin is safe and effective. With this combination, a lower dose of cisplatin seems to have an efficacy similar to that in previous reports.     

A phase 2 study of gemcitabine and epirubicin for the treatment of pleural mesothelioma: a North Central Cancer Treatment Study, N0021

BACKGROUND: The North Central Cancer Treatment Group (NCCTG) conducted a phase 2 study to evaluate the antitumor activity of the combination of gemcitabine and epirubicin in patients with pleural mesothelioma who received no more than 1 prior chemotherapy regimen. METHODS: A total of 23 patients were accrued between August 2001 and April 2002 and received gemcitabine at a dose of 1000 mg/m(2) intravenously over 30 minutes weekly every 2 weeks and epirubicin at a dose of 90 mg/m(2) intravenously on Day 1 on an every-21-days cycle (high-dose patient group). Between August 2002 and April 2004, an additional 45 patients were treated at a reduced dose of gemcitabine of 750 mg/m(2) and epirubicin at a dose of 70 mg/m(2) with the same schedule (low-dose patient group). RESULTS: In the high-dose patient group, the confirmed response rate was 13% (95% confidence interval [95% CI], 3-34%). The median survival was 9.3 months (95% CI, 7.4-10.7 months) and the median time to disease progression was 6.3 months (95% CI, 3.0-7.6 months). In the low-dose patient group, the confirmed response rate was 7% (95% CI, 0-28%). The median survival was 5.7 months (95% CI, 4.7-8.7 months) and the median time to disease progression was 4.2 months (95% CI, 2.7-5.6 months). Toxicity was moderate to severe. In the high-dose and low-dose groups, 87% and 60% of patients, respectively, experienced at least 1 adverse event of grade 4 or higher (according to National Cancer Institute Common Toxicity Criteria [version 2.0]). The quality of life remained similar from baseline to the end of the 2 cycles of treatment in the high-dose group but worsened in the low-dose group. CONCLUSIONS: In the current study, the combination regimen of gemcitabine and epirubicin was found to demonstrate minimal antitumor activity against pleural mesothelioma.     

A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma.

BACKGROUND: The purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated. PATIENTS AND METHODS: Patients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m(2) i.v., 3-weekly), cisplatin (60 mg/m(2) i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m(2) bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1. RESULTS: Thirty-two patients, median age 63 years (range 32-76 years), ECOG performance status < or =2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m(2) bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses [24% response rate [95% confidence interval (CI) 10% to 44%]], a median PFS of 22 weeks (95% CI 17-27 weeks) and median overall survival of 34 weeks (95% CI 19-49 weeks). Capecitabine was rapidly absorbed after oral administration, with a t(max) of 1-2 h for capecitabine, DFCR (5'-deoxy-5-fluorocytidine) and DFUR (5'-deoxy-5-fluorouridine). The C(max) and AUC(0-)( infinity ) for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food. CONCLUSION: A dose of 1000 mg/m(2) bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.     

Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as first-line chemotherapy in metastatic breast cancer

In this phase II, multicentre trial, patients with metastatic breast cancer (MBC) were treated with a combination of gemcitabine, epirubicin and paclitaxel (GET). The primary objective of this study was to determine the tolerability and activity in terms of complete responce (CR) and overall response rate of the GET combination in this patient population. Patients with no prior treatment for MBC, and at least one bidimensionally measurable lesion received gemcitabine 1000 mg m(-2) intravenously (i.v.) over 30 min on days 1 and 4, followed by epirubicin i.v. at 90 mg m(-2) on day 1, and paclitaxel 175 mg m(-2) over 3 h on day 1, every 21 days, up to eight courses. From May 1999 to June 2000, 48 patients were enrolled from seven Italian institutions. A total of 297 chemotherapy courses were administered with a median of six cycles patient(-1) (range 1-8). Seven patients (15%) obtained CR and 27 patients (56%) had partial responce, for an overall response rate of 71% (95% CI: 58.3-83.7). After a median follow-up of 23.7 months (range 7.0-34.4), median progression-free survival was 10.5 months (95% CI: 9.2-11.7), and median overall survival 25.9 months. The main haematological toxicity consisted of grade 3 or 4 neutropenia that occurred in 62% of cycles (22% grade 4 and 40% grade 3). The GET combination is active and well tolerated as first-line chemotherapy for MBC.     

Phase I dose escalation study of gemcitabine and paclitaxel plus colony-stimulating factors in previously treated patients with advanced breast and ovarian cancer

Gemcitabine and paclitaxel (PTX) are among the most active new drugs in advanced breast and ovarian cancer. In this Phase I study, we used fixed doses of gemcitabine administered on days 1 and 8 and escalating doses of paclitaxel on day 1 of a 21-day cycle in patients with pretreated metastatic breast or ovarian cancer. The dose of gemcitabine was fixed at 1,000 mg/m2; PTX was commenced in the first small patient group at a dose of 90 mg/m2, which was then escalated in subsequent groups by 30 mg/m2 per step. From the third dose level onwards, all patients received granulocyte colony-stimulating factor 300 microg by subcutaneous injection on days 5 and 6, and granulocyte macrophage colony-stimulating factor on days 15-18. Cohorts of at least 3 patients were treated at each dose level. Dose escalation was stopped if at least a third of the patients in a given cohort had dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia, or grade 3-4 non-haematological toxicity. The maximum tolerated dose (MTD) was defined as the dose level immediately below that causing DLT in one-third of the patients or more. Evaluation of the tumour response was performed every three cycles. Forty-five patients (31 with breast cancer, 14 with ovarian cancer) were treated at seven different dose levels. Only at the seventh PTX dose level was DLT observed after the first course of therapy: three grade 4 neutropenia, one grade 4 thrombocytopenia, and one grade 4 anaemia. DLT occurred in 5/6 patients at at PTX dose of 270 mg/m2; therefore dose escalation was stopped at that level and the dose immediately before it (PTX 240 mg/m2) was considered as the MTD and recommended for further studies. No toxic deaths occurred. Grade 3-4 uncomplicated neutropenia was observed in four patients. Three had uncomplicated grade 3-4 thrombocytopenia. One patient had grade 3 and one grade 4 anaemia. Nonhaematological side effects were generally mild. Among 30 evaluable patients with metastatic breast cancer, four complete responses (CR) (13%) and 12 partial responses (PR) (40%) were observed, for an overall response rate of 53% (95% confidence interval (CI) 34-72). The median duration of response was 31 weeks. Among 13 evaluable patients with advanced ovarian cancer, one CR (8%) and five PRs (38%) were observed, for an overall response rate of 46% (95% CI 19-78). The median duration of response was 32 weeks. Our study shows that gemcitabine and PTX can be administered in combination in patients with breast and ovarian cancer without unexpected toxicities and with encouraging therapeutic results.     

A Phase II Trial of Neoadjuvant Gemcitabine,Epirubicin, and Docetaxel as Primary Treatment of Patients With Locally Advanced or Inflammatory Breast Cancer

BackgroundThree-drug regimens containing gemcitabine, an anthracycline, and a taxane produce response rates of 70%-90% in patients with metastatic breast cancer (MBC) although accompanied by considerable hematologic toxicity. We explored the combination of gemcitabine/epirubicin/docetaxel as neoadjuvant therapy. Docetaxel was administered weekly to decrease myelosuppression.Patients and MethodsA total of 110 patients with locally advanced or inflammatory breast cancer received neoadjuvant gemcitabine 800 mg/m² intravenously (I.V.) days 1 and 8, epirubicin 75 mg/m² I.V. day 1, and docetaxel 30 mg/m² I.V. days 1 and 8, repeated every 21 days for 4 cycles. Then patients had either mastectomy or breast conservation surgery, and pathologic treatment responses were assessed. After surgery, 4 cycles of adjuvant gemcitabine 1000 mg/m² I.V. days 1 and 8 and docetaxel 35 mg/m² I.V. days 1 and 8 were administered at 21-day intervals. After patients completed chemotherapy, locoregional radiation therapy and/or anti-estrogen therapy was administered per standard guidelines.ResultsTreatment with 4 cycles of neoadjuvant gemcitabine, epirubicin, and weekly docetaxel resulted in an objective response in 79 of 110 patients enrolled (72%; 95% CI, 63-80%). Twenty of 103 patients (19%) who had surgery had pathologic complete response (pCR). Moderate hematologic toxicity was evident during neoadjuvant therapy, with grade 3/4 neutropenia in 41% and febrile neutropenia in 11% of the patients. Protocol-specified dose modifications were required in 35% of the patients, and 58% of the patients used myeloid growth factors.ConclusionThe pCR rate of 19% achieved with gemcitabine, epirubicin, and weekly docetaxel confirms previous reports with similar 3-drug regimens. The use of a weekly schedule of docetaxel did not appear to reduce the incidence of grade 3/4 hematologic toxicity.     

A phase II study of days 1 and 8 combination of docetaxel plus gemcitabine for the second-line treatment of patients with advanced non-small-cell lung cancer and good performance status

OBJECTIVE: We conducted a phase II trial to evaluate the efficacy and toxicity of a combination consisting of second-line docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Eligibility criteria: histologically confirmed advanced NSCLC with progressive disease to platinum-based chemotherapy, ECOG performance status (PS) 0 or 1, and adequate kidney, liver and bone marrow function. Treatment consisted of docetaxel 36 mg/m(2) i.v. over 60 min followed by gemcitabine 1000 mg/m(2) i.v. over 30 min on days 1 and 8 of each 3-week cycle for a planned six cycles or unacceptable toxicity. RESULTS: Of the 52 patients enrolled, 50 were evaluable for response and toxicity. The mean age was 59 years (range 42-79), 46 male and 4 female. Histology subtypes were: adenocarcinoma 26 patients, bronchioloalveolar 1 patient, large cell carcinoma 5 patients, and squamous cell carcinoma 18 patients. Thirty-eight patients had ECOG PS 1 and 12 patients had PS 0. The median number of cycles administered was four (range 2-6). The overall response rate was 28%. The median follow-up was 9 months (range 5-34 months). The median survival time (MST) was 8.2 months (95% CI, 4-12%), and the 1-year survival was 25%. The median progression-free survival was 4.4 months (95% CI, 2-6%). In the Cox regression model, survival was only significantly affected by the PS. The median survival in patients with PS 0 was 17.8 months (95% CI, 18.8-21.8%) compared with a median survival for patients with PS 1 of 6.1 months (95% CI, 4.1-8.2%) (P=0.0057). Toxicity: three patients had grade 3 anemia, three patients had grade 3 thrombocytopenia, four patients had grade 3 neutropenia and only one patient developed grade 4 febrile neutropenia. Non-hematologic toxicity was also mild; the most frequent was asthenia, with grade 3 in eight patients (16%), and one patient with grade 4. CONCLUSION: This regimen of docetaxel in combination with gemcitabine in advanced second-line NSCLC is an active and safe regimen.     

Weekly docetaxel and gemcitabine as first-line treatment for metastatic breast cancer: results of a multicenter phase II study

OBJECTIVES: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. METHODS: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m2 and gemcitabine 800 mg/m2 i.v. on days 1, 8, 15 every 28 days. RESULTS: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53-28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71-16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3-4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. CONCLUSION: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study.     

Gemcitabine in locally advanced and metastatic non-small cell lung cancer: the Central European phase II study

The efficacy and toxicity profile of gemcitabine was evaluated in this phase II study of chemonaive patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). Eighty patients (62 males, 18 females) were entered into this study. The disease stage was IIIA in ten patients, IIIB in 32, and IV in 38 patients. The median age was 61 (range 41 - 78). Karnofsky performance status was > or = 80 in 88% of patients. All patients were chemonaive, but five patients had received prior radiotherapy and 34 patients had undergone prior surgery. Gemcitabine 1250 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Patients received up to nine cycles (median three cycles). Of 872 doses 815 (93%) were administered without dose delay or modification. Of the 80 patients enrolled, 76 were evaluable for efficacy analysis, and 16 patients had a partial response for an overall response rate of 21.1% (95% CI, 11.9-30.3%). A further 47 patients (61.8%) had stable disease. Partial responses were seen in eight of 41 stage III patients (19.5%) and in eight of 35 stage IV patients (22.9%). The median time to progressive disease was 4.6 months. Median survival for all 80 patients was 7.1 months. Haematological toxicity was mild with grade 3 4 neutropenia in 6.3% of patients, grade 3 thrombocytopenia in 3.8% of patients, and grade 3 anaemia in 2.5% of patients. Grade 3 non-laboratory toxicity was: somnolence (1.3% of patients), infection (1.3%), nausea and vomiting (6.4%) and dyspnoea (5.1%). This study confirms that single-agent gemcitabine is active in advanced NSCLC and its well-tolerated safety profile makes it particularly suited to outpatient use.     

Alternating weekly administration of paclitaxel and gemcitabine: a phase II study in patients with advanced non-small-cell lung cancer

Background We sought to evaluate toxicity and efficacy of an alternating week schedule of paclitaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC).Methods Patients (n=27, mean age 56 years, range 27–73 years) received paclitaxel (100 mg/m² i.v. infusion over 1 h) on days 1 and 15 alternating with gemcitabine (1000 mg/m²) on days 8 and 22 of a 36-day cycle. Responses were evaluated after three cycles, and after the proposed six cycles.Results In total, 116 cycles were administered (mean 4.25 cycles per patient). Haematological toxicity was slight: febrile neutropenia (n=1) and neutropenia grade III–IV (n=5). Non-haematological toxicities included arthromyalgia grade II (n=6) and neurotoxicity grade III (n=1). Objective response was 29%, stable disease 25% and disease progression 46%. Median duration of response was 8 months (95% CI 5–11 months), median progression-free survival was 7 months (95% CI 4–11 months), median overall survival was 13 months (95% CI 7–17 months) and survival at 1 year was 52%.Conclusions A regimen of alternating weekly paclitaxel and gemcitabine is feasible in patients with advanced NSCLC, showing a lower toxicity profile compared with other platinum-based combinations, which makes this novel scheme attractive for these patients.     

A phase II trial of a combination of pemetrexed and gemcitabine in patients with metastatic breast cancer: an NCCTG study.

PURPOSE: This phase II study was undertaken to define the efficacy and toxicity of pemetrexed in combination with gemcitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer who had previously received an anthracycline and a taxane in either the adjuvant or metastatic setting were treated with gemcitabine 1250 mg/m2 (intravenous; days 1 and 8) and pemetrexed 500 mg/m2 (intravenous; day 8) every 21 days. RESULTS: Fifty-nine patients received a median of five cycles (range one to 22) of treatment and were followed until death or for a median of 28 months (range 19.4-36.6) among living patients. Fourteen partial responses for an overall response rate of 24% [95% confidence interval (CI) 16% to 39%] were documented. Nine (15%; CI 5% to 32%) patients had stable disease for >6 months. The median survival time was 10.3 months (95% CI 8.3-18.9) and the 1 year survival rate was 49% (95% CI 38% to 64%). The median time to progression was estimated to be 3.7 months (95% CI 2.3-5.3). The most common grade 3 or 4 toxicities were neutropenia and thrombocytopenia in 83% and 27% of patients, respectively. Fourteen percent of patients experienced febrile neutropenia. Other common grade 3 or 4 non-hematological toxicities included fatigue (17%), dyspnea (15%), rash (7%) and anorexia (5%). CONCLUSIONS: The combination of pemetrexed and gemcitabine is clinically active, with an overall response rate of 24% in patients with metastatic breast cancer who have previously been treated with an anthracycline and a taxane. Myelosuppression (66% grade 4 neutropenia and 14% febrile neutropenia) was the major treatment-related toxicity observed for this combination.     

Decreased myelotoxicity of gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC) with cisplatin infusion on day 15

In a multicenter phase II Italian trial that used a 28-day dosing schedule of gemcitabine on days 1, 8, and 15 and cisplatin on day 2, thrombocytopenia and neutropenia were the main dose-limiting toxicities observed. The aim of the present study was to determine whether using 15-day cisplatin in lieu of the standard 2-day schedule in combination with weekly gemcitabine would decrease expected myelotoxicities, particularly thrombocytopenia. Fifty-one patients with advanced non-small cell lung cancer (NSCLC), a median age of 62 years (range 31-76) and baseline Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1, were enrolled. Twenty-four patients had stage IIIA-B disease and 27 had stage IV. Patients received gemcitabine 1000 mg/m(2) on days 1, 8, 15, and cisplatin 100 mg/m(2) on day-15, every 28 days for a total of 151 cycles. All patients were evaluable for toxicity. Grades 3 and 4 thrombocytopenia was observed in 16% of patients, grades 3 and 4 neutropenia in 35% of patients, and grade 3 anemia in 4% of patients (no grade 4 anemia). Nonhematologic toxicity was mild. Two patients had grade 3 vomiting, and another had grade 4 hepatic toxicity only after gemcitabine administration. The dose intensity of gemcitabine and cisplatin was well maintained. Of the 45 patients evaluable for response, there were 22 (49%) partial responders, 7 (15.5%) minimal responders, 9 (20%) with stable disease, and 7 (15.5%) progressions. Compared with the schedule used in a multicenter phase II Italian trial (day 2 cisplatin), day-15 cisplatin decreases incidences of thrombocytopenia (16 vs. 52%) and anemia (4 vs. 25%); the occurrence of neutropenia is similar (35 vs. 36%). Response rates are also similar (49 vs. 54%).     

Phase II trial of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site

BACKGROUND: The purposes of this study were to evaluate efficacy and toxicity of the combination of carboplatin, gemcitabine, and capecitabine in patients with carcinoma of unknown primary site (CUP). METHODS: Patients with CUP received carboplatin AUC 5 mg/mL a minute intravenously Day 1, gemcitabine 1000 mg/m(2) intravenously Days 1 and 8, and capecitabine 1600 mg/m(2) orally in divided doses, Days 1-14 of a 21-day cycle for up to 8 cycles. The primary endpoint of the study was objective response rate by intent-to-treat analysis. RESULTS: Thirty-three patients were treated (median age, 58 years; men:women ratio, 19:14). Most patients had a baseline performance status of 1. The objective response rate was 39.4% (95% CI, 22.9%-57.9%) in all patients, 36.4% in 22 patients with well to moderately differentiated adenocarcinoma, and 40.0% in 20 patients with liver metastases. Median progression-free survival time was 6.2 months (95% CI, 5.4%-8.0%), and median survival time was 7.6 months (95% CI, 6.3-14.1). One and 2-year survival rates were 35.6% and 14.2%, respectively. The most frequent grade > or =3 adverse events were neutropenia (67%), thrombocytopenia (48%), and anemia (33%). CONCLUSIONS: The combination of carboplatin, gemcitabine, and capecitabine is active in CUP, especially in patients with liver metastases. This regimen may be a potential therapy for CUP patients with good performance status, particularly those with a suspected origin below the diaphragm.     

A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium.

BACKGROUND: Both pemetrexed and gemcitabine have single-agent activity in bladder cancer, but the combination of these two drugs has not been previously evaluated for safety and efficacy in this disease. Thus, the objectives in the current study were to determine overall response rate (ORR), progression-free survival, overall survival and safety and toxicity in chemonaive patients with locally advanced and/or metastatic transitional cell carcinoma of the urothelium. PATIENTS AND METHODS: Gemcitabine 1250 mg/m2 was administered over 30 min i.v. on days 1 and 8, and pemetrexed 500 mg/m2 over 10 min i.v. on day 8 after gemcitabine, every 21 days. RESULTS: Sixty-four patients were enrolled, 11 female and 53 male, median age 65 years (range 38-81), median WHO performance status of 1. Visceral metastases were present in 55% of patients. ORR among 47 patients evaluable for response was 28% (95% CI 16% to 43%) and ORR for the intention-to-treat population was 20% (95% CI 11% to 32%) with three CR and 10 PR. Median response duration was 11.2 months and median overall survival 10.3 months (95% CI 8.1-14.6 months). CTC grade 3/4 hematologic toxicities included anemia (19%), thrombocytopenia (9%), neutropenia (38%), febrile neutropenia (17%) and neutropenic sepsis (3%). Grade 3/4 non-hematologic toxicities included elevated transaminases (12%), dyspnea (8%), fatigue (8%) and stomatitis (5%). There was one toxic death due to neutropenic sepsis. CONCLUSIONS: The combination of pemetrexed and gemcitabine had a manageable safety profile. However, efficacy was apparently not superior to that of single-agent gemcitabine.     

Phase II trial assessing the combination of gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC)

BACKGROUND: There is need for more active and better tolerated combinations in non-small cell lung cancer (NSCLC). The Spanish Lung Cancer Group (SLCG) therefore conducted this phase II study to define the efficacy and toxicity profile of the combination of higher doses than usual of gemcitabine along with cisplatin in patients with advanced NSCLC. PATIENTS AND METHODS: Forty patients with pathologically documented advanced NSCLC were included in this trial (34 men, six women; aged 34-74 years; mean 64 years). Twenty-two patients had unresectable stage IIIB disease and 18 had stage IV disease. Karnofsky performance status was > or =70%. In five patients, surgery had previously been performed and four patients had received radiotherapy. Gemcitabine at a dose of 1200 mg/m2 was administered weekly (days 1, 8 and 15) and cisplatin 100 mg/m2 on day 15 of each 28-day cycle. RESULTS: Responses were scored according to standard World Health Organization criteria. Of 40 assessable patients, 19 had a partial response for an overall response rate of 47.5% (95% confidence interval (CI) 32-64%). To date, median survival for the whole group is 10.4 months (95% CI 6.2-11.7 months), with a 1-year survival rate of 35%. Toxicity was mainly haematological. Seven patients (18%) had grade 4 neutropenia (one episode of febrile neutropenia). Thrombocytopenia (12.8% grade 3 and 2.6% grade 4) was not associated with clinical bleeding. One patient had a grade 4 transient rise in transaminase. There was no grade 3 or 4 renal toxicity. There was no grade 4 symptomatic toxicity. The most common grade 3 toxicities were nausea and vomiting (28.2%) and alopecia (10.3%) both related to cisplatin. CONCLUSIONS: Gemcitabine can be safely administered at a dose of 1200 mg/m2 in combination with cisplatin. Thrombocytopenia seems to be less than in schedules with cisplatin given on day 1. The results of this studyshow promising activity (47.5% response rate) with modest toxicity. As this combination of gemcitabine and cisplatin deserves further evaluation in prospective randomized trials, the SLCG is comparing gemcitabine-cisplatin with etoposide-cisplatin in a phase III randomized study.     

Unfavorable therapeutic index of cisplatin/gemcitabine/vinorelbine in advanced non-small-cell lung cancer

In view of favorable reports with the 3-drug combination of PGV (cisplatin/gemcitabine/vinorelbine), this multicenter phase II study evaluated the therapeutic index of PGV in patients with advanced non-small-cell lung cancer (NSCLC). Thirty-two patients with stage IV NSCLC and 1 with stage IIIB were studied. There were 23 men and 10 women, with a median age of 63 years (range, 38-80 years). Twelve patients had a performance status (PS) of 0, and 21 patients had a PS of 1. Treatment consisted of cisplatin 50 mg/m2, gemcitabine 1000 mg/m2, and vinorelbine 25 mg/m2 all given intravenously on days 1 and 8, in 21-day cycles. Fifteen patients (45%; 95% confidence interval (CI), 28%-64%) achieved a partial response. Median response duration was 3 months (range, 1-9 months). The median and 1-year survival rates were 9.4 months and 39% (95% CI, 23%-58%), respectively. The median number of cycles was 4. Only 3 patients (9%) completed treatment without regimen modifications. Median dose intensity (% planned) was cisplatin 24 mg/m2/week (72%), gemcitabine 483 mg/m2/week (72%), and vinorelbine 12 mg/m2/week (72%). Toxicities were predominantly hematologic, with grade 3/4 neutropenia (67%), febrile neutropenia (21%), and thrombocytopenia (67%). There were 3 (9%) treatment-related deaths due to neutropenic complications. This study confirms the substantial antineoplastic activity of PGV. We observed a high rate of severe hematologic toxicity, especially febrile neutropenia, despite a lower delivered dose intensity of PGV. Given these results, PGV appears to offer no therapeutic advantage to current doublet regimens.     

Activity of gemcitabine and carboplatin in advanced non-small cell lung cancer: a phase II trial

This phase II trial was designed to investigate the efficacy and tolerability of gemcitabine combined with carboplatin in patients with advanced or metastatic NSCLC. Patients were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle and carboplatin AUC 5 mg/ml/min on day 2 of each cycle. Fifty patients (Zubrod-ECOG-WHO performance status 0/1 in 70/30%, stage IV disease in 64%) entered the study and were evaluable for response and toxicity. There was 1 complete response and 24 partial responses among 50 evaluable patients, for a response rate of 50% (95% CI: 36.0-64.1%). The median survival time was 13 months (range: 6-22 months), and the 1-year survival rate was 54%. Hematologic toxicities included grades 3 and 4 neutropenia in 24 and 8% of patients, respectively, and grades 3 and 4 thrombocytopenia in 48 and 8% of patients, respectively. These were without clinical sequelae. Seven (14%) patients had grade 3 nausea and vomiting. The combination of gemcitabine and carboplatin is highly active and well tolerated in patients with advanced or metastatic NSCLC.     

First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study.

BACKGROUND: This randomized, phase III study compared the efficacy and safety of first-line gemcitabine versus epirubicin in the treatment of postmenopausal women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients aged > or = 60 years (median 68 years) with clinically measurable MBC received either gemcitabine 1200 mg/m(2) or epirubicin 35 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. RESULTS: Of 410 patients entered, 397 (198 gemcitabine and 199 epirubicin) were randomized and qualified for the time to progressive disease (TTP) and survival analyses. Total cycles administered in 185 gemcitabine and 192 epirubicin patients, respectively, were 699 (mean 3.5, range 0-12) and 917 (mean 4.6, range 0-10). Epirubicin demonstrated statistically significant superiority in TTP (6.1 and 3.4 months, P=0.0001), overall survival (19.1 and 11.8 months, P=0.0004), and independently assessed response rate (40.3% and 16.4% in 186 and 183 evaluable patients, P <0.001). For gemcitabine (n=190) and epirubicin (n=192), respectively, common WHO grade 3/4 toxicities were neutropenia (25.3% and 17.9%) and leukopenia (14.3% and 19.3%). Of the 28 on-study deaths (17 gemcitabine, 11 epirubicin), three were considered possibly or probably related to treatment (gemcitabine). CONCLUSIONS: Postmenopausal women > or =60 years of age with MBC tolerate chemotherapy well. In this study, epirubicin was superior to gemcitabine in the treatment of MBC in women age > or =60, confirming that anthracyclines remain important drugs for first-line treatment of MBC.