A pilot phase II trial of valspodar modulation of multidrug resistance to paclitaxel in the treatment of metastatic carcinoma of the breast (E1195): a trial of the Eastern Cooperative Oncology Group

Background: To assess the activity and toxicity of valspodar (PSC-833) in combination with paclitaxel in women with anthracycline refractory, metastatic breast cancer. Patients and Methods: Limited, multi-institutional, Phase II trial of valspodar at 5 mg/kg/dose orally every 6 hours for 12 doses in combination with paclitaxel 70 mg/m² administered intravenously as a 3-hour infusion beginning 4 hours after the fifth dose of valspodar, every 3 weeks. Eligible patients had bi-dimensionally measurable metastatic carcinoma of the breast, prior anthracycline therapy or a medical contraindication to anthracycline therapy, no more than one prior chemotherapy for recurrent or metastatic breast cancer, and adequate organ function. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-four patients are evaluable for response and 37 for toxicity. Two (6 percent) patients achieved a complete response and 5 (15 percent) a partial response for an objective response rate of 21 percent (95 percent confidence interval of 9 to 38 percent). Median duration of response was 9.7 months (95 percent confidence interval 8.0-17.2 months), median time to progression was 3.3 months (95 percent confidence interval 2.0-4.2 months), and median survival was 12 months (95 percent confidence interval 8.1-17.3 months). The toxicity experienced was acceptable. Conclusions: Combination valspodar plus paclitaxel is an active regimen and has acceptable toxicity. The combination is not clearly more active than single agent paclitaxel.     

Phase I trial of fixed dose rate infusion gemcitabine with gefitinib in patients with pancreatic carcinoma

Purpose: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of gemcitabine using a fixed dose rate infusion (FDRI) in combination with gefitinib in patients (pts) with pancreatic adenocarcinoma (PCa). Patients and methods: Patients with advanced PCa were given gemcitabine at the FDRI of 10 mg/m²/min IV on Days 1, 8, and 15 of a 28-day cycle. Dose levels of 1000, 1200, and 1500 mg/m² were evaluated. Oral gefitinib 250 mg was given daily. DLTs were defined as 2 instances of Grade 3 hematologic or 4 nonhematologic or any Grade 4 hematologic toxicity. At least 4 patients were treated at each dose level. Dose escalation occurred in the absence of DLTs. Results: Five women and 8 men were enrolled. Median age was 59 and performance status 1. All had metastatic disease. Four patients received prior adjuvant chemoradiation for PCa, and one chemotherapy for lung cancer. Median cycles were 4 per patient. The MTD was 1,200 mg/m². Toxicity was predominantly hematologic. At 1,500 mg/m², 1 patient had Grade 4 granulocytopenia and 3 patients Grade 3 granulocytopenia. Overall, 8 patients (60 percent) developed Grade 1 or 2 acneiform rashes. One patient had Grade 3 vomiting; no significant diarrhea or liver toxicity was seen. There were no objective responses seen. Median time to progression and overall survival were 4.57 months and 7.13 months, respectively. Conclusion: Combining FDRI gemcitabine with gefitinib is feasible and tolerable. The recommended dose of gemcitabine is 1,200 mg/m² when used with gefitinib 250 mg daily.     

A phase II study of gemcitabine plus paclitaxel in patients with metastatic breast cancer and prior anthracycline treatment

Aim: To investigate the efficacy and safety of gemcitabine‐paclitaxel in Chinese patients with metastatic breast cancer following anthracycline failure in a multicenter, open‐label, single‐arm, phase II clinical trial. Methods: Chinese female patients with unresectable, locally recurrent or metastatic breast cancer who had relapsed after neo‐adjuvant anthracycline‐based chemotherapy were included. All patients had measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 at baseline. Gemcitabine (1250 mg/m²)‐paclitaxel (175 mg/m²) was administered on a 3‐weekly schedule until disease progression, and patients were followed up for 12 months (post‐enrolment). The primary end point was objective response rate; secondary end points included duration of response, progression‐free survival and overall survival. Results: Overall 60 patients were enrolled. Their mean age was 46.9 (SD ± 9.0) years and 90% of patients had metastatic disease. All patients had previously received chemotherapy. A total of 48 patients (80%) completed the 12‐month follow up, and 40 patients (67%) completed at least six cycles of study therapy. The objective response rate (complete response + partial response) was 50% (95% CI: 36.6–63.4). Median duration of response was 5.6 months (95% CI: 4.4–7.6) and median progression‐free survival was 7.6 months (95% CI: 5.8–8.8). Overall survival at 12 months was 87% (95% CI: 77.9–95.2). Laboratory toxicities were primarily hematologic, including Grade 3 and 4 neutropenia (n = 27 [45%]) and leukopenia (n = 18 [30%]). Eight patient deaths (13%) were not treatment‐related. Conclusion: Gemcitabine‐paclitaxel combination therapy is an active and well‐tolerated chemotherapy regimen, with expected and manageable toxicity in Chinese patients with metastatic breast cancer.     

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.     

Phase I trial of gemcitabine and paclitaxel in advanced solid tumors

Purpose. Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen. Patients and Methods. Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m² while paclitaxel was administered at an initial dose of 60 mg/m², then escalated by 15 mg/m² increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m². Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed. Results. All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m²/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease. Conclusion. This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m² and paclitaxel 150 mg/m² on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.     

Phase I clinical trial of topotecan and pegylated liposomal doxorubicin

Background: The objective of this study was to determine the feasibility and maximum tolerated dose (MTD) of combination topotecan and pegylated liposomal doxorubicin (PLD) administered in 4- or 3-week cycles in patients with advanced or refractory solid tumors. Patients and Methods: Patients were treated with intravenous topotecan (0.75-1.25 mg/m²) for 3 days followed by PLD (25-40 mg/m²) on Day 4. The following dose combinations (topotecan/PLD, mg/m²) were explored: 0.75/40, 1.0/40, and 1.25/40 every 28 days; and 1.0/25 and 1.0/30 every 21 days. Results: Thirty-two patients were enrolled, and all had received prior chemotherapy. Most (84 percent) patients had ovarian cancer. A total of 157 cycles (median, 4 cycles; range, 1-19 cycles) of chemotherapy were administered. Dose-limiting toxicities were Grade 4 neutropenia and death at dose level 3 (1.25/40 mg/m² every 28 days), and neutropenic fever, Grade 3 stomatitis, and Grade 3 peripheral neuropathy (all in one patient) at dose level 5 (1/30 mg/m² every 21 days). Myelosuppression was the most common serious toxicity. Twenty-six patients were evaluable for response and 7 (27 percent) had partial responses. All responses were seen in patients with ovarian cancer. Conclusions: This combination is feasible and well tolerated; encouraging activity was observed in heavily pretreated patients with ovarian cancer. The recommended regimens for a Phase II study are topotecan 1.0 mg/m² on Days 1-3 followed by PLD 40 mg/m² on Day 4 of a 28-day cycle, and topotecan 1.0 mg/m² on Days 1-3 and PLD 30 mg/m² on Day 4 of a 21-day cycle.     

A Phase I dose-finding study using an innovative sequential biweekly schedule of irinotecan followed 24 hours later by capecitabine

Background: Irinotecan and capecitabine have a broad spectrum of activity in human malignancy and are synergistic in an animal model when irinotecan precedes capecitabine. Patients and Methods: A Phase I design of the combination of irinotecan IV Day 1 with capecitabine on Days 2-8 every 2 weeks was evaluated in 27 adult patients with solid tumors. Two sequential schema were used: Arm A fixed the dose of irinotecan at 100 mg/m² and escalated capecitabine in cohorts, and arm B fixed the dose of capecitabine at 750 mg/m² PO BID and escalated the dosage of irinotecan. Results: Neutropenia was dose limiting with nausea and diarrhea as the most common nonhematological toxicities. Significant interpatient variation in toxicity occurred despite uniform dosing. No Grade IV toxicities were encountered. Grade III toxicity occurred in first cycle in 15 percent (3/20) patients in arm A and 29 percent (2/7) of patients in arm B. All toxicities were reversible. Repetitive dosing was feasible with prolonged disease stabilization in 8 patients. Conclusions: The suggested Phase II dose of this combination and schedule is irinotecan 100 mg/m² and capecitabine 1000 mg/m² BID. Some patients tolerated a capecitabine dose as high as 1250 mg/m² BID.     

Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma

Purpose. To assess the efficacy and toxicity of combination therapy with gemcitabine and docetaxel in patients with unresectable pancreatic carcinoma. Patients and Methods. Thirty-four patients with unresectable stage III, IVA, and IVB pancreatic carcinoma were eligible for this study. The first 18 patients received gemcitabine 800 mg/m² intravenously (IV) on days 1, 8, and 15 and docetaxel 75 mg/m² IV on day 1, repeated every 28 days. Due to a high incidence of myelosuppression in this first group, the treatment schedule was modified in the remaining patients to gemcitabine 1,000 mg/m² IV and docetaxel 40 mg/m² IV on days 1 and 8 of a 21-day schedule. The primary study endpoints were objective response rate and duration of survival. Results. Ten of 33 evaluable patients achieved a partial response, for an overall response rate of 30.3% (95% CI, 16.21%-48.87%). Partial responses noted in the pancreas and a variety of metastatic sites were maintained for 4 to 12 months (median 6 months). Twelve additional patients (36%) experienced stable disease. The median time to progression was 6 months, and median survival was 10.5 months. The toxicity profile of the modified gemcitabine/docetaxel schedule was more favorable than that associated with the initial regimen, particularly with respect to hematologic toxicity. Conclusion. The response and survival data reported here for combination therapy with gemcitabine and docetaxel are encouraging given the poor prognosis associated with unresectable pancreatic cancer. These data suggest that gemcitabine plus docetaxel may be more effective than either agent alone in the treatment of pancreatic cancer and warrants further study.     

Chemotherapy with an every-2-week regimen of gemcitabine and paclitaxel in patients with transitional cell carcinoma who have received prior cisplatin-based therapy.

BACKGROUND: An every-2-week regimen of gemcitabine and paclitaxel was adapted for patients with advanced transitional cell carcinoma (TCC) who had received prior cisplatin-based chemotherapy. METHODS: Forty-one patients with advanced or metastatic TCC who had received prior cisplatin-based systemic chemotherapy were treated with an outpatient regimen of gemcitabine 2500-3000 mg/m(2) and paclitaxel 150 mg/m(2) every 2 weeks. RESULTS: Forty of 41 patients had measurable disease. Response was observed in 24 patients (60%; 95% confidence interval [CI], 45-75%). Eleven (28%) achieved complete response, and 13 (33%) obtained partial response. Twenty of 25 patients (80%; 95% CI, 64-96%) who had been previously treated in the neoadjuvant or adjuvant setting responded versus 4 of 15 (27%; 95% CI, 5-49%) in patients who received prior methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) for metastatic disease. The median duration of survival for patients given gemcitabine and paclitaxel after failing neoadjuvant or adjuvant M-VAC was 12 months (range, 2-43+), as compared with only 8 months (range, 2-28) for patients who had been treated after failure of prior therapy for metastatic disease. For all patients, the median duration of response was 6.4 months (range, 2-43.3+ months), and the median survival was 14.4 months (range, 2-43+). Thirteen patients (32%) developed World Health Organization Grade 3-4 neutropenia, with febrile neutropenia in 3 (7%) patients. Granulocyte colony-stimulating factor was given to 10 (24%) patients. There was no Grade 3-4 anemia or thrombocytopenia. CONCLUSIONS: The combination of gemcitabine and taxol in previously treated patients with recurrent TCC is highly effective and produces objective durable responses. This every-2-week schedule is a well tolerated outpatient regimen with minimal toxicity.     

Paclitaxel, cisplatin, and gemcitabine combination chemotherapy within a multidisciplinary therapeutic approach in metastatic nonsmall cell lung carcinoma

BACKGROUND: Cisplatin-based chemotherapy combinations improve quality of life and survival in advanced nonsmall cell lung carcinoma (NSCLC). The emergence of new active drugs might translate into more effective regimens for the treatment of this disease. METHODS: The objective of this study was to determine the feasibility, response rate, and toxicity of a paclitaxel, cisplatin, and gemcitabine combination to treat metastatic NSCLC. Thirty-five consecutive chemotherapy-naive patients with Stage IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0-2 were treated with a combination of paclitaxel (135 mg/m(2) given intravenously in 3 hours) on Day 1, cisplatin (120 mg/m(2) given intravenously in 6 hours) on Day 1, and gemcitabine (800 mg/m(2) given intravenously in 30 minutes) on Days 1 and 8, every 4 weeks. Although responding patients were scheduled to receive consolidation radiotherapy and 24 patients received preplanned second-line chemotherapy after disease progression, the response and toxicity rates reported refer only to the chemotherapy regimen given. RESULTS: All the patients were examined for toxicity; 34 were examinable for response. An objective response was observed in 73.5% of the patients (95% confidence interval [CI], 55.6-87.1%), including 4 complete responses (11.7%). According to intention-to-treat, the overall response rate was 71.4% (95% CI, 53. 7-85.4%). After 154 courses of therapy, the median dose intensity was 131 mg/m(2) for paclitaxel (97.3%), 117 mg/m(2) for cisplatin (97.3%), and 1378 mg/m(2) for gemcitabine (86.2%). World Health Organization Grade 3-4 neutropenia and thrombocytopenia occurred in 39.9% and 11.4% of patients, respectively. There was one treatment-related death. Nonhematologic toxicities were mild. After a median follow-up of 22 months, the median progression free survival rate was 7 months, and the median survival time was 16 months. CONCLUSIONS: The combination of paclitaxel, cisplatin, and gemcitabine is well tolerated and shows high activity in metastatic NSCLC. This treatment merits further comparison with other cisplatin-based regimens.     

Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer

Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I–II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m² on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m² on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m²; the paclitaxel dose level just below (210 mg/m²) was selected for phase II evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23–57%). Median duration of response was 35 weeks (range, 8–102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8–108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.     

Gemcitabine Plus Paclitaxel as Second-line Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Purpose: The aim of this retrospective study was to determine response rates, progression-free survival(PFS), overall survival (OS) and toxicity of gemcitabine and paclitaxel combinations with advanced or metastaticnon-small cell lung cancer patients (NSCLC) who have progressive disease after platinum-based first-linechemotherapy. Methods: We retrospectively evaluated the file records of patients treated with gemcitabine pluspaclitaxel in advanced or metastatic NSCLC cases in a second-line setting. The chemotherapy schedule was asfollows: gemcitabine 1500 mg/m2 and paclitaxel 150 mg/m2 administered every two weeks. Results: Forty-eightpatients (45 male, 3 female) were evaluated; stage IIIB/IV 6/42; PS0, 8.3%, PS1, 72.9%, PS2, 18.8%; medianage, 56 years old (range 38-76). Six (12.5%) patients showed a partial response (PR), 13 (27.1%) stable disease(SD), and 27 (56.3%) progressive disease (PD). The median OS was 6.63 months (95% CI 4.0-9.2); the medianPFS was 2.7 months (95% CI 1.8-3.6). Grade 3 and 4 hematologic toxicities, including neutropenia (n=4, 8.4%),and anemia (n=3, 6.3%) were encountered, but no grade 3 or 4 thrombocytopenia. One patient developed febrileneutropenia. There were no interruption for reasons of toxicity and no exitus related to therapy. Conclusion:The combination of two-weekly gemcitabine plus paclitaxel was an effective and well-tolerated second-linechemotherapy regimen for advanced or metastatic NSCLC patients previously treated with platinum-containingchemotherapy. Although the most common and dose limiting toxicities were neutropenia and neuropathy, thisregimen was tolerated well by the patients.     

Paclitaxel and Mitoxantrone in the Treatment of Metastatic Breast Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network

Background and rationale: The combination of paclitaxel and doxorubicin is highly active in the treatment of metastatic breast cancer, but is associated with substantial toxicity. In this phase II trial, we evaluated the combination of paclitaxel and mitoxantrone in an attempt to maintain efficacy and improve tolerability of this regimen.

Patients and methods: Sixty-three patients with metastatic breast cancer were treated with paclitaxel 200 mg/m², 1 hr IV infusion, and mitoxantrone 10 mg/m² IV, every 21 days. Responding patients received at least six courses of therapy. Ninety-three percent of patients in this trial were receiving first-line treatment for metastatic breast cancer; 62% of patients had received previous adjuvant chemotherapy, and 26% had received previous doxorubicin.

Results: Objective responses were seen in 24 of 61 evaluable patients (39%). Median response duration was 9 months (range 4-37+ months); actuarial 1-, 2-, and 3-year survivals were 62, 32, and 25%, respectively. The treatment was generally well tolerated; 78% of patients had grade 3 or 4 leukopenia at sometime during their treatment course, but only 14 hospitalizations for neutropenia and fever were necessary (4% of courses). Grade 3 fatigue was experienced by 30% of patients. Cardiotoxicity was not observed.

Conclusions: The combination of paclitaxel and mitoxantrone is active, easily administered, and well tolerated in the treatment of metastatic breast cancer. Its activity appears similar to several other taxane-based combination regimens recently evaluated for the treatment of advanced breast cancer.     

Doxorubicin and paclitaxel in advanced breast carcinoma: importance of prior adjuvant anthracycline therapy

BACKGROUND: The authors undertook a Phase II multicenter trial to assess the efficacy and toxicity of doxorubicin and paclitaxel in combination in the treatment of patients with metastatic breast carcinoma. METHODS: Doxorubicin (50 mg/m2, bolus) followed by paclitaxel (175 mg/m2 over 3 hours) was administered every 21 days (for a maximum of 10 cycles) as first-line chemotherapy in 77 patients, 41 of whom had received prior adjuvant chemotherapy. Monitoring of cardiac function (left ventricular ejection fraction[LVEF]) and total doxorubicin cumulative dose were included in the study protocol. RESULTS: Grade 4 hematologic toxicities were neutropenia (58%) and thrombocytopenia (4%). Neutropenic fever occurred in 9% of patients. Nonhematologic Grade 4 toxicity was limited to mucositis (3%). Grade 3 toxicities were neutropenia (35%), anemia (3%), alopecia (93%), peripheral neuropathy (18%), arthralgia/myalgia (8%), and mucositis (9%). No clinical cardiotoxicity (Grades 3 or 4) occurred. Treatment was discontinued in 5 patients who showed a decrease of LVEF of greater than 15% during therapy. Of 73 patients assessable for response, 15 were complete response, 42 partial response, 15 stable disease, and 1 disease progression; overall response rate being 78% (95% confidence interval [CI], 67-87). Median follow-up was 22 months. Median time to progression (TP) was 10 months (95% CI, 7-12). Time to progression was poorer in cases with adjuvant anthracycline therapy than those without adjuvant chemotherapy (7 vs. 12.3 months; P = 0.022), but TP in patients with adjuvant chemotherapy not containing anthracyclines was not different from the cases without adjuvant chemotherapy (8.6 months). Estimated 2-year survival was 51% (standard error, 7%). CONCLUSIONS: Our results confirm that the combination of paclitaxel and doxorubicin is effective in the treatment of metastatic breast carcinoma, and that it is well tolerated. No clinical cardiotoxicity was observed on close cardiac monitoring, and prior adjuvant anthracycline treatment compromised its efficacy.     

Ifosfamide/mesna as salvage therapy in platinum pretreated ovarian cancer patients--long-term results of a phase II study

Purpose: Salvage chemotherapy in advanced ovarian cancer is not yet standardized. Patients: Twenty-one consecutive patients progressing on or relapsing after previous platinum-containing treatment were eligible for treatment with ifosfamide 5 g/m² infused over a 24-hour period every 3 weeks in a Phase II trial. After an initial bolus of 1 g/m² of mesna, mesna was applied at a dosage of 5 g/m² concomitantly with ifosfamide followed by additional dosages of 200 mg 3 times at 4-hour intervals after termination of the ifosfamide infusion. Results: The rate of objective responses was 19 percent, with a 95%CI [5.45-41.91 percent]. One patient achieved a pathologic complete remission (pCR) and 3 patients a clinical partial remission (PR). Median time-to-progression was 3 months. One patient was a long-term survivor. Main toxicities according to NCI-CTC included Grade 4 neurotoxicity in one patient, Grade 3 gastrointestinal toxicity in 5 patients, Grade 3 infection in one patient, and Grade 3 and 4 leucopenia in 6 and 2 patients, respectively. Conclusions: Monotherapy with ifosfamide represents an active regimen for salvage chemotherapy in advanced ovarian cancer patients progressing on or relapsing after previous platinum-pretreatment, even yielding a long-term surivor.     

Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG)

Purpose: Advanced breast cancer (ABC) is an incurable disease. Standard first-line treatment for patients with HER-2/neu overexpressing tumors includes the combination of the humanized monoclonal antibody trastuzumab with chemotherapy, mainly paclitaxel. This combination is the first to demonstrate a survival advantage in this group of patients. To improve on these results, we investigated a triplet, paclitaxel-gemcitabine-trastuzumab (TGH), in a phase II study. Patients and Methods: Patients with ABC were accrued to the study. Treatment consisted of paclitaxel 80 mg/m²/week, gemcitabine 1000 mg/m² every 2 weeks, and trastuzumab 4 mg/kg loading dose and then 2 mg/kg/week. Patients were treated on study for a total of 12 weeks. Response evaluation was performed at the end of the 12 weeks. Continuation of treatment beyond the 12 weeks was left to the discretion of the investigator. Primary study endpoint was response. Toxicity assessment and survival were secondary endpoints. Results: Between November 2000 and May 2002, 40 patients were accrued and 32 patients completed all 12 weeks of therapy. One patient died of septic shock during therapy. Grade III and IV neutropenia was seen in 12.5% of cases each. Grade III anemia was seen in two patients, and grade III and IV thrombocytopenia in three and two patients, respectively. Both paclitaxel and gemcitabine were delivered at 86% of the planned dose intensity. Six patients achieved a complete response (CR) and 15 a partial response for an overall response rate of 52.5%. An additional 25% demonstrated stable disease and 20% progressive disease. Median duration of response was 14 months. All six patients who achieved CR are still in CR for 6 to 19 months. After a median follow up of 12.2 months, 19 patients have progressed and 7 have died. Median time to progression is 13.7 months, whereas median survival has not been reached. Conclusion: TGH is a well-tolerated and effective regimen for the first-line treatment of ABC. Randomized comparison between paclitaxel, trastuzumab, and triplets are warranted.     

Paclitaxel, carboplatin, and gemcitabine in metastatic nasopharyngeal carcinoma: a Phase II trial using a triplet combination

BACKGROUND: Patients with nasopharyngeal carcinoma (NPC) are treated primarily with radiotherapy. In the disseminated state, platinum-based, 2-drug combination regimens yielded response rates of 55-75%, achieving a median survival of 10-12 months. With the proven efficacy of second-generation cytotoxics like paclitaxel and gemcitabine in patients with metastatic NPC, the authors hypothesized that a triplet combination incorporating these newer cytotoxics may improve treatment results. METHODS: Thirty-two patients with metastatic NPC were treated with combination chemotherapy that included paclitaxel 70 mg/m(2) on Days 1 and 8, carboplatin dosed to area under curve of 5 on Day 1, and gemcitabine 1000 mg/m(2) on Days 1 and 8 every 21 days for a maximum of 8 cycles. RESULTS: Two patients achieved a complete response, and 23 patients achieved a partial response, for an overall response rate of 78%. The main toxicities were hematologic, with 41% of patients experiencing Grade 3 or 4 anemia, 41% of patients experiencing Grade 3 or 4 thrombocytopenia, and 78% of patients experiencing Grade 3 or 4 neutropenia. The median time to disease progression was 8.1 months, and the median overall survival was 18.6 months. CONCLUSIONS: The combination of paclitaxel, carboplatin, and gemcitabine showed promising efficacy against metastatic NPC but at the expense of considerable toxicity.     

Biweekly paclitaxel and gemcitabine for patients with advanced urothelial cancer ineligible for cisplatin-based regimen

BACKGROUND: To avoid cisplatin-related gastrointestinal, renal and other toxicity while maintaining efficacy in the palliative setting or second line chemotherapeutic regimen for cisplatin-resistant urothelial cancer, chemotherapeutic regimens have been investigated that do not include cisplatin. The current study was designed to evaluate efficacy, clinical feasibility and safety of gemcitabine and paclitaxel (GP) regimen in patients with metastatic urothelial cancer who were ineligible for standard cisplatin-based combination chemotherapy. METHODS: Gemcitabine 2500 mg/m(2) and paclitaxel 150 mg/m(2) were administered intravenously every 2 weeks for 23 patients (17 males and 6 females) with advanced urothelial cancer who were ineligible for cisplatin-based chemotherapy; metastatic disease being resistant to cisplatin-based chemotherapy regimen in 14, heavy toxicity in prior cisplatin-based chemotherapy in three, poor ECOG performance in two and impaired renal function in four. Average age was 67 (53-77). Performance status was 0 in 18 patients, 1 in three patients and 2 in two patients. RESULTS: The overall response rate was 30% (95% CI 15.6-50.8%). Of the 23 patients, no patient attained CR and 7 patients had PR. In the cisplatin-resistant group, the response rate was 14.2% (2/14; 95% CI 4.0-39.9%). In the remaining patients ineligible for cisplatin, the response rate was 55.5% (5/9; 95% CI 26.6-81.1%). The median duration of response was 4 months (range 3-8). The median duration of survival for all patients was 12.1 months (95% CI 8.6-15.5). Myelosuppression, predominantly neutropenia, was the most common serious toxicity and toxicity of Grade 3 or greater was observed in six patients (26%). Among non-hematological toxicity, neuralgia was the most commonly observed and occurred in nine patients (39%) although no patient had toxicity of Grade 3 or greater. Three patients had interstitial pneumonitis possibly attributed to gemcitabine. One patient developed severe bilateral disease after two cycles of the regimen, which was partially resolved with corticosteroid therapy. CONCLUSION: GP regimen is effective in some patients with cisplatin-resistant urothelial cancer and promising as second line chemotherapy. GP regimen is more effective and well tolerated as first line chemotherapy in patients ineligible for cisplatin-based chemotherapy. Toxicity is generally mild but care must be taken for patients with risk of interstitial pneumonitis. A further larger scale study is required to confirm the efficacy of the GP regimen.     

A Phase II NCCTG study of irinotecan and docetaxel in previously treated patients with non-small cell lung cancer

Purpose: This Phase II study was undertaken to define the efficacy and toxicity of the combination of docetaxel and irinotecan for the second-line treatment of non-small cell lung cancer (NSCLC). Patients and Methods: Forty-six patients with measurable NSCLC who had relapsed after an initial response to chemotherapy or who had failed to respond to initial chemotherapy, received 130 mg/m² of irinotecan IV over 90 minutes and 50 mg/m² docetaxel IV over 60 minutes on Day 1 q3 weeks for 6 cycles. Dexamethasone and diphenhydramine pretreatment were given. Response to treatment was evaluated by response evaluation criteria in solid tumors RECIST criteria, and toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 2.0. Results: The most common severe (NCI CTC Grade 3+) adverse events were neutropenia (67 percent), diarrhea (28 percent), fatigue (20 percent), nausea (17 percent), infection (15 percent), vomiting (13 percent), leucopenia (13 percent), abdominal pain (11 percent), and dyspnea (11 percent). Grade 5 toxic events were seen in 2 patients. One of these 2 cases was a possibly-treatment related event (intestinal fistula). The median number of treatment cycles received was 3. Twelve patients (26 percent) received all 6 cycles of treatment. Five patients (11 percent) had a confirmed response (complete response (CR), partial response (PR), or regression). Median follow-up for the five surviving patients is 26.5 months (range: 25.1-28.4). Forty-two patients have reported progressive disease and 41 patients have died. Median time-to-progression (TTP) and survival are 2.6 months and 7.5 months, respectively. Conclusion: This second-line treatment regimen of irinotecan and docetaxel in NSCLC patients has shown activity, but can not be recommended over single-agent regimens because of significant toxicity.     

Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study

Purpose. To investigate the response rate of the triple combination of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) and 5-fluorouracil (5-FU) and to assess its impact on secondary resectability of previously non-resectable liver metastasis (LM). Patients and methods. Patients≥18 with MCRC, ECOG grade 0-2, and no prior treatment received L-OHP (85 mg/m²), CPT-11 (150 mg/m²) and 5-FU (2 250 mg/m² in 48 h CI) on D1 every 15 days. Results. Forty-seven patients with initially non-resectable metastatic disease were included. Median age 62 years (38-76); 28 males; 26 patients with 0 performance status (ECOG) 40 patients had prior surgery and four adjuvant chemotherapy. All patients were evaluable for toxicity and 42 for response. Main grade 3-4 toxicities were neutropenia (40%), febrile neutropenia (4%), diarrhea (21%), nausea/vomiting (11%/15%), fatigue (11%), anemia and alopecia (9% each); grade 3-4 neurotoxicity was observed in 28% patients. Secondary surgery was possible in 15 of 47 (31.9%) patients and 12/30 (40%) patients with only LM: in this cohort, median OS has not been reached at 22 months median follow-up, with 2/12 patients having died. Overall response rate was 69% (95% CI, 53-82%); 13 (31%) had stable disease. Median time to progression and overall survival (OS) were 10.9 (95% CI, 9.9-13.2) and 19.9 (95% CI, 11.7-TBD) months, respectively. Conclusion. This combination has shown promising activity with manageable toxicity as front-line treatment in MCRC, and has allowed the resectability of LM in a considerable number of patients, offering them the possibility of long-term survival.