Paclitaxel, gemcitabine, and cisplatin in non-resectable non-small-cell lung cancer

Background: Paclitaxel, gemcitabine, and cisplatin are each active in non-small-cell lung cancer (NSCLC), and with different modes of action. Hence, a phase II study combining these drugs were conducted.Patients and methods: Treatment was paclitaxel 110 mg/m² and cisplatin 60 mg/m² day 1 and 15, with gemcitabine 800 mg/m² day 1, 8, and 15, every four weeks. Patients had previously untreated NSCLC, measurable disease, age 18–70 years, performance status 2, and no brain metastases.Results: Among 49 patients, 6 (group 1) received chemotherapy as described above, while 43 patients (group 2) did not receive gemcitabine day 8. In group 1, all experienced grade 4 neutropenia and four achieved a partial response (67%). In group 2, neutropenia grade 4 occured in 58%, with one episode of febrile neutropenia and no toxic death. No other grade 4 toxicities occured, while grade 3 toxicity occured with respect to thrombocytopenia (9%), nausea/vomiting (12%), neurotoxicity (12%), and nephrotoxicity (7%). There were 3 complete and 20 partial responses (response rate 54%, 95% confidence limits 38%–69%), median response duration 29 weeks (range 10–66+), median time to progression 28 weeks (range 4–66+), median survival 46 weeks (4–89+) and one-year survival rate 42%.Conclusion: This regimen of paclitaxel, gemcitabine, and cisplatin has neutropenia as dose limiting toxicity, but septicemic episodes were rare and toxic death did not occur. Other grade 4 toxicities than neutropenia did not occur. The regimen appears safe and with a noteworthy activity both in terms of response rate, time to progression, and survival.     

Epirubicin/vinorelbine as first line therapy in metastatic breast cancer

This study was aimed at investigating the toxicity and activity of the combination epirubicin and vinorelbine in chemotherapy-naive patients with metastatic breast cancer. Fifty-one patients with measurable or evaluable metastatic breast cancer entered the study. The regimen consisted of epirubicin 90 mg/m² as a slow i.v. infusion on day 1, followed by vinorelbine 25 mg/m² by 30-minute intravenous infusion on days 1 and 8; the courses were repeated every 21 days for a maximum of 8 cycles. All the patients were assessable for toxicity and 47 were evaluable for response according to the World Health Organization (WHO) criteria.Objective responses were observed in 33 out of 47 evaluable patients (70.2%; 95% C.I. 55.1%–82.6%) with 4 complete (8.5%) and 29 partial responses (61.7%); 11 patients had stable disease (23.4%) and 3 patients progressed while on treatment. The median time to progression was 10 months (range 1 – 21) and the median overall survival was 23 months (range 2 – 32+). Neutropenia was the most frequent toxicity: a grade 4 neutropenia (WHO) was reported in 70% of 252 courses with a median duration of 3 days (range 1–6). Seventeen episodes of febrile neutropenia were observed but only 1 patient required hospital admission. Other hematologic toxicities were negligible. One patient experienced a paralytic ileus requiring hospitalization; no peripheral neuropathy such as muscle weakness or paresthesia was observed. No treatment-related cardiotoxicity was reported. The encouraging response rate achieved with epirubicin/vinorelbine, the easily manageable toxicities of the combination, and its feasibility in an outpatient setting make this combination worthy of further comparative trials with standard regimens.     

Docetaxel-cisplatin combination (DC) chemotherapy in patients with anthracycline-resistant advanced breast cancer.

Purpose: The safety and efficacy of a docetaxel-cisplatin combination (DC) were evaluated in 41 patients pretreated for advanced breast cancer (ABC).Patients and methods: The first 2 patients received 85 mg/m² docetaxel followed, 6 hours later, by 80 mg/m² cisplatin repeated every 3 weeks; the other 39 received the same regimen, with 75 mg/m² docetaxel. Appropriate dose reductions but no growth factor administration were planned. Treatment was continued until disease progression, excessive toxicity or patient refusal.Results: A total of 223 chemotherapy courses were administered, with a median of 6 cycles per patient (range 1–8). All 41 patients were assessed for toxicity using NCI-CTC. Severe neutropenia was experienced by 38 patients (93%) (11 at grade 3, 27 at grade 4, 10 with febrile neutropenia). There was one death due to neutropenic septic shock. Grade 3 thrombocytopenia occurred in three patients (7%). Five patients (12%) had grade 2 neurosensory toxicity, two (5%) experiencing partial hearing loss. Grade 3 fluid retention occurred in three patients (7%).Of 38 anthracycline-resistant patients, 33 were evaluable for response. Two had a complete response (CR) and ten a partial response (PR), giving an objective response rate of 36%, (95% CI: 20%–55%). Stable disease (SD) was observed in 14 patients (42%), 7 (21%) had progressive disease (PD). Among the three non-resistant patients, two PRs and one SD were observed. Median duration of response was 29 weeks (range 18–70), median time to progression 21 weeks (4–70), and median overall survival 50 weeks (4–104+).Conclusions: This DC regimen is active, with an acceptable safety profile in anthracycline-resistant ABC patients. Its place as a second-line treatment alternative to docetaxel alone or to other second-line combination regimens remains to be determined.     

Phase II study of epirubicin and vinorelbine with granulocyte colony-stimulating factor: A high-activity, dose-dense weekly regimen for advanced breast cancer

Background: This study was designed to explore the effectiveness and tolerability of a weekly regimen of epirubicin and vinorelbine plus granulocyte colony-stimulating factor (G-CSF).Patients and methods: Fifty-two patients with previously untreated advanced breast cancer were treated with epirubicin (25 mg/m²/week) and vinorelbine (25 mg/m²/week) with G-CSF support, for 24 consecutive weeks.Results: The median number of courses per patient was 22 (range 10–24). The administered dose intensity was 23 mg/m² for both epirubicin and vinorelbine. Ten complete responses (19%) and 30 partial responses (58%) were obtained, for an overall response rate of 77%. None of the patients progressed during treatment. The median response duration and time to progression were both 10 months. A total of 1065 courses were assessed for toxicity. Grade 3 neutropenia was the most common toxic manifestation, (39% of patients), without febrile neutropenia or neutropenic sepsis. Two patients had grade 3 cardiac toxicity, which regressed without sequelae. Median survival was 31 months, with a median follow-up of 24 months (range 9–40).Conclusions: Owing to its effectiveness and tolerability, the weekly regimen of epirubicin and vinorelbine plus G-CSF may represent an acceptable alternative for patients with untreated metastatic breast cancer. It could be tested in the adjuvant and neoadjuvant setting.     

Docetaxel in combination with mitoxantrone and granulocyte colony-stimulating factor as front-line chemotherapy in metastatic breast?cancer: A?multicenter phase II study

Purpose:To evaluate the activity and tolerance of docetaxelin combination with mitoxantrone and granulocyte colony-stimulatingfactor (G-CSF) as front-line treatment in patients with metastaticbreast cancer (MBC). Patients and methods:Fifty-four previously untreatedpatients with MBC who had bidimensionally measurable disease wereenrolled onto the study. Forty-eight (89%) patients had visceralmetastases and nineteen (36%) had relapsed within twelve monthsfollowing adjuvant chemotherapy. Docetaxel (100 mg/m²) wasgiven on day 1 after appropriate premedication and mitoxantrone (20mg/m²) on day 8. G-CSF (150 mcg/m²/d s.c.) wasadministered from day 2 to day 6 and from day 9 to day 15. The regimenwas repeated every three weeks, on an outpatient basis. Results:In an intention-to-treat analysis, 9 (17%)CRs, 24 (44%) PRs, (overall response rate 61%; 95%confidence interval (CI): 48.1%–74.1%), 12(22%) SD and 9 (17%) PD were observed. The median durationof response and the median time to tumor progression was 12.5 and 14months, respectively. The overall median survival was 16.5 months,whilst the probability for one- and three-year survival was 61%and 35%, respectively. Grade 3–4 neutropenia occurred in 37(69%) patients, and febrile neutropenia in 16 (30%); therewas one death due to sepsis. Grade 3–4 thrombocytopenia occurredin four (8%) patients. Grade 2–3 neurosensory toxicity wasobserved in 8 (15%) patients and grade 2–3 asthenia in 24(45%). Conclusions:Docetaxel in combination with mitoxantrone andG-CSF support is an intensified and active front-line regimen forpatients with MBC; despite its hematological toxicity, this regimenmerits further comparison with other standard anthracycline- and/ortaxane-based combinations.     

First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): A phase II study conducted by the Hellenic Cooperative Oncology Group

Purpose: To evaluate the activity and toxicity of the combination of paclitaxel given by three-hour infusion, and carboplatin as first-line chemotherapy in patients with advanced breast cancer (ABC).Background: Paclitaxel is an active agent in ABC. Furthermore, our group has shown that the combination of paclitaxel and carboplatin is effective in anthracycline-resistant ABC.Patients and methods: From January 1996 until March 1997, 66 women with ABC were treated with paclitaxel (175 mg/m²) by three-hour infusion followed by carboplatin at an AUC of 6 mg × min/ml every three weeks. The median age of the patients was 56 years (range 28–75). A total of 39 patients had received adjuvant chemotherapy and 22 of them were treated with an anthracycline or mitoxantrone-containing regimen.Results: A total of 324 cycles (median: six) were administered, 273 (85%) of them at full dose. The median number of delivered cycles was six. The median delivered dose intensity (DI) of paclitaxel was 55.1 mg/m²/week (range 30.5–69.3) and the relative DI was 0.95 (range 0.5–1.2). Eight patients (12%, 95% confidence interval (CI): 5%–22%) achieved complete and 28 (42%, 95% CI: 30%–55%) partial responses. Grade 3–4 toxicities included anemia (5%), granulocytopenia (24%), thrombocytopenia, nausea/vomiting and allergic reaction (3% each), myalgias/arthralgias and neurotoxicity (1,5% each). Febrile neutropenia occurred in eight (12%) patients. Alopecia was universal. After a median follow-up of 17.3 (range 0.07–24.5) months, 48 (72%) patients have demonstrated tumor progression and 24 (36%) have died. Median time to progression was 8.6 (range 0.07–23+) months and median survival 20.4 (range 0.07–24.5+) months.Conclusions: The combination of paclitaxel and carboplatin has moderate activity in ABC and can be easily delivered on an outpatient basis with manageable toxicity. This regimen may be useful especially in patients to whom anthracyclines or cisplatin administration is precluded because of other concomitant diseases.     

Docetaxel plus vinorelbine as salvage chemotherapy in advanced breast cancer: a phase II study

Précis Administration of a combined regimen of docetaxel plus vinorelbine every 4 weeks is feasible and shows activity in heavily pretreated patients with advanced breast cancer. Purpose. To determine the activity and tolerance of docetaxel plus vinorelbine in heavily pretreated patients with advanced breast cancer. Methods. Thirty-five metastatic breast cancer patients with ECOG performance status of 0–2 received docetaxel (80 mg/m² given intravenously) on day 1 and vinorelbine (30 mg/m² given intravenously) on days 1 and 14, every 4 weeks. The median number of prior chemotherapy regimens was 2 (range: 1–4). Twenty-five patients (71.4%) had been treated previously using intensive therapy approaches with peripheral blood-derived stem cell (PBSC) support, including high-dose chemotherapy (11 patients), multicyclic dose-intensive chemotherapy supported with repeated PBSC infusions (seven patients), or both (seven patients). Twenty-eight patients (80%) received previous chemotherapy for metastatic disease. Adjuvant therapy in the remaining seven patients consisted of high-dose chemotherapy and PBSC support or an anthracycline-containing regimen. Results. The total number of courses was 229, and the median number of courses per patient was 6 (range: 1–16). There was one toxic death (2.8%). Grade 3–4 toxicities included mucositis (17.1%), neutropenia (37.1%), anemia (5.7%), vomiting (2.9%), and asthenia (14.3%). Eighteen patients (58%; 95% CI: 40.6–75.4%) achieved an objective response, including four complete responses (12.9%) and 14 partial responses (45.1%). Overall response rate was 51.4% (95% CI: 34.8–67.9%). After a median follow-up of 20 months (range: 2–42), overall survival was 20 months (95% CI: 16–24), and median time to progression was 13 months (95% CI: 7–19). Conclusion. This combination shows activity and an acceptable toxicity profile in patients with advanced breast cancer.     

Second-line treatment with oxaliplatin + raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin-based chemotherapy

Background:To evaluate the efficacy and tolerance of combined raltitrexed and oxaliplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidine–leucovorin-based chemotherapy. Patients and methods:Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within six months after withholding palliative chemotherapy with fluoropyrimidines–leucovorin ± irinotecan, participated in this study. Treatment consisted of oxaliplatin 130 mg/m² and raltitrexed 3.0 mg/m² both given on day 1 every three weeks for a total of eight courses unless prior evidence of progressive disease. Results:The overall objective response rate was 33.3% for all 36 evaluable patients (95% confidence interval (CI): 18.6%–51%). Seventeen additional patients (47.2%) had stable disease, and only seven (19.5%) progressed. The median progression-free survival was 6.5 months (range 1.2–14.0). After a median follow-up time of 12 months, 23 patients (63.8%) are still alive. The tolerance of treatment was acceptable with only 8 of 36 patients (22%) experiencing grade 3 or 4 neutropenia. Grade 3 non-haematological adverse reactions included peripheral sensory neuropathy in three, asthenia in one, diarrhea in two, and clinically insignificant increase in serum transaminases in two patients, respectively. Conclusions:Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine–leucovorin ± irinotecan pretreated colorectal cancer. Because of its favorable toxicity profile and convenient three-weekly outpatient administration schedule, further evaluation of this regimen seems warranted.     

Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer

Purpose:To evaluate the safety and efficacy of docetaxel andcarboplatin as first-line therapy for patients with advanced non-small-celllung cancer (NSCLC). Patients and methods:In this multicenter, phase II trial, 33patients with previously untreated stage IIIB (n = 8) or IV(n = 25) NSCLC received intravenous infusions of docetaxel 80mg/m² followed immediately by carboplatin dosed to AUC of 6mg/ml/min (Calvert's formula) every three weeks. Patients also receiveddexamethasone 8 mg orally twice daily for three days beginning one day beforeeach docetaxel treatment. Filgrastim was not allowed during the first cycleand was added only if a patient experienced febrile neutropenia or grade 4neutropenia lasting 7 days. Results:There were 1 complete and 11 partial responses for anobjective response rate of 43% (95% CI:24%–63%) in 28 evaluable patients and 36%(95% CI: 20%–55%) in the intent-to-treatpopulation. The median duration of response was 5.5 months (range3.0–12.5 months). The median survival was 13.9 months (range 1–35+months); one-year survival was 52%. The most common toxicity washematologic, which included grade 4 neutropenia (79% of patients and7% percent of cycles) and febrile neutropenia (15% of patients);there were no episodes of grade 3 or 4 infection. The most common severenonhematologic toxicities were asthenia (24%) and myalgia (12%);there were no grade 3 or 4 neurologic effects. Conclusions:The combination of docetaxel and carboplatin has anacceptable toxicity profile and is active in the treatment of previouslyuntreated patients with advanced NSCLC. This combination is being evaluatedin a randomized phase III trial involving patients with advanced andmetastatic NSCLC.     

Ifosfamide and paclitaxel salvage chemotherapy for advanced epithelial ovarian cancer

Objective: To evaluate the efficacy and toxicity of the combinationof ifosfamide (1.5 g/m² i.v. on days 1, 2, 3) and paclitaxel(135 mg/m² i.v. over 3 hours on day 3) with G-CSF (5µg/kg/d subcutaneously, days 7–11) administered every 3 weeks onan outpatient basis in patients with advanced epithelial ovarian cancerpreviously treated with platinum-based chemotherapy.Patients and methods: Thirty-five consecutive patients were treated,12 of whom had previously received two regimens. Twelve of the 35 were definedas platinum-resistant and 23 as potentially platinum-sensitive.Results: Fifteen patients (43%; 95% CI:26%–61%) achieved objective responses, five of themcomplete and ten partial. Objective responses occurred in 17% of theplatinum-resistant patients and in 57% of those with potentiallyplatinum-sensitive disease. The median duration of response was seven monthsand the median overall survival 11 months. The treatment was well toleratedand only 15% of the patients developed grade 3 or 4 neutropenia. Withthe exception of alopecia there were no other grade 3 or 4 toxicities.Conclusions: The combination of ifosfamide and paclitaxel was welltolerated and showed activity in patients with ovarian cancer who hadpreviously undergone platinum-based chemotherapy.     

A phase II study of a novel gemcitabine plus cisplatin regimen administered every three weeks for advanced non-small-cell lung cancer

Background: The aim of this study was to determine the clinical activity and toxicity of a novel chemotherapy combination regimen of gemcitabine plus cisplatin, administered every three weeks, in patients with advanced non-small-cell lung cancer (NSCLC).Patients and methods: Twenty-six previously untreated stages III (14) and IV (12) patients were included. Gemcitabine was administered on days 1 and 8 at a dose of 1250 mg/m² and cisplatin was administered at a dose of 100 mg/m² on day 1, every 21 days.Results: Twenty-five patients were evaluable for response. One patient achieved a complete response, and 16 patients partial responses. The overall response rate was 65.3% (95% CI: 45%–82%). The main toxicity was hematological: neutropenia NCIC-CTC grade 3–4 in 54% of the patients, and thrombocytopenia grade 3–4 in 23%. The non-hematological toxicity was mild and tolerable. Only 13% of gemcitabine injections were dose-reduced or omitted due to toxicity. The actual dose-intensity of gemcitabine was 715 mg/m²/week, and 31 mg/m²/week for cisplatin. These figures represent the 86% and 93% of the theoretical dose intensity of both drugs, respectively. With a median follow-up of 10 months (range 7–13), 17 patients are still alive and nine have died. The median overall survival is 12 months.Conclusion: This novel combination of gemcitabine and cisplatin administered every three weeks is well tolerated and induces a remarkably high response rate. The regimen proves more interesting than the four-week schedules, particularly regarding patients who are candidates for local therapy.     

Efficacy and safety of the paclitaxel and carboplatin combination in patients with previously treated advanced ovarian carcinoma

Background: Platinum compounds are the most active drugs in ovarian cancer treatment; cisplatin and carboplatin demonstrated similar efficacies but different toxicity profiles. Paclitaxel combined with cisplatin as first-line treatment improved overall survival when compared to a cisplatin-cyclophosphamide combination, but generated higher rates of neutropenia, febrile neutropenia and neurotoxicity. The paclitaxel-carboplatin combination may be better tolerated than cisplatin–paclitaxel.Design: The objective of the present study was to assess the efficacy and safety of the combination of paclitaxel and carboplatin in previously treated advanced ovarian cancer patients.Patients and methods: During or after platinum-based chemotherapy, 73 patients with progressive advanced epithelial ovarian carcinoma were enrolled to receive every four weeks a three-hour infusion of paclitaxel 175 mg/m² followed by a 30-minute carboplatin infusion. The carboplatin dose was calculated to obtain the recommended area concentration-versus-time under the curve of 5 mg·ml^-1·min.Results: Toxicity and response could be evaluated for 72 and 62 patients, respectively. Eleven complete and 15 partial responses gave an overall response rate of 42% (95% CI: 30%–54%). Response rates for platinum-refractory patients and those with early (3 and <12 months) and late (>12 months) relapses were 24%, 33% and 70%, respectively. The respective median response duration, the median progression-free survival and median overall survival were 8, 6 and 14 months. Myelosuppression was the most frequent and severe toxicity. Grade 3 and 4 neutropenia occurred, respectively in 30% and 23% of the cycles; 6% of the cycles benefited from medullary growth factors. Only one episode of febrile neutropenia was observed. Grade 3 and 4 thrombocytopenia occurred, respectively during 3% and 1% of the cycles. Alopecia was frequent. Transient peripheral neuropathy developed in 47% of patients but was severe in only one patient. One early death was attributed to progressive disease and possibly to therapy.Conclusion: This combined paclitaxel–carboplatin therapy is effective and can be safely administered to ovarian cancer patients who relapse after one or two regimens of platinum-based chemotherapy.     

Four-step high-dose sequential chemotherapy with hematopoietic progenitor-cell support as induction treatment for patients with solid tumors

Background: Despite recent progress in modern chemotherapy, metastatic solid tumors still have a poor outcome. The delivery of increased dose intensities of cytotoxic agents could improve response rates. We assessed the feasibility and safety of a high-dose sequential chemotherapy program in chemotherapy-naive patients with solid tumors.Patients and methods: Thirty patients (14 with carcinoma of unknown primary site, seven with metastatic breast cancer, six with small-cell lung cancer, and three with other diseases) were treated by an induction therapy regimen consisting of four cycles of high-dose chemotherapy with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m², cyclophosphamide 6000 mg/m²). Patients then received two cycles of etoposide (800 mg/m²) and carboplatin (900 mg/m²) separated by one cycle of doxorubicin (75 mg/m²) and cyclophosphamide (3000 mg/m²). G-CSF (5 µg/kg/d) was given until engraftment. Cycles were scheduled to be delivered every three weeks.Results: A total of 108 cycles of chemotherapy were administered. Six patients went off study before the end of the program (three because of progressive disease, three because of toxicity). After the first cycle, a median number of 10 × 10⁶/kg CD34+ cells (range 8–30) were collected. The median number of apheresis procedures was 1 (range 1–3). From cycle 2 to cycle 4, the median number of days when there was an absolute neutrophil count of less than 500/µl increased from three to five, and the median number of days when the platelet count was less than 25,000/µl increased from three to six. Episodes of febrile neutropenia occurred in 36%, 50% and 46% of cycles during cycles 2, 3 and 4, respectively. The median numbers of days between cycle 1 and cycle 2, cycle 2 and cycle 3, cycle 3 and cycle 4 were 24 (range 20–30), 22 (range 20–36) and 22 (range 18–35), respectively. There were no treatment-related deaths. Non-hematologic toxicity included severe (WHO grades 3 or 4) nausea/vomiting in 19 (18%) cycles, mucositis in 8 (7%) cycles and diarrhea in 7 (6%) cycles.Conclusion: Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high-dose chemotherapy in chemotherapy-naive patients, resulting in a significant increase in dose intensity. Toxicity is noteworthy but manageable and does not compromise further therapy.     

A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer.

Background:Previous phase I–II studies have shown that the combination of paclitaxel–cisplatin–etoposide (TEP) is very active and well tolerated in patients with small-cell lung cancer (SCLC). In order to compare the TEP combination to cisplatin–etoposide (EP) regimen as front-line treatment in patients with SCLC, we conducted a randomised multicenter study. Patients and methods:One hundred thirty-three chemotherapy-naïve patients with histologically proven limited or extensive stage SCLC were randomised to receive either paclitaxel 175 mg/m² i.v. three-hour infusion on day 1 and cisplatin 80 mg/m² i.v. on day 2 and etoposide 80 mg/m² i.v. on days 2–4 with G-CSF support (5 mcg/kg s.c. days 5–15) or cisplatin 80 mg/m² i.v. on day 1 and etoposide 120 mg/m² i.v. on days 1–3 in cycles every twenty-eight days. Results:Due to excessive toxicity and mortality observed in the TEP arm, an early interim analysis was performed and the study was closed. Sixty-two patients received two hundred sixty-one cycles of TEP and seventy-one patients three hundred twenty-three cycles of EP. The two patient groups were well balanced for age, sex, performance status, stage of disease and the presence of abnormal LDH at diagnosis. In an intention-to-treat overall analysis both regimens were equally active with a complete and partial response rate of 50% (95% confidence interval (CI): 37.5%–62.4%) for TEP and 48% (95% CI: 36.2%–59.5%) for EP (P = 0.8). The median time to disease progression was 11 months for TEP and 9 months for EP (P = 0.02). The duration of response, one-year survival and overall survival were similar in the two arms. Similarly, in an intention-to-treat subgroup analysis of patients with limited or extensive stage disease, there was no difference in the activity between the two regimens except of a longer median time to disease progression in the extensive stage in favour of the TEP regimen, eight versussix months (P = 0.04). However, there were eight toxic deaths in the TEP arm versusnone in the EP arm (P = 0.001). Moreover, the TEP regimen was associated with more severe toxicity than the EP regimen in terms of grade 4 neutropenia (P = 0.04), grade 3–4 thrombocytopenia (P = 0.02), febrile neutropenia (P = 0.08), grade 3–4 diarrhea (P = 0.01), grade 3–4 asthenia (P = 0.05) and grade 3 neurotoxicity (P = 0.06). Conclusions:In this early terminated study, the TEP regimen was significantly more toxic than the EP regimen. The TEP regimen is associated with significant toxicity and mortality, and should not be used outside of a protocol setting. For future investigations, dose and schedule modifications are necessary to reduce toxicity.     

A phase II study of cisplatin, ifosfamide and doxorubicin in operable primary, axial skeletal and metastatic osteosarcoma

Background: Despite advances in the treatment of primary limb osteosarcoma, the outcome of patients with primary metastatic and axial skeletal disease remains poor. The European Osteosarcoma Intergroup have assessed a combination chemotherapy regimen consisting of ifosfamide (IFOS) 3 g/m²/d1–2, doxorubicin (DOX) 25 mg/m²/d1–3 i.v. bolus and cisplatin (CDDP) 100 mg/m²/d1.Patients and methods: One hundred nine previously untreated patients with primary osteosarcoma were registered. Eligibility was confirmed in 103. At presentation, 45 eligible patients had metastatic disease, 15 axial skeletal primary tumours and 43 non-metastatic limb tumours.Results: The major toxicities were myelosuppression (90%, grade 3 or 4) and nausea and vomiting (74%, grade 3 or 4). Overall mean relative dose intensity (RDI) was 80% (88% CDDP, 75% IFOS, 81% DOX). Clinical response as measured by reduction in tumour volume occurred in 36% (95% confidence interval (95% CI): 27%–47%) of primary tumours. Response of pulmonary metastases to chemotherapy was seen in 33% (95% CI: 19%–49%). Good histological response (90% necrosis of the tumour) occurred in 33% (95% CI: 22%–45%) of resected tumours. Five-year survival was 62% in limb-non-metastatic, 41% in axial skeletal and 16% in limb metastatic patients.Conclusions: This regimen is active in osteosarcoma but does not appear to be more active than the two-drug CDDP–DOX regimen currently recommended by EOI.     

Combination therapy with docetaxel and low dose of cisplatin in elderly patients with advanced non-small cell lung cancer: multicenter phase II study

Purpose  To determine the efficacy and safety of the combination therapy with docetaxel and cisplatin (CDDP) at low doses in elderly patients with advanced NSCLC. Patients and methods  A total of 42 patients aged ≥70 years with previously untreated advanced NSCLC received docetaxel 75 mg/m² plus CDDP 50 mg/m² on day 1. The regimen was repeated every 21 days. Patients received a minimum of three courses unless progressive disease was detected. Results  By intent-to-treat analysis, the overall response rate was 31% (95% CI, 17.8–47.2%). A total of 18 patients (43%) had stable disease and 11 (26%) progressed. Median time to progression was 5.2 months. Overall median survival was 8.9 months, with 1-year actuarial survival rate of 41%. Eastern Cooperative Oncology Group performance status was improved in 18 patients (43%). The chemotherapy regimen was well tolerated. A total of 11 patients (26%) had grade 3/4 adverse events: 7 (17%) neutropenia (one of them was diagnosed with febrile neutropenia), 3 (7%) asthenia, 3 (7%) nausea/vomiting, 1 (2%) diarrhea, 1 (2%) thrombocytopenia and 1 (2%) neurotoxicity. No death due to toxicity was seen. Conclusion  The combination of low-dose CDDP and docetaxel for elderly patients with advanced NSCLC is an efficient and well-tolerated chemotherapeutic approach.     

Sequential therapy in advanced non-small-cell lung cancer with weekly paclitaxel followed by cisplatin-gemcitabine-vinorelbine. A phase II study.

Objectives:New effective therapies are needed to improvethe outcome of patients with advanced non-small-cell lung cancer(NSCLC). The aim of this study was to assess the response rate andsurvival obtained with a sequential regimen of chemotherapy. Patients and methods:Patients with newly diagnosed stageIIIb–IV NSCLC were included. They all had measurable disease and agood performance status (0–2 in the Eastern Cooperative OncologyGroup scale). Chemotherapy consisted of weekly paclitaxel 150mg/m² × 6, followed two weeks later by cisplatin 100mg/m² on day 1, gemcitabine 1000 mg/m² on days 1and 14, and vinorelbine 25 mg/m² on days 1 and 14 (CGV). CGVwas administered every 28 days for a maximum of six courses. Results:Fifty-two patients were included, 19 (37%)with stage IIIb and 33 (63%) with stage IV disease. After therapywith weekly paclitaxel, 29 partial responses were obtained (56%,95% confidence interval (95% CI):38%–67%), whereas 15 patients had stable disease(29%) and eight had a progression (15%). After CGV, therewere four complete remissions (8%) and 24 partial responses(46%), for an overall response rate of 54% (95% CI:37%–65%). Eight patients had stable disease(15%) and 16 had a progression (31%). No patientprogressing after paclitaxel responded to CGV, whereas 5 out of 15patients with stable disease reached a partial response with CGV(33%). On the contrary, 5 out of 29 patients with a partialresponse to paclitaxel progressed after CGV (17%). Mediansurvival has not been reached after a median follow-up of 14 months.Median time to progression was nine months. Fifty-six percent ofpatients remain alive at one year. Two hundred eighty-nine courses ofpaclitaxel and 170 of CGV were given, with a median of 5.5 and 3.4 perpatient, respectively (ranges 2–6 and 0–6, respectively).WHO grade 3–4 toxicities for paclitaxel were: neutropenia in twopatients (4%) and peripheral neuropathy in five (10%). Twopatients had allergic reactions requiring paclitaxel withdrawal, whereasfour (8%) had hyperglycemia >250 mg/ml. Grade 3–4toxicities for CGV were: neutropenia in ten patients (20%),peripheral neuropathy in six (12%), anemia in four (8%),nausea/vomiting in five (10%), thrombocytopenia in two(4%), and fatigue in four (8%). Conclusion:Our results suggest that sequential chemotherapy with weeklypaclitaxel followed by CGV is highly active in patients with advancedNSCLC and has an acceptable toxicity. This schedule deserves furtherevaluation in a phase III study.     

Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM)

Background:Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin–5-FU and gemcitabine combination. Patients and methods:This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m² in a two-hour infusion, followed by 5-fluorouracil 400 mg/m² bolus and 2 or 3 g/m² continuous infusion over 46 hours; gemcitabine 1 g/m² was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m² every two cycles up to 1500 mg/m²) in the absence of NCI-CTC toxicity >2. Results:Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%–37.8%) and 22.6% (95% CI: 12%–33.2%) in the intent-to-treat population; the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression-free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3–4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients. Conclusions:Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.     

Treatment of pancreatic cancer with a combination of docetaxel, gemcitabine and granulocyte colony-stimulating factor: A phase II study of the Greek Cooperative Group for Pancreatic Cancer

Purpose:To evaluate the tolerance and efficacy of front-linedocetaxel plus gemcitabine treatment in patients with inoperable pancreaticcancer. Patients and methods:Fifty-four patients with locally advancedor metastatic pancreatic cancer were enrolled. Gemcitabine (1000mg/m²) was administered on days 1 and 8 and docetaxel (100mg/m²) on day 8, every three weeks; rh-G-CSF (150ìg/m² s.c.) was given prophylactically on days9–15. Results: Seven (13%) patients achieved partial response and18 (33%) stable disease (intent-to-treat). The median duration ofresponse was 24 weeks, time to tumour progression 32 weeks, and overallsurvival 26 weeks. Performance status was improved in 33% of patients,pain in 43%, asthenia in 16%, weight gain in 28% andappetite in 27%. Grade 3–4 neutropenia occurred in 17(31%)patients and grade 3–4 thrombocytopenia in four (4%). Six(11%) patients developed febrile neutropenia and one of them died fromsepsis. Conclusions:This combination is a relatively well-toleratedout-patient regimen for patients with inoperable pancreatic cancer.     

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.