Dose-dense Schedule Research Articles

Sequential dose-dense paclitaxel followed by topotecan in untreated extensive-stage small-cell lung cancer: a Spanish Lung Cancer Group phase II study

BackgroundPoor survival rates in extensive-stage small-cell lung cancer (SCLC) patients prompted us to evaluate a sequential dose-dense schedule of paclitaxel followed by topotecan. Patients and methodsForty-three patients with previously untreated, extensive-stage SCLC received three cycles of paclitaxel 250 mg/m2 over 3 h every 14 days followed by three cycles of topotecan 2.5 mg/m2 for 5 days every 21 days. Granulocyte colony-stimulating factor was given after every cycle. Patients progressing at any time and those not achieving complete response (CR) subsequently received four cycles of standard-dose etoposide–cisplatin. ResultsA total of 118 cycles of paclitaxel were administered with minimal hematological toxicity. Grade 2/3 peripheral neuropathy was observed in 21% of patients. Response rate to paclitaxel was 48.8%, and 25.6% had stable disease (SD). Thirty-two patients achieving SD or response to paclitaxel subsequently received a total of 90 topotecan cycles. Topotecan-related toxicities included febrile neutropenia in 15.6% of patients with one toxic death, grade 3/4 anemia in 25% of patients and grade 3/4 thrombocytopenia in 31.3%. Non-hematological toxicities were mild. At completion of sequential paclitaxel–topotecan treatment the overall response rate was 55.8% (22 partial response, two CRs). Median survival for all patients was 10.5 months and median progression-free survival was 8.5 months. ConclusionsSequential treatment with dose-dense paclitaxel followed by topotecan is feasible despite significant hematological toxicity during topotecan treatment. This schedule is an active regimen in extensive-stage SCLC and merits further investigation.

Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus

BackgroundWe have previously reported a favourable response rate in patients with advanced esophageal cancer after treatment with a biweekly regimen of paclitaxel and cisplatin. In this study we investigate the feasibility and efficacy of this regimen in a neo-adjuvant setting. Patients and methodsPatients with resectable squamous cell carcinoma of the esophagus received paclit-axel 180 mg/m2 and cisplatin 60 mg/m2 every 2 weeks. Patients received three courses and responding patients received three additional courses; thereafter, patients were referred for surgery. Patient characteristics of 50 eligible patients were as follows: male, 60%; median age, 62 years (range 45–78); median World Health Organization performance status of 1 (range 0–2). ResultsNinety-four per cent of patients received at least three courses of chemotherapy. Haematological toxicity consisted of National Cancer Institute–Common Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with neutropenic fever occurring in only two patients (4%). The overall response rate was 59%. Pathological examination showed tumour-free margins in 38 patients. In seven patients no residual tumour was found. The median overall survival was 20 months and the 1- and 3-year survival rates were 68% and 30%, respectively. ConclusionsThis dose-dense schedule of paclitaxel and cisplatin administered biweekly is well tolerated and the observed overall and complete response rates are promising.

Phase I study of a weekly schedule of a fixed dose of cisplatin and escalating doses of paclitaxel in patients with advanced oesophageal cancer

The objective of this study was to determine the toxicities and maximum tolerated dose (MTD) of a dose-dense schedule with a fixed dose of cisplatin and escalating doses of paclitaxel in patients with metastatic or irresectable squamous cell-, adeno-, or undifferentiated carcinoma of the oesophagus. Patients received paclitaxel over 3 h followed by a 3-h infusion of a fixed dose of cisplatin of 70 mg/m 2 on days 1, 8, 15, 29, 36 and 43. The starting dose of paclitaxel was 80 mg/m 2. Patients were re-treated if white blood cell count (WBC) was ⩾1×10 9 cells/l, except for day 29 when the WBC had to be ⩾3×10 9 cells/l. Six patients were treated at each dose level. The dose of paclitaxel was increased by 10 mg/m 2 per level. Of the 24 patients enrolled, 13 had adenocarcinoma, 10 had squamous cell carcinoma and one had an undifferentiated carcinoma. All patients were evaluable for toxicity and 22 of 24 patients were evaluable for response. The paclitaxel dose could be escalated to 110 mg/m 2. At this dose, 3 out of 6 patients developed dose-limiting toxicity (DLT) including neutropenic enterocolitis with sepsis, vomiting and diarrhoea. Diarrhoea grades 3 and 4 was seen in 4 (17%) patients. Two of these patients died of neutropenic enterocolitis. Neutropenia grades 3 or 4 was seen in 20 (83%) patients, but apart from the two patients with neutropenic enterocolitis no other infectious complications were seen. Mild to moderate sensory neurotoxicity was seen in 11 (46%) patients (grade 1 in 8 patients and grade 2 in 3 patients). Other toxicities were mild and easily manageable. Of the 22 evaluable patients, 11 (50%) patients achieved a partial or complete response with a median duration of 13 months. Ten patients with either locally advanced disease or supraclavicular or celiac lymph nodes received additional local treatment after response to chemotherapy, seven patients are still without evidence of disease after a median follow-up of 32 months. Paclitaxel at a dose 100 mg/m 2 infused over 3 h followed by a 3-h infusion of 70 mg/m 2 cisplatin can be recommended for further studies in patients with metastatic or unresectable oesophageal cancer. Occurring diarrhoea should be handled with caution because it may be a sign of neutropenic enterocolitis. The response rate of this dose-dense schedule seems encouraging.

New strategies for therapy of breast cancer. San Antonio Breast Cancer Symposium, 2002

New strategies concerning the adjuvant chemotherapy for breast cancer have been introduced by the canadian group. A dose-dense schedule seems to be more effective than a conventional one. But there was no difference if the agents had been given in a sequential or equivalence way. The International Breast Cancer Study Group demonstrated their data on combined chemo- hormone treatment in the adjuvant setting for pre and postmenopausal women. New data in the metastatic treatment of breast cancer have been shown including the biologicals as a new strategy. There are very promising results of the triple combination trastuzumab, herceptin, paclitaxel. But data on ZD1839 or anti-VEGF have been disapointing.

Theoretical Concepts and the Emerging Role of Taxanes in Adjuvant Therapy

The proven benefits of adjuvant chemotherapy on disease-free and overall survival in breast cancer can be explained by concepts of cell kill. Interventions which result in greater log kill can be expected to produce improved clinical results. The application of log-kill concepts to human breast cancer growth, which appears to follow Gompertzian kinetics, suggests not only that the use of non-cross-resistant drugs is important, but that dose-dense schedules may have an advantage over conventional schedules of drug administration. Sequential therapy may allow dose-dense administration of cytotoxic agents and encourage the integration of new biological agents into combination regimens, particularly with the taxanes. Ongoing trials in these concepts are reviewed.

Recent developments in weekly paclitaxel therapy in lung cancer.

Paclitaxel has undergone a remarkable evolution of schedule and dosage based on observed schedule-dependent toxicity and consequent improvement of therapeutic index. A weekly schedule of administration was originally developed to exploit opportunities for radiation synergy and was subsequently explored without radiation to evaluate the potential for reduced toxicity. Three weekly schedules have emerged: paclitaxel 50 mg/m(2)/wk with concurrent radiation, paclitaxel 80 to 90 mg/m(2)/wk as a dose-dense schedule without radiation, and paclitaxel 150 to 175 mg/m(2)/wk as a dose-intensive schedule. The efficacy of these schedules, their integration as combination treatment with chemotherapy and nonchemotherapeutic agents, and their role are the subjects of substantial investigation.