Is 'one cycle every three or four weeks' obsolete? A critical review of dose-dense chemotherapy in solid neoplasms

Background: Shortening the interval between cycles is one means of increasing the dose intensity of chemotherapy, and can be supported by biological and mathematical rationales. Our objective was to assess the clinical relevance of the rapid repetition of regimens (so-called 'dose-dense chemotherapy') in various solid neoplasms. Design: The medical literature was reviewed in accord with Mulrow's recommendations. Randomised studies comparing frequently-repeated chemotherapy to standard regimens as well as open studies are described and critically examined. Results: Dose-dense regimens were widely found to be feasible. In small-cell lung cancer, survival of patients receiving dose-dense regimens was better than that of patients treated by standard chemotherapy in three trials, two of which reached significance, when these intensive regimens allowed better dose intensity. In poor-prognosis germ-cell tumors, a dose-dense regimen was not better than standard therapy, perhaps because of an excessively high toxicity-related death rate. However, recent phase II studies have provided encouraging results. In early breast cancer, the one published randomized study in the adjuvant setting showed only a trend towards better disease-free survival in node-positive women receiving a weekly-repeated regimen. Two randomized trials failed to show any benefit in the neoadjuvant setting with a dose-dense regimen. No evidence of a benefit was provided in metastatic breast cancer. In advanced colorectal cancer, evidence of an improvement in survival with weekly or bi-weekly 5-FU-leucovorin compared to a classic monthly schedule has recently been shown in two randomized trials, and dose-dense regimens are recognized as standard therapy in many countries. Phase II studies of dose-dense regimens have also shown high response rates and long survival in many neoplasms, including Ewing's sarcoma, gestational trophoblastic disease, ovarian carcinoma and gastric cancer. Conclusions: A considerable amount of experience has been gained with frequently-repeated regimens. A few randomized trials have demonstrated a benefit for survival on standard chemotherapy in small-cell lung cancer and advanced colorectal cancer. However, this benefit appears to be weak. The combination of dose-dense chemotherapy regimens with new anti-cancer strategies based on our insights into the mechanisms of oncogenesis is a challenge on the eve of the millennium.