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 increasi ng the dose intensity of chemotherapy, and can be supported by biological a nd mathematical rationales. Our objective was to assess the clinical releva nce 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 recomme ndations. Randomised studies comparing frequently-repeated chemotherapy to standard regimens as well as open studies are described and critically exam ined. Results: Dose-dense regimens were widely found to be feasible. In small-cell lung cancer, survival of patients receiving dose-dense regime ns was better than that of patients treated by standard chemotherapy in thr ee 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 tha n standard therapy, perhaps because of an excessively high toxicity-related death rate. However, recent phase II studies have provided encouraging res ults. In early breast cancer, the one published randomized study in the adjuvant setting showed only a trend towards better disease-free survival in node-po sitive women receiving a weekly-repeated regimen. Two randomized trials fai led to show any benefit in the neoadjuvant setting with a dose-dense regime n. 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 a re 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, gestationa l trophoblastic disease, ovarian carcinoma and gastric cancer. Conclusions: A considerable amount of experience has been gained with frequ ently-repeated regimens. A few randomized trials have demonstrated a benefi t for survival on standard chemotherapy in small-cell lung cancer and advan ced colorectal cancer. However, this benefit appears to be weak. The combin ation of dose-dense chemotherapy regimens with new anti-cancer strategies b ased on our insights into the mechanisms of oncogenesis is a challenge on t he eve of the millennium.