Why Doesn’t High-Dose Chemotherapy Improve Survival, as Was Expected, in Advanced or Relapsed Germ Cell Tumours?

Abstract

There are several reasons why drugs may not reach therapeutic levels within cancer cells. Since the drug concentration in the cell is limited by the dosage that can be usually given, the increased number of target molecules means thatmany of the targets are not affected by the drug: There are just too many for the number of drug molecules present [1]. Consequently, oncologists thought that just increasing the dosage of active drugswould increase the cell kill. Therefore, as soon as autologous bone marrow transplantation became available, they started to give high-dose chemotherapy (HDCT) with stem cell support. The most-used drugs are etoposide and alkylating agents. Connolly andMcCaffrey [2] presented awell-written and well-documented review paper on HDCT supported by autologous stem cell transplant in advanced or relapsed male germ cell tumours (GCTs). They performed an accurate search in the English language literature of the last 20 yr for HDCT with SCT in first-line treatment for poor prognosis and in the salvage setting for relapse after failure of firstline standard chemotherapy. While several phase 2 studies claimed a therapeutic advantage of HDCT over conventional chemotherapy in high-risk patients, phase 3 trials failed to confirm such results. There were only two randomised studies for each clinical situation, and the authors correctly expressed some criticism. As for HDCT in the first-line treatment of poor-prognosis patients, the authors expressed some difficulties in interpreting the French study because of low dose intensity in the high-dose arm and the use of a nonstandard regimen (references 22 and 23 in Connolly and McCaffrey [2]). Furthermore, the phase 3 American study did not achieve the patient accrual and complete overall responses were not different in the two arms; however, in a subanalysis of patients with slow