Rodenhuis et al.28 randomized 885 patients with four or more involved lymph nodes to receive four cycles of conventional-dose chemotherapy followed by one more cycle of conventional-dose chemotherapy or one cycle of HDC. At a median follow-up of 57 months, there was a trend for an EFS advantage in favor of high-dose therapy (65% vs 59%, P = 0.09), with no significant OS differences. The EFS of those patients randomized to high-dose therapy who were actually transplanted appeared superior to those in the control arm (P = 0.03). Prospectively planned subset analysis showed that highdose therapy improved EFS among patients with 10 or more involved nodes (68% vs 49%, P = 0.05).
In the Cancer and Leukemia Group B (CALGB) 9082 trial, Peters et al.29 randomized 785 patients with
10 or more positive nodes to receive four conventional-dose chemotherapy cycles followed by one cycle of cyclophosphamide/cisplatin/BCNU or by one additional cycle of those drugs at intermediate doses with granulocyte colony-stimulating factor support. Twenty-five patients who relapsed on the intermediate-dose arm (15%) received subsequent salvage highdose therapy. At a median follow-up of 5 years, the intent-to-treat EFS (61% vs 60%, P = 0.5) and OS rates (70% vs 72%, P = 0.2) were similar in the high- and intermediate-dose arms. There were fewer relapses in the transplant arm (32% vs 43%), which represented a 31% relative reduction in the incidence of relapses. Unfortunately, the high 10% treatment-related mortality rate observed in the high-dose arm of this trial (versus 0% in the other arm) offset the decrease in recurrences.
The Eastern Cooperative Oncology Group (ECOG) randomized 540 patients with 10 or more involved nodes to receive six cycles of conventional-dose chemotherapy with or without consolidation with one cycle of high-dose cyclophosphamide/thiotepa with BM support and, towards the end of the study, with PBPC support. With a median follow-up of 6.1 years, there was no significant difference between the highdose and conventional-dose chemotherapy arms in EFS (55% vs 48%, P = 0.1) or OS (58% vs 62%, P = 0.3).30
In the Anglo-Celtic trial, Crown et al.31 randomized 605 patients with four or more positive nodes to receive conventional-dose chemotherapy followed by one high-dose therapy cycle or maintenance conventional-dose chemotherapy. At a median follow-up of 4 years, the first planned analysis did not reveal differences in EFS (51% vs 54%, P = 0.6) or OS (63% vs 62%, P = 0.8).
Nitz et al.32 enrolled 403 patients with 10 or more positive nodes to receive a modern dose-dense regimen or two sequential cycles of high-dose therapy with PBPC support. At a median follow-up of 39 months, there was superiority of the transplant arm in EFS (62% vs 48%, P = 0.001) and OS (75.6% vs 66%, P = 0.05).
In a French trial, Roch et al.33 randomized 314 patients to receive conventional-dose chemotherapy followed by one cycle of high-dose therapy or observation. At a median follow-up of 33 months, there was an EFS benefit in favor of high-dose therapy in EFS (71% vs 55%, P = 0.002), but not OS (84% vs 85%, P = 0.3).
In summary, review of these randomized studies presents a conflicting picture. A common theme is relatively short follow-up. While there are several negative trials after fairly long follow-up,29'30'34'35 other studies have already shown superiority of transplant in their first analyses,32 33 or suggested a nonsignificant trend in favor of transplant.28 36 Unfortunately the situation in high-risk breast cancer is similar to that in metastatic disease, with further follow-up needed to see if the consistent advantage in EFS translates into an improvement in OS.
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