Abstract P1-13-07: Superiority of tandem high-dose chemotherapy (HDC) versus conventionally dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): Long term follow-up of IBDIS: A prospective random assignment trial (PRT)
Authors: Crown J 
Published: May 2016

Background

The partial chemo-sensitivity of MBC, together with pre-clinical models, provided a rationale for studies of extreme dose-escalation with autologous haematopoietic progenitor support (ASCT). Early studies of HDC as salvage following failure of CDC produced high rates of temporary response. Subsequent single arm studies in pts who were preselected for responsiveness to CDC yielded 10-20% durable remissions suggesting that HDC might cure some MBC pts. The likelihood of selection bias mandated randomised trials of this CDC induction-HDC consolidation approach. We hypothesised that an alternative strategy-accelerated multi-cycle HDC- might provide an optimal HDC strategy (Crown J, Norton L, Ann Oncol 1996).

Methods

In IBDIS, pts received a brief phase of CDC induction (doxorubicin/docetaxel-"AT"), followed by tandem cycles of HDC, or, further CDC (AT followed by CMF), as initial CRx for MBC. Hormone receptor-positive patients received endocrine therapy post-chemotherapy, and pts with localized metastases received consolidative radiotherapy.

Results: Accrual failed in the aftermath of the disclosure of research fraud involving a South African HDC study, and the reporting of negative PRCTs at ASCO 1999. Only 110 of a planned 264 patients were enrolled, but it was decided to maintain follow-up, which is now 15 years. HDC and CDC groups were well-balanced for prior adjuvant (25 v 25), prior anthracycline (8 v 10), positive receptor status (32 v 31). There were 8 treatment-related deaths (6-HDC, 2 CDC). Complete and overall response rates (CR/OR) were significantly superior for HDC v CDC (CR-29% v 6%, OR-71% v 44%). Event-free-survival at median 5 yrs were HDC 6 (11%) versus CDC 0 (p=.027). At fifteen years three HDC pts remain alive and free from relapse. All CDC are deceased. The hazard ratio for PFS is currently 0.59 (0.39-0.88) favouring HDC p=.009. The HR for overall survival is 0.72 (0.48-1.08)p=.11

Discussion:

Despite accrual failure, IBDIS was and remains a positive study for its primary endpoint of PFS. The 100% relapse and death rate for CDC on our study is typical of the published literature. Data from IBDIS are included in the Cochrane meta-analysis of HDC which showed an advantage for PFS. The contention that HDC produced superior activity to CDC appears to have been correct, however the magnitude of the benefit is smaller than was hoped by investigators in the field.

While our data support the hypothesis that there is a dose response relationship in the chemotherapy of MBC, the small benefit and high toxicity of HDC, preclude it being recommended as a standard treatment for any pts with MBC.

Citation Format: Crown J. Superiority of tandem high-dose chemotherapy (HDC) versus conventionally dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): Long term follow-up of IBDIS: A prospective random assignment trial (PRT). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-07.