Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208

Abstract

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

Figure 1

Trial design of Japan Clinical Oncology Group study, JCOG 9208. ABMT, autologous bone marrow transplantation; CAF, cyclophosphamide, doxorubicin, 5‐fluorouracil; G‐CSF, granulocyte colony‐stimulating factor; HDC, high‐dose chemotherapy; PBSC, peripheral blood stem cell; STD, standard‐dose; TAM, tamoxifen.

Figure 2

Trial profile of Japan Clinical Oncology Group study, JCOG 9208. *Registered after the start of cyclophosphamide, doxorubicin, 5‐fluorouracil (CAF; violation). **Bone marrow involvement was revealed before the start of CAF.

Figure 3

Relapse‐free survival (RFS) of all eligible patients in the Japan Clinical Oncology Group study, JCOG 9208. At 5 years, the intent‐to‐treat RFS of 47 eligible patients in the standard‐dose (STD) arm and 48 eligible patients in the high‐dose chemotherapy (HDC) arm was 37% and 52%, respectively (one‐sided log–rank, P = 0.17). Estimated median RFS time was 36 months for the STD arm and 60 months for the HDC arm.

Figure 4

Overall survival (OS) of all randomized patients in the Japan Clinical Oncology Group study, JCOG 9208. Five‐year OS of all randomized patients was 62% for the standard‐dose arm and 63% for the high‐dose chemotherapy arm (one‐sided log–rank, P = 0.78).