The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up

BACKGROUND: Adjuvant systemic therapy prolongs disease-free and overallsurvival in both pre- and postmenopausal patients. Availabledata shown benefit from multi-agent chemotherapy, prolongedtamoxifen treatment, and ovarian ablation, and that the combinationof chemo- and endocrine therapy might be advantageous. In 1978the International (Ludwig) Breast Cancer Study Group (IBCSG)initiated four complementary randomized controlled clinicaltrials to evaluate the roles of chemo-endocrine combinationsor endocrine therapy alone in specific populations defined byrisk (for pre- and perimenopausal patients) or by age (for postmenopausalpatients). The results at 10 and 13 years' median follow-upfor these trials are summarized in this report and are comparedto those of the Overview meta-anal-ysis with regard to chemo-endocrineor endocrine therapy combinations. Furthermore, types of firstrelapses by sites and second malignant diseases are reported. PATIENTS AND METHODS: 1601 evaluable patients with node positive disease were includedinto the studies I–IV. In Trial I (491 premenopausal patientswith 1–3 positive axillary nodes) we studied the additionof low-dose continuous prednisone (p) to a cyclophosphamide-methotrexate-fluorouracil(CMF) combination. In Trial n 327 premenopausal patients withfour or more positive axillary nodes were randomized to oneyear CMFp or to a surgical oophorectomy followed by CMFp. InTrial III (463 postmenopausal patients 65 years old or younger),combined chemoendocrine therapy (one year of CMFp plus tamoxifen(T)) was compared to endocrine therapy (1 year of p + T) orto surgery alone. In Trial IV 320 postmenopausal patients 66to 80 years old were treated either by surgery alone or by surgeryfollowed by 1 year prednisone and tamoxifen. RESULTS: In Trial I the addition of prednisone allowed a higher doseof cytotoxics to be administered compared with CMF alone. Despitethis increased dose intensity, 13-year disease-free survival(DFS) and overall survival (OS) were similar for the two treatmentgroups (49% vs. 52% DFS, 59% vs. 65% OS for CMFp vs. CMF). InTrial II the addition of surgical oophorectomy to CMFp yieldedan improved outcome which approached statistical significancefor the subset of 107 patients known to have estrogen receptor-positivetumors (DFS, 23% vs. 15%, p