CALGB Tormey 1984a.

Study characteristics
Methods	Multi‐centre international randomised controlled trial. 3 arm trial. Method of randomisation and allocation concealment not reported. Accrual commenced in 1974. Baseline comparability achieved.
Participants	396 randomised (302 evaluable). Women with progressive metastatic breast carcinoma. No prior chemotherapy Median age of entry 54‐57 yrs across each arm.
Interventions	Comparison 1: CAFVP vs CMFVP‐Continuous Arm A: CAFVP cyclophosphamide 80mg/m2 po q day, adriamycin 25mg/m2 iv q week, 5‐fluorouracil 500mg/m2 i.v. q week, vincristine 1.0mg/m2 iv q week, prednisone 40mg/m2 po day 1‐14. 28 day cycles. After 6 cycles of CAFVP, cross‐over to CMFVP‐I. Arm B: CMFVP‐C cyclophosphamide 80mg/m2 po.daily, methotrexate 40mg/m2 iv weekly, 5‐fluorouracil 500mg/m2 iv weekly, vincristine 1.0mg/m2 iv weekly, prednisone 30mg/m2 days 1‐21 then tapering to zero over 7 days. 12 weeks of therapy then a 2 week break followed by maintenance therapy with cyclophosphamide 80mg/m2 po daily, methotrexate 40mg/m2 i. q 3weeks, 5‐fluorouracil 500mg/m2 iv q 3weeks, vincristine 1.0mg/m2 iv q6weeks, and from week 18 additional prednisone 30mg/m2 po days 1‐7
Outcomes	Response Overall survival Time to treatment failure Toxicity
Notes	3 arm trial. 2 comparisons used in this meta‐analysis: CAFVP vs CMFVP‐C, CAFVP vs CMFVP‐I. ITT analysis not followed. Time to event data based on 302/396 patients. Follow‐up time not reported. Est min f/up =9.3 months (median time to treat failure, average over 3 arms), est max f/up = 48 months (from survival curve). The median time for overall survival was 19 months for CAFVP compared to 13 months for CMFVP‐I (p=0.01) and 16 months for CMFVP‐I (p=0.24). The time to treatment failure for CAFVP was also statistically significantly longer than CMFVP‐I (p=0.01) but not CMFVP‐C (p=0.09). The CR+PR median remission duration was 14 months for CAFVP compared to 7 months for CMFVP‐I (p<0.01) and 9 months for CMFVP‐C (p=0.07). Using reported table percentages, 10% of deaths associated with toxicities in CAFVP arm (cardiac toxicity 1%, sepsis 4%, leukopenia 3%, thrombocytopenia 1%, GI toxicity 1%); 10% in the CMFVP‐C arm (cardiac toxicity 1%, sepsis 5%, leukopenia 3%, thrombocytopenia 1%); and 18% in the CMFVP‐I arm (cardiac toxicity 1%, sepsis 8%, leukopenia 7%, thrombocytopenia 1%, GI toxicity 1%). Total number of treatment‐related deaths not estimable from table. One death associated with cardiac toxicity in each arm, and 2 additional pts with severe non‐fatal cardiac toxicity and 4 pts with mild CHF observed in CAFVP arm.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear