MILESTONES IN ADJUVANT THERAPY BREAST CANCER
In 1950s 2000
1950s Survival rate for stage IV breast cancer patients at MDA 1944 1954: 10.9% at 60 months, 3.3% at 120 months. (Previously untreated, systemic metastatic disease.)
1957 NSABP (National Surgical Adjuvant Breast Program) formed. Howard E. Skipper and Frank M. Shabel, Jr. show breast cancer can be cured by chemotherapy.
1958 First adjuvant therapy clinical trial: Halstead radical mastectomy1perioperative ThioTEPA.
1960s Survival rate for stage IV breast cancer patients at MDA 1955 1964: 9.9% at 60 months, 4.0% at 120 months.
1965 Roar Nissen-Meyer evaluates perioperative Cytoxan adjuvant therapy.
1966 Ezra M. Greenspan at Mount Sinai reports increased response to combination chemotherapy of
advanced breast cancer.
1968 Bernard Fisher reports significant increase in 5-year survival of premenopausal patients with .4
1969 Richard Cooper reports significant response in metastatic breast cancer from CMFVP. (ASCO
1970s Survival rate for stage IV breast cancer patients at MDA 1965 1974: 12.8% at 60 months, 4.7% at 120 months.
1973 Gianni Bonadonna begins Milan CMF-12 adjuvant therapy trial; Blumenschein and Geoffrey
Gottlieb write FAC protocol; MDA begins metastatic breast cancer trial.
1974 Aman Buzdar begins MDA adjuvant therapy trial with FAC.
1975 L-PAM NSABP trial in premenopausal patients; Stephen E. Jones and Sydney E. Salmon report adjuvant therapy with AC; CMF36 vs. CMF312 initiated by Bonadonna.
1976 NSABP moves to combination therapy with L-PAM and 5-FU; Milan CMF trial reported as positive for premenopausal patients with one to three positive nodes; FAC adjuvant therapy reported as positive by Buzdar as both pre- and postmenopausal patients with positive nodes have increased relapse-free survival.
1977 Buzdar, Blumenschein, and Gabriel Hortobagyi are criticized at meetings for being too aggressive and for using historical controls; NSABP moves to PMF, then to PFT and the breast oncology studies surge on; Bonadonna adds Adriamycin to CMF with CMFP1AV.
1978 The East Coast, Midwest, and West Coast go with CMF; Texas and Arizona stay with
1979 By this time, Adriamycin issues are clarified with respect to: (1) dose response, (2) dose rate,
(3) timing with irradiation, (4) pathologic prognostic factors, (5) combination with hormone
therapy, and (6) superiority to CMF questions answered with therapy of metastatic disease.
Kenneth D. Swenerton’s paper on prognostic factors is a cornerstone.
1980s Survival rate for stage IV breast cancer patients at MDA 1975 1984: 16.1% at 60 months, 7.4% at 120 months.
1980 NSABP discovers Adriamycin. First consensus report: No adjuvant therapy indicated for stage I breast cancer; adjuvant therapy indicated for node positive premenopausal patients and perhaps
for postmenopausal patients, if full dose used. FAC trial not recognized despite its superiority to
CMF because its evaluation was based on historical controls.
1981 PAFT introduced for patients who had failed CMF; VATH reported by James Holland.
1982 Sewa Legha reports decreased cardiac toxicity of Adriamycin using continuous infusion schedule. Bonadonna reports significance of ER status and dose on CMF outcomes.
1983 Study of Adriamycin followed by CMF vs. CMF alternating with Adriamycin begun by Milan
1985 First meta-analysis; Second Consensus Conference:
(1) established chemotherapy as standard of care for premenopausal patients with positive nodes.
(2) Adjuvant therapy not generally recommended for premenopausal patients with negative nodes.
(3) Tamoxifen recommended for postmenopausal patients with positive node and positive hormone receptor levels.
(4) Chemotherapy may be considered but cannot be recommended as standard practice for
postmenopausal patients with positive nodes and negative hormone receptor levels.
(5) Routine adjuvant therapy not recommended for postmenopausal patients with negative nodes but may be considered in high risk patients.
1986 MDA reports improved relapse-free survival of stage II patients with non-cross-resistant drug
combination consolidation therapy: MTX VLB following completion of FAC.
1987 NHDB (natural history database) and adjuvant therapy comparison study published by Jones.
Dose response relationship for Adriamycin in FAC clearly established using stage IV breast
1988 CALGB 8081 puts combined CAF1tamoxifen to rest.
1990s Survival rate for stage IV breast cancer patients at MDA 1985 1994: 17.4% at 60 months, 11.2% at 120 months.
1991 Arrival of Neupogen enables more intensive chemotherapeutic regimens. CALGB 8541 raises
issues regarding significance of HER2 receptor in adjuvant therapy outcomes: (1) confirms plateau
of Adriamycin efficacy at doses of 50 60 mg/m2 in adjuvant patients, (2) suggests deintensification
is not the same as intensification, (3) raises issue of studying dose response relationships in
adjuvant patients, (4) results misinterpreted with respect to optimum number of courses for
Adriamycin adjuvant therapy.
1991 Demonstration that a chemotherapeutic program could or would not induce permanent drug
resistance allowed reuse of Adriamycin to be considered if continuous infusion was used.
1992 Second meta-analysis of clinical trials.
1993 The drought of new chemotherapeutic agents is over with the introduction of Taxol followed by
Navelbine, Taxotere, Gemzar (gemcitabine).
1995 The East Coast returns to single agent dose-dense sequential trials in the adjuvant setting without trials in stage IV breast cancer. Dose intense Adriamycin followed by Taxol followed by Cytoxan. NSABP shows no benefit from Cytoxan escalation. After the third meta-analysis, 5-FU vanishes from FAC and CAF.
1996 The efficacy of two non-cross-resistant adjuvant programs is established, but there is a continuing need for improved non-cross-resistant combinations.
1998 CALGB 9344: AC34 followed by T34 vs. AC34. At the 18-month follow-up, AC34 followed
by T34 becomes the gold standard “penicillin” for breast cancer. Herceptin becomes available for
1999 Hortobagyi asks relevant questions regarding high-dose chemotherapy for breast cancer patients. High dose with autologous bone marrow transplantation is discredited. AC34 followed by Taxol34 sputters.
2000 Buzdar’s MDA data remains reliable and becomes a standard.
2000s Survival rate for stage IV breast cancer patients at MDA 1995 2004: 36.0% at 60 months, 22.2% at 120 months.