Aust. N . Z . J . Surg.
1992,62,450-462
ADJUVANT SYSTEMIC THERAPY IN BREAST CANCER PART II: ADJUVANT CHEMOTHERAPY KEN w. TIVERAND JOHN BOYAGES Department of Radiation Oncology, Westmead Hospital, Westmead, New South Wales, Australia
Introduction Initial clinical investigation of adjuvant chemotherapy was based on laboratory studies from the 1950s. These studies suggested that chemotherapy may be more effective in conjunction with surgical removal of the primary tumour when tumour burden is least.’.’ Further, there was an increasing awareness that patients were not often cured by local treatments alone. The success of adjuvant chemotherapy for some childhood malignancies and the suggestion of some benefit from adjuvant ovarian ablation led to the intensive study of adjuvant chemotherapy in adult solid turnours such as breast cancer. Initial trials of adjuvant chemotherapy involved short courses of single drugs administered intra-operatively or in the immediate postoperative period (peri-operative therapy). Subsequent trials involved the study of long-term administration of single agent chemotherapy. More recent studies have involved long-term administration of multiple drugs in combination. This report examines the published randomized controlled trials of adjuvant chemotherapy (single or multi-agent). Randomized studies that have been published only in abstract form were excluded from this review because detailed methodology and results were not available. The effect of adjuvant chemotherapy on diseasefree survival (defined as time from diagnosis until first relapse), overall survival (defined as time from diagnosis until death) and local tumour control are examined. Improvements in these parameters referable to adjuvant treatment were considered statistically significant if the published or calculated (x2)P value was S 0.05. The effect of adjuvant chemotherapy on disease-free survival by menopausal and nodal status and issues such as optimal dose and duration, toxicity and mechanism of action of adjuvant chemotherapy are also discussed.
Correspondence: J. Boyages, Westmead Hospital, Westmead, NSW 2145, Australia. Accepted for publication 14 November 1991.
Adjuvant single agent chemotherapy EARLY PERl-OPERATIVE STUDIES
Peri-operative chemotherapy was primarily devised to counter the possible dissemination of tumour cells at the time of mastectomy. Six studies have reported evaluable data (Table 1). Three showed a significant improvement in disease-free survival and none showed a significant overall survival advantage for the use of peri-operative chemotherapy. 3-8 A large Scandinavian trial provided long-term follow-up data for over 1000 patients. At 10 of the 11 participating hospitals, patients who were randomized to the treatment arm received intravenous cyclophosphamide for 6 days commencing immediately after closure of the surgical wound (‘surgical series’). At the other hospital, the same chemotherapy was given 2-4 weeks after surgery following referral for postoperative radiation therapy (‘radiological series’).’ In subsequent publications, analysis was restricted to the surgical series in which immediate peri-operative chemotherapy significantly improved disease-free survival by 10%. This improvement was maintained for up to 20 years of follow-up. A significant overall survival benefit was demonstrated for the treated group up to 6 years after mastectomy. After 6 years differences in overall survival between the two arms were not statistically significant although when survival was corrected for intercurrent deaths, a significant difference (P < 0.02) favouring chemotherapy was maintained for up to 20 years.’ In the radiological series, in whom chemotherapy was delayed, no significant improvement in disease-free survival or overall survival was found. These data suggest that the timing of the initiation of chemotherapy may be important. In 1980 the Cancer Research Campaign (CRC) in the United Kingdom repeated the Scandinavian study in over 2000 patients. At a median follow-up of 40 months, disease-free survival was significantly improved by 3% (73 vs 70%; P = 0.045) but overall survival was not improved by treatment with cycloph~sphamide.~
1962-7 1 1965-75 1980-85
?
1958-61 1961-67
Accrual dates
826 657 83 287 1026 2230
No. patients Both Both Both Both Both Both
Menopausal status Nf N+ N+ N+ N+ N t
Nodal status THIO 5-FU CPM CPM CPM CPM
Drug
1956-? 1962-76 1963-72 1972-74 1975-79 1975-79 1977-82 1977-83
Illinois-USA" Japan15 Col~mbia-USA'~ NSABP-BO5 I USSR' G~ys-Manchester'~ Denmark"' Oxford-UK'2
Menopausal status Both Both Both Both Both Both Pre & Peri Both
No. oatients
I56 324 I67 380 408 370 61 1 175
See table I and appendix for abbreviations; PRE = premenopausal, PER1
Accrual dates
Trial
=
NM CPM THIO LPAM THIO LPAM CPM LPAM
Drug
perimenopausal
N+ N+ N+ N+ N+ N+ Nf
N+
Nodal status
Table 2. Randomized trials of adjuvant single agent chemotherapy: Postoperative
= actuarial.
51 52 63 72 40 70 0.045
1992,62,450-462
ADJUVANT SYSTEMIC THERAPY IN BREAST CANCER PART II: ADJUVANT CHEMOTHERAPY KEN w. TIVERAND JOHN BOYAGES Department of Radiation Oncology, Westmead Hospital, Westmead, New South Wales, Australia
Introduction Initial clinical investigation of adjuvant chemotherapy was based on laboratory studies from the 1950s. These studies suggested that chemotherapy may be more effective in conjunction with surgical removal of the primary tumour when tumour burden is least.’.’ Further, there was an increasing awareness that patients were not often cured by local treatments alone. The success of adjuvant chemotherapy for some childhood malignancies and the suggestion of some benefit from adjuvant ovarian ablation led to the intensive study of adjuvant chemotherapy in adult solid turnours such as breast cancer. Initial trials of adjuvant chemotherapy involved short courses of single drugs administered intra-operatively or in the immediate postoperative period (peri-operative therapy). Subsequent trials involved the study of long-term administration of single agent chemotherapy. More recent studies have involved long-term administration of multiple drugs in combination. This report examines the published randomized controlled trials of adjuvant chemotherapy (single or multi-agent). Randomized studies that have been published only in abstract form were excluded from this review because detailed methodology and results were not available. The effect of adjuvant chemotherapy on diseasefree survival (defined as time from diagnosis until first relapse), overall survival (defined as time from diagnosis until death) and local tumour control are examined. Improvements in these parameters referable to adjuvant treatment were considered statistically significant if the published or calculated (x2)P value was S 0.05. The effect of adjuvant chemotherapy on disease-free survival by menopausal and nodal status and issues such as optimal dose and duration, toxicity and mechanism of action of adjuvant chemotherapy are also discussed.
Correspondence: J. Boyages, Westmead Hospital, Westmead, NSW 2145, Australia. Accepted for publication 14 November 1991.
Adjuvant single agent chemotherapy EARLY PERl-OPERATIVE STUDIES
Peri-operative chemotherapy was primarily devised to counter the possible dissemination of tumour cells at the time of mastectomy. Six studies have reported evaluable data (Table 1). Three showed a significant improvement in disease-free survival and none showed a significant overall survival advantage for the use of peri-operative chemotherapy. 3-8 A large Scandinavian trial provided long-term follow-up data for over 1000 patients. At 10 of the 11 participating hospitals, patients who were randomized to the treatment arm received intravenous cyclophosphamide for 6 days commencing immediately after closure of the surgical wound (‘surgical series’). At the other hospital, the same chemotherapy was given 2-4 weeks after surgery following referral for postoperative radiation therapy (‘radiological series’).’ In subsequent publications, analysis was restricted to the surgical series in which immediate peri-operative chemotherapy significantly improved disease-free survival by 10%. This improvement was maintained for up to 20 years of follow-up. A significant overall survival benefit was demonstrated for the treated group up to 6 years after mastectomy. After 6 years differences in overall survival between the two arms were not statistically significant although when survival was corrected for intercurrent deaths, a significant difference (P < 0.02) favouring chemotherapy was maintained for up to 20 years.’ In the radiological series, in whom chemotherapy was delayed, no significant improvement in disease-free survival or overall survival was found. These data suggest that the timing of the initiation of chemotherapy may be important. In 1980 the Cancer Research Campaign (CRC) in the United Kingdom repeated the Scandinavian study in over 2000 patients. At a median follow-up of 40 months, disease-free survival was significantly improved by 3% (73 vs 70%; P = 0.045) but overall survival was not improved by treatment with cycloph~sphamide.~
1962-7 1 1965-75 1980-85
?
1958-61 1961-67
Accrual dates
826 657 83 287 1026 2230
No. patients Both Both Both Both Both Both
Menopausal status Nf N+ N+ N+ N+ N t
Nodal status THIO 5-FU CPM CPM CPM CPM
Drug
1956-? 1962-76 1963-72 1972-74 1975-79 1975-79 1977-82 1977-83
Illinois-USA" Japan15 Col~mbia-USA'~ NSABP-BO5 I USSR' G~ys-Manchester'~ Denmark"' Oxford-UK'2
Menopausal status Both Both Both Both Both Both Pre & Peri Both
No. oatients
I56 324 I67 380 408 370 61 1 175
See table I and appendix for abbreviations; PRE = premenopausal, PER1
Accrual dates
Trial
=
NM CPM THIO LPAM THIO LPAM CPM LPAM
Drug
perimenopausal
N+ N+ N+ N+ N+ N+ Nf
N+
Nodal status
Table 2. Randomized trials of adjuvant single agent chemotherapy: Postoperative
= actuarial.
51 52 63 72 40 70 0.045
