SYSTEMIC CHEMOTHERAPY AS AN ADJUVANT T O SURGERY IN THE TREATMENT

OF BREAST CANCER BERNARD FISHER, MD

HE CONCEPT OF ADMINISTERING A CHEMO- T therapeutic agent systemically in con- junction with radical mastectomy to decrease the recurrence rate and enhance survival of patients with breast cancer is an appealing one. It might be anticipated that such a thera- peutic regimen could destroy cells dislodged into the blood and lymph during surgical manipulation and,/or destroy minute meta- static foci of tumor which defy detection. To verify the value of such a therapeutic effort, a series of clinical trials involving the coopera- tive efforts of 45 institutions (Addendum) was begun in 1957 and became known as the National Surgical Adjuvant Breast Project. As a result of publicity accorded these studies at their onset-before their worth or danger was remotely established-adjuvant chemo- therapy was widely employed by many in the treatment of breast cancer. Only recently have definitive results of this project become known. While detailed findings have been published elsewhere,lv 2 this report will clar- ify the present status of such therapy in the treatment of breast cancer.

Women with clinically curable breast can- cer who met all of the protocol requirements were entered into the study between 1958 and 1961. They were randomized in double-blind fashion between the 2 treatment groups: 1. conventional Halsted radical mastectomy and Thio-TEPA (triethylenethiophosphoramide or TSPA), and 2. radical mastectomy with or without placebo (control). Patients received TSPA intravenously in a dose of either 0.8 or 0.6 mg/kg of body weight-0.2 or 0.4 mg/kg at the time of operation and 0.2 mg/kg on each of the first 2 postoperative days. Since analysis of data revealed no difference in

Presented at the First National Conference on Breast Cancer, Washington, D.C., May 8-10, 1969.

Supported by USPHS Grants CA-04180, CA-05848, CA-10377, HM-00474, and FR-5562.

Chairman, National Surgical Adjuvant Breast Proj- ect.

Address for reprints: Bernard Fisher, MD, Professor of Surgery, University of Pittsburgh School of Medi- cine, Pittsburgh, Pa. 15213.

Received for publication September 24, 1969.

those receiving one or the other dose, results have been combined. Direct recurrence and survival rate calculations were obtained from 826 acceptable study patients who com- pleted 5 years of follow-up.

There was no statistically significant differ- ence in incidence or type of local complica- tions encountered between those receiving TSPA or placebo. It was of interest, how- ever, to observe that approximately one third of the patients in each group had some un- desirable local surgical complication. Systemic complications were minimal and varied. There were fewer patients with such compli- cations in the TSPA group than in the con- trol group.

Recurrence and survival data were grouped according to nodal and menopausal status. Positive node patients were further subdi- vided into those having 1 to 3 or 4 or more such nodes. At the end of 5 years, there was no significant difference in recurrence rate between patients receiving TSPA or placebo in any of these 6 principal categories. If, how- ever, recurrence rates for TSPA -and placebo groups were plotted against time following surgery (similar to a plot of life table values), significant information was revealed which was not obtained by examination of data only at the end of 5 years. Whereas there was no significant difference between the 2 treatment groups at any time in 5 of the 6 menopausal and nodal categories, a difference was dis- cernible between the TSPA and placebo groups of premenopausal patients who had 4 or more positive nodes. TSPA-treated pa- tients in that category demonstrated a recur- rence rate between the eighteenth and thirty-sixth postoperative months which was approximately 40 percent less than in the placebo group. After that time, the number of recurrences in the TSPA-treated patients gradually increased so that by 48 months the groups were no longer significantly different. T h e effect of TSPA in this category is best demonstrated by the observation that 50 per- cent of patients in the placebo series had re-

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No. 6 SURGICAL ADJUVANT CHEMOTHERAPY IN BREAST CA * Fisher 1287

currences by the thirteenth month after sur- gery, whereas recurrences did not occur in half of the TSPA patients until the forty- fifth month of follow-up.

After 5 years of follow-up, survival rates for TSPA and placebo groups were not ap- preciably different except in those premeno- pausal patients with 4 or more positive nodes. In that category, there was a 33 per- cent greater survival rate for those patients who had received TSPA. The observation that 50 percent of those receiving TSPA were still living reflected the difference in recur- rence between the 2 groups. It might be an- ticipated that, since patients survive for a period of time following discovery of metasta- ses, the dissimilar survival would no longer be apparent at a later follow-up time.

The 5-year survival was 58 percent for all premenopausal patients and 65 percent for those postmenopausal. When menopausal status was disregarded, and patients were grouped according to nodal involvement, there was found to be a 5-year survival of 76 percent for all patients, treated or untreated, with negative nodes, and a 49 percent sur- vival in patients having any number of posi- tive lymph nodes. Those with 1-3 positive lymph nodes had a significantly greater sur- vival (62%) than did those with 4+ positive nodes. In the latter group, those receiving placebo had a 29 percent 5-year survival, whereas 40 percent were alive when TSPA was administered. The survival of all patients in the study regardless of nodal or meno- pausal status was 63 percent for those receiv- ing TSPA and 62 percent when placebo was administered.

With termination of patient entry in the above study in 1961, a new protocol was in- troduced. Its objective was to evaluate the worth of 5-fluorouracil (5-FU) compared to TSPA as an adjunct to surgery and to simi- larIy ascertain the value of postoperative ra- diotherapy and prophylactic oophorectomy. It was also hoped that confirmation or denial of the effects of TSPA observed in the first study would be forthcoming. By January 1968, there were 1341 patients who had re- ceived TSPA, placebo, or 5-FU and who had been followed for at least 18 months. More patients (1,725) were available for evaluation of postoperative complications and drug tox- icity. In this study, all TSPA patients received a total dose of 0.8 mg/kg-0.4 mg/kg on the day of surgery and 0.2 mg/kg on each of the

next 2 days. Those who were administered 5- FU received 15 mg/kg intravenously on each of 4 consecutive days beginning postopera- tive day 7 for a total of 60 mg/kg.

Fifty-two percent of patients who received 5-FU suffered local complications, and signifi- cantly more patients receiving that drug dem- onstrated systemic complications. Moreover, 42 percent of patients administered 5-FU be- came leukopenic and almost half of those had counts < 2,500. Of the 16 deaths occur- ring within 60 days following surgery in the 1,725 patients of this second study, 8 were re- cipients of 5-FU and all demonstrated toxic manifestations of the drug.

Just as in the first study, the only difference of note between TSPA treated and untreated patients was in premenopausal patients with 4+ positive nodes. Even here, the results were not as impressive as in the first study. While there was a 21 percent difference in favor of TSPA-treated patients, this difference was not statistically significant, there being a con- siderable overlap of confidence limits for the 2 groups (i.e., treated and placebo). Results obtained with 5-FU were not impressive. The tumor recurrence rate at 18 and 36 months following administration of 5-FU was essen- tially the same as that which was observed for those patients in both studies receiving pla- cebo, and demonstrated no improvement over those patients receiving TSPA in either men- opausal or nodal category. The recurrence rate in patients with 4+ positive nodes who were given 5-FU was significantly greater than for similar patients receiving TSPA (54% versus 36%).

Aside from the observation that TSPA de- layed recurrence of tumor in premenopausal patients with 4 or more positive nodes, results obtained with the 2 chemotherapeutic agents (TSPA and 5-FU) were disappointing. In no other subgroup of patients were there benefits which could be attributed to either drug. Consequently, further use of either agent as employed in these studies seems unwar- ranted in postmenopausal women with or without positive lymph nodes. While there is reason to use TSPA in premenopausal pa- tients-those with more than 3 positive lymph nodes-the high incidence of local, hemic, and systemic complications as well as its failure to elicit an antitumor effect pre- cludes further use of 5-FU in the regimen de- scribed as an adjunct to surgery in such pa- tients.

1288 CANCER December 1969 Vol. 24

I t is to be emphasized that the findings to date, while not dramatic, do not repudiate the concept of systemic adjuvant therapy. Un- til cancer of the breast can be prevented or a therapy becomes available which is capable by nonsurgical means of destroying both pri- mary and secondary tumors, systemic therapy as an adjunct to surgery should provide the most likely means for escape from the pla- teau on wilich the salvage rate of this d: isease has been ensnared for 30 or more years. Knowledge and hypotheses which have ac- cumulated since the advent of the studies re- ported here suggest that perhaps the original considerations upon which they were based resulted from oversimplification of the b i e logical complexities of such therapeutic regi- mens. Information relative to cell cycling time and the possibility that a. cells are drug sensitive during only part of their mitotic cy- cle; b. therapeutic success may be equally or more dependent upon destruction of occult metastases than upon free cells in the circula- tion; c. the percent reduction of neoplastic cells for a given treatment is constant regard- less of the number of cells present; and d. host immunologic factors may be involved, has assumed importance in this regard.

The concept of prolonged adjuvant chem- otherapy utilizing either a single or combina- tion of chemotherapeutic agents has arisen from these considerations. Justification for such administration of potentially hazardous chemotherapeutic agents to patients with clinically curable cancer may be challenged. At the present time such criticism may be justified in so far as their use in patients with

negative axillary nodes is concerned. The rel- atively low 5-year recurrence rate (20%) in that group makes it mandatory to carefully appraise the risks involved with the benefits to be obtained. In patients with positive lymph nodes, and, in particular, those with 4 or more involved where the 5-year recur- rence rate is approximately 75 percent, greater toxicity would be tolerable if a signifi- cant reduction in development of metastases could be effected.

As a consequence, it would seem that rig- idly controlled clinical trials by cooperative groups utilizing only high risk patients with curatiue breast cancer, i.e., those with positive nodes, will supply the most meaningful re- sults relative to the worth of an adjuvant therapeutic agent in the shortest period of time. It has been pointed out3 that “a diver- sity of trials in a diversity of places at differ- ent times-is possibly the strongest evidence one can see oE the worth of treatment before it is employed on the whole population.”

The National Surgical Adjuvant Breast Project has been established for such a pur- pose. I t provides the opportunity for such cooperative endeavors having as their objec- tive the clinical evaluation of the worth of certain modalities which may in conjunction with surgery improve results. Those institu- tions whose members recognize the urgency of such an effort are invited to participate. Only when enough of those concerned with the primary treatment of breast cancer appre- ciate their obligation in this regard, is there apt to be further progress in the treatment of this disease.

ADDENDUM

Administration of National Surgical Adjuvant Breast Project was composed of the following:

Executive committee: Bernard Fisher, MD, Chair- man, Pittsburgh; George E. Moore, MD, PhD, Ros- well Park; Robert K. Ausman, MD, Roswell Park: Patrick J. Cavanaugh, MD, Duke; Isidore Cohn, Jr.. MD, L.S.U.; Lewis W. Cuiss, MD, Southern California; Edward F. Lewison, MD, Johns Hopkins; James J. Nickson, MD, Michael Reese: Robert G. Ravdin, MD, Pennsylvania: Louis M. Rousselot, MD, Deputy As- sistant Secretary of Defense for Health and Medicine; Robert Robbins, MD, Temple.

Statistical seruice: Roswell Park Memorial Institute, Buffalo: Irwin D. J . Bross, PhD, Chief; Nelson H. Slack, PhD.

Project pathologist: Roswell Park Memorial Insti- tute, Buffalo: John Pickren, MD.

Participating institutions:

Hospital or University

Alabama Albany Albert Einstein American Oncologic

Baylor Boston California Cincinnati Cornell Duke

Emory George Washington

Hospital

Principa I Investigator Champ Lyons, MD Charles Eckert, MD Herbert Volk. MD

Joseph C . Strawitz, MD Michael E. DeBakey, MD Henry M. Lemon, MD Leon Goldman, MD William Altemeier, MD George N. Cornell, MD William W. Shingleton,

John D. Martin, Jr.. MD T. Crandall Alford, MD

MD

No. 6 SURGICAL ADJUVANT CHEMOTHERAPY IN BREAST CA - Graduate Hospital of

Univ. of Pennsylvania

Hahnemann Harbor General Hospital Iowa Johns Hopkins Kings County Louisiana State Louisville Marquette Maryland

McGill Medical College of

Memorial Hospital (N.Y.) Miami Michael Reese Hospital Mississippi

Evangelists

William S. Blakemore,

John M. Howard, MD James C. Thompson, MD R. T. Tidrick, MD Edward F. Lewison, MD Bernard Gardner, MD Isidore Cohn, Jr., MD Rudolf J. Noer, MD Edwin H. Ellison, MD Arlie E. Mansberger, Jr.,

John D. Palmer, MD Clarence E. Stafford, MD

Joseph H. Farrow, MD Daniel S. Martin, MD Gerald Peskin, MD James D. Hardy, MD

MD

MD

Nebraska Ohio State Oregon

Pennsylvania Penrose Cancer Hospital Pittsburgh Puerto Rico Roswell Park Southern California St. Luke’s Hospital St. Vincent’s Hospital Temple Tulane

UCLA Vanderbilt Wayne State

Wisconsin

Fisher 1289 Daniel M. Miller, MD Neil C . Andrews, MD William W. Krippaehne,

Robert G. Ravdin, MD Juan A. del Regato, MD Bernard Fisher, MD Luis A. Vallecillo, MD Thomas L. Dao, MD Lewis W. Guiss, MD Harold A. Zintel, MD Louis M. Rousselot, MD George P. Rosemond, MD Edward T. Krementz,

Donald B. Rochlin, MD William Scott, Jr., MD Henry J. VandenBerg,

Anthony R. Curreri, MD

MD

MD

Jr., MD

REFERENCES

1. Cohn, I., Slack, N. H., and Fisher, B.: Complica- a decade of cooperative investigation. Ann Smrg. 168: tions and toxic manifestations of surgical adjuvant 337-356, 1968. chemotherapy for breast cancer. Surg. Gynec. Obstet. 127:1201-1209, 1968. 3. Schneiderman, M. A.: The value of controlled 2. Fisher, B., Ravdin, R. G., Ausman, R. K., Slack, trials. I n Clinical Evaluation in Breast Cancer, J. L.

N. H., Moore, G. E., and Noer, R. J.: Surgical adju- Hayward and R. D. Bulbrook, eds. New York, Aca- vant chemotherapy in cancer of the breast: results of demic Press, 1966; pp. 249-255.