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The Management of Metastatic Breast Cancer
The Management of Metastatic Breast Cancer Prom the Department of Surgery, Presbyterian Medical Center, San Francisco, California
LEONARD DOBSON, M.D. Clinical Professor of Surgery, Stanford University School of Medicine, Palo Alto; Chief of the Tumor Clinic, Presbyterian Medical Center
GENERAL PROBLEM CANCER of the breast is the most common cancer of the female in the United States. Of an annual incidence of 60,000 cases, about 18,000 will be inoperable when first examined. Of the 42,000 operated upon, 60 per cent or more will have recurrence or metastases within ten years. Thus, there is constantly a very large group of women with various stages of metastatic cancer. Since the problem of obtaining maximum palliation for this large group is so tremendous, the medical literature dealing with all stages of breast cancer is probably larger than that of any other malignant disease. Although breast cancer has been studied extensively for more than 70 years, there are few situations in the management that are not controversial. There continue to be debates concerning the best initial treatment, the role of irradiation, which chemotherapeutic agent, if any, should be used initially, and the role of prophylactic castration. When metastases appear, arguments arise as to which hormones should be used first and subsequently. Should the endocrine therapy be staged and lead gradually to ablative therapy, or will the longest palliation be obtained by going directly to hypophysectomy or adrenalectomy? Of the many chemotherapeutic agents now available, which is most effective under different conditions? Several recent articles 1- 6 have dealt with the general problem of metastatic breast cancer. An attempt will be made to correlate the material and bring it up to date. 861
862
LEONARD DoBSON
THE SELECTION AND SEQUENCE OF THERAPY
There are two main schools of thought regarding the most effective sequence of various methods of treatment. Realizing that palliation is all that is possible in metastatic breast cancer, the aim of everyone treating this disease is to give the patient the longest, happiest, most comfortable remaining period of life that is possible with our present knowledge. Probably the majority of doctors favor the "step-by-step" method of obtaining the longest possible remission from one hormone or procedure before trying another. This has been likened to a "delaying action" in military parlance. The advocates of this method believe that the combined periods of remission will be longer than can be obtained by going directly to hypophysectomy or adrenalectomy. On the other hand, there are strong proponents for what has been called the "blockbuster" or "massive assault" approach, with adrenalectomy or hypophysectomy as the initial method. However, it has not yet been definitely established which sequence of treatment gives the longest period of comfortable life. We have subscribed to the "step-by-step" school (Stanford University Hospitals in San Francisco previous to 1959 and the Presbyterian Medical Center since 1959). A patient's menstrual age is most important in deciding on the initial method of treatment. The Subcommittee on Breast and Genital Cancer of the Committee on Research,1 2 which reported on the results obtained in 944 patients, concluded that after the fourth postmenopausal year estrogens are the agents of choice. The overall regression rate for estrogens was 38 per cent and for androgens 27 per cent. Further conclusions of this extensive and carefully controlled study were that estrogens are superior to androgens in soft tissue and equal or superior for skeletal and visceral metastases. Another interesting observation was that androgens were more effective with postmenopausal patients after 17 or more years, for they produced objective regressions in nearly 30 per cent of these patients, but in only 20 per cent of premenopausal women. Table 1 shows the suggested sequence of therapy for the group of women from premenopause through the fourth year of postmenopause. This group should be castrated, preferably by surgery. Thirty to 40 per cent of those castrated will have remissions of approximately ten months' duration. When the benefits of the castration cease, a course of androgens (Table 3) should be tried. When the benefits of that treatment cease, either adrenalectomy or hypophysectomy should be done. A regression rate of about 30 per cent is obtained from each of these procedures (Table 6). A higher rate of regression is obtained by these ablative procedures when they are done in patients who have had a good response to previous hormonal alterations. One of the cortico-
The M anagernent of Metastatic Breast Cancer Table 1.
863
Suggested Sequence of Therapy in Patients Premenopausal and Through the Fourth Postmenopausal Year
PREMENOPAUSAL +5th year POSTMENOPAUSAL BILATERAL OOPHORECTOMY
J
~
PREDNISONE
ADRENALECTOMY
HYPOP~~/ CHEMOTHERAPY 5·FU Thio-TEPA
Cytoxan
Table 2.
Suggested Sequence of Therapy in Patients Five or More Years Postmenopausal POSTMENOPAUSAl • 5 yrs plus ESTROGENS
J
~
PREDNISONE
ADRENALECTOMY
HYPOP:~/ CHEMOTHERAPY 5-FU Thio-TEPA
Cytoxan
steroids (Table 5) should be tried if the patient refuses further ablative therapy. When these drugs are no longer effective a course of nonhormonal chemotherapy (Table 7) should be tried. During the past two years the percentage of remissions has improved through more experience in the administration of these toxic drugs. (See section on Nonhormonal Chemotherapy.) The second main group of patients, those who are postmenopausal by five or more years, is shown on Table 2. If those nearest the menopause have elevated estrogen levels as shown by vaginal smears and by significant urinary estrogen excretion, then we would do a castration. Most patients in this group in Table 2 we would treat with estrogens
864
LEONARD DOBSON
(Table 4). (References on hormone therapy include 7 through 21.) The steps in therapy are shown. The standard of reference for estrogens is diethylstilbestrol and for androgens testosterone proprionate. ENDOCRINE TREATMENT
ADDITIVE HoRMONES The additive hormones which are most effective in treating recurrent breast cancer include androgens, estrogens and corticosteroids: Androgens
Adair 7 in 1946 described the beneficial effects of testosterone in advanced breast cancer. This has been confirmed by numerous reports.8· 10 • 12-15, 1 7, 20 • 21 The Subcommittee on Breast and Genital Cancer in 196012 reported an objective regression rate of 20 per cent in premenopausal women and an overall regression rate of 27 per cent. Testosterone is most effective in the postmenopausal group. The androgens most commonly used are listed in Table 3. If regression occurs, the androgen Table 3.
Androgens Commonly Used in Additive Hormone Therapy SYSTEMIC
THERAPY .. ·ADDITIVE (J) ANDROGENS
Testosterone proprio nate Fluoxymesterone (HalotestinJ Testosterone enanthate (Delatestryl)
JOO mg.
JO mg.
200 mg.
3 x weekly
I. M.
3 x claily
Oral
q.2 weeks
I.M.
should be continued until it is no longer effective. The indications and complications of the use of androgens have been thoroughly described in many articles. REBOUND PHE~OMENON. It has long been noted that in a small percentage of cases (2 per cent in androgens and 5 per cent in estrogens 16 ) there are remissions lasting as long as six or more months after a discontinuance of the use of the drug. Estrogens
The beneficial effects of estrogens in advanced breast cancer were first reported in 1944. 9 The indication for the use of estrogens depends on
The Management of Metastatic Breast Cancer Table 4.
865
Estrogens Commonly Used in Additive Hormone Therapy SYSTEMIC THERAPY ... ADDITIVE (2)
ESTROGENS
Diethylstilbestrol
5 mg. t.i.d. Oral (enteric coated)
Ethinyl estradiol
l mg.
t.i.d.
Estradiol benzoate
5 mg.
3 x weekly I. M.
Estradiol valerate
30 mg.
Oral
q. 2 weeks
the menopausal status rather than the sites of disease, and patients with recurrent breast cancer who are more than four years postmenopausal should have estrogens as their primary therapy (Table 2). The Subcommittee on Breast and Genital Cancer12 reports an overall regression rate of 38 per cent. The indications for the use of estrogens are listed in the section on "Selection and Sequence of Therapy." The estrogen should be continued as long as it is effective. A few patients have obtained remission for three or more years from this treatment alone. The most commonly used estrogens are listed in Table 4. The indications and complications have been described in numerous publications. Corticosteroids Cortisone and its derivatives have generally been reserved for usage late in the course of the disease, or when adrenalectomy or hypophysectomy has been refused (Tables 1 and 2). Frequently used corticosteroids are listed in Table 5 .. Corticoids are particularly useful in Table 5. Corticosteroids Commonly Used in Additive Hormone Therapy SYSTEMIC THERAPY···ADDITIVE [3] CORTICOSTEROID
Prednisone
20-60 mg Oral daily
Cortisone
J00•300 mg Oral daily
Decadron
2 - 6 mg Oral daily
866
LEONARD DoBSON
hypercalcemia, impaired liver function, and central nervous system involvement. 2- 6 • 11 • 18 • 19 ABLATIVE THERAPY
Castration
The value of bilateral oophorectomy in the palliation of inoperable advanced breast cancer has been repeatedly established during the past 60 years. Beatson in 189623 first pointed out the beneficial effects of castration in advanced inoperable breast cancer. Lett in 190527 confirmed Beatson's results by reporting the effects of castration in 99 cases of inoperable breast cancer. Numerous articles, 22 • 24- 26 • 28- 33 have appeared since Lett's article and it is accepted that 30 to 40 per cent remissions can be expected from castration in selected cases. The value of castration as a prophylactic measure is very difficult to prove. Horsley, 26 Treves, 33 Rosenberg/ 8 Hadfield25 and Smith29 have advocated prophylactic castration in premenopamal women with breast cancer. Others, including Taylor 30 and Kraft and Block, 5 state that they ran a series of prophylactic castrations and have given up this treatment as a prophylactic measure. Most authorities employ castration only in the presence of advancing disease. All premenopausal women with progressive recurrent breast cancer and postmenopausal patients who have elevated estrogen levels, as shown by vaginal smears and significant urinary estrogen excretions, should be castrated. To accomplish the castration, bilateral oophorectomy is the generally accepted method of choice. Adequate irradiation of the ovaries will accomplish castration, but since it requires as long as 120 days to bring the estrogen down to the minimum level, it is much slower than is surgical castrati0n. Because about 40 to 45 per cent of breast cancers are hormone controlled, remissions are obtained in about 40 per cent of cases selected for castration, and the remission continues for ten months on the average. Castration in the male with breast cancer is often more effective than in the female. 32 Choice Between Adrenalectomy and Hypophysectomy
When cortisone became available for general use in 1951, it became possible to remove the pituitary or both adrenals in the treatment of malignant tumors. This procedure was of particular value in those breast cancers that were hormone controlled. Trials of one or both procedures were begun in centers throughout the world. Consequently, techniques for both the medical management and the operative procedures were
867
The Management of Metastatic Breast Cancer
gradually developed, and the morbidity and mortality considerably lessened. Some centers confined their investigations to one or the other of the ablative procedures, and a few used randomized cases to compare both procedures. The conclusions from these studies were often entirely different. For example, Atkins 35 • 36 concluded that hypophysectomy was more effectual and that the mortality was lower than in their experience with adrenalectomy. Kraft and Block, 5 however, report a higher remission rate and lower mortality and morbidity rate with adrenalectomy. Numerous articles have been published during the past eight years with the results favoring one or the other of the procedures. Then the Joint Committee on Endocrine Ablative Procedures published a preliminary report 34 with the conclusions that the results of the two procedures were nearly identical in all respects~mortality, percentage of regressions, and duration of regressions (Table 6). Table 6 COMPARISON OF REGRESSIONS FOLLOWING ADRENALECTOMY AND HYPOPHYSECTOMY* Adrenalectomy Total cases P.O. Deaths Cases evaluated Regression Per cent regression Ablation to death Number Months (mean) R+ R-
Hypophysectomy
404 37 315 100
467 42 358 112 31.3
31.7
R+ 78 22.0
R203 7.6
R+ 78 20.6
R221 6.5
Responsive to ablation Nonresponsive to ablation
*Report of Joint Committee on Endocrine Ablative Procedures. J.A.M.A. 175: 787-790 March 4, 1961
It would appear, therefore, that once the decision is made to do either an adrenalectomy or hypophysectomy, the degree of perfection in the performance of either operation in that particular institution or locality is more important than the type of operation. Throughout the world there are differences of opinion as to whether the adrenalectomy or hypophysectomy should be done early or late in the disease. Pearson and Ray, 59- 62 Luft and Olivecrona55 • 56 • 57 and McCalister58 favor early hypophysectomy. Cade37 advocated earlier
868
LEONARD DoBSON
adrenalectomy. Oberhelman21 states he is conducting a study on the value of the prophylactic use of oophorectomy and adrenalectomy in premenopausal and early postmenopausal patients with extensive axillary metastases or with an unusually large, rapidly growing tumor. Such a case was reported by Dragstedt. 39 Adrenalectomy
Postmenopausal women often continue to secrete significant amounts of estrogen. After castration there is only a temporary absence of estrogen in the urine. The adrenal glands secrete estrogens, and to eliminate this source, Huggins performed the first successful adrenalectomy for breast cancer in 1951. 42 The correctness of Huggins' deductions for the palliation of hormone-controlled breast cancer has been verified by numerous articles. 34- 46 It would be extremely valuable to determine which cases would respond favorably to adrenalectomy or hypophysectomy. Patients who are most likely to be benefited by adrenalectomy or hypophysectomy are (1) those who were benefited by castration, (2) those who are in their forties or fifties, and (3) those who had a period of three or more years before metastases appeared. There is general agreement that patients with brain and liver metastases do not respond favorably to either of the ablative procedures. Kambouris43 states that 948 cases of bilateral adrenalectomy had been reported by June, 1960, so probably more than 2000 adrenalectomies have been done by January, 1962. The Joint Committee on Endocrine Ablative Procedures34 reported a regression rate of 31.7 per cent with a duration of 22 months in responsive cases and of 7.6 months in nonresponsive cases (Table 6). Hypophysectomy
Luft and Olivecrona55 were the first to report a concerted effort to determine the effects of hypophysectomy in cancer patients. Since then, an extensive bibliography has accumulated from the experience gained from hundreds of hypophysectomies. Because estrogenic hormones, androgenic hormones, and growth hormones are, under certain physiologic conditions, a stimulus to the growth of breast cancer, the removal of the pituitary gland should eliminate these stimulating factors. Numerous articles have been published concerning the technique and results of hypophysectomyY· 48 • 52 • 53 • 55-6 2 The Preliminary Report of the Joint Committee on Endocrine Ablative Procedures34 listed a regression rate of 31 per cent for periods of 6.5 months in nonresponsive cases to 20.6 months in responsive cases.
869
The Management of Metastatic Breast Cancer OTHER METHODS
OF ATTEMPTING ABLATION
OF THE
PITUITARY.
Attempts to destroy or remove the pituitary by means other than a craniotomy include (1) proton irradiation, 54 (2)_ interstitial irradiation by Yttrium-90, 50 (3) alpha particle irradiation of the pituitary, 49 and (4) transseptal-sphenoid subtotal hypophysectomy. 51 These procedures are still in the experimental stage and so far have not been as effective as adrenalectomy and hypophysectomy. NONENDOCRINE TREATMENT
Radiation Therapy*
Irradiation is the most effective method for direct palliation and is the method of choice for localized recurrent or metastatic disease. As long as recurrent or metastatic breast cancer can be included in the field of irradiation, it should be the first choice, because higher rates of objective and subjective improvement are obtained from radiotherapy than by hormonal alteration. Metastatic lesions in weight-bearing bones should be irradiated to help prevent pathological fracture. When dissemination requires hormone alteration, radiotherapy is still of great value in the treatment of dominant areas of involvement. Surgery
The chief role of surgery in the palliative treatment of recurrent breast cancer is the performance of ablative endocrine procedures. The value of bilateral oophorectomy, bilateral adrenalectomy, and hypophysectomy is well established. Sometimes it is possible to excise a local recurrence or to do a simple mastectomy in order to remove an ulcerated, fungating mass. Severe pain may be controlled in selected cases by chordotomy, nerve section, or rhizotomy. Cord compression, which occurs rarely, can be temporarily relieved by a prompt laminectomy to permit time for x-ray therapy to be effective. Metastases may obstruct the gastrointestinal or biliary tracts and require surgical excision. In rare cases the removal of a painful, useless, massively edematous arm by an interscapulothoracic amputation will add to a patient's comfort. Another worthwhile procedure is the internal fixation of pathological fractures. Nonendocrine Chemotherapy
Numerous chemotherapeutic drugs have been used in the treatment *Radiation therapy is considered in detail by Dr. L. Henry Garland eslewhere in this volume.
870
LEONARD DoBSON
of metastatic breast cancer (see Tables 1, 2, 7). These have been used singly, in various combinations, or combined with radiotherapy. It has been repeatedly emphasized that no patient should be treated with cytotoxic agents until the effect of hormonal manipulation has been determined. Premenor:auml women should be castrated and appropriate patients given adequate trials of estrogens, androgens, corticoids and ablative therapy, as described earlier in this paper. As a rule, this regimen will produce remissions of greater degree, longer duration and with fewer toxic effects than can be obtained by cytotoxic agents. There is now considerable experience with the use of nonhormonal chemotherapeutic agents in the treatment of breast cancer. All nonhormonal oncolytic drugs are toxic in varying degrees and primarily affect the hematopoietic and gastrointestinal systems. Furthermore, the white and platelet counts are often seriously depressed. The effects on the gastrointestinal system are shown by anorexia, nausea and vomiting, stomatitis, abdominal cramps, and diarrhea. Skin rash, alopecia and hypotension are other less frequent effects of these drugs. The nonhormonal chemotherapeutic agents used are of three general classes-alkylating agents, antimetabolites and antibiotics. Examples of alkylating agents are nitrogen mustard, Thio-TEPA or TSPA and Cytoxan. Antimetabolites tried have been Methotrexate and 5-fluorouracil. The antibiotics have been of little value in treating advanced breast cancer. The drugs proved most valuable in metastatic breast cancer are 5-fluorouracil (5-FU), triethylenethiophosphoramide (ThioTEPA or TSPA), cyclophosphamide (Cytoxan), and nitrogen mustard (HN2). In order to be most effective, the oncolytic drug must be administered to toxicity or nearly to toxicity. 5-FU produces the highest number of toxic complications, whereas Thio-TEPA is reported to have the lowest incidence of toxicity. Nitrogen mustard is of value in the treatment of lymphangiectatic metatases in the lungs and of pleural malignant effusions. Triethylenethiophosphoramide (TSP A or thio-TEPA) has been used for several years and a considerable list of references has accumulated. 63-65 , 72- 77 · 81 • 82 This drug has proved effective for advanced breast cancer. The percentage of response is reported to be from 40 to 60 per cent for seven or more months. The drug is effective when injected into tumor nodules, and it can be administered by mouth, intravenously, or into the pleura and peritoneal cavities. Cyclophosphamide (Cytoxan), a new alkylating agent which was first synthesized in 1957, has proved effective in breast cancer. 66 • 68 • 70 · 73 The earlier published results reported a remission rate of 25 per cent, but a recent publication 73 reported a 59 per cent remission rate but stated
The 111anagement of Metastatic Breast Cancer
871
that the duration of remission was shorter than that obtained with 5-FU or Thio-TEPA. The chief toxic manifestations are leukopenia, nausea and vomiting, and alopecia. The drug may be administered intravenously, intramuscularly, intraperitoneally, intrapleurally, or directly into the tumor. 5-Fluorouracil (5-FU), a pyrimidine antagonist, has proved to be one of the most effective nonhormonal chemotherapeutic drugs for advanced breast cancer although it is also the most toxicY· 69 • 71 • 73 • 78- 80 It is administered only intravenously. Toxic manifestations include leukopenia, diarrhea, stomatitis, alopecia and thrombocytopenia. Only leukopenia presents any significant problem, for this occurs in nearly all cases, but it is usually temporary and the blood count returns to normal when the 5-FU is stopped. The reports on the use of 5-FU a year ago gave a 10 to 15 per cent remission rate, whereas the more recent reports give a 40 to 50 per cent remission rate for breast cancer. This improvement probably is due to further experience with this very toxic drug, so that the toxic effects are minimized by smaller doses in the initial course and then by keeping the patient on maintenance therapy at a subtoxic dosage level. This course of treatment has produced remissions in a few cases for as long as two years. Hurley, Trump, Flatley and Riesch recently reported a method for selecting patients for cancer chemotherapy. 73 Table 7 shows the results they obtained in comparing the various drugs. Table 7.
A Comparison of Commonly Used Chemotherapeutic Drugs NONHORMONAL CHEMOTHERAPY
EFFECT OF ANTITUMOR AGENT EMPLOYED* Drug used
No. of Response Per Ave, Dur. patients cent response
Toxicity (total No.J
Drug deaths
5•FU
82
42
51
6.8
45
4
Thio-TEPA
60
25
42
7.2
15
J
Cytoxan
39
23
59
4.3
24
2
Combination
29
J4
48
7. J
9
3
HN2
TOTAL
56
J4
25
-
-
-
266
JJ8
44
5.0
-6,4
*Hurley et a/ Arch, Surg. 83:613 Oct, J96J
J8
0
--
-
JJJ
10(4%)
872
LEONARD DoBSON
CONCLUSIONS
1. The tremendous reservoir of women with recurrent and metastatic breast cancer provides a constant challenge to provide maximum palliation for the longest possible length of time. 2. Radiotherapy is the most effective treatment of localized disease. X-ray is also very valuable in treating dominant areas of involvement in disseminated disease. 3. The chief role of surgery in the treatment of advanced breast cancer is the performance of ablative endocrine procedures. Surgery is also helpful in relieving pain, cord compression, and obstructions in gastrointestinal and biliary tracts, and removing fungating, ulcerated local lesions. 4. Since about 45 per cent of breast cancers are hormone controlled, it is possible to produce remissions repeatedly by hormone manipulation for long periods in these cases. This may be accomplished by additive therapy-estrogens, androgens and corticosteroids, or by ablative endocrine procedures-oophorectomy, adrenalectomy and hypophysectomy. 5. During the past few years nonhormonal chemotherapy has become increasingly valuable. Several drugs, 5-FU, thio-TEPA and Cytoxan, have proved effective in breast cancer and their value has been enhanced by increased knowledge of how to keep their toxic manifestations to a minimum. Various combinations are proving valuable. Since endocrine manipulation in hormone-controlled cancer is effective for long periods of time, the use of nonhormonal chemotherapy should be restricted to tumors that are not hormone controlled or have escaped hormone control. REFERENCES General 1. Allen, J. G. and Rigler, S. P.: Problems in Evaluating Clinical Results ofTreatment of Carcinoma of the Breast. S. CLIN. NoRTH AMERICA 38: 197-210 (Feb.) 1958. 2. Burdick, D.: Experiences with a Program to Achieve Palliation of Incurable Carcinoma of the Breast. Surg. Gynec. & Obst. 112: 334-342 (March) 1961. 3. Escher, G. C. and Kaufman, R. J.: Current Views on the Management of Metastatic Mammary Carcinoma. M. Clin. North America 45: 613-626 (May) 1961. 4. Hosbein, D. J. and Mithoefer, J.: Treatment of Elderly Women with Cancer of the Breast. S. CLIN. NoRTH AMERICA 40: 889-898 (Aug.) 1960. 5. Kraft, R. 0. and Block, G. E.: Approach to the Problem of Mammary Cancer. S. CLIN. NoRTH AMERICA 41: 1219-1231 (Oct.) 1961. 6. Macdonald, I. and Yettra, M.: Medical Treatment of Cancer. M. Clin. North America 43: 971-1002 (July) 1959. Endocrine Treatment 7. Adair, F. E. and Herrmann, J. B.: Use of Testosterone Proprionate in the Treatment of Advanced Cancer of the Breast. Ann. Surg. 123: 1023 1946.
The Management of Metastatic Breast Cancer
873
8. Baker, W. H., Kelley, R. M. and Sohier, W. D.: Hormonal Treatment of Metastatic Carcinoma of the Breast. Am. J. Surg. 99: 538-543 (April) 1960. 9. Binnie, G. C.: Regression of Tumors Following Treatment with Stilbestrol and X-ray Therapy with Notes on a Case of Breast Tumor which Regressed with Stilbestrol Alone. Brit. J. Radial. 17: 42, 1944. 10. Block, G. E.: Endocrine Treatment of Advanced Mammary Cancer. GP 20 85-96 (Oct.) 1959. 11. Brinkley, D. M. and Kingsley-Fillers, E.: Treatment of Advanced Carcinoma of the Breast by Bilateral Oophorectomy and Prednisone. Lancet 1: 123-126, 1960. 12. Council on Drugs; Report to the Council: Androgens and Estrogens in Treatment of Disseminated Mammary Carcinoma. Retroactive Study of 944 Patients. J.A.M.A. 172: 1271-1283 (March 19) 1960. 13. Currie, A. R. (Ed.): Endocrine Aspects of Breast Cancer. Proceedings of a Conference held at the University of Glasgow-8th to lOth July, 1957. Edinburgh & London, E. & S. Livingstone Ltd., 1958. 14. Farrow, J. J.: Effect of Sex Hormones on Skeletal Metastases from Breast Carcinoma. Surgery 16: 141-151, 1944. 15. Huseby, R. A.: Endocrinologic Treatment of Advanced Breast Cancer. Am. Surgeon 26: 87-94 (Feb.) 1960. 16. Kaufman, R. J. and Escher, G. C.: Rebound Regression. Improvement After Cessation of Additive Hormonal Treatment in Women with Advanced Mammary Carcinoma. Proc. Am. A. Cancer Res. 3: 124, 1960. 17. Kennedy, B. J.: Fluoxymesterone in the Treatment of Advanced Breast Cancer. Cancer 10: 813-818 (July-Aug.) 1957. 18. Kofman, D., Buenger, R. E. E., Nagamani, D. and Taylor, S. G.: Use of Prednisolone in the Treatment of Disseminated Breast Carcinoma. Cancer 11: 226-232 (Jan.-Feb.) 1958. 19. Lemon, H. M.: Prednisone Therapy of Advanced Mammary Cancer. Cancer 12: 93-107 (Jan.-Feb.) 1959. 20. Nathanson, I. T.: Relationship of Hormones to Diseases of the Breast. Surgery 16: 108-140, 1944 (Extensive bibliography). 21. Oberhelman, H. A.: Hormonal Treatment of Mammary Cancer. S. CLIN. NoRTH AMERICA 39: 3-12 (Feb.) 1959.
Ablative Treatment-Castration 22. Adair, F. E., Treves, N., Farrow, J. H. and Scharnagel, I. M.: Clinical Effects of Surgical and X-ray Castration in Mammary Cancer. J.A.M.A. 128: 161-167, 1945. 23. Beatson, G. T.: On the Treatment of Inoperable Cases of Carcinoma of Mamma. Suggestion for New Method of Treatment, with Illustrative Cases. Lancet 2: 104-107, 162-165, 1896. 24. Block, G. F., Lampe, I., Vial, A. B. and Coller, F. A.: Therapeutic Castration for Advanced Mammary Cancer. Surgery 47: 877-884 (May) 1960. 25. Hadfield, G. J. and Holt, J. A. G.: Physiological Castration Syndrome in Breast Cancer. Brit. M. J. 2: 972-973 (Oct. 27) 1956. 26. Horsley, G. W.: Treatment of Cancer of the Breast in Premenopausal Patients with Radical Amputation and Bilateral Oophrectomy. Ann. Surg. 125: 703-712, 1947. 27. Lett, H.: Analysis of 99 Cases of Inoperable Carcinoma of the Breast Treated by Oophrectomy. J. Med.-Chir. Soc. London 88: 147-189, 1905. 28. Rosenberg, M. F. and Uhlmann, E. M.: Prophylactic Castration in Carcinoma of the Breast. A.M.A. Arch. Surg. 78: 376 (March) 1959. 29. Smith, G. V. and Smith, 0. W.: Carcinoma of the Breast. Results, Evaluation of X-radiation and Relation of Age and Surgical Castration to Length of Survival. Surg. Gynec. & Obst. 97: 508-516, 1953. 30. Taylor, G. W.: Evaluation of Ovarian Sterilization for Breast Cancer. Surg. Gynec. & Obst. 68: 452-456, 1939.
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LEONARD DoBSON
31. Treves, N. and Finkbeiner, J.: Evaluation of Therapeutic Surgical Castration in the Treatment of Metastatic, Recurrent and Primary Inoperable Mammary Carcinoma in Women. Cancer 11: 42Q-438 (March-April) 1958. 32. Treves, N.: Treatment of Cancer, Especially Inoperable Cancer of the Male Breast by Ablative Surgery (Orchiectomy, Adrenalectomy and Hypophysectomy.) and Hormone Therapy (Estrogens and Corticosteroids). An Analysis of 42 Patients. Cancer 12: 820-832 (July-Aug.) 1959. 33. Treves, N.: Evaluation of Prophylactic Castration in the Treatment of Mammary Carcinoma. Cancer 10: 393-407 (March-April) 1957.
Ablative Treatment-Adrenalectomy 34. Adrenalectomy and Hypophysectomy in Disseminated Mammary Carcinoma. A Preliminary Statement by the Joint Committee on Endocrine Ablative Procedures in Disseminated Mammary Carcinoma. J.A.M.A. 175: 787-790 (March 4) 1961. 35. Atkins, H. J., Falconer, M.A., Hayward, J. L. and MacLean, K. S.: Adrenalectomy and Hypophysectomy for Advanced Cancer of the Breast. Lancet 1: 489-496 (March 9) 1957. 36. Atkins, H. J., Falconer, M. A., Hayward, J. L., MacLean, K. S., Schurr, P. H. and Armitage, P.: Adrenalectomy and Hypophysectomy for Advanced Cancer of the Breast. Lancet 1: 1148-1153 (May 28) 1960. 37. Cade, S.: Role of Adrenalectomy in Cancer of the Breast. Cancer 10: 777-788, 1957. 38. Dao, T. and Huggins, C.: Metastatic Cancer of the Breast Treated by Adrenalectomy. J.A.M.A. 165: 1973 (Dec. 7) 1957. 39. Dragstedt, L. R., Humphreys, E. M. and Dragstedt, L. R. II: Prophylactic Bilateral Adrenalectomy and Oophorectomy for Advanced Cancer of the Breast. Surgery 47: 885-890 (June) 1960. 40. Fracchia, A. A., Holleb, A. I., Farrow, J. H., Treves, N. E., Randall, H. T., Finkbeiner, J. A. and Whitmore, W. F. Jr.: Results of Bilateral Adrenalectomy in the Management of Incurable Breast Cancer. Cancer 12: 58-68 (Jan.-Feb.) 1959. 41. Galante, M., Fournier, D. J. and Wood, D. A.: Adrenalectomy for Metastatic Breast Carcinoma. J.A.M.A. 163: 1011-1016 (March 23) 1957. 42. Huggins, C. B. and Bergenstal, D. M.: Surgery of the Adrenals. J.A.M.A. 147: 101-106 (Sept. 1) 1951. 43. Kambouris, A. A., Saltzstein, H. C. and Scheinberg, S.: Bilateral Adrenalectomy for Advanced Breast Cancer. Review of the Literature and Analysis of 25 Cases. Am. J. Surg. 103: 651-656 (Nov.) 1961. 44. Lipsett, M. B., Whitmore, W. F. Jr., Treves, N., West, C. D., Randall, H. T. and Pearson, 0. H.: Cancer 10: 111-119 (Jan.-Feb.) 1957. 45. Nelsen, T. S. and Dragstedt, L. R.: Adrenalectomy and Oophorectomy for Breast Cancer. J.A.M.A. 175: 379-383 (Feb. 4) 1961. 46. Randall, H. T.: Oophorectomy and Adrenalectomy in Patients with Inoperable or Recurrent Cancer of the Breast. Am. J. Surg. 99: 553-561 (April) 1960. Ablative Treatment-Hypophyectomy 47. Anderson, E.: Hypophysectomy in Disseminated Cancer of the Breast. Acta endocrinol. 29: 295 (Oct.) 1958. 48. Baron, D. N., Gurling, K. J. and Smith, Jr.: Effect of Hypophysectomy in Advanced Carcinoma of the Breast. Brit. J. Surg. 45: 593-606 (May) 1958. 49. Cleveland, A., Braun-Cantilo, J., LaRoche, G., Tobias, C., Constable, J., Born, J., Sangalli, F., Carlson, R. and Lawrence, J. H.: Alpha Particle Pituitary Irradiation in Metastatic Carcinoma of the Breast. Metabolic Effects. Proc. Conf. Res. Radiother. Cancer, June 16-18, 1960, pp. 190-198. 50. Forrest, A. P. M., Blair, D. W., Peebles Brown, D. A., Stewart, H. J., Sandison, A. T., Harrington, R. W., Valentine, J. M. and Carter, P. T.: Radio-active Implantation of the Pituil;ary. Brit. J. Surg. 47: 61-70 (July) 1959.
The Management of Metastatic Breast Cancer
875
51. Heck, W. F., McNaught, R. C., Dobson, L. G. and Greenspan, F. S.: Palliation for Advanced Cancer of the Breast. Transseptal-Sphenoid Subtotal Hypophysectomy. California Med. 92: 201-203 (March) 1960. 52. Jessiman, A. G., Matson, D. D. and Moore, F. D.: Hypophysectomy in the Treatment of Breast Cancer. New England J. Med. 261: 1199-1207 (Dec. 10) 1959. 53. Kennedy, B. J .. French, L. A. and Peyton, W. T.: Hypophysectomy in Advanced Breast Cancer. New England J. Med. 255: 1165-1172, 1956. 54. Lawrence, J. H.: Proton Irradiation of the Pituitary. Cancer 10: 795-798 (JulyAug.) 1957. 55. Luft, R. and Olivecrona, H.: Experiences with Hypophysectomy in Man. J. Neurosurg. 10: 301-316 (May) 1953. 56. Luft, R. and Olivecrona, H.: Hypophysectomy in Man; Experience in Metastatic Cancer of the Breast. Cancer 8: 261-270 (March-April) 1955. 57. Luft, R. and Olivecrona, H.: Hypophysectomy in the Treatment of Malignant Tumors. Cancer 10: 789-794 (July-Aug.) 1957. 58. McCalister, A., Welbourn, R. B., Edelstyn, G. J. A., Lyons, A. R., Taylor, A. R., Gleadhill, C. A., Gordon, D. S. and Cole, J. 0.: Factors Influencing Response to Hypophysectomy for AdvanceJ Cance.· of the Breas_. Brit. M. J. 1: 613619, 1961. 59. Pearson, 0. H., Ray, B.S., Harrold, C. C., West, C. D., Li, M. C., Maclean, J.P. and Lipsett, M. B.: Hypophysectomy in Treatment of Advanced Cancer. J.A.M.A. 161: 17-21 (May 5) 1956. 60. Pearson, 0. H. and Ray, B.S.: Hypophysectomy in Metastatic Breast Cancer. Cancer 12: 85-92 (Jan.-Feb.) 1959. 61. Pearson, 0. H. and Ray, B.S.: Results of Hypophysectomy in the Treatment of Metastatic Mammary Carcinoma. Cancer 12: 85-92 (Jan.-Feb.) 1959. 62. Pearson, 0. H. and Ray, B. S.: Hypophysectomy in the Treatment of Metastatic Mammary Carcinoma. Am. J. Surg. 99: 544-552 (April) 1960. N onendocrine Chemotherapy 63. Bateman, J. C. and Carolton, H. N.: Palliation of Mammary Carcinoma with Phosphoramide Drugs. J.A.M.A. 162: 701-706, 1956. 64. Batemen, J. C. and Carolton, H. N.: Role of Chemotherapy in the Treatment Breast Cancer. Surgery 47: 895-907 (June) 1960. 65. Bateman, J. C. and Carlton, H. N.: Role of Chemotherapy in the Treatment of Breast Cancer. Surgery 47: 895-907 (June) 1960. 66. Bergagel, D. E. and Levin, W. C.: A Prelusive Clinical Trial of Cyclophosphamide. Cancer Chemotherapy Reports 6: 120-134 (July) 1960. 67. Brennan, M. J. and Vaitkevicius, V. K.: 5-Fluorouracil in Clinical Cancer Experience in 155 Patients. Cancer Chemotherapy Reports 6: 8-11 (Feb.) 1960. 68. Coggins, P.R., Ravdin, R. G. and Eisrr:.an, S. H.: Clinical Evaluation of a New Alkylating Agent: Cytoxan (Cyclophosphamide). Cancer 13: 1254-1260 (Nov.-Dec.) 1960. 69. Curreri, A. R., Ansfield, F. J., Mciver, F. A, Waisman, H. A. and HeidelbPrger, C.: Clinical Studies with 5-Fluorouracil. Cancer Res. 18: 478-484, 1958. 70. Haar, H., Marshall, G., Bierman, H. and Steinfeld, J.: Influence of Cyclophosphamide upon Neoplastic Diseases in Man. Cancer Chemotherapy Reports 6: 41-51, 1960. 71. Hall, B. E. and Good, J. W.: Advanced Neoplastic Disease. Treatment with 5-Fluorouracil and Irradiation. California Med. 95: 303-308 (Nov.) 1961. 72. Humphrey, E. W. and Hitchcock, C. R.: A Study of the Biological Effects of the Phosphoramides in Patients with Advanced Cancer. Cancer 10: 231-238, 1957. 73. Hurley, J.D., Trump, D. S., Flatley, T. J. and Riesch, J.D.: A Method of Selecting Patients for Cancer Chemotherapy. A.M.A. Arch. Surg. 83: 611-620 (Oct.) 1961. 74. Moore, G. E. and Pickran, J. W.: Response of Breast Cancer to Triethylene Thiophosphoramide. A.M.A. Arch. Path. 65: 93-103, 1958.
876
LEONARD DoBSON
75. Noer, R. J.: Breast Adjuvant Chemotherapy; Effectiveness of Thio-Tepa as Adjuvant to Radical Mastectomy for Breast Cancer. Ann. Surg. 151,.: 629647 (Oct.) 1961. 76. Ravdin, R. G. and Elkins, W. E.: Chemotherapy of Solid Tumors. S. CLIN. NoRTH AMERICA 1,.0: 1641-1656 (Dec.) 1960. 77. Schell, R. F. and Hall, B. E.: Experience with TriethyleneMelamine (TEM) and Triethylene Thiophosphoramide (Thio-TEPA) in Recurrent or Metastatic Solid Tumors. Surg. Gynec. & Obst. 106: 459-465 (April) 1958. 78. Staley, C. J., Kerth, J.D., Cotres, N. and Preston, F. W.: Treatment of Advanced Cancer with 5-Fluorouracil. Surg. Gynec. & Obst. 112: 185-190 (Feb.) 1961. 79. Vaitkevicius, V. K., Brenna, M. J., Beckett, V. L., Kelly, J. E. and Talley, R. W.: Clinical Evaluation of Cancer Chemotherapy with 5-Fluorouracil. Cancer 11,.: 131-154 (Jan.-Feb.) 1961. 80. Wilson, W. L.: Chemotherapy of Solid Tumors with 5-Fluorouracil. Cancer 13: 123Q-1239 (Nov.-Dec.) 1960. 81. Wright, J. C., Cobb, J.P., Golomb, F. M., Gumport, S. L., Lyall, D. and Safadi, D.: Chemotherapy of Disseminated Carcinoma of the Breast. Ann. Surg. 150: 221-240, 1959. 82. Wright, J. C., Foster, F., Billow, B., Gumport, S. L. and Cobb, I. P.: Effect of Triethylenethiophosphoramide on Fifty Patients with Incurable Neoplastic Diseases. Cancer 10: 239-245 (March-April) 1957. 350 Post Street San Francisco 8, California
LEONARD DOBSON, M.D. Clinical Professor of Surgery, Stanford University School of Medicine, Palo Alto; Chief of the Tumor Clinic, Presbyterian Medical Center
GENERAL PROBLEM CANCER of the breast is the most common cancer of the female in the United States. Of an annual incidence of 60,000 cases, about 18,000 will be inoperable when first examined. Of the 42,000 operated upon, 60 per cent or more will have recurrence or metastases within ten years. Thus, there is constantly a very large group of women with various stages of metastatic cancer. Since the problem of obtaining maximum palliation for this large group is so tremendous, the medical literature dealing with all stages of breast cancer is probably larger than that of any other malignant disease. Although breast cancer has been studied extensively for more than 70 years, there are few situations in the management that are not controversial. There continue to be debates concerning the best initial treatment, the role of irradiation, which chemotherapeutic agent, if any, should be used initially, and the role of prophylactic castration. When metastases appear, arguments arise as to which hormones should be used first and subsequently. Should the endocrine therapy be staged and lead gradually to ablative therapy, or will the longest palliation be obtained by going directly to hypophysectomy or adrenalectomy? Of the many chemotherapeutic agents now available, which is most effective under different conditions? Several recent articles 1- 6 have dealt with the general problem of metastatic breast cancer. An attempt will be made to correlate the material and bring it up to date. 861
862
LEONARD DoBSON
THE SELECTION AND SEQUENCE OF THERAPY
There are two main schools of thought regarding the most effective sequence of various methods of treatment. Realizing that palliation is all that is possible in metastatic breast cancer, the aim of everyone treating this disease is to give the patient the longest, happiest, most comfortable remaining period of life that is possible with our present knowledge. Probably the majority of doctors favor the "step-by-step" method of obtaining the longest possible remission from one hormone or procedure before trying another. This has been likened to a "delaying action" in military parlance. The advocates of this method believe that the combined periods of remission will be longer than can be obtained by going directly to hypophysectomy or adrenalectomy. On the other hand, there are strong proponents for what has been called the "blockbuster" or "massive assault" approach, with adrenalectomy or hypophysectomy as the initial method. However, it has not yet been definitely established which sequence of treatment gives the longest period of comfortable life. We have subscribed to the "step-by-step" school (Stanford University Hospitals in San Francisco previous to 1959 and the Presbyterian Medical Center since 1959). A patient's menstrual age is most important in deciding on the initial method of treatment. The Subcommittee on Breast and Genital Cancer of the Committee on Research,1 2 which reported on the results obtained in 944 patients, concluded that after the fourth postmenopausal year estrogens are the agents of choice. The overall regression rate for estrogens was 38 per cent and for androgens 27 per cent. Further conclusions of this extensive and carefully controlled study were that estrogens are superior to androgens in soft tissue and equal or superior for skeletal and visceral metastases. Another interesting observation was that androgens were more effective with postmenopausal patients after 17 or more years, for they produced objective regressions in nearly 30 per cent of these patients, but in only 20 per cent of premenopausal women. Table 1 shows the suggested sequence of therapy for the group of women from premenopause through the fourth year of postmenopause. This group should be castrated, preferably by surgery. Thirty to 40 per cent of those castrated will have remissions of approximately ten months' duration. When the benefits of the castration cease, a course of androgens (Table 3) should be tried. When the benefits of that treatment cease, either adrenalectomy or hypophysectomy should be done. A regression rate of about 30 per cent is obtained from each of these procedures (Table 6). A higher rate of regression is obtained by these ablative procedures when they are done in patients who have had a good response to previous hormonal alterations. One of the cortico-
The M anagernent of Metastatic Breast Cancer Table 1.
863
Suggested Sequence of Therapy in Patients Premenopausal and Through the Fourth Postmenopausal Year
PREMENOPAUSAL +5th year POSTMENOPAUSAL BILATERAL OOPHORECTOMY
J
~
PREDNISONE
ADRENALECTOMY
HYPOP~~/ CHEMOTHERAPY 5·FU Thio-TEPA
Cytoxan
Table 2.
Suggested Sequence of Therapy in Patients Five or More Years Postmenopausal POSTMENOPAUSAl • 5 yrs plus ESTROGENS
J
~
PREDNISONE
ADRENALECTOMY
HYPOP:~/ CHEMOTHERAPY 5-FU Thio-TEPA
Cytoxan
steroids (Table 5) should be tried if the patient refuses further ablative therapy. When these drugs are no longer effective a course of nonhormonal chemotherapy (Table 7) should be tried. During the past two years the percentage of remissions has improved through more experience in the administration of these toxic drugs. (See section on Nonhormonal Chemotherapy.) The second main group of patients, those who are postmenopausal by five or more years, is shown on Table 2. If those nearest the menopause have elevated estrogen levels as shown by vaginal smears and by significant urinary estrogen excretion, then we would do a castration. Most patients in this group in Table 2 we would treat with estrogens
864
LEONARD DOBSON
(Table 4). (References on hormone therapy include 7 through 21.) The steps in therapy are shown. The standard of reference for estrogens is diethylstilbestrol and for androgens testosterone proprionate. ENDOCRINE TREATMENT
ADDITIVE HoRMONES The additive hormones which are most effective in treating recurrent breast cancer include androgens, estrogens and corticosteroids: Androgens
Adair 7 in 1946 described the beneficial effects of testosterone in advanced breast cancer. This has been confirmed by numerous reports.8· 10 • 12-15, 1 7, 20 • 21 The Subcommittee on Breast and Genital Cancer in 196012 reported an objective regression rate of 20 per cent in premenopausal women and an overall regression rate of 27 per cent. Testosterone is most effective in the postmenopausal group. The androgens most commonly used are listed in Table 3. If regression occurs, the androgen Table 3.
Androgens Commonly Used in Additive Hormone Therapy SYSTEMIC
THERAPY .. ·ADDITIVE (J) ANDROGENS
Testosterone proprio nate Fluoxymesterone (HalotestinJ Testosterone enanthate (Delatestryl)
JOO mg.
JO mg.
200 mg.
3 x weekly
I. M.
3 x claily
Oral
q.2 weeks
I.M.
should be continued until it is no longer effective. The indications and complications of the use of androgens have been thoroughly described in many articles. REBOUND PHE~OMENON. It has long been noted that in a small percentage of cases (2 per cent in androgens and 5 per cent in estrogens 16 ) there are remissions lasting as long as six or more months after a discontinuance of the use of the drug. Estrogens
The beneficial effects of estrogens in advanced breast cancer were first reported in 1944. 9 The indication for the use of estrogens depends on
The Management of Metastatic Breast Cancer Table 4.
865
Estrogens Commonly Used in Additive Hormone Therapy SYSTEMIC THERAPY ... ADDITIVE (2)
ESTROGENS
Diethylstilbestrol
5 mg. t.i.d. Oral (enteric coated)
Ethinyl estradiol
l mg.
t.i.d.
Estradiol benzoate
5 mg.
3 x weekly I. M.
Estradiol valerate
30 mg.
Oral
q. 2 weeks
the menopausal status rather than the sites of disease, and patients with recurrent breast cancer who are more than four years postmenopausal should have estrogens as their primary therapy (Table 2). The Subcommittee on Breast and Genital Cancer12 reports an overall regression rate of 38 per cent. The indications for the use of estrogens are listed in the section on "Selection and Sequence of Therapy." The estrogen should be continued as long as it is effective. A few patients have obtained remission for three or more years from this treatment alone. The most commonly used estrogens are listed in Table 4. The indications and complications have been described in numerous publications. Corticosteroids Cortisone and its derivatives have generally been reserved for usage late in the course of the disease, or when adrenalectomy or hypophysectomy has been refused (Tables 1 and 2). Frequently used corticosteroids are listed in Table 5 .. Corticoids are particularly useful in Table 5. Corticosteroids Commonly Used in Additive Hormone Therapy SYSTEMIC THERAPY···ADDITIVE [3] CORTICOSTEROID
Prednisone
20-60 mg Oral daily
Cortisone
J00•300 mg Oral daily
Decadron
2 - 6 mg Oral daily
866
LEONARD DoBSON
hypercalcemia, impaired liver function, and central nervous system involvement. 2- 6 • 11 • 18 • 19 ABLATIVE THERAPY
Castration
The value of bilateral oophorectomy in the palliation of inoperable advanced breast cancer has been repeatedly established during the past 60 years. Beatson in 189623 first pointed out the beneficial effects of castration in advanced inoperable breast cancer. Lett in 190527 confirmed Beatson's results by reporting the effects of castration in 99 cases of inoperable breast cancer. Numerous articles, 22 • 24- 26 • 28- 33 have appeared since Lett's article and it is accepted that 30 to 40 per cent remissions can be expected from castration in selected cases. The value of castration as a prophylactic measure is very difficult to prove. Horsley, 26 Treves, 33 Rosenberg/ 8 Hadfield25 and Smith29 have advocated prophylactic castration in premenopamal women with breast cancer. Others, including Taylor 30 and Kraft and Block, 5 state that they ran a series of prophylactic castrations and have given up this treatment as a prophylactic measure. Most authorities employ castration only in the presence of advancing disease. All premenopausal women with progressive recurrent breast cancer and postmenopausal patients who have elevated estrogen levels, as shown by vaginal smears and significant urinary estrogen excretions, should be castrated. To accomplish the castration, bilateral oophorectomy is the generally accepted method of choice. Adequate irradiation of the ovaries will accomplish castration, but since it requires as long as 120 days to bring the estrogen down to the minimum level, it is much slower than is surgical castrati0n. Because about 40 to 45 per cent of breast cancers are hormone controlled, remissions are obtained in about 40 per cent of cases selected for castration, and the remission continues for ten months on the average. Castration in the male with breast cancer is often more effective than in the female. 32 Choice Between Adrenalectomy and Hypophysectomy
When cortisone became available for general use in 1951, it became possible to remove the pituitary or both adrenals in the treatment of malignant tumors. This procedure was of particular value in those breast cancers that were hormone controlled. Trials of one or both procedures were begun in centers throughout the world. Consequently, techniques for both the medical management and the operative procedures were
867
The Management of Metastatic Breast Cancer
gradually developed, and the morbidity and mortality considerably lessened. Some centers confined their investigations to one or the other of the ablative procedures, and a few used randomized cases to compare both procedures. The conclusions from these studies were often entirely different. For example, Atkins 35 • 36 concluded that hypophysectomy was more effectual and that the mortality was lower than in their experience with adrenalectomy. Kraft and Block, 5 however, report a higher remission rate and lower mortality and morbidity rate with adrenalectomy. Numerous articles have been published during the past eight years with the results favoring one or the other of the procedures. Then the Joint Committee on Endocrine Ablative Procedures published a preliminary report 34 with the conclusions that the results of the two procedures were nearly identical in all respects~mortality, percentage of regressions, and duration of regressions (Table 6). Table 6 COMPARISON OF REGRESSIONS FOLLOWING ADRENALECTOMY AND HYPOPHYSECTOMY* Adrenalectomy Total cases P.O. Deaths Cases evaluated Regression Per cent regression Ablation to death Number Months (mean) R+ R-
Hypophysectomy
404 37 315 100
467 42 358 112 31.3
31.7
R+ 78 22.0
R203 7.6
R+ 78 20.6
R221 6.5
Responsive to ablation Nonresponsive to ablation
*Report of Joint Committee on Endocrine Ablative Procedures. J.A.M.A. 175: 787-790 March 4, 1961
It would appear, therefore, that once the decision is made to do either an adrenalectomy or hypophysectomy, the degree of perfection in the performance of either operation in that particular institution or locality is more important than the type of operation. Throughout the world there are differences of opinion as to whether the adrenalectomy or hypophysectomy should be done early or late in the disease. Pearson and Ray, 59- 62 Luft and Olivecrona55 • 56 • 57 and McCalister58 favor early hypophysectomy. Cade37 advocated earlier
868
LEONARD DoBSON
adrenalectomy. Oberhelman21 states he is conducting a study on the value of the prophylactic use of oophorectomy and adrenalectomy in premenopausal and early postmenopausal patients with extensive axillary metastases or with an unusually large, rapidly growing tumor. Such a case was reported by Dragstedt. 39 Adrenalectomy
Postmenopausal women often continue to secrete significant amounts of estrogen. After castration there is only a temporary absence of estrogen in the urine. The adrenal glands secrete estrogens, and to eliminate this source, Huggins performed the first successful adrenalectomy for breast cancer in 1951. 42 The correctness of Huggins' deductions for the palliation of hormone-controlled breast cancer has been verified by numerous articles. 34- 46 It would be extremely valuable to determine which cases would respond favorably to adrenalectomy or hypophysectomy. Patients who are most likely to be benefited by adrenalectomy or hypophysectomy are (1) those who were benefited by castration, (2) those who are in their forties or fifties, and (3) those who had a period of three or more years before metastases appeared. There is general agreement that patients with brain and liver metastases do not respond favorably to either of the ablative procedures. Kambouris43 states that 948 cases of bilateral adrenalectomy had been reported by June, 1960, so probably more than 2000 adrenalectomies have been done by January, 1962. The Joint Committee on Endocrine Ablative Procedures34 reported a regression rate of 31.7 per cent with a duration of 22 months in responsive cases and of 7.6 months in nonresponsive cases (Table 6). Hypophysectomy
Luft and Olivecrona55 were the first to report a concerted effort to determine the effects of hypophysectomy in cancer patients. Since then, an extensive bibliography has accumulated from the experience gained from hundreds of hypophysectomies. Because estrogenic hormones, androgenic hormones, and growth hormones are, under certain physiologic conditions, a stimulus to the growth of breast cancer, the removal of the pituitary gland should eliminate these stimulating factors. Numerous articles have been published concerning the technique and results of hypophysectomyY· 48 • 52 • 53 • 55-6 2 The Preliminary Report of the Joint Committee on Endocrine Ablative Procedures34 listed a regression rate of 31 per cent for periods of 6.5 months in nonresponsive cases to 20.6 months in responsive cases.
869
The Management of Metastatic Breast Cancer OTHER METHODS
OF ATTEMPTING ABLATION
OF THE
PITUITARY.
Attempts to destroy or remove the pituitary by means other than a craniotomy include (1) proton irradiation, 54 (2)_ interstitial irradiation by Yttrium-90, 50 (3) alpha particle irradiation of the pituitary, 49 and (4) transseptal-sphenoid subtotal hypophysectomy. 51 These procedures are still in the experimental stage and so far have not been as effective as adrenalectomy and hypophysectomy. NONENDOCRINE TREATMENT
Radiation Therapy*
Irradiation is the most effective method for direct palliation and is the method of choice for localized recurrent or metastatic disease. As long as recurrent or metastatic breast cancer can be included in the field of irradiation, it should be the first choice, because higher rates of objective and subjective improvement are obtained from radiotherapy than by hormonal alteration. Metastatic lesions in weight-bearing bones should be irradiated to help prevent pathological fracture. When dissemination requires hormone alteration, radiotherapy is still of great value in the treatment of dominant areas of involvement. Surgery
The chief role of surgery in the palliative treatment of recurrent breast cancer is the performance of ablative endocrine procedures. The value of bilateral oophorectomy, bilateral adrenalectomy, and hypophysectomy is well established. Sometimes it is possible to excise a local recurrence or to do a simple mastectomy in order to remove an ulcerated, fungating mass. Severe pain may be controlled in selected cases by chordotomy, nerve section, or rhizotomy. Cord compression, which occurs rarely, can be temporarily relieved by a prompt laminectomy to permit time for x-ray therapy to be effective. Metastases may obstruct the gastrointestinal or biliary tracts and require surgical excision. In rare cases the removal of a painful, useless, massively edematous arm by an interscapulothoracic amputation will add to a patient's comfort. Another worthwhile procedure is the internal fixation of pathological fractures. Nonendocrine Chemotherapy
Numerous chemotherapeutic drugs have been used in the treatment *Radiation therapy is considered in detail by Dr. L. Henry Garland eslewhere in this volume.
870
LEONARD DoBSON
of metastatic breast cancer (see Tables 1, 2, 7). These have been used singly, in various combinations, or combined with radiotherapy. It has been repeatedly emphasized that no patient should be treated with cytotoxic agents until the effect of hormonal manipulation has been determined. Premenor:auml women should be castrated and appropriate patients given adequate trials of estrogens, androgens, corticoids and ablative therapy, as described earlier in this paper. As a rule, this regimen will produce remissions of greater degree, longer duration and with fewer toxic effects than can be obtained by cytotoxic agents. There is now considerable experience with the use of nonhormonal chemotherapeutic agents in the treatment of breast cancer. All nonhormonal oncolytic drugs are toxic in varying degrees and primarily affect the hematopoietic and gastrointestinal systems. Furthermore, the white and platelet counts are often seriously depressed. The effects on the gastrointestinal system are shown by anorexia, nausea and vomiting, stomatitis, abdominal cramps, and diarrhea. Skin rash, alopecia and hypotension are other less frequent effects of these drugs. The nonhormonal chemotherapeutic agents used are of three general classes-alkylating agents, antimetabolites and antibiotics. Examples of alkylating agents are nitrogen mustard, Thio-TEPA or TSPA and Cytoxan. Antimetabolites tried have been Methotrexate and 5-fluorouracil. The antibiotics have been of little value in treating advanced breast cancer. The drugs proved most valuable in metastatic breast cancer are 5-fluorouracil (5-FU), triethylenethiophosphoramide (ThioTEPA or TSPA), cyclophosphamide (Cytoxan), and nitrogen mustard (HN2). In order to be most effective, the oncolytic drug must be administered to toxicity or nearly to toxicity. 5-FU produces the highest number of toxic complications, whereas Thio-TEPA is reported to have the lowest incidence of toxicity. Nitrogen mustard is of value in the treatment of lymphangiectatic metatases in the lungs and of pleural malignant effusions. Triethylenethiophosphoramide (TSP A or thio-TEPA) has been used for several years and a considerable list of references has accumulated. 63-65 , 72- 77 · 81 • 82 This drug has proved effective for advanced breast cancer. The percentage of response is reported to be from 40 to 60 per cent for seven or more months. The drug is effective when injected into tumor nodules, and it can be administered by mouth, intravenously, or into the pleura and peritoneal cavities. Cyclophosphamide (Cytoxan), a new alkylating agent which was first synthesized in 1957, has proved effective in breast cancer. 66 • 68 • 70 · 73 The earlier published results reported a remission rate of 25 per cent, but a recent publication 73 reported a 59 per cent remission rate but stated
The 111anagement of Metastatic Breast Cancer
871
that the duration of remission was shorter than that obtained with 5-FU or Thio-TEPA. The chief toxic manifestations are leukopenia, nausea and vomiting, and alopecia. The drug may be administered intravenously, intramuscularly, intraperitoneally, intrapleurally, or directly into the tumor. 5-Fluorouracil (5-FU), a pyrimidine antagonist, has proved to be one of the most effective nonhormonal chemotherapeutic drugs for advanced breast cancer although it is also the most toxicY· 69 • 71 • 73 • 78- 80 It is administered only intravenously. Toxic manifestations include leukopenia, diarrhea, stomatitis, alopecia and thrombocytopenia. Only leukopenia presents any significant problem, for this occurs in nearly all cases, but it is usually temporary and the blood count returns to normal when the 5-FU is stopped. The reports on the use of 5-FU a year ago gave a 10 to 15 per cent remission rate, whereas the more recent reports give a 40 to 50 per cent remission rate for breast cancer. This improvement probably is due to further experience with this very toxic drug, so that the toxic effects are minimized by smaller doses in the initial course and then by keeping the patient on maintenance therapy at a subtoxic dosage level. This course of treatment has produced remissions in a few cases for as long as two years. Hurley, Trump, Flatley and Riesch recently reported a method for selecting patients for cancer chemotherapy. 73 Table 7 shows the results they obtained in comparing the various drugs. Table 7.
A Comparison of Commonly Used Chemotherapeutic Drugs NONHORMONAL CHEMOTHERAPY
EFFECT OF ANTITUMOR AGENT EMPLOYED* Drug used
No. of Response Per Ave, Dur. patients cent response
Toxicity (total No.J
Drug deaths
5•FU
82
42
51
6.8
45
4
Thio-TEPA
60
25
42
7.2
15
J
Cytoxan
39
23
59
4.3
24
2
Combination
29
J4
48
7. J
9
3
HN2
TOTAL
56
J4
25
-
-
-
266
JJ8
44
5.0
-6,4
*Hurley et a/ Arch, Surg. 83:613 Oct, J96J
J8
0
--
-
JJJ
10(4%)
872
LEONARD DoBSON
CONCLUSIONS
1. The tremendous reservoir of women with recurrent and metastatic breast cancer provides a constant challenge to provide maximum palliation for the longest possible length of time. 2. Radiotherapy is the most effective treatment of localized disease. X-ray is also very valuable in treating dominant areas of involvement in disseminated disease. 3. The chief role of surgery in the treatment of advanced breast cancer is the performance of ablative endocrine procedures. Surgery is also helpful in relieving pain, cord compression, and obstructions in gastrointestinal and biliary tracts, and removing fungating, ulcerated local lesions. 4. Since about 45 per cent of breast cancers are hormone controlled, it is possible to produce remissions repeatedly by hormone manipulation for long periods in these cases. This may be accomplished by additive therapy-estrogens, androgens and corticosteroids, or by ablative endocrine procedures-oophorectomy, adrenalectomy and hypophysectomy. 5. During the past few years nonhormonal chemotherapy has become increasingly valuable. Several drugs, 5-FU, thio-TEPA and Cytoxan, have proved effective in breast cancer and their value has been enhanced by increased knowledge of how to keep their toxic manifestations to a minimum. Various combinations are proving valuable. Since endocrine manipulation in hormone-controlled cancer is effective for long periods of time, the use of nonhormonal chemotherapy should be restricted to tumors that are not hormone controlled or have escaped hormone control. REFERENCES General 1. Allen, J. G. and Rigler, S. P.: Problems in Evaluating Clinical Results ofTreatment of Carcinoma of the Breast. S. CLIN. NoRTH AMERICA 38: 197-210 (Feb.) 1958. 2. Burdick, D.: Experiences with a Program to Achieve Palliation of Incurable Carcinoma of the Breast. Surg. Gynec. & Obst. 112: 334-342 (March) 1961. 3. Escher, G. C. and Kaufman, R. J.: Current Views on the Management of Metastatic Mammary Carcinoma. M. Clin. North America 45: 613-626 (May) 1961. 4. Hosbein, D. J. and Mithoefer, J.: Treatment of Elderly Women with Cancer of the Breast. S. CLIN. NoRTH AMERICA 40: 889-898 (Aug.) 1960. 5. Kraft, R. 0. and Block, G. E.: Approach to the Problem of Mammary Cancer. S. CLIN. NoRTH AMERICA 41: 1219-1231 (Oct.) 1961. 6. Macdonald, I. and Yettra, M.: Medical Treatment of Cancer. M. Clin. North America 43: 971-1002 (July) 1959. Endocrine Treatment 7. Adair, F. E. and Herrmann, J. B.: Use of Testosterone Proprionate in the Treatment of Advanced Cancer of the Breast. Ann. Surg. 123: 1023 1946.
The Management of Metastatic Breast Cancer
873
8. Baker, W. H., Kelley, R. M. and Sohier, W. D.: Hormonal Treatment of Metastatic Carcinoma of the Breast. Am. J. Surg. 99: 538-543 (April) 1960. 9. Binnie, G. C.: Regression of Tumors Following Treatment with Stilbestrol and X-ray Therapy with Notes on a Case of Breast Tumor which Regressed with Stilbestrol Alone. Brit. J. Radial. 17: 42, 1944. 10. Block, G. E.: Endocrine Treatment of Advanced Mammary Cancer. GP 20 85-96 (Oct.) 1959. 11. Brinkley, D. M. and Kingsley-Fillers, E.: Treatment of Advanced Carcinoma of the Breast by Bilateral Oophorectomy and Prednisone. Lancet 1: 123-126, 1960. 12. Council on Drugs; Report to the Council: Androgens and Estrogens in Treatment of Disseminated Mammary Carcinoma. Retroactive Study of 944 Patients. J.A.M.A. 172: 1271-1283 (March 19) 1960. 13. Currie, A. R. (Ed.): Endocrine Aspects of Breast Cancer. Proceedings of a Conference held at the University of Glasgow-8th to lOth July, 1957. Edinburgh & London, E. & S. Livingstone Ltd., 1958. 14. Farrow, J. J.: Effect of Sex Hormones on Skeletal Metastases from Breast Carcinoma. Surgery 16: 141-151, 1944. 15. Huseby, R. A.: Endocrinologic Treatment of Advanced Breast Cancer. Am. Surgeon 26: 87-94 (Feb.) 1960. 16. Kaufman, R. J. and Escher, G. C.: Rebound Regression. Improvement After Cessation of Additive Hormonal Treatment in Women with Advanced Mammary Carcinoma. Proc. Am. A. Cancer Res. 3: 124, 1960. 17. Kennedy, B. J.: Fluoxymesterone in the Treatment of Advanced Breast Cancer. Cancer 10: 813-818 (July-Aug.) 1957. 18. Kofman, D., Buenger, R. E. E., Nagamani, D. and Taylor, S. G.: Use of Prednisolone in the Treatment of Disseminated Breast Carcinoma. Cancer 11: 226-232 (Jan.-Feb.) 1958. 19. Lemon, H. M.: Prednisone Therapy of Advanced Mammary Cancer. Cancer 12: 93-107 (Jan.-Feb.) 1959. 20. Nathanson, I. T.: Relationship of Hormones to Diseases of the Breast. Surgery 16: 108-140, 1944 (Extensive bibliography). 21. Oberhelman, H. A.: Hormonal Treatment of Mammary Cancer. S. CLIN. NoRTH AMERICA 39: 3-12 (Feb.) 1959.
Ablative Treatment-Castration 22. Adair, F. E., Treves, N., Farrow, J. H. and Scharnagel, I. M.: Clinical Effects of Surgical and X-ray Castration in Mammary Cancer. J.A.M.A. 128: 161-167, 1945. 23. Beatson, G. T.: On the Treatment of Inoperable Cases of Carcinoma of Mamma. Suggestion for New Method of Treatment, with Illustrative Cases. Lancet 2: 104-107, 162-165, 1896. 24. Block, G. F., Lampe, I., Vial, A. B. and Coller, F. A.: Therapeutic Castration for Advanced Mammary Cancer. Surgery 47: 877-884 (May) 1960. 25. Hadfield, G. J. and Holt, J. A. G.: Physiological Castration Syndrome in Breast Cancer. Brit. M. J. 2: 972-973 (Oct. 27) 1956. 26. Horsley, G. W.: Treatment of Cancer of the Breast in Premenopausal Patients with Radical Amputation and Bilateral Oophrectomy. Ann. Surg. 125: 703-712, 1947. 27. Lett, H.: Analysis of 99 Cases of Inoperable Carcinoma of the Breast Treated by Oophrectomy. J. Med.-Chir. Soc. London 88: 147-189, 1905. 28. Rosenberg, M. F. and Uhlmann, E. M.: Prophylactic Castration in Carcinoma of the Breast. A.M.A. Arch. Surg. 78: 376 (March) 1959. 29. Smith, G. V. and Smith, 0. W.: Carcinoma of the Breast. Results, Evaluation of X-radiation and Relation of Age and Surgical Castration to Length of Survival. Surg. Gynec. & Obst. 97: 508-516, 1953. 30. Taylor, G. W.: Evaluation of Ovarian Sterilization for Breast Cancer. Surg. Gynec. & Obst. 68: 452-456, 1939.
874
LEONARD DoBSON
31. Treves, N. and Finkbeiner, J.: Evaluation of Therapeutic Surgical Castration in the Treatment of Metastatic, Recurrent and Primary Inoperable Mammary Carcinoma in Women. Cancer 11: 42Q-438 (March-April) 1958. 32. Treves, N.: Treatment of Cancer, Especially Inoperable Cancer of the Male Breast by Ablative Surgery (Orchiectomy, Adrenalectomy and Hypophysectomy.) and Hormone Therapy (Estrogens and Corticosteroids). An Analysis of 42 Patients. Cancer 12: 820-832 (July-Aug.) 1959. 33. Treves, N.: Evaluation of Prophylactic Castration in the Treatment of Mammary Carcinoma. Cancer 10: 393-407 (March-April) 1957.
Ablative Treatment-Adrenalectomy 34. Adrenalectomy and Hypophysectomy in Disseminated Mammary Carcinoma. A Preliminary Statement by the Joint Committee on Endocrine Ablative Procedures in Disseminated Mammary Carcinoma. J.A.M.A. 175: 787-790 (March 4) 1961. 35. Atkins, H. J., Falconer, M.A., Hayward, J. L. and MacLean, K. S.: Adrenalectomy and Hypophysectomy for Advanced Cancer of the Breast. Lancet 1: 489-496 (March 9) 1957. 36. Atkins, H. J., Falconer, M. A., Hayward, J. L., MacLean, K. S., Schurr, P. H. and Armitage, P.: Adrenalectomy and Hypophysectomy for Advanced Cancer of the Breast. Lancet 1: 1148-1153 (May 28) 1960. 37. Cade, S.: Role of Adrenalectomy in Cancer of the Breast. Cancer 10: 777-788, 1957. 38. Dao, T. and Huggins, C.: Metastatic Cancer of the Breast Treated by Adrenalectomy. J.A.M.A. 165: 1973 (Dec. 7) 1957. 39. Dragstedt, L. R., Humphreys, E. M. and Dragstedt, L. R. II: Prophylactic Bilateral Adrenalectomy and Oophorectomy for Advanced Cancer of the Breast. Surgery 47: 885-890 (June) 1960. 40. Fracchia, A. A., Holleb, A. I., Farrow, J. H., Treves, N. E., Randall, H. T., Finkbeiner, J. A. and Whitmore, W. F. Jr.: Results of Bilateral Adrenalectomy in the Management of Incurable Breast Cancer. Cancer 12: 58-68 (Jan.-Feb.) 1959. 41. Galante, M., Fournier, D. J. and Wood, D. A.: Adrenalectomy for Metastatic Breast Carcinoma. J.A.M.A. 163: 1011-1016 (March 23) 1957. 42. Huggins, C. B. and Bergenstal, D. M.: Surgery of the Adrenals. J.A.M.A. 147: 101-106 (Sept. 1) 1951. 43. Kambouris, A. A., Saltzstein, H. C. and Scheinberg, S.: Bilateral Adrenalectomy for Advanced Breast Cancer. Review of the Literature and Analysis of 25 Cases. Am. J. Surg. 103: 651-656 (Nov.) 1961. 44. Lipsett, M. B., Whitmore, W. F. Jr., Treves, N., West, C. D., Randall, H. T. and Pearson, 0. H.: Cancer 10: 111-119 (Jan.-Feb.) 1957. 45. Nelsen, T. S. and Dragstedt, L. R.: Adrenalectomy and Oophorectomy for Breast Cancer. J.A.M.A. 175: 379-383 (Feb. 4) 1961. 46. Randall, H. T.: Oophorectomy and Adrenalectomy in Patients with Inoperable or Recurrent Cancer of the Breast. Am. J. Surg. 99: 553-561 (April) 1960. Ablative Treatment-Hypophyectomy 47. Anderson, E.: Hypophysectomy in Disseminated Cancer of the Breast. Acta endocrinol. 29: 295 (Oct.) 1958. 48. Baron, D. N., Gurling, K. J. and Smith, Jr.: Effect of Hypophysectomy in Advanced Carcinoma of the Breast. Brit. J. Surg. 45: 593-606 (May) 1958. 49. Cleveland, A., Braun-Cantilo, J., LaRoche, G., Tobias, C., Constable, J., Born, J., Sangalli, F., Carlson, R. and Lawrence, J. H.: Alpha Particle Pituitary Irradiation in Metastatic Carcinoma of the Breast. Metabolic Effects. Proc. Conf. Res. Radiother. Cancer, June 16-18, 1960, pp. 190-198. 50. Forrest, A. P. M., Blair, D. W., Peebles Brown, D. A., Stewart, H. J., Sandison, A. T., Harrington, R. W., Valentine, J. M. and Carter, P. T.: Radio-active Implantation of the Pituil;ary. Brit. J. Surg. 47: 61-70 (July) 1959.
The Management of Metastatic Breast Cancer
875
51. Heck, W. F., McNaught, R. C., Dobson, L. G. and Greenspan, F. S.: Palliation for Advanced Cancer of the Breast. Transseptal-Sphenoid Subtotal Hypophysectomy. California Med. 92: 201-203 (March) 1960. 52. Jessiman, A. G., Matson, D. D. and Moore, F. D.: Hypophysectomy in the Treatment of Breast Cancer. New England J. Med. 261: 1199-1207 (Dec. 10) 1959. 53. Kennedy, B. J .. French, L. A. and Peyton, W. T.: Hypophysectomy in Advanced Breast Cancer. New England J. Med. 255: 1165-1172, 1956. 54. Lawrence, J. H.: Proton Irradiation of the Pituitary. Cancer 10: 795-798 (JulyAug.) 1957. 55. Luft, R. and Olivecrona, H.: Experiences with Hypophysectomy in Man. J. Neurosurg. 10: 301-316 (May) 1953. 56. Luft, R. and Olivecrona, H.: Hypophysectomy in Man; Experience in Metastatic Cancer of the Breast. Cancer 8: 261-270 (March-April) 1955. 57. Luft, R. and Olivecrona, H.: Hypophysectomy in the Treatment of Malignant Tumors. Cancer 10: 789-794 (July-Aug.) 1957. 58. McCalister, A., Welbourn, R. B., Edelstyn, G. J. A., Lyons, A. R., Taylor, A. R., Gleadhill, C. A., Gordon, D. S. and Cole, J. 0.: Factors Influencing Response to Hypophysectomy for AdvanceJ Cance.· of the Breas_. Brit. M. J. 1: 613619, 1961. 59. Pearson, 0. H., Ray, B.S., Harrold, C. C., West, C. D., Li, M. C., Maclean, J.P. and Lipsett, M. B.: Hypophysectomy in Treatment of Advanced Cancer. J.A.M.A. 161: 17-21 (May 5) 1956. 60. Pearson, 0. H. and Ray, B.S.: Hypophysectomy in Metastatic Breast Cancer. Cancer 12: 85-92 (Jan.-Feb.) 1959. 61. Pearson, 0. H. and Ray, B.S.: Results of Hypophysectomy in the Treatment of Metastatic Mammary Carcinoma. Cancer 12: 85-92 (Jan.-Feb.) 1959. 62. Pearson, 0. H. and Ray, B. S.: Hypophysectomy in the Treatment of Metastatic Mammary Carcinoma. Am. J. Surg. 99: 544-552 (April) 1960. N onendocrine Chemotherapy 63. Bateman, J. C. and Carolton, H. N.: Palliation of Mammary Carcinoma with Phosphoramide Drugs. J.A.M.A. 162: 701-706, 1956. 64. Batemen, J. C. and Carolton, H. N.: Role of Chemotherapy in the Treatment Breast Cancer. Surgery 47: 895-907 (June) 1960. 65. Bateman, J. C. and Carlton, H. N.: Role of Chemotherapy in the Treatment of Breast Cancer. Surgery 47: 895-907 (June) 1960. 66. Bergagel, D. E. and Levin, W. C.: A Prelusive Clinical Trial of Cyclophosphamide. Cancer Chemotherapy Reports 6: 120-134 (July) 1960. 67. Brennan, M. J. and Vaitkevicius, V. K.: 5-Fluorouracil in Clinical Cancer Experience in 155 Patients. Cancer Chemotherapy Reports 6: 8-11 (Feb.) 1960. 68. Coggins, P.R., Ravdin, R. G. and Eisrr:.an, S. H.: Clinical Evaluation of a New Alkylating Agent: Cytoxan (Cyclophosphamide). Cancer 13: 1254-1260 (Nov.-Dec.) 1960. 69. Curreri, A. R., Ansfield, F. J., Mciver, F. A, Waisman, H. A. and HeidelbPrger, C.: Clinical Studies with 5-Fluorouracil. Cancer Res. 18: 478-484, 1958. 70. Haar, H., Marshall, G., Bierman, H. and Steinfeld, J.: Influence of Cyclophosphamide upon Neoplastic Diseases in Man. Cancer Chemotherapy Reports 6: 41-51, 1960. 71. Hall, B. E. and Good, J. W.: Advanced Neoplastic Disease. Treatment with 5-Fluorouracil and Irradiation. California Med. 95: 303-308 (Nov.) 1961. 72. Humphrey, E. W. and Hitchcock, C. R.: A Study of the Biological Effects of the Phosphoramides in Patients with Advanced Cancer. Cancer 10: 231-238, 1957. 73. Hurley, J.D., Trump, D. S., Flatley, T. J. and Riesch, J.D.: A Method of Selecting Patients for Cancer Chemotherapy. A.M.A. Arch. Surg. 83: 611-620 (Oct.) 1961. 74. Moore, G. E. and Pickran, J. W.: Response of Breast Cancer to Triethylene Thiophosphoramide. A.M.A. Arch. Path. 65: 93-103, 1958.
876
LEONARD DoBSON
75. Noer, R. J.: Breast Adjuvant Chemotherapy; Effectiveness of Thio-Tepa as Adjuvant to Radical Mastectomy for Breast Cancer. Ann. Surg. 151,.: 629647 (Oct.) 1961. 76. Ravdin, R. G. and Elkins, W. E.: Chemotherapy of Solid Tumors. S. CLIN. NoRTH AMERICA 1,.0: 1641-1656 (Dec.) 1960. 77. Schell, R. F. and Hall, B. E.: Experience with TriethyleneMelamine (TEM) and Triethylene Thiophosphoramide (Thio-TEPA) in Recurrent or Metastatic Solid Tumors. Surg. Gynec. & Obst. 106: 459-465 (April) 1958. 78. Staley, C. J., Kerth, J.D., Cotres, N. and Preston, F. W.: Treatment of Advanced Cancer with 5-Fluorouracil. Surg. Gynec. & Obst. 112: 185-190 (Feb.) 1961. 79. Vaitkevicius, V. K., Brenna, M. J., Beckett, V. L., Kelly, J. E. and Talley, R. W.: Clinical Evaluation of Cancer Chemotherapy with 5-Fluorouracil. Cancer 11,.: 131-154 (Jan.-Feb.) 1961. 80. Wilson, W. L.: Chemotherapy of Solid Tumors with 5-Fluorouracil. Cancer 13: 123Q-1239 (Nov.-Dec.) 1960. 81. Wright, J. C., Cobb, J.P., Golomb, F. M., Gumport, S. L., Lyall, D. and Safadi, D.: Chemotherapy of Disseminated Carcinoma of the Breast. Ann. Surg. 150: 221-240, 1959. 82. Wright, J. C., Foster, F., Billow, B., Gumport, S. L. and Cobb, I. P.: Effect of Triethylenethiophosphoramide on Fifty Patients with Incurable Neoplastic Diseases. Cancer 10: 239-245 (March-April) 1957. 350 Post Street San Francisco 8, California