By Author
  By Title
  By Keywords

December 1991, Volume 41, Issue 12

Original Article

SURGICAL DJUVANT CHEMOTHERAPY FOR BREAST CANCER: A COMPARISON OF CMF AND CAF REGIMENS

Abdul Mannan Babar  ( East Surgical Unit, Department of Surgery, University of the Punjab, King Edward Medical College. Mayo Hospital, Lahore. )

ABSTRACT

Combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) was compared with cyclophosphamide, adriamycin and fluorouracil (CAF) as adjuvant to modified radical mastectomy in primary operable breast cancer with positive axillary lymph nodes. After 18 months of study, treatment failure occurred in 10% patients in each group. The new clinical manifestations occurred locally in 75% and at distant site in 25% of relapsed patients. Long term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. This study suggests that CMF and OAF regimens have comparable efficacy and toxicity in surgical adjuvant chemotherapy for breast cancer (JPMA 41: 293, 1991).

INTRODUCTION

The ideal treatment for primary operable breast cancer has been the subject of controversy for decades. Despite different approaches of surgical and radio-therapeutic treatments, the overall cure rate has remained essentially unchanged. Differences among case series probably reflect patient selection rather than actual therapeutic improvement. To overcome the plateau reached by curative operations, new approaches were attempted. The first of there was postoperative oophorectomy. However, results showed that prophylactic endocrine therapy prolonged the disease-free period in some series but failed to improve the overall survival1-3. The favourable effects of chemotherapeutic agents in advanced malig­nancies4 as well as reports of the frequent presence of cancer cells in the circulating blood of patients during operative manipulations5 provided the rationale for undertaking systemic adjuvant treatments. The results of early controlled studies were conflicting6-11. In retrospect the short-term single agent therapy used in practically all series was thought to represent the major cause of treatment failure. In the last two decades many clinical findings affected the design of new adjuvant trials. The high correlation between positive axillary nodes and relapse rate12, as well as the observation that postoperative radiotherapy was unable to influence the prognosis significantly13, led to the conclusion that in most patients with regional nodes involved, the disease was already disseminated at the time of mastectomy. Consequently there was a conceptual change in emphasis from destruc­tion of free cells in the circulation at the time of surgery to the need to destroy the micro-metastases14. From this emerged the concept of prolonged adjuvant chemotherapy for high risk patients. Many controlled trials were performed using single agent chemotherapy, but with conflicting results15-21. Based upon the fact that combination chemotherapy is superior to single agents in advanced breast cancer22-24 and CMF is the active component25, a controlled trial was conducted by the Instituto Nazionale Tumori, Milan, using CMF. The results were superior to those with single agent chemotherapy26. Many other trials of adjuvant chemotherapy with CMF or one of its variant have shown encouraging results27-29. Adriamycin is one of the most active single agent used in advanced carcinoma of the breast. It is also being used in various combination regimens30,31. Recently some studies have been reported on the use of adriamycin containing regimens in adjuvant chemotherapy for breast cancer. The initial results are very encouraging32,33. During the last decade adjuvant antioestrogens have also been tried either alone or in conjunction with chemotherapy34,35. This study consists of a comparison of efficacy and toxicity of CMF & CAF regimens in surgical adjuvant chemotherapy for primary operable breast cancer.

PATIENTS AND METHODS

The study was carried out on patients admitted to the East Surgical and Radiotherapy-Oncology Units, Mayo Hospital, Lahore.
Selection of patients
All female patients who had undergone modified radical mastectomy for potentially curable breast car­cinoma and who had one or more axillary lymphnodes positive on histologic study were eligible for inclusion in the study provided they satisfied the following protocol requirements: tumour confined to the breast or breast and axilla, extent of primary tumour and axillary lymph node metasta.sis - T1, T2, T3 N0, N1, negative radiologic studies (chest and skeletal x-rays and liver scan) and adequate bone marrow reserve (WBC count more than 4000/mm3 and platelet count more than 130,000/mm3). The following conditions made patients ineligible: age over 75 years, pregnancy or lactation, previous treatment for current neoplasms, previous or concomitant neo plasms, bilateral breast cancer, malignant breast tumour other than carcinoma and poor risk patients having non-malignant systemic disease.
Treatment
The modified radical mastectomy consisted of removal of the breast and axillary contents enbioc. The primary neoplasm and all lymphnodes removed at operation were histologically examined. Chemotherapy was started two to four weeks after mastectomy and continued for 6 cycles. CMF consisted of cyclophosphamide (100 mg/m2, p.o., days 1-14), methotrexate (40 mg/m2, i.v., days 1,8) and fluorouracil (600 mg/m2, i.v., days 1,8). CAP con­sisted of adriarnycin (30 mg/m2, i.v., days 1,8) and cyclophospharnide and fluorouracil (doses similar to that in CMF regimen). The next cycle was started after a two week rest (days 15-28). The total dose of cyclophos­phamide was adjusted to the nearest 50 mg since fractions of tablets cannot be. administered. In patients over 65 years of age the initial dose of methotrexate was reduced to 30 mg/rn2 and that of fluorouracil to 400 mg/m2. A reduced schedule was used in the presence of myelosuppression, determined on the first day of each cycle. If no toxicity was evident or Grade 0 (leukocyte count more than 4000/mm3 and platelet count more than 130,000/mm3), 100% of each drugwas administered. For Grade 1 toxicity (leukocyte count of 3999 to 2500/mm3 or platelet count of 129,000 to 75,000/mm3 or both), 50% of the calculated dose was given. In the presence of Grade 2 toxicity (leukocyte count less than 2500/mm3 or platelet count less than 75,000/mm3 or both) no drug was administered unless grades I toxicity was reached.
Follow-up study
Radiograph of the chest was performed every three months and a skeletal survey and liver scan every six months. Bone scan was performed only in the presence of either suspicious osseous lesions on x-rays or persist­ing bone pain. Blood chemical studies (urea, sugar, transaminases, alkaline phosphatase, bilirubin and cal­cium) were carried out every three months.

RESULTS



Table I presents the characteristics of patients with treatment failure. There was no difference in total rate of treatment failure in each group (10%). There was no significant difference in the incidence of relapse between pre-menopausal and post- menopausal patients. The rate of recurrence increased as the size of primary tumour increased (T3 > T2). The histologic characteristics of the tumour showed no relationship to the rate of recur rence. In both the groups the most frequent site of recurrence was chest wall (2 cases in CMF group and one case in CAP group). The only other site of recurrence was the skeletal metastasis in one case of CMF group. There was no case of second primary breast carcinoma. As various degrees of nausea and vomiting were expected, all patients were given metocloperamide 10mg intravenously before the start of intravenous drug ad­ministration. Inspite of that a good proportion of patients had nausea and vomiting. The frequency of vomiting showed a tendency to decrease after the initial cycles. About 10% of the patients did not complain of nausea and vomiting. The most important abdominal disturbance was prolonged nausea and anorexia produced by the Continuous administration of oral cyclophosphamide. The toxic manifestations are listed in Table II.

Leukopenia and thrombocytopenia, as detected on the first and eighth day of each treatment cycle, represented the most frequent sign of toxicity in each group. Prolonged haematosuppression was rare. No increased rate of infections was observed. Different degrees of loss of hair occurred in about half the patients in each group. The loss of hair usually started after the first cycle and in most cases stopped after cessation of chemotherapy. In most cases regrowth of hair was observed at the end of therapy. Mild oral mucositis occurred in CMF group (6.6%). Conjunctivities occurred in 10% of cases in each group. Chemical cystitis produced by cyclophosphamide oc­curred in one sixth and one fifth of the patients in CMF and CAF groups respectively. Haemorrhagic cystitis was not seen in any patient. One patient in CAF group developed cardiomyopathy during the follow-up period. One case in CMF group developed impairment of biochemical liver function tests; she however did not develop any clinical manifestation and liver functions returned to normal after cessation of therapy. In more than half the premenopausal patients in each group, amenorrhoea occurred; it was reversible in some patients.

DISCUSSION

Surgical adjuvant chemotherapy is being increas­ingly used in potentially curable breast cancer with positive axillary lymphnodes, as it reduces chances of recurrence36. This study shows that both CMF and CAF regimens are equally effective in preventing recurrence during first 18 months after mastectomy. New manifestations of disease occurred at distant site in a quarter of the recurred patients. This observation confirms that many patients with involved axillary lymph nodes have microscopic metastatic disease at the time of mastectomy. This finding represents the best indicator that systemic approach is necessary in the subgroup of high risk patients in the attempt to eradicate subclinical or minimal residual disease. Prolonged chemotherapy produced an acceptable rate and type of toxic manifestations, thus allowing the administration of a high percentage of drug dosage. Among the agents employed cyclophosphamide was responsible for some unpleasant sequelae such as prolonged gastric disturbances, cystitis and amenorrhoea. Furthermore, this drug was probably the major cause for loss of hair. All side effects were reversible in most patients. The prolonged cessation of menses in some patients may represent premature ovarian failure37. My results support and extend the Fisher and Bonadonna studies21,26. This study may be helpful in devising a more practical approach to the treatment of early breast cancer.

ACKNOWLEDGEMENT

I am greatly indebted to Prof S. Zafar Haider for his supervision and guidance during this study. I am also thankful to the staff of the East Surgical and Radiotherapy-Oncology Units, Mayo Hospital, Lahore for their cooperation.

REFERENCES

1. Taylor, G.W. Evaluation of ovarian sterilization for breast cancer. SLtrg. GynecoL Obstet., 1939: 68:452.
2. Kennedy, 8.3.. Miclke, P.W. Jr. and Fortuny. I.E. Therapeulic castration venus prophylactic castration in breast cancer. Surg. Gynecol. Obstet., 1964; 118:524.
3. Ravdin, R.G., L.ewison, E.P., Slack, N.H., Gardner, B., State, 0. and Fither, B. Retultt of a clinical trial coneerning tbeworth of prophylactic oophorectomy for breaatcarcinoma. Surg. Gynecol. Obstet., 1970; 131:1055.
4. Carter, S.K. Single and combination nonhorrnonal chemotherapy in breast cancer. cancer. 1972;30:1543.
5. Fisher, ER. and Turnbull, R.B. Jr. The cytologic demonstration and significance of tumour cells in mesenteric venous blood in patients with colorectal carcinoma. Surg. Gynecol. Obstet., 1955; 100:102.
6. Fisher, B., R.avdin, R.G., Ausman, R.K., Slack, N.H., Moore, G.E. Noer, R.J. and Cooperative Investigators. Surgical adjuvant chemotherapy in breast cancerof a decade of cooperative investigation. Ann. Surg., 1968; 168:337.
7. Finney, R. Adjuvant chemotherapy in the radical treatment of carcinoma of the breastS a clinical trial. AJR., 1971; 111:137.
8. Nissen-Meyer, It, Kjellgren, K. and Manaon, B. Preliminaty report from the Scan­dinavian sdjuvantchemotherapy study group. Cancer Chemother. Rep., 1971; 55:561.
9. Rieche, K., Berndt. H. and Prohl, B. Continuous postoperative treatment with cyclophosphamide in breast carcinoma - a random ized clinical study. Arch Getchwulstforsch., 1972; 40:349.
10. Garin, A.M., Dsrev, NI. and Bashenovoc, A.P. A summers’ of com parative studies of the efficacy of different techniques in treatment of early forms of the mammary gland cancer. Vopr. OnkoL 1973; 3:87.
11. Yoshida, M., Miura, S. and Muroi, H. Late results in combined chemotherapy for cure ofbreastcancer (axiltary lymph nodes metastases and therapeuticeffecta). Abstract 117. Presented in the 10th Annual Meeting of the Japanese Society for Cancer Thera py,1973.
12. Fisher, B., Slack, N.H., Broas, D.J. and Cooperative Inveatiga tora. Cancer of the breast; size of neoptaam and prognosis. Cancer, 1969; 24:1071.
13. Fisher, B., Slack, N.H.. Cavanaugh, P.J., Gardner, B., Ravdin, R.G. and Cooperative lnveetigatora. Postoperative radiotherapy in the treatment of breast csncer; results of the NSABP clinical trial. Ann. Surg., 1970; 172:711.
14. Schabel, F.M. Jr. Concepts for systemic treatment of micrometas tases. Cancer, 1975;35:15.
15. Long. R.T., Donegart. W.L and Evans, A.M. Extended surgical adjuvant chemotherapy for breast carcinoma. Ami. Surg,, 1969; 117:701.
16. Mrazek., It. Adjuvant chemotherapy of cancer of the breast at one institution, in chemotberapyof cancer. Edited by W.H. Cole. Philadelphia, Lea and Febiger, 1972; p.289.
17. Donegan, W.L. Extended surgical adjuvant thiotepa for mammary carcinoma. Arch. Surg,, 1974; 109:187.
18. Kholdin, S.A., Deemarsky, LY. and Bavly, J.L. Adjuvant long-term chemotherapy complex treatment of operable breast cancer. Cancer, 1974; 33:903. ­
19. Anslield, P.1. 5-Fu as an adjuvant to mastectomy in high risk paticnts. Proc. Am. Assoc. Cancer Res.IAm. Soc. Clin. Oncol., 1974; 15:177.
20. Ramirez, G. C.ombined chemotherapy- radiotherapy stan adjuvant to maatectomy in patientawith positive nodes. Proc. Am. Assoc. Cancer Res/Am. Soc. Clin. Oncol., 1975; 16:224.
21. Fisher, B., Carborne, P., Economou, S.G. et al. L-Phenylalanine mustard (L-PAM) in the management of primary breast cancer; a report of early findings. N. Engi 3. Med., 1975; 292:117.
22. Canettoa, G.P., DeVita, VT., Gold, G.L., Chabner, B.A., Schein, P.S. and Young, R.C. Cyclical combination chemotherapy for ad vanced breast carcinoma. Br. Med. J., 1974:1:218.
23. DeVita, VT. Jr., Young, R.C. and Canellos, G.P. Combination versus single agent chemotherapy: a review of the basis for selection of drug treatment of cancer. Cancer, 1975; 35:98.
24. Frei, E. III Rationale for combined therapy. Cancer, 1977; 46:1- 13.
25. Otis, P.T. and Armentrout, S.A. Combination chemotherapy in metaataticcarcinoma of the breast: results with a three-drug combination. Cancer, 1975; 36:311.
26. Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugna teth, L, Brambilla, C., DeLens, M., Tancini, G., Bajetta, E., Musumeci, It and Veroneai, V. Combination chemotherapyasan adjuvanttreatmentin operable bresatcancer. N. EngI. 3. Med., 1976; 294:405.
22. Glucksberg H., Rivkin, SE., Raamussen, S., Tranum, B., Gad-el- Mawla, N., Gostanzi, J., Hoogstraten, B., Athens, 3., Maloney, T., McCracken, 3. and Vaughn, C. Combina­tion chemotherapy (CMFVP) vs L-phenylalanine mustard (L-PAM) for operable breaat çancerwith positive axillary nodes. A Southweat OncotogyGroup Study. Cancer, 1982; 50:423.
28. Rutqvist, L.E., Barat, E., Cedarmark, B. et at. The present result of the Second Stockholm Breast Cancer Trial. Proc. Am.Soc. Clin. Oncol., 1986; 5:72.
29. Rsgsz, 3., Baird, It., Rebbeck, P. et al. Neoadjuvsnt (preopera tive) chemotherapy for breast cancer. Cancer, 1985; 56:719.
30. Jones, S.E., Dune, B.G. and Salmon, S.E. Combination chemothera pywith adriamycin and cyclophosphamide for advanced breast cancer. Cancer, 1975; 36:90.
31. De Lena, M., Brambilla. C., Morabita, A. and Bonadonna, G. Adria myein plus vincriatine compared to and combined with cyclophoa phamide, methotrexate, and 5-fluorouracil foradvsnced breast cancer. Cancer, 1975; 35:1108.
32. Buzdar, A.U., Blumenschein, Ga., Smith,T.L, Powell, K.Y.C., Hortobagyi, G.N., Yap, H.Y., Schell, P.C., Barnes, B.C., Ames, P.C., Martin, R.G. and Herah, EM. Aduvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without bacillus calmette-guerin and with or withottt irradiation in operable breast cancer. Cancer, 1984; 53:384.
33. Mendez, P.E., Petera-Dundey, 8.3., Bultuck, P., etat. Acompari ton ofmethotrexateand adriamycin based combination chemotherapy regimens in stage II carcinoma of the breatt. Proc. Am. Soc. Clin. Oncol., 1986; 5:64.
34. Fiaher, B., Redmond, C., Brown, A. et si. Adjuvsnt chemotherapy with or without
35. Hubay, C.A., Pearson, OH., Gordon, N.H. et aL Randomized trial of endocrine versus endocrine plus cytotoxic chemotherapy in women with stage II. estrogen receptor positive breast cancer. Proc. Am. Soc. Clin. Oncol., 1986; 5:63.
36. Bonadonns, G.. Valagussa, P., Rossi, A. et al. Are surgical adjuvant trials altering the course of breast cancer? Semin. Oncol., 1978; 5:450.
37. Warne, G.L., Fairley, K.F., Hobbs, J.B. et al. Cyclophosphamide induced ovarian failure. N. Engl.J. Med., 1973; 289:1159.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: