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.
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.
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.
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.