Systemic Adjuvant (Combined Modality) Therapy in the Treatment of Primary Breast Cancer

  • Bernard Fisher
  • Norman Wolmark


Despite the use of expansive surgical procedures on women with primary breast cancers, noteworthy gains relative to survival and freedom from disease have not occurred during the past three or four decades. Elsewhere in this volume, it has been documented that operation alone is all too frequently inadequate to effect a cure. There is increasing acceptance of the consideration that most, if not all, such patients have disseminated disease at the time of diagnosis. Consequently, improvement in survival is only apt to result from the employment of effective systemic therapy in conjunction with those modalities used to control locoregional disease, i.e., operation and radiation. The use of chemo-, mmuno-, or hormonal therapy in conjunction with operation has been inappropriately designated as “adjuvant” therapy. Recent advances in knowledge support the contention that operation and/or radiation, by reducing tumor burden, may actually serve as the “adjuvant” to systemic therapy. Consequently, the term “combined modality” therapy seems more appropriate to describe the various conglomerate treatment regimens. Nonetheless, because of its common usage and the general familiarity with its connotation, the term “adjuvant therapy” will be employed in this review.


Breast Cancer Adjuvant Chemotherapy Positive Node Primary Breast Cancer Radical Mastectomy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M.L. Mendelsohn, The growth fraction: A new concept applied to tumors, Science 132, 1496 (1960).Google Scholar
  2. 2.
    H.E. Skipper and F.M. Schabel, Jr., Quantitative and cytokinetic studies in experimental tumor models, in: Cancer Medicine (J-F. Holland and E. Frei, III, eds.), pp. 629–650, Lea and Febiger, New York (1973).Google Scholar
  3. 3.
    H.E. Skipper, Kinetics of mammary tumor cell growth and implications for therapy, Cancer 28, 1479–1499 (1971).PubMedCrossRefGoogle Scholar
  4. 4.
    D.M. Shapiro and R.A. Fugmann, A role for chemotherapy as an adjunct to surgery, Cancer Res. 17, 1098–1101 (1957).PubMedGoogle Scholar
  5. 5.
    M.A. Chirigos, J. Colsky, S.R. Humphreys, J.P. Glynn, and A. Goldin, Evaluation of surgery and chemotherapy in the treatment of mouse mammary adenocarinoma 755, Cancer Chemother. Rep. 22, 49–53 (1962).PubMedGoogle Scholar
  6. 6.
    H. Druckrey, B.T. Kirk, D. Schmahl, and D. Steinhoff, Kombination von operation und Chemotherapie biem krebs: Modeliver suche an einem resistenten tumor der ratte, Muench. Med. Wochenschr. 100, 1913–1918 (1958).Google Scholar
  7. 7.
    N. Brock, Neue experimentelle ergebnisse mit N-Lost-Phosphamidestern, Stahlentherapie 41, 347–350 (1959).Google Scholar
  8. 8.
    Y.N. Molkov, Prevention by aurantin of recurrence and metastases after surgical removal of transplantable tumors, Vopr. Onkol. 6, 19–25 (1960).Google Scholar
  9. 9.
    K. Karrer, S.R. Humphreys, and A. Goldin, An experimental model for studying factors which influence metastasis of malignant tumors, Int. J. Cancer 2, 213–223 (1967).PubMedCrossRefGoogle Scholar
  10. 10.
    K. Karrer and S.R. Humphreys, Continuous and limited courses of cyclophosphamide (NSC-26271) in mice with pulmonary metastasis after surgery, Cancer Chemother. Rep. 51, 439–449 (1967).Google Scholar
  11. 11.
    S.R. Humphreys and K. Karrer, Relationship of dose schedules to the effectiveness of adjuvant chemotherapy, Cancer Chemother. Rep. 54, 379–392 (1970).PubMedGoogle Scholar
  12. 12.
    J.G. Mayo, W.R. Laster, Jr., CM. Andrews, and F.M. Schabel Jr., Success and failure in the treatment of solid tumors. III. “Cure” of metastatic Lewis lung carcinoma with methyl-CCNU (NSC-95441) and surgery-chemotherapy, Cancer Chemother. Rep. 56, 183–195 (1972).PubMedGoogle Scholar
  13. 13.
    H.E. Skipper, Combination therapy: Some concepts and results, Cancer Chemother. Rep. Part 2 4, 137–145 (1974), as mentioned by D.P. Griswold, Jr.Google Scholar
  14. 14.
    M.J. Straus, V. Sege, and S.C. Choi, The effect of surgery and pretreatment or post-treatment adjuvant chemotherapy on primary tumor growth in an animal model, J.Surg. Oncol. 7, 497–512 (1975).PubMedCrossRefGoogle Scholar
  15. 15.
    D.S. Martin, P.W. Hayworth, and R.A. Fugmann, Enhanced cures of spontaneous murine mammary tumors with surgery, combination chemotherapy, and immunotherapy, Cancer Res. 30, 709–716 (1970).PubMedGoogle Scholar
  16. 16.
    R.A. Fugmann, D.S. Martin, P.E. Hayworth, and R.L. Stolfi, Enhanced cures of spontaneous murine mammary carcinomas with surgery and five-compound combination chemotherapy, and their immunotherapeutic interrelationships, Cancer Res. 30, 1931–1936 (1970).PubMedGoogle Scholar
  17. 17.
    T.R. Ashworth, A case of cancer in which cells similar to those in the tumours were seen in the blood after death, Aust. Med. J. 14, 146 (1869).Google Scholar
  18. 18.
    H. Marcus, Krebzellen im stromenden blut, Z. Krebsforsch. 16, 217–230 (1917).CrossRefGoogle Scholar
  19. 19.
    K. Schleip, Zur diagnose von knochenmarkstumoren aus dem blut-befunde, Z. Klin. Med. 59, 261–282 (1906).Google Scholar
  20. 20.
    G.R. Ward, The blood in cancer with bone metastases, Lancet 1, 676 (1913).CrossRefGoogle Scholar
  21. 21.
    E.H. Pool and G.R. Dunlop, Cancer cells in bloodstream, Am. J. Cancer 21, 99–102 (1934).Google Scholar
  22. 22.
    E.R. Fisher and R.B. Turnbull, Jr., Cytologic demonstration and significance of tumor cells in the mesenteric venous blood in patients with colorectal carcinoma, Surg. Gynecol. Obstet. 100, 102–108 (1955).PubMedGoogle Scholar
  23. 23.
    H.C. Engell, Cancer cells in the circulating blood, Acta Chir. Scand. Suppl. 201, 1–70 (1955).PubMedGoogle Scholar
  24. 24.
    G.E. Moore, A.A. Sanberg, and J.R. Schubarg, Clinical and experimental observations of the occurrence and fate of tumor cells in the bloodstream, Ann. Surg. 146, 580–587 (1957).PubMedCrossRefGoogle Scholar
  25. 25.
    J.C. Pruitt, A.W. Hilberg, and R.F. Kaiser, Malignant cells in peripheral blood, N. Engl. J. Med. 259, 1161–1164 (1958).PubMedCrossRefGoogle Scholar
  26. 26.
    R. Reiss, Demonstration of carcinoma cells in the bloodstream, J. Mt. Sinai Hosp. N.Y. 26, 171–176 (1959).PubMedGoogle Scholar
  27. 27.
    W.S. Fletcher and J.W. Stewart, Tumor cells in the blood with special reference to pre-and post-hepatic blood, Br. J. Cancer 13, 33–37 (1959).PubMedCrossRefGoogle Scholar
  28. 28.
    H.T. Langston, J.F. Laws, E.A. McGrew, C. Heidenreich, and M. Slominski, The incidence of blood vessel invasion in bronchogenic carcinoma, Surg. Gynecol. Obstet. 107, 704–708 (1958).PubMedGoogle Scholar
  29. 29.
    T.P. Morley, The recovery of tumor cells from venous blood draining cerebral gliomas, Can. J. Surg. 2, 363–365 (1959).PubMedGoogle Scholar
  30. 30.
    A.W. Diddle, D.M. Sholes, Jr., J. Hollingsworth, and S. Kinlaw, Cervical carcinoma; cancer cells in the circulating blood, Am. J. Obstet. Gynecol. 78, 582–585 (1959).PubMedGoogle Scholar
  31. 31.
    W. Coutts, E. Silva-Inzunza, R. Bulnes, and D. Rosenberg, Cytologic investigation of malignant cells in peripheral blood and testicular substance from patients orchiec-tomized for prostatic carcinoma, J. Urol. 82, 607–609 (1959).Google Scholar
  32. 32.
    M. Romsdahl, S. Potter, R. Malmgren, E. Chu, C. Brindley, and R. Smith, A clinical study of circulating tumor cells in malignant melanoma, Surg. Gynecol. Obstet. 111, 675–681 (1960).PubMedGoogle Scholar
  33. 33.
    W. Grove, A. Warne, O. Jonasson, and S. Roberts, The vascular dissemination of cancer in children, Am. Med. Assoc. Arch. Surg. 78, 698–702 (1959).CrossRefGoogle Scholar
  34. 34.
    S. Roberts, A. Watne, R. McGrath, E. McGrew, and W.H. Cole, Technique and results of isolation of cancer cells from the circulating blood, Am. Med. Assoc. Arch. Surg. 76, 334–346 (1958).CrossRefGoogle Scholar
  35. 35.
    L. Long, O. Jonasson, S. Roberts, R. McGrath, E. McGrew, and W.H. Cole, Cancer cells in the blood; results of simplified isolation technique, Am. Med. Assoc. Arch. Surg. 80, 910–919 (1960).CrossRefGoogle Scholar
  36. 36.
    S. Roberts, L. Long, O. Jonasson, R. McGrath, E. McGrew, and W.H. Cole, The isolation of cancer cells from the bloodstream during uterine curettage, Surg. Gynecol. Obstet. 111, 3–11 (1960).PubMedGoogle Scholar
  37. 37.
    O. Jonasson, L. Long, S. Roberts, E. McGrew, and J. McDonald, Cancer cells in the circulating blood during operative management of genitourinary tumors, J urol. 85, 1–12 (1961).Google Scholar
  38. 38.
    N.C. Delarue, The free cancer cell, Can. Med. Assoc. J. 82, 1175–1182 (1960).PubMedGoogle Scholar
  39. 39.
    E.P. Cruz, G.O. McDonald, and W.H. Cole, Prophylactic treatment of cancer; the use of chemotherapeutic agents to prevent tumor metastasis, Surgery 40, 291–296 (1956).PubMedGoogle Scholar
  40. 40.
    G.O. McDonald, E.P. Cruz, and W.H. Cole, The effect of cancer inhibitor drugs on the “take” of Walker carcinosarcoma 256 in rats, Surg. Forum 7, 486–489 (1956).Google Scholar
  41. 41.
    G.O. McDonald, C. Livingston, C.F. Boyles, and W.H. Cole, The prophylactic treatment of malignant disease, with nitrogen mustard and triethylenethiophosphoramide (Thio-TEPA), Ann. Surg. 145, 624–629 (1957).PubMedCrossRefGoogle Scholar
  42. 42.
    B. Fisher, R.G. Ravdin, R.K. Ausman, N.H. Slack, G.E. Moore, and R.J. Noer, Surgical adjuvant chemotherapy in cancer of the breast: Results of a decade of cooperative investigation. Ann. Surg. 168, 337–356 (1968).PubMedCrossRefGoogle Scholar
  43. 43.
    B. Fisher, N. Slack, D. Katrych, and N. Wolmark, Ten year follow-up of breast cancer patients in a cooperative clinical trial evaluating surgical adjuvant chemotherapy, Surg. Gynecol. Obstet. 140, 528–534 (1975).PubMedGoogle Scholar
  44. 44.
    H.E. Skipper, Some thoughts on surgery-chemotherapy trials against breast cancer, in: Monograph, Southern Research Institute, Birmingham, Alabama (1971), p. 1.Google Scholar
  45. 45.
    R. Nissen-Meyer, K. Kjellgren, and B. Mansson, Preliminary report from the Scandinavian Adjuvant Chemotherapy Study Group, Cancer Chemother. Rep. 55, 561–566 (1971).PubMedGoogle Scholar
  46. 46.
    B. Mansson, K. Kjellgren, and R. Nissen-Meyer, Cyclophosphamide as adjuvant to primary surgery for breast cancer, a cooperative controlled clinical study, in: Proceedings of the 11th International Cancer Congress, Florence, Italy, Vol. 3 (1974), p. 531.Google Scholar
  47. 47.
    R. Finney, Adjuvant chemotherapy in the radical treatment of carcinoma of the breast—a clinical trial, Am. J. Roentgenol. 111, 137–141 (1971).Google Scholar
  48. 48.
    A.M. Garin, N.I. Darev, and A.P. Bashenovoc, A summary of the comparative studies of the efficacy of different techniques in treatment of early forms of the mammary gland cancer, Vopr. Onkol. 3(19), 87–93 (1973).Google Scholar
  49. 49.
    K. Rieche, H. Berndt, and B. Prahl, Continuous postoperative treatment with cyclophosphamide in breast carcinoma. A randomized clinical study, Arch. Geschwulst-forsch. 40, 349–354(1972).Google Scholar
  50. 50.
    Y. Yoshida, S. Mivra, and H. Muroi, Late results in combined chemotherapy for cure of breat cancer (axillary lymph node metastases and therapeutic effect), in: 10th Annual Meeting of the Japanese Society for Cancer Therapy (1973) (abstract 177).Google Scholar
  51. 51.
    R.G. Mrazek and G.O. McDonald, Surgery and adjuvant chemotherapy in treatment for breast carcinoma, in: Abstracts of the Tenth International Cancer Congress, Houston, Texas (1970), p. 501.Google Scholar
  52. 52.
    W.L. Donegan, Prolonged surgical adjuvant chemotherapy with Thio-TEPA for mammary carcinoma: A progress report, in: Abstracts of the Tenth International Cancer Congress, Houston, Texas (1970), p. 500.Google Scholar
  53. 53.
    W.L. Donegan, Extended surgical adjuvant Thio-TEPA for mammary carcinoma, Arch. Surg. 109, 187–192 (1974).PubMedCrossRefGoogle Scholar
  54. 54.
    S.A. Kholdin, L.Y. Deemarsky, and J.L. Bavly, Adjuvant long-term chemotherapy in complex treatment of operable breast cancer, Cancer 33, 903–906 (1974).PubMedCrossRefGoogle Scholar
  55. 55.
    F.J. Ansfield, 5-FU as an adjuvant to mastectomy in high-risk patients, Proc. Am. Assoc. Cancer Res. and Am. Soc. Clin. Oncol. 15, 177 (1974) (abstract).Google Scholar
  56. 56.
    G. Ramirez, Combined chemotherapy-radiotherapy as an adjuvant to mastectomy in patients with positive nodes, Proc. Am. Assoc. Cancer Res. and Am. Soc. Clin. Oncol. 16, 224 (1975) (abstract).Google Scholar
  57. 57.
    L.H. Schmidt, R. Fradkin, R. Sullivan, and A. Flowers, Comparative pharmacology of alkylating agents, Cancer Chemother. Rep. Suppl. 2, 1–1528 (1965).Google Scholar
  58. 58.
    M.E. Sears, A. Haut, and N. Eckles, Melphalan (NSC-8806) in advanced breast cancer, Cancer Chemother. Rep. 50, 271–297 (1966).PubMedGoogle Scholar
  59. 59.
    E.M. Greenspan, M. Fieber, G. Lesnick, and S. Edelman, Response of advanced breast carcinoma to the combination of the antimetabolite methotrexate and the alkylating agent Thio-TEPA, Mt. Sinai J. Med. N.Y. 30, 246–267 (1963).Google Scholar
  60. 60.
    E.M. Greenspan, Combination cytotoxic chemotherapy in advanced disseminated breast carcinoma, Mt. Sinai J. Med. N.Y. 33, 1–26 (1966).Google Scholar
  61. 61.
    R.G. Cooper, Combination chemotherapy in hormone resistant breast cancer, Proc. Am. Assoc. Cancer Res. abstract 57 (1969).Google Scholar
  62. 62.
    S.K. Carter, Reported at National Surgical Adjuvant Group Meeting, Bethesda, Maryland (October 10–11, 1973).Google Scholar
  63. 63.
    F.M. Schabel, Jr., Synergism and antagonism among antitumor agents, in: Pharmacological Basis of Cancer Chemotherapy (27th Annual Symposium on Fundamental Cancer Research at M.D. Anderson Hospital, Houston, Texas), pp. 595–621, Williams and Wilkins, Baltimore (1975).Google Scholar
  64. 64.
    B. Fisher, P. Carbone, S.G. Economou, R. Frelick, A. Glass, H. Lerner, C. Redmond, M. Zelen, D.L. Katrych, N. Wolmark, P. Band, E.R. Fisher, and Other Cooperating Investigators, L-Phenylalanine mustard (l-PAM) in the management of primary breast cancer; a report of early findings, N. Engl. J. Med. 292, 117–122 (1975).PubMedCrossRefGoogle Scholar
  65. 65.
    G. Bonadonna, E. Brusamalino, P. Valagussa, A. Rossi, L. Brugnatelli, C. Brambilla, M. DeLena, G. Tancini, E. Baietta, R. Musumeci, and U. Veronesi, Combination chemotherapy as an adjuvant treatment in operable breast cancer, N. Engl. J. Med. 294, 406–410 (1976).CrossRefGoogle Scholar
  66. 66.
    B.N. Halpern, A.R. Prevot, G. Biozzi, C. Stiffel, D. Mouton, J.C. Morard, Y. Bouthillier, and C. Decreusefond, Stimulation of the phagocytic activity of the RES provoked by C. parvum, J. Reticuloendothel. Soc. 1, 77–96 (1963).Google Scholar
  67. 67.
    M.T. Scott, Biological effects of adjuvant C. parvum. I. Inhibition of PHA, mixed lymphocytes and GVH reactivity, Cell. Immunol. 5, 459–468 (1972).PubMedCrossRefGoogle Scholar
  68. 68.
    L.H. Smith and M.F. A. Woodruff, Comparative effect of 2 strains of C. parvum on the phagocytic activity and tumor growth, Nature 219, 197–198 (1968).PubMedCrossRefGoogle Scholar
  69. 69.
    C. Adlam, E.S. Broughton, and M.T. Scott, Enhanced resistance of mice to infection with bacteria following pretreatment with C. parvum, Nature (London) New Biol. 235, 219–220 (1972).CrossRefGoogle Scholar
  70. 70.
    T. Neveu, A. Branellec, and G. Biozzi, Adjuvant effect of C. parvum on antibody production and delayed hypersensitivity conjugated proteins, Ann. Inst. Pasteur (Paris) 106, 771–777 (1964).Google Scholar
  71. 71.
    B. Halpern, G. Biozzi, C. Stiffel, and D. Mouton, Inhibition of tumor growth by administration of killed C. parvum, Nature 212, 853–854 (1966).Google Scholar
  72. 72.
    M.F.A. Woodruff and J.L. Boak, Inhibitory effect of injection of C. parvum on the growth of tumor transplants in isogenic hosts, Br. J. Cancer 20, 345–355 (1966).PubMedCrossRefGoogle Scholar
  73. 73.
    M.F.A. Woodruff and M.P. Inchley, Synergistic inhibition of mammary carcinoma transplants in A-strain mice by antitumor globulin and C. parvum, Br. J. Cancer 25, 584–593 (1971).Google Scholar
  74. 74.
    G.H. Currie and D. Bagshawe, Active immunotherapy with C. parvum and chemotherapy in murine fibrosarcomas, Br. Med. J.. 1, 541–544 (1970).PubMedCrossRefGoogle Scholar
  75. 75.
    B. Fisher, N. Wolmark, E. Saffer, and E.R. Fisher, Inhibitory effect of prolonged Corynebacterium parvum and cyclophosphamide administration on the growth of established tumors, Cancer 35, 134–143 (1975).PubMedCrossRefGoogle Scholar
  76. 76.
    L. Israel and R. Edelstein, Nonspecific immunostimulation with C. parvum in human cancer, in: 26th Annual Symposium on Fundamental Cancer Research at M.D. Anderson Hospital, Houston, Texas (1973), pp. 485–504.Google Scholar
  77. 77.
    . L. Israel and R. Edelstein, A phase II study of daily intravenous Corynebacterium in 33 disseminated cancers, Proc. Am. Assoc. Cancer Res. 16, 67 (1975).Google Scholar
  78. 78.
    L. Israel and B. Halpern, C. parvum in advanced cancers: Initial evaluation of therapeutic activity, Nouv. Presse Med. 1, 19–23 (1972).PubMedGoogle Scholar
  79. 79.
    B. Fisher, H. Rubin, G. Sartiano, L. Ennis, and N. Wolmark, Observations following Corynebacterium parvum administration to patients with advanced malignancy: A phase I study, Cancer 38, 119–130 (1976).PubMedCrossRefGoogle Scholar
  80. 80.
    B. Fisher, H. Rubin, E. Saffer, and N. Wolmark, Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide. II. Effect of cortisone acetate, /. Natl. Cancer Inst. 56, 571–574 (1976).Google Scholar
  81. 81.
    B. Fisher, N. Wolmark, H. Rubin, and E. Saffer, Further observations on the inhibition of tumor growth by C. parvum with cyclophosphamide: I. Variation in administration of both agents, J.Natl. Cancer Inst. 55,1147–1153 (1975).PubMedGoogle Scholar
  82. 82.
    B. Fisher, H. Rubin, E. Saffer, and N. Wolmark, Effect of Corynebacterium parvum in combination with 5-fluorouracil, L-phenylalanine mustard or methotrexate on the inhibition of tumor growth, Cancer Res. 36, 2714–2719 (1976).PubMedGoogle Scholar
  83. 83.
    M.J.K. Harper and A.L. Walpole, A new derivative of triphenylethylene: Effect on implantation and mode of action in rats, J. Reprod. Fertil. 13, 101–119 (1967).PubMedCrossRefGoogle Scholar
  84. 84.
    J.R. Skidmore, A.L. Walpole, and J. Woodburn, Effect of some triphenylenthylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary, J. Endocrinol 52, 289–298 (1972).CrossRefGoogle Scholar
  85. 85.
    V.C. Jordon, Steroid Biochem. 5, 354 (1974), as mentioned by Band in personal communication.CrossRefGoogle Scholar
  86. 86.
    M.P. Cole, C.T.A. Jones, and I.D.H. Todd, A new anti-oestrogenic agent in late breast cancer: An early clinical appraisal of ICI 464, Br. J. Cancer 25, 270–275 (1971).PubMedCrossRefGoogle Scholar
  87. 87.
    H.W.C. Ward, Anti-oestrogen therapy for breast cancer: A trial of tamoxifen at two dose levels, Br. Med. J. 1, 13–14 (1973).PubMedCrossRefGoogle Scholar
  88. 88.
    P. Band, H. Lerner, L. Israel, and B. Leung, Personal communication (1976).Google Scholar
  89. 89.
    O. Pearson, Personal communication (1975).Google Scholar
  90. 90.
    H.J. Tagnon, Reported at the National Conference on Breast Cancer, Montreal, Canada (1975).Google Scholar

Copyright information

© Springer Science+Business Media New York 1977

Authors and Affiliations

  • Bernard Fisher
    • 1
  • Norman Wolmark
    • 1
  1. 1.Department of SurgeryUniversity of PittsburghPittsburghUSA

Personalised recommendations