From screening to clinical research: The cure of leukemia and the early development of the cooperative oncology groups, 1955-1966

Bulletin of the History of Medicine

Volumn 76, Issue 2, 2002, Pages 299-334

  Keating, Peter ^a   Cambrosio, Alberto ^a  

^a NONE

Author keywords

Cancer chemotherapy; Clinical research; Clinical trials; Cooperative oncology groups; Leukemia; National Cancer Institute; Screening; United States

Indexed keywords

ARTICLE; CLINICAL TRIAL; DRUG SCREENING; HEALTH CARE ORGANIZATION; HISTORY; HUMAN; LEUKEMIA; ONCOLOGY; ORGANIZATION AND MANAGEMENT; RESEARCH; UNITED STATES;

CLINICAL TRIALS; DRUG EVALUATION, PRECLINICAL; HISTORY, 20TH CENTURY; HUMANS; LEUKEMIA; MEDICAL ONCOLOGY; NATIONAL INSTITUTES OF HEALTH (U.S.); RESEARCH; UNITED STATES;

EID: 0036615782     PISSN: 00075140     EISSN: None     Source Type: Journal    
DOI: 10.1353/bhm.2002.0074     Document Type: Review

References (161)

1. Howard E. Skipper, "Historic Milestones in Cancer Biology: A Few Things That Are Important in Cancer Treatment (Revisited)," Semin. Oncol., 1979, 6: 506-14, quotation on p. 506.
2. For an overview of this work, see Alberto Cambrosio and Peter Keating, "Biomedical Sciences and Technology, History and Sociology of," in International Encyclopedia of the Social and Behavioral Sciences, ed. Neil J. Smelser and Paul B. Baltes (Amsterdam: Pergamon Press, 2001), 2:1222-26. On the novelty of biomedicine, see Peter Keating and Alberto Cambrosio, "Biomedical Platforms," Config., 2000, 8: 337-87. For an analysis of French developments in this field, albeit from a different theoretical viewpoint, see Jean-François Picard, "De la médecine expérimentale (1865) à l'INSERM (1964)," in Les sciences biologiques et médicales en France, 1920-1950, ed. Claude Debru, Jean Gayon, and Jean-François Picard (Paris: CNRS, 1994), pp. 329-44; Jean-Paul Gaudillière, "Les biochimistes français entre légitimité médicale et légitimité biologique 1930-1960," in ibid., pp. 265-82.
3. For an overview of this work, see Alberto Cambrosio and Peter Keating, "Biomedical Sciences and Technology, History and Sociology of," in International Encyclopedia of the Social and Behavioral Sciences, ed. Neil J. Smelser and Paul B. Baltes (Amsterdam: Pergamon Press, 2001), 2:1222-26. On the novelty of biomedicine, see Peter Keating and Alberto Cambrosio, "Biomedical Platforms," Config., 2000, 8: 337-87. For an analysis of French developments in this field, albeit from a different theoretical viewpoint, see Jean-François Picard, "De la médecine expérimentale (1865) à l'INSERM (1964)," in Les sciences biologiques et médicales en France, 1920-1950, ed. Claude Debru, Jean Gayon, and Jean-François Picard (Paris: CNRS, 1994), pp. 329-44; Jean-Paul Gaudillière, "Les biochimistes français entre légitimité médicale et légitimité biologique 1930-1960," in ibid., pp. 265-82.
4. For an overview of this work, see Alberto Cambrosio and Peter Keating, "Biomedical Sciences and Technology, History and Sociology of," in International Encyclopedia of the Social and Behavioral Sciences, ed. Neil J. Smelser and Paul B. Baltes (Amsterdam: Pergamon Press, 2001), 2:1222-26. On the novelty of biomedicine, see Peter Keating and Alberto Cambrosio, "Biomedical Platforms," Config., 2000, 8: 337-87. For an analysis of French developments in this field, albeit from a different theoretical viewpoint, see Jean-François Picard, "De la médecine expérimentale (1865) à l'INSERM (1964)," in Les sciences biologiques et médicales en France, 1920-1950, ed. Claude Debru, Jean Gayon, and Jean-François Picard (Paris: CNRS, 1994), pp. 329-44; Jean-Paul Gaudillière, "Les biochimistes français entre légitimité médicale et légitimité biologique 1930-1960," in ibid., pp. 265-82.
5. For an overview of this work, see Alberto Cambrosio and Peter Keating, "Biomedical Sciences and Technology, History and Sociology of," in International Encyclopedia of the Social and Behavioral Sciences, ed. Neil J. Smelser and Paul B. Baltes (Amsterdam: Pergamon Press, 2001), 2:1222-26. On the novelty of biomedicine, see Peter Keating and Alberto Cambrosio, "Biomedical Platforms," Config., 2000, 8: 337-87. For an analysis of French developments in this field, albeit from a different theoretical viewpoint, see Jean-François Picard, "De la médecine expérimentale (1865) à l'INSERM (1964)," in Les sciences biologiques et médicales en France, 1920-1950, ed. Claude Debru, Jean Gayon, and Jean-François Picard (Paris: CNRS, 1994), pp. 329-44; Jean-Paul Gaudillière, "Les biochimistes français entre légitimité médicale et légitimité biologique 1930-1960," in ibid., pp. 265-82.
6. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
7. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
8. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
9. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
10. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
11. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
12. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
13. See, for example, Ilana Löwy, "Experimental Systems and Clinical Practices: Tumor Immunology and Cancer. Immunotherapy, 1895-1980," J. Hist. Biol., 1994, 27: 403-35; Michel Morange, La part des gènes (Paris: Odile Jacob, 1998); Simon D. Feldman and Alfred I. Tauber, "Sickle Cell Anemia: Reexamining the First 'Molecular Disease,'" Bull. Hist. Med., 1997, 71: 623-50; Jean-Paul Gaudillière, "Oncogenes as Metaphors for Human Cancer: Articulating Laboratory Practices and Medical Demands," in Medicine and Change: Historical and Sociological Studies of Medical Innovation, ed. Ilana Löwy (London: John Libbey, 1993), pp. 213-48. For prewar articulations of the laboratory and the clinic, see Keith Wailoo, "A Disease Sui Generis: The Origins of Sickle Cell Anemia and the Emergence of Modern Clinical Research, 1904-1924," Bull. Hist. Med., 1991, 65: 185-208; Olga Amsterdamska, "Between Medicine and Science: The Research Career of Oswald T. Avery, in Löwy, Medicine and Change (n. 3), pp. 181-212; Olga Amsterdamska, "Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke," in Molecularizing Biology and Medicine: New Practices and Alliances, 1910s-1970s, ed. Soraya de Chadarevian and Harmke Kamminga (Amsterdam: Harwood, 1998), pp. 47-82; Christiane Sinding, Le clinicien et le chercheur: Des grandes maladies de carence à la médecine moléculaire (1880-1980) (Paris: Presses Universitaires de France, 1991).
14. For an initial analysis, see Peter Keating and Alberto Cambrosio, "Transplantation, Tumor, or Differentiation Antigens? The View from Biology and the View from Pathology" (paper presented to the seventy-third annual meeting of the American Association for the History of Medicine, Bethesda, Md., 20 May 2000); idem, "The New Genetics and Cancer: The Contributions of Clinical Medicine in the Era of Biomedicine," J. Hist. Med., 2001, 56: 321-52.
15. For an initial analysis, see Peter Keating and Alberto Cambrosio, "Transplantation, Tumor, or Differentiation Antigens? The View from Biology and the View from Pathology" (paper presented to the seventy-third annual meeting of the American Association for the History of Medicine, Bethesda, Md., 20 May 2000); idem, "The New Genetics and Cancer: The Contributions of Clinical Medicine in the Era of Biomedicine," J. Hist. Med., 2001, 56: 321-52.
16. But not from the point of view of the actors, where they can indeed be quite useful: see Edward H. Ahrens, Jr., The Crisis in Clinical Research: Overcoming Institutional Obstacles (New York: Oxford University Press, 1992).
17. Jeff Lyon and Peter Gorner, Altered Fates: Gene Therapy and the Retooling of Human Life (New York: Norton, 1996); Ilana Löwy, Between Bench and Bedside: Science, Healing, and Interleukin-2 in a Cancer Ward (Cambridge: Harvard University Press, 1996); Stephen S. Hall, A Commotion in the Blood: Life, Death, and the Immune System (New York: Henry Holt, 1997).
18. Jeff Lyon and Peter Gorner, Altered Fates: Gene Therapy and the Retooling of Human Life (New York: Norton, 1996); Ilana Löwy, Between Bench and Bedside: Science, Healing, and Interleukin-2 in a Cancer Ward (Cambridge: Harvard University Press, 1996); Stephen S. Hall, A Commotion in the Blood: Life, Death, and the Immune System (New York: Henry Holt, 1997).
19. Jeff Lyon and Peter Gorner, Altered Fates: Gene Therapy and the Retooling of Human Life (New York: Norton, 1996); Ilana Löwy, Between Bench and Bedside: Science, Healing, and Interleukin-2 in a Cancer Ward (Cambridge: Harvard University Press, 1996); Stephen S. Hall, A Commotion in the Blood: Life, Death, and the Immune System (New York: Henry Holt, 1997).
20. C. Thomas Caskey, "DNA-Based Medicine: Prevention and Therapy," in The Code of Codes: Scientific and Social Issues in the Human Genome Project, ed. Daniel J. Kevles and Leroy Hood (Cambridge: Harvard University Press, 1992), pp. 112-35; Jean Dausset, Clin d'oeil à la vie: La grande aventure HLA (Paris: Odile Jacob, 1998).
21. C. Thomas Caskey, "DNA-Based Medicine: Prevention and Therapy," in The Code of Codes: Scientific and Social Issues in the Human Genome Project, ed. Daniel J. Kevles and Leroy Hood (Cambridge: Harvard University Press, 1992), pp. 112-35; Jean Dausset, Clin d'oeil à la vie: La grande aventure HLA (Paris: Odile Jacob, 1998).
22. Stanley L. Lee, Dorothy Livings, G. Watson James, et al., "Morphologic Classification of Acute Leukemias," Cancer Chemother. Rep., 1962, 16: 151-53.
23. James M. Bennet and Kenneth A. Foon, Immunologic Approaches to the Classification and Management of the Leukemias (Boston: Kluwer, 1988).
24. Yun-Ping Li, Janet Anderson, Arthur Zelent, et al., "RAR 1/RAR 2-PML mRNA Expression in Acute Promyelocytic Leukemia Cells: A Molecular and Laboratory-Clinical Correlative Study," Blood, 1997, 90: 306-12.
25. Harry M. Marks, The Progress of Experiments: Science and Therapeutic Reform in the United States, 1900-1990 (Cambridge: Cambridge University Press, 1997); Marcia Lynn Meldrum, "'Departures from the Design': The Randomized Clinical Trial in Historical Context, 1946-1970" (Ph.D. diss., State University of New York at Stony Brook, 1994).
26. Harry M. Marks, The Progress of Experiments: Science and Therapeutic Reform in the United States, 1900-1990 (Cambridge: Cambridge University Press, 1997); Marcia Lynn Meldrum, "'Departures from the Design': The Randomized Clinical Trial in Historical Context, 1946-1970" (Ph.D. diss., State University of New York at Stony Brook, 1994).
27. See, for example, Rachel Nowak, "Problems in Clinical Trials Go Far Beyond Misconduct," Science, 1994, 264: 1538-41.
28. Löwy, Between Bench and Bedside (n. 6), pp. 36-83.
29. Ibid., pp. 54-64. See also Ilana Löwy, "'Nothing More to Be Done': Palliative Care Versus Experimental Therapy in Advanced Cancer," Sci. Context, 1995, 8: 209-29.
30. Ibid., pp. 54-64. See also Ilana Löwy, "'Nothing More to Be Done': Palliative Care Versus Experimental Therapy in Advanced Cancer," Sci. Context, 1995, 8: 209-29.
31. The four-page pull-out can be found in C. G. Zubrod, S. Schepartz, J. Leiter, et al., "The Chemotherapy Program of the National Cancer Institute: History, Analysis, and Plans," Cancer Chemother. Rep., 1966, 50: 349-540, on p. 537. Despite the single title, this special issue is divided into three major articles, all of them unsigned. In a recent interview, however, Zubrod has credited J. Leiter as one of the authors of the "history" and a committee headed by himself as lhe author of the "plan"; the committee included C. G. Baker, S. Schepartz, J. Leiter, L. Carrese, and D. Rall. For the sake of simplicity, we refer to Zubrod as the author of the diagram. See "Interviews with C. Gordon Zubrod," NCI Oral History Project, History Associates Incorporated, 27 May and 27 June 1997, p. 71. On the recourse to managerial models in postwar American biomedicine, see Jean-Paul Gaudillière, "The Molecularization of Cancer Etiology in the Postwar United States: Instruments, Politics, and Management," in de Chadarevian and Kamminga, Molecularizing Biology and Medicine (n. 3), pp. 139-70.
32. The four-page pull-out can be found in C. G. Zubrod, S. Schepartz, J. Leiter, et al., "The Chemotherapy Program of the National Cancer Institute: History, Analysis, and Plans," Cancer Chemother. Rep., 1966, 50: 349-540, on p. 537. Despite the single title, this special issue is divided into three major articles, all of them unsigned. In a recent interview, however, Zubrod has credited J. Leiter as one of the authors of the "history" and a committee headed by himself as lhe author of the "plan"; the committee included C. G. Baker, S. Schepartz, J. Leiter, L. Carrese, and D. Rall. For the sake of simplicity, we refer to Zubrod as the author of the diagram. See "Interviews with C. Gordon Zubrod," NCI Oral History Project, History Associates Incorporated, 27 May and 27 June 1997, p. 71. On the recourse to managerial models in postwar American biomedicine, see Jean-Paul Gaudillière, "The Molecularization of Cancer Etiology in the Postwar United States: Instruments, Politics, and Management," in de Chadarevian and Kamminga, Molecularizing Biology and Medicine (n. 3), pp. 139-70.
33. The four-page pull-out can be found in C. G. Zubrod, S. Schepartz, J. Leiter, et al., "The Chemotherapy Program of the National Cancer Institute: History, Analysis, and Plans," Cancer Chemother. Rep., 1966, 50: 349-540, on p. 537. Despite the single title, this special issue is divided into three major articles, all of them unsigned. In a recent interview, however, Zubrod has credited J. Leiter as one of the authors of the "history" and a committee headed by himself as lhe author of the "plan"; the committee included C. G. Baker, S. Schepartz, J. Leiter, L. Carrese, and D. Rall. For the sake of simplicity, we refer to Zubrod as the author of the diagram. See "Interviews with C. Gordon Zubrod," NCI Oral History Project, History Associates Incorporated, 27 May and 27 June 1997, p. 71. On the recourse to managerial models in postwar American biomedicine, see Jean-Paul Gaudillière, "The Molecularization of Cancer Etiology in the Postwar United States: Instruments, Politics, and Management," in de Chadarevian and Kamminga, Molecularizing Biology and Medicine (n. 3), pp. 139-70.
34. Zubrod et al., "Chemotherapy Program" (n. 15), pp. 482-83.
35. Ibid., p. 485.
36. Ibid., p. 479. Skipper and his colleagues offer a general summary of their previous fifteen years' work in Howard E. Skipper, Frank M. Schabel, and William S. Wilcox, "Changing Concepts in Cancer Chemotherapy," Bull. Southern Res. Inst., 1964, 17: 3-14.
37. Ibid., p. 479. Skipper and his colleagues offer a general summary of their previous fifteen years' work in Howard E. Skipper, Frank M. Schabel, and William S. Wilcox, "Changing Concepts in Cancer Chemotherapy," Bull. Southern Res. Inst., 1964, 17: 3-14.
38. C. Gordon Zubrod, "Historic Milestones in Curative Chemotherapy," Semin. Oncol., 1979, 6: 490-505, quotation on p. 500.
39. See the diagram describing the new organization in Zubrod et al., "Chemotherapy Program" (n. 15), p. 538.
40. Hugh L. Davis, John R. Durant, and James F. Holland, "Interrelationships: The Groups, The NCI and Other Governmental Agencies," in Cancer Research: Impact of the Cooperative Groups, ed. Barth Hoogstraten (New York: Masson, 1980), pp. 371-90.
41. On this notion in experimental science, see Hans Jörg Rheinberger, Toward a History of Epistemic Things: Synthesizing Proteins in the Test Tube (Stanford: Stanford University Press, 1997).
42. Robert F. Bud, "Strategy in American Cancer Research after World War II: A Case Study," Soc. Stud. Sci., 1978, 8: 425-59, see especially p. 441. The institutes in question are the Sloan-Kettering Institute and the Institute for Cancer Research (Philadelphia). Sloan-Kettering was the first institution to screen drugs for anticancer properties for drug companies; by 1950, it had screened 3,000 compounds. Zubrod has briefly described the prewar program in Britain and Germany in Zubrod et al., "Chemotherapy Program" (n. 15), pp. 349-50.
43. Robert F. Bud, "Strategy in American Cancer Research after World War II: A Case Study," Soc. Stud. Sci., 1978, 8: 425-59, see especially p. 441. The institutes in question are the Sloan-Kettering Institute and the Institute for Cancer Research (Philadelphia). Sloan-Kettering was the first institution to screen drugs for anticancer properties for drug companies; by 1950, it had screened 3,000 compounds. Zubrod has briefly described the prewar program in Britain and Germany in Zubrod et al., "Chemotherapy Program" (n. 15), pp. 349-50.
44. See Ilana Löwy and Jean-Paul Gaudillière, "Disciplining Cancer: Mice and the Practice of Genetic Purity," in The Invisible Industrialist: Manufactures and the Production of Scientific Knowledge, ed. idem (London: Macmillan, 1998), pp. 209-49.
45. Indeed, one of the earliest screening programs set up in the United States had begun toward the end of World War II; it consisted of a program to screen bacterial polysaccharides and synthetic organic compounds for anticancer activity, with little clinical evaluation. Run by M. J. Shear out of the Office of Cancer Investigations of the U.S. Public Health Service at Harvard University, the program was discontinued in 1953. It was within this program that Coley's celebrated toxins were tested. See Ilana Löwy, "Immunotherapy of Cancer from Coley's Toxins to Interferons: Molecularization of Therapeutic Practice," in de Chadarevian and Kamminga, Molecularizing Biology and Medicine (n. 3), pp. 249-71. See also M. J. Shear, J. L. Hartwell, V. B. Peters, et al., "Some Aspects of a Joint Institutional Research Program on Chemotherapy of Cancer: Current Laboratory and Clinical Experiments with Bacterial Polysaccharide and with Synthetic Organic Compounds," in Approaches to Tumor Chemotherapy, ed. F. R. Mouton (Washington, D.C.: American Association for the Advancement of Science, 1947), pp. 236-84; Bud, "Strategy" (n. 23), pp. 445-46.
46. Indeed, one of the earliest screening programs set up in the United States had begun toward the end of World War II; it consisted of a program to screen bacterial polysaccharides and synthetic organic compounds for anticancer activity, with little clinical evaluation. Run by M. J. Shear out of the Office of Cancer Investigations of the U.S. Public Health Service at Harvard University, the program was discontinued in 1953. It was within this program that Coley's celebrated toxins were tested. See Ilana Löwy, "Immunotherapy of Cancer from Coley's Toxins to Interferons: Molecularization of Therapeutic Practice," in de Chadarevian and Kamminga, Molecularizing Biology and Medicine (n. 3), pp. 249-71. See also M. J. Shear, J. L. Hartwell, V. B. Peters, et al., "Some Aspects of a Joint Institutional Research Program on Chemotherapy of Cancer: Current Laboratory and Clinical Experiments with Bacterial Polysaccharide and with Synthetic Organic Compounds," in Approaches to Tumor Chemotherapy, ed. F. R. Mouton (Washington, D.C.: American Association for the Advancement of Science, 1947), pp. 236-84; Bud, "Strategy" (n. 23), pp. 445-46.
47. Indeed, one of the earliest screening programs set up in the United States had begun toward the end of World War II; it consisted of a program to screen bacterial polysaccharides and synthetic organic compounds for anticancer activity, with little clinical evaluation. Run by M. J. Shear out of the Office of Cancer Investigations of the U.S. Public Health Service at Harvard University, the program was discontinued in 1953. It was within this program that Coley's celebrated toxins were tested. See Ilana Löwy, "Immunotherapy of Cancer from Coley's Toxins to Interferons: Molecularization of Therapeutic Practice," in de Chadarevian and Kamminga, Molecularizing Biology and Medicine (n. 3), pp. 249-71. See also M. J. Shear, J. L. Hartwell, V. B. Peters, et al., "Some Aspects of a Joint Institutional Research Program on Chemotherapy of Cancer: Current Laboratory and Clinical Experiments with Bacterial Polysaccharide and with Synthetic Organic Compounds," in Approaches to Tumor Chemotherapy, ed. F. R. Mouton (Washington, D.C.: American Association for the Advancement of Science, 1947), pp. 236-84; Bud, "Strategy" (n. 23), pp. 445-46.
48. K. M. Endicott, "Interim Report of the Cancer Chemotherapy National Service Center to the Cancer Chemotherapy National Committee," 25 January 1957, National Cancer Institute Archives, National Institutes of Health, Bethesda, Md. (hereafter cited as NCI Archives), p. 1.
49. James F. Holland, "CALGB-The Early Years," CALGB Newsl., 1995, 4: 6; Lloyd W. Law, "Effects of Combinations of Antileukemic Agents on an Acute Lymphocytic Leukemia of Mice," Cancer Res., 1952, 13: 871-78. For Law's work within the larger context of the creation of mouse-tumor models of cancer, see Jean-Paul Gaudillière, "Circulating Mice and Viruses: The Jackson Memorial Laboratory, the National Cancer Institute, and the Genetics of Breast Cancer, 1930-1965," in The Practices of Human Genetics, ed. Michael Fortun and Everett Mendelsohn (Dordrecht: Kluwer, 1999), pp. 89-124.
50. James F. Holland, "CALGB-The Early Years," CALGB Newsl., 1995, 4: 6; Lloyd W. Law, "Effects of Combinations of Antileukemic Agents on an Acute Lymphocytic Leukemia of Mice," Cancer Res., 1952, 13: 871-78. For Law's work within the larger context of the creation of mouse-tumor models of cancer, see Jean-Paul Gaudillière, "Circulating Mice and Viruses: The Jackson Memorial Laboratory, the National Cancer Institute, and the Genetics of Breast Cancer, 1930-1965," in The Practices of Human Genetics, ed. Michael Fortun and Everett Mendelsohn (Dordrecht: Kluwer, 1999), pp. 89-124.
51. James F. Holland, "CALGB-The Early Years," CALGB Newsl., 1995, 4: 6; Lloyd W. Law, "Effects of Combinations of Antileukemic Agents on an Acute Lymphocytic Leukemia of Mice," Cancer Res., 1952, 13: 871-78. For Law's work within the larger context of the creation of mouse-tumor models of cancer, see Jean-Paul Gaudillière, "Circulating Mice and Viruses: The Jackson Memorial Laboratory, the National Cancer Institute, and the Genetics of Breast Cancer, 1930-1965," in The Practices of Human Genetics, ed. Michael Fortun and Everett Mendelsohn (Dordrecht: Kluwer, 1999), pp. 89-124.
52. Edmund A. Gehan and Marvin A. Schneiderman, "Historical and Methodological Developments in Clinical Trials at the National Cancer Institute," Statist. Med., 1990, 9: 871.
53. Twenty years later, the situation had been reversed: in 1976,9 percent, or $68,000,000, was devoted to clinical trials research.
54. Zubrod et al., "Chemotherapy Program" (n. 15), p. 352.
55. See Löwy, "'Nothing More to Be Done'" (n. 14), pp. 212-19. On Lasker's lobbying efforts, see James T. Patterson, The Dread Disease: Cancer and Modern American Culture (Cambridge: Harvard University Press, 1987), pp. 172-200.
56. See Löwy, "'Nothing More to Be Done'" (n. 14), pp. 212-19. On Lasker's lobbying efforts, see James T. Patterson, The Dread Disease: Cancer and Modern American Culture (Cambridge: Harvard University Press, 1987), pp. 172-200.
57. Zubrod et al., "Chemotherapy Program" (n. 15), p. 355.
58. Zubrod was recruited as a consultant for the Clinical Panel. As he recalled in a 1997 interview: "I told him [Dr. Radvin, chairman of the clinical activities for CCNSC] of my ideas about controlled clinical trials. Most clinical trials, not all clinical trials, in cancer and in other diseases were hit or miss, haphazard, you know, you'd treat twenty patients and see what happened without any kinds of controls. . . . We fortunately attracted members to the Clinical Panel who were also convinced that this was the way to go" ("Interviews with C. Gordon Zubrod" [n. 15], p. 69).
59. John Laszlo, The Cure of Childhood Leukemia: Into the Age of Miracles (New Brunswick, N.J.: Rutgers University Press, 1995), p. 220. Emil Frei ran Acute Leukemia Group B from 1955 until 1965; during that time, he organized nine different clinical trials.
60. Hoogstraten, Cancer Research (n. 21), p. iii.
61. Ibid.
62. Endicott, "Interim Report" (n. 26), p. 2.
63. Ibid., pp. 2-3.
64. National Institutes of Health, National Cancer Institute, Annual Report of Program Activities, 1958, 1: 52. See also K. M. Endicott, "The National Chemotherapy Program," J. Chron. Dis., 1958, 8: 171-77.
65. National Institutes of Health, National Cancer Institute, Annual Report of Program Activities, 1958, 1: 52. See also K. M. Endicott, "The National Chemotherapy Program," J. Chron. Dis., 1958, 8: 171-77.
66. Endicott, "Interim Report" (n. 26), p. 10.
67. NIH, NCI, Annual Report (n. 39), p. 50.
68. Vincent J. DeVita, Jr., "On Special Initiatives, Critics, and the National Cancer Program," Cancer Treat. Rep., 1984, 68: 1-4, quotation on p. 1.
69. C. Gordon Zubrod, "Origins and Development of Chemotherapy Research at the National Cancer Institute," Cancer Treat. Rep., 1984, 68: 9-19, see especially p. 11.
70. Not to be confused with the Institute of Cancer Research in Philadelphia: this one is affiliated with Columbia University in New York.
71. For example, in the NCI's Annual Report for 1958 we read: "The Eastern Solid Tumor Group . . . has completed a comparative study of therapeutic effectiveness of thioTEPA and nitrogen mustard in 260 patients. . . . Nitrogen mustard is clearly superior to thioTEPA in the management of Hodgkin's disease; remissions are induced with equal frequency but duration of remissions is longer and more complete" (NIH, NCI, Annual Report [n. 39], pp. 50-51). To this Gellhorn replied: "Who really cares whether or not nitrogen mustard is a fraction better or a fraction worse than thioTEPA in the treatment of Hodgkin's disease when it is clearly known that neither of these substances constitutes an adequate answer to the problem of disseminated lymphoma" (Alfred Gellhorn, "Invited Remarks on the Current Status of Research in Clinical Cancer Chemotherapy," Cancer Chemother. Rep., 1959, 5: 1-12, especially p. 7).
72. Gellhorn, "Invited Remarks" (n. 45), pp. 8-9.
73. Ibid., p. 7. Fluorouracil is still used in cancer chemotherapy.
74. Zubrod et al., "Chemotherapy Program" (n. 15), p. 375.
75. Ibid.
76. Memorandum from Clinical Director (Zubrod), NCI, to Director, NCI, 22 December 1959, "Recommendations on Reorganization of CCNSC," p. 1, NCI Archives.
77. Ibid.
78. Ibid., pp. 1-2.
79. NIH, NCI, Annual Report of Program Activities, 1960, 1: 12.
80. Ibid., p. 16.
81. Ibid., p. 20.
82. Ibid.
83. Sec Alfred Gellhorn and Erich Hirschberg, eds., "Investigation of Diverse Systems for Cancer Chemotherapy Screening," Cancer Res., 1955, Suppl. 3: 1-125.
84. H. F. Bisel, Letter to the Editor, "Criteria for the Evaluation of Response to Treatment in Acute Leukemia," Blood, 1956, 11: 676-77. This definition of complete remission was subsequently adopted in Britain: see Working Party on the Evaluation of Different Methods of Therapy in Leukemia, "Treatment of Acute Leukemia in Adults: Comparison of Steroid Therapy at High and Low Dosage in Conjunction with 6-Mercaptopurine: First Report to the Medical Research Council of the Working Party on the Evaluation of Different Methods of Therapy in Leukemia," Brit. Med. J., 1963, 5: 7-14, especially p. 11. It should be noted that this is just the hematological part of the definition. The original clinical notion of remission comes from the disappearance of fever, infection, and hemorrhage in patients following treatment. The disappearance of clinical symptoms, first provoked by Sidney Farber in 1947, was subsequently correlated with the bone-marrow phenomena.
85. H. F. Bisel, Letter to the Editor, "Criteria for the Evaluation of Response to Treatment in Acute Leukemia," Blood, 1956, 11: 676-77. This definition of complete remission was subsequently adopted in Britain: see Working Party on the Evaluation of Different Methods of Therapy in Leukemia, "Treatment of Acute Leukemia in Adults: Comparison of Steroid Therapy at High and Low Dosage in Conjunction with 6-Mercaptopurine: First Report to the Medical Research Council of the Working Party on the Evaluation of Different Methods of Therapy in Leukemia," Brit. Med. J., 1963, 5: 7-14, especially p. 11. It should be noted that this is just the hematological part of the definition. The original clinical notion of remission comes from the disappearance of fever, infection, and hemorrhage in patients following treatment. The disappearance of clinical symptoms, first provoked by Sidney Farber in 1947, was subsequently correlated with the bone-marrow phenomena.
86. Laszlo, Cure (n. 34), p. 100.
87. Joseph Burchenal, Ruth Heyn, W. W. Sutow, Emil J. Freireich, Richard Whittington, and John Louis, "Investigations in Acute Leukemia," in Conference on Experimental Clinical Cancer Chemotherapy, National Cancer Institute Monograph no. 3 (Washington, D.C.: U.S. Government Printing Office, 1960), 149-68, quotation on p. 167.
88. Ibid. One should not conclude that clinical trials are devoid of all "theory": Freireich's colleague Emil Frei pointed out that their first trial was designed using input "not only from investigators directly involved in the chemotherapy of acute leukemia but also, for example, from biostatisticians, basic scientists working with leukemia models and pharmacologists" (Emil Frei III, "Intramural Therapeutic Research at the National Cancer Institute, Department of Medicine: 1955-1965," Cancer Treat. Rep., 1984, 68: 21-20); unfortunately, he does not detail the input from "basic scientists."
89. Ibid. One should not conclude that clinical trials are devoid of all "theory": Freireich's colleague Emil Frei pointed out that their first trial was designed using input "not only from investigators directly involved in the chemotherapy of acute leukemia but also, for example, from biostatisticians, basic scientists working with leukemia models and pharmacologists" (Emil Frei III, "Intramural Therapeutic Research at the National Cancer Institute, Department of Medicine: 1955-1965," Cancer Treat. Rep., 1984, 68: 21-20); unfortunately, he does not detail the input from "basic scientists."
90. Gordon Zubrod, George C. Escher, Johannes Ipsen, et al., "Newer Techniques and Some Problems in Cooperative Group Studies," in Conference (n. 60), pp. 277-92, especially pp. 281-82.
91. Ibid., p. 280.
92. An indication of the road traveled since can be found in the fact that none of these categories is presently in use, and that the current list of lymphomatic entities numbers more than twenty: see Nancy L. Harris, Elaine S. Jaffe, J. Diebold, et al., "The World Health Organization Classification of Neoplastic Diseases of the Hematopoietic and Lymphoid Tissues: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November, 1997," Ann. Oncol, 1999, 10: 1419-32.
93. R. Wayne Rundles, Robert J. Lukes, Lauren Ackerman, et al., "Investigations in Malignant Lymphomas," in Conference (n. 60), pp. 193-227, quotation on p. 199.
94. Ibid., p. 200.
95. Ibid.
96. Ibid., p. 201.
97. "Background Information on NCI Task Force, Prepared for NACC, November 1906," NCI Archives, p. I.
98. Laszlo, Cure (n. 34), p. 102.
99. "Background Information" (n. 69), pp. 1-2.
100. "Frei, Freireich Share One GM Award," The Cancer Letter, 1983, 9: 5.
101. Skipper's citation read: "For his contributions to biology, biochemistry and pharmacology which have laid the foundations for the chemotherapy of cancer"; this information can be found at the Albert and Mary Lasker Foundation Living Library Web site (www.laskerfoundation.org).
102. Ibid.
103. This withdrawal is the reason for the omission of the VAMP protocol from the cooperative groups' review in 1980 of their contributions to the management of childhood cancers: see Denman Hammond, Ronald L. Chard Jr., Giulio J. D'Angio, et al., "Pediatric Malignancies," in Hoogstraten, Cancer Research (n. 21), pp. 1-23.
104. The protocol and the kinetic data are described in James Holland, "Clinical Studies of Unmaintained Remissions in Acute Lymphocytic Leukemia," in (no editor) The Proliferation and Spread of Neoplastic Cells: A Collection of Papers Presented at the Twenty-First Annual Symposium on Fundamental Cancer Research, 1967 (Baltimore: Williams and Wilkins, 1968), pp. 453-62.
105. Holland is interviewed in Laszlo, Cure (n. 34), p. 223.
106. Joseph H. Burchenal, "From Wild Fowl to Stalking Horses: Alchemy in Chemotherapy. Fifth Annual David A. Karnofsky Memorial Lecture," Cancer, 1975, 35: 1121-35, quotation on p. 1126. Burchenal cites the abstract that announced the protocol: E. J. Freireich, M. Karon, and E. Frei III, "Quadruple Combination Therapy (VAMP) for Acute Lymphocytic Leukemia of Childhood," Proc. Amer. Assoc. Cancer Res., 1964, 5: 20 (abstr.). Freireich has pointed out that the group never did publish a paper on this protocol because "they were so anxious to undertake the next combination" (Emil J. Freireich and Noreen A. Lemak, Milestones in Leukemia Research and Therapy [Baltimore: Johns Hopkins University Press, 1991], p. 78).
107. Joseph H. Burchenal, "From Wild Fowl to Stalking Horses: Alchemy in Chemotherapy. Fifth Annual David A. Karnofsky Memorial Lecture," Cancer, 1975, 35: 1121-35, quotation on p. 1126. Burchenal cites the abstract that announced the protocol: E. J. Freireich, M. Karon, and E. Frei III, "Quadruple Combination Therapy (VAMP) for Acute Lymphocytic Leukemia of Childhood," Proc. Amer. Assoc. Cancer Res., 1964, 5: 20 (abstr.). Freireich has pointed out that the group never did publish a paper on this protocol because "they were so anxious to undertake the next combination" (Emil J. Freireich and Noreen A. Lemak, Milestones in Leukemia Research and Therapy [Baltimore: Johns Hopkins University Press, 1991], p. 78).
108. Joseph H. Burchenal, "From Wild Fowl to Stalking Horses: Alchemy in Chemotherapy. Fifth Annual David A. Karnofsky Memorial Lecture," Cancer, 1975, 35: 1121-35, quotation on p. 1126. Burchenal cites the abstract that announced the protocol: E. J. Freireich, M. Karon, and E. Frei III, "Quadruple Combination Therapy (VAMP) for Acute Lymphocytic Leukemia of Childhood," Proc. Amer. Assoc. Cancer Res., 1964, 5: 20 (abstr.). Freireich has pointed out that the group never did publish a paper on this protocol because "they were so anxious to undertake the next combination" (Emil J. Freireich and Noreen A. Lemak, Milestones in Leukemia Research and Therapy [Baltimore: Johns Hopkins University Press, 1991], p. 78).
109. C. G. Zubrod, "The Cure of Cancer by Chemotherapy: Reflections of How It Happened," Med. Pediatr. Oncol., 1980, 8: 107-14, quotation on p. 113.
110. Skipper, "Historic Milestones" (n. 1), p. 513. This was not to minimize or deny the importance of his own work: "Parenthetically, I cannot agree with those who state and write that knowledge of the mechanisms of action of anticancer drugs at the biochemical level and knowledge of the cytokinetic behavior of normal and neoplastic cells have not contributed to the stepwise advancement of cancer treatment. Almost all experimentalists and clinicians that I know are influenced by basic knowledge and documented concepts that are compatible with clinical observations and goals - and they plan accordingly. In my opinion, knowledge gained in the areas mentioned herein has improved the planning of experimental and clinical trials more than some know" (ibid., p. 510-11).
111. Skipper, "Historic Milestones" (n. 1), p. 513. This was not to minimize or deny the importance of his own work: "Parenthetically, I cannot agree with those who state and write that knowledge of the mechanisms of action of anticancer drugs at the biochemical level and knowledge of the cytokinetic behavior of normal and neoplastic cells have not contributed to the stepwise advancement of cancer treatment. Almost all experimentalists and clinicians that I know are influenced by basic knowledge and documented concepts that are compatible with clinical observations and goals - and they plan accordingly. In my opinion, knowledge gained in the areas mentioned herein has improved the planning of experimental and clinical trials more than some know" (ibid., p. 510-11).
112. BCNU stands for bis-chloronitrosourea. The other compounds are still in use. See, for example, Lawrence M. Tierney, Jr., Stephen J. McPhee, and Maxine A. Papadakis, eds., Current Medical Diagnosis and Treatment (Norwalk, Conn.: Appleton & Lange, 1994), pp. 67-71.
113. See Sydney Farber, Rudolf Toch, Edward Manning Sears, and Donald Pinkel, "Advances in Chemotherapy of Cancer in Man," Adv. Cancer Res., 1956, 4: 1-71; M. C. Spencer, D. H. Algire, and N. G. Smith, "Cancer Chemotherapy: A Bibliography of Agents; Supplement, 1955-1959," Cancer Res., 1965, Suppl. 25: 1-436.
114. See Sydney Farber, Rudolf Toch, Edward Manning Sears, and Donald Pinkel, "Advances in Chemotherapy of Cancer in Man," Adv. Cancer Res., 1956, 4: 1-71; M. C. Spencer, D. H. Algire, and N. G. Smith, "Cancer Chemotherapy: A Bibliography of Agents; Supplement, 1955-1959," Cancer Res., 1965, Suppl. 25: 1-436.
115. Although the compound had been used since the First World War, Louis Goodman and Alfred Gilman of Yale University undertook the first pharmacologic studies in 1941, under contract to the army. They noticed that the compound destroyed lymph nodes and bone marrow in mice, and so they tried it in a situation where one would deliberately seek such a reduction - namely, in mice with cancer of the lymph nodes. Having caused a reduction in the mouse tumor, they moved on to humans the following year, injecting the compound into an individual suffering from terminal lymphoma. The result was a qualified success: although the patient died, the swelling of the tumorous masses decreased, leading to a dramatic remission. Notice here that the work relied on a visual analogy and not on an understanding of the chemical reaction. See L. Goodman, "The Initial Clinical Trial of Nitrogen Mustard," Amer. J. Surg., 1963, 105; 574-78.
116. Freireich and Lemak, Milestones (n. 78), p. 40.
117. C. Gordon Zubrod, "Some Problems of Acute Leukemia Research" (paper presented at the 4th IBM Medical Symposium, 22-26 October 1962), NCI Archives.
118. Freireich and Lemak, Milestones (n. 78), p. 74, referring to Howard E. Skipper, "Carbamates in the Chemotherapy of Leukemia: V. Observation of a Possible Antileukemic Synergism between Urethane and Methyl-bis (ß-chloroethyl) amine," Cancer, 1949, 2: 475-79.
119. Freireich and Lemak, Milestones (n. 78), p. 74, referring to Howard E. Skipper, "Carbamates in the Chemotherapy of Leukemia: V. Observation of a Possible Antileukemic Synergism between Urethane and Methyl-bis (ß-chloroethyl) amine," Cancer, 1949, 2: 475-79.
120. Burchenal, "From Wild Fowl to Stalking Horses" (n. 78), p. 1125, referring to Jean Bernard, J. Marie, J. Salet, and C. Cruciani, "Essai de traitement des leucémies aiguës de l'enfance par l'association aminoptérine-cortisone," Bulletin et mémoires de la société des médecins des hôpitaux, 1951, 16: 621-29.
121. Burchenal, "From Wild Fowl to Stalking Horses" (n. 78), p.
122. Emil Frei, James F. Holland, Marvin A. Schneiderman, Donald Pinkel, et al., "A Comparative Study of Two Regimens of Combination Chemotherapy in Acute Leukemia," Blood, 1958, 13: 1126-18; Pinkel has described this study as the result of animal studies: "Based on results with a mouse leukemia model, children with ALL were given combinations of 6-mercaptopurine and methotrexate without evidence of benefit greater than that of sequential or cyclic use of these agents" (Malcolm K. Brenner and Donald Pinkel, "Cure of Leukemia," Semin. Hemat., 1999, 36 (4), Suppl. 7 (October): 73-83, quotation on p. 74).
123. Emil Frei, James F. Holland, Marvin A. Schneiderman, Donald Pinkel, et al., "A Comparative Study of Two Regimens of Combination Chemotherapy in Acute Leukemia," Blood, 1958, 13: 1126-18; Pinkel has described this study as the result of animal studies: "Based on results with a mouse leukemia model, children with ALL were given combinations of 6-mercaptopurine and methotrexate without evidence of benefit greater than that of sequential or cyclic use of these agents" (Malcolm K. Brenner and Donald Pinkel, "Cure of Leukemia," Semin. Hemat., 1999, 36 (4), Suppl. 7 (October): 73-83, quotation on p. 74).
124. Frei et al., "Comparative Study" (n. 88), p. 1126.
125. Emil Frei III, Emil J. Freireich, Edmund Gehan, et al., "Studies of Sequential and Combination Antimetabolite Therapy in Acute Leukemia: 6-Mercaptopurine and Methotrexate," Blood, 1961, 18: 431-54, especially p. 451. The study had also been designed to deal with problems that arose because the trials, as part of a screen for new agents, tended to use late-phase patients. In particular: "A problem in clinical cancer chemotherapy studies is that new agents are for the most part studied in patients with late, i.e. advanced disease. In transplanted rodent tumors there is ample evidence that responsiveness to a given agent decreases with time. Were this true in man, studies of new agents in patients with late, refractory acute leukemia would be relatively ineffective in that drugs which might be active earlier in the disease would be missed. Our studies indicate strongly that such is not the case" (ibid., p. 450).
126. Emil Frei III, Emil J. Freireich, Edmund Gehan, et al., "Studies of Sequential and Combination Antimetabolite Therapy in Acute Leukemia: 6-Mercaptopurine and Methotrexate," Blood, 1961, 18: 431-54, especially p. 451. The study had also been designed to deal with problems that arose because the trials, as part of a screen for new agents, tended to use late-phase patients. In particular: "A problem in clinical cancer chemotherapy studies is that new agents are for the most part studied in patients with late, i.e. advanced disease. In transplanted rodent tumors there is ample evidence that responsiveness to a given agent decreases with time. Were this true in man, studies of new agents in patients with late, refractory acute leukemia would be relatively ineffective in that drugs which might be active earlier in the disease would be missed. Our studies indicate strongly that such is not the case" (ibid., p. 450).
127. Lloyd W. Law, "Effects of Combinations of Antileukemic Agents on an Acute Lymphocytic Leukemia of Mice," Cancer Res., 1952, 12: 871-78, quotation on p. 875.
128. Farber et al., "Advances in Chemotherapy" (n. 82); Edmund E. Osgood and Arthur J. Seaman, "Treatment of Chronic Leukemias: Results of Therapy by Titrated, Regularly Spaced Total Body Radioactive Phosphorus, or Roentgen Irradiation," JAMA, 1952, 150: 1372-79. The whole history of adjuvant therapy is reviewed in Marjorie Perloff, John F. Holland, and Emil Frei III, "Adjuvant Therapy," in Cancer Medicine, ed. John F. Holland and Emil Frei III (Philadelphia: Lea & Febiger, 1982), pp. 515-27.
129. Farber et al., "Advances in Chemotherapy" (n. 82); Edmund E. Osgood and Arthur J. Seaman, "Treatment of Chronic Leukemias: Results of Therapy by Titrated, Regularly Spaced Total Body Radioactive Phosphorus, or Roentgen Irradiation," JAMA, 1952, 150: 1372-79. The whole history of adjuvant therapy is reviewed in Marjorie Perloff, John F. Holland, and Emil Frei III, "Adjuvant Therapy," in Cancer Medicine, ed. John F. Holland and Emil Frei III (Philadelphia: Lea & Febiger, 1982), pp. 515-27.
130. Farber et al., "Advances in Chemotherapy" (n. 82); Edmund E. Osgood and Arthur J. Seaman, "Treatment of Chronic Leukemias: Results of Therapy by Titrated, Regularly Spaced Total Body Radioactive Phosphorus, or Roentgen Irradiation," JAMA, 1952, 150: 1372-79. The whole history of adjuvant therapy is reviewed in Marjorie Perloff, John F. Holland, and Emil Frei III, "Adjuvant Therapy," in Cancer Medicine, ed. John F. Holland and Emil Frei III (Philadelphia: Lea & Febiger, 1982), pp. 515-27.
131. For this trial, see Emil J. Freireich, Edmund Gehan, E. Frei III, et al. (Acute Leukemia Group B), "The Effect of 6-Mercaptopurine on the Duration of Steroid Induced Remissions in Acute Leukemia: A Model for Evaluation of Other Potentially Useful Therapies," Blood, 1963, 21: 699-716. There were no differences between the placebo and 6-MP in the production of complete remission. There were, however, significant differences in terms of remission maintenance.
132. Acute Leukemia Group B's previous study, for example, which introduced the notion of "phases," was presented at the 1959 conference as follows: "I am sure you are familiar with the work of Dr. Lloyd Law, and others, which has shown that animal tumors resistant to 6-mercaptopurine or to azaserine show enhanced sensitivity to the antifolics. Our study was designed to determine whether this particular phenomenon occurs in man" (Burchenal et al., "Investigations in Acute Leukemia" [n. 60], p. 158). The fact that it did not occur in man became irrelevant for, as we have seen, another conclusion became possible: since there was no enhancement, "We can conclude from this preliminary analysis that resistance or refractoriness to a drug does not condition the response rate to the second agent, provided it is a different class of activity" (ibid., p. 160). Notice how we have moved here from synergy to independent sequential action.
133. Freireich et al., "Effect of 6-Mercaptopurine" (n. 93), p. 699.
134. Ibid., p. 711.
135. Laszlo, Cure (n. 34), p. 145. According to James Holland, Li's work, in turn, can be traced back one step further: Holland recounts how Abe Goldin, a mouse researcher at the NCI, had asked a clinician, Paul Condit, to follow up on patients some work that Goldin had conducted in mice using methotrexate. Li allowed Condit to try methotrexate on his choriocarcinoma patients. In the course of the treatment, Li noticed that the doses given by Condit caused the HCG (human chorionic gonadotropin) hormone levels to drop; he subsequently took over the therapy, giving the patients high doses of methotrexate in 5-day periods after the clinical symptoms had disappeared, until the HCG levels had returned to normal. According to Holland, however, the relation between the mouse work and the methotrexate treatment was entirely gratuitous: "It's true that Li recognized the fall in HCG, which was the critical observation. However, the actual giving of methotrexate to the patient was not related to the mouse experiments by Goldin on the best way to shrink tumors with methotrexate. It was serendipity" ("James Holland, M.D.," in ibid., p. 227).
136. Laszlo, Cure (n. 34), p. 145. According to James Holland, Li's work, in turn, can be traced back one step further: Holland recounts how Abe Goldin, a mouse researcher at the NCI, had asked a clinician, Paul Condit, to follow up on patients some work that Goldin had conducted in mice using methotrexate. Li allowed Condit to try methotrexate on his choriocarcinoma patients. In the course of the treatment, Li noticed that the doses given by Condit caused the HCG (human chorionic gonadotropin) hormone levels to drop; he subsequently took over the therapy, giving the patients high doses of methotrexate in 5-day periods after the clinical symptoms had disappeared, until the HCG levels had returned to normal. According to Holland, however, the relation between the mouse work and the methotrexate treatment was entirely gratuitous: "It's true that Li recognized the fall in HCG, which was the critical observation. However, the actual giving of methotrexate to the patient was not related to the mouse experiments by Goldin on the best way to shrink tumors with methotrexate. It was serendipity" ("James Holland, M.D.," in ibid., p. 227).
137. Zubrod, "Historic Milestones" (n. 19), p. 497.
138. Howard E. Skipper, Frank M. Schabel, and William S. Wilcox, "On the Criteria and Kinetics Associated with 'Curability' of Experimental Leukemia," Cancer Chemother. Rep. 1964, 35: 1-111, especially pp. 9-12, quotation on p. 27.
139. In particular, Jacob Furth and Morton Kahn at Cornell had succeeded in reducing the transfer to one or a few cells: see Jacob Furth and Morton C. Kahn (with the assistance of Charles Breedis), "The Transmission of Leukemia of Mice with a Single Cell," Amer. J. Cancer, 1937, 31: 276-82. Their work, however, had been ignored.
140. Skipper, "Historic Milestones" (n. 1), p. 506.
141. This relationship is described by Skipper in Gillian Goodrich, Southern Research Institute: An Oral History (Birmingham, Ala.: EBSCO Media, 1991), pp. 64-67.
142. Skipper, Schabel, and Wilcox, "On the Criteria" (n. 99), p. 46.
143. Ibid, (emphasis in original).
144. Ibid., p. 47. Skipper et al. go on to mention the crucial problem of eliminating leukemic cells that enter the central nervous system. We do not deal with this problem here except to point out that it was definitively settled in the clinical situation by Donald Pinkel at St. Jude's Hospital in Tennessee through the use of radiation.
145. As they put it: "Although the objective of the intensive chemotherapy programs outlined in Fig. 9 was to eradicate the total leukemic cell population, it is clear that this is a 'long shot' and that it will be highly important to know (1) whether we have reduced the number of leukemic cells below that of conventional therapy, and (2) how close to eradication we have come" (Emil Frei III and Emil J. Freireich, "Progress and Perspectives in the Chemotherapy of Acute Leukemia," Adv. Chemother., 1965, 2: 265-98, on p. 284).
146. Ibid., pp. 287-89.
147. Ibid., p. 294.
148. Dean E. Wooldridge (Wooldridge Committee), Biomedical Science and Its Administration: A Study of the National Institutes of Health (Washington, D.C.: The White House, 1965), p. 85.
149. Ibid., p. 86. For the reception of the report, see Joseph D. Cooper, "Onward the Management of Science: The Wooldridge Report," Science, 11 June 1965, 148: 1433-39.
150. Ibid., p. 86. For the reception of the report, see Joseph D. Cooper, "Onward the Management of Science: The Wooldridge Report," Science, 11 June 1965, 148: 1433-39.
151. Margaret Sloan, "Proposal for the Establishment of a Cancer Therapy Evaluation Center as a Part of Collaborative Research," 9 December 1964, NCI Archives.
152. Arthur P. Richardson (Chairman), "Report of the Cancer Chemotherapy Collaborative Program Review Committee," June 1966, NCI Archives, p. 58.
153. Ibid., p. 25.
154. Ibid., p. 27.
155. Ibid., p. 10.
156. Ibid., p. 22.
157. Memorandum from Kenneth M. Endicott (Director, NCI) to James A. Shannon (Director, NIH), "Preliminary Comments on Report of the Richardson Committee," 17 September 1966, NCI Archives.
158. Memorandum from Kenneth M. Endicott (Director, NCI) to Deputy Director (NIH), "Formulation of a Body of Outside Experts to Review for Scientific Merit Applications for the Support of Collaborative Clinical Trials," 24 June 1966, NCI Archives.
159. See National Cancer Institute, Annual Report of Program Activities, 1967-68, vol. 1, Cancer Therapy Evaluation Branch (Chemotherapy), pp. 97-141. As of 1966, the Cancer Therapy Evaluation Branch oversaw seven cooperative groups, five Task Forces, and five Veterans Administration Groups: ibid., p. 101.
160. See National Cancer Institute, Annual Report of Program Activities, 1967-68, vol. 1, Cancer Therapy Evaluation Branch (Chemotherapy), pp. 97-141. As of 1966, the Cancer Therapy Evaluation Branch oversaw seven cooperative groups, five Task Forces, and five Veterans Administration Groups: ibid., p. 101.
161. Farber et al., "Advances in Chemotherapy" (n. 82), p. 54.