Cytostatic anticancer drug development

Journal of Experimental Therapeutics and Oncology

Volumn 4, Issue 1, 2004, Pages 9-18

  Gardner, Shea N ^a   Fernandes, Michael ^b  

^a LAWRENCE LIVERMORE NATIONAL LABORATORY   (United States)

^b Medbase LLC   (United States)

Author keywords

Anticancer drugs; cDNA microarrays; Clinical trials; Computational models; Cytostatics; Tailored treatment

Indexed keywords

ANASTROZOLE; ANTINEOPLASTIC AGENT; CYTOSTATIC AGENT; EXEMESTANE; FULVESTRANT; IMATINIB; LETROZOLE; NEW DRUG; RITUXIMAB; TRASTUZUMAB;

ANTINEOPLASTIC ACTIVITY; CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER SIZE; CANCER SURVIVAL; CELL KINETICS; CLINICAL TRIAL; CYTOSTASIS; DNA MICROARRAY; DRUG APPROVAL; DRUG DESIGN; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; FOOD AND DRUG ADMINISTRATION; GROWTH INHIBITION; HISTOPATHOLOGY; HUMAN; PRIORITY JOURNAL; REVIEW; TUMOR GROWTH;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS; DRUG APPROVAL; DRUG DESIGN; DRUG EVALUATION; DRUG EVALUATION, PRECLINICAL; HUMANS; NEOPLASMS;

EID: 2142772775     PISSN: 13594117     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (106)

1. Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus Rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346: 235-242, 2002.
2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-92, 2001.
3. Buzdar A.U. Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer. Oncologist 8: 335-341, 2003.
4. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, CapdeviUe R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031-37, 2001.
5. Traxler P. Tyrosine kinases as targets in cancer therapy - successes and failures. Expert Opin Ther Targets 7: 215-234, 2003.
6. Camero A. Targeting the cell cycle for cancer therapy. British J Cancer 87: 29-33, 2002.
7. Cristofanilli M, Charnsangavej C, Hortobagyi GN. Angiogenesis modulation in cancer research: novel clinical approaches. Nat Rev Drug Discovery 1: 415-26, 2002.
8. Vihinen P, Kahari V-M. Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 99: 157-66, 2002
9. Bagnato A, Spinella F. Emerging tole of endothelin-1 in tumor angiogenesis. Trends Endoc Metab 14: 44-50, 2002.
10. Shay JW, Wright WE. Telomerase: a target for cancer therapeutics. Cancer Cell 2: 257-265, 2002.
11. Vigushin DM, Coombes RC. Histone deacetylase inhibitors in cancer treatment. Anti-Cancer Drugs 13: 1-13, 2002
12. Makin G, Dive C. Recent advances in understanding apoptosis: new therapeutic opportunities in cancer chemotherapy. Trends Mol Med 9: 251-55, 2003.
13. Ramaswamy S, Golub TR. DNA microarrays in clinical oncology. J. Clin. Oncol. 20: 1932-1941, 2001.
14. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100: 8418-23, 2003.
15. van 't Veer LJ, Dai H, van de Vijver MI, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530-536, 2002.
16. Gardner SN. Modeling multi-drug chemotherapy: tailoring treatment to individuals. J Theor Biol 214: 181-207, 2002.
17. Nygren P, Larsson R. Overview of the clinical efficacy of investigational anticancer drugs. J Int Med 253: 46-75, 2003.
18. Goldie JH. Drug resistance in cancer: a perspective. Cancer Metastasis Rev 20: 63-68, 2001.
19. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 21: 1404-1411, 2003.
20. Fernandes M. Cancer Science vs. Archaic Bureaucracy. The Wall Street Journal. March 4, 2002.
21. Barr LC, Baum M. Time to abandon TNM staging of breast cancer? Lancet 339: 915-917, 1992.
22. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF. New TNM melanoma staging system: Linking biology and natural history to clinical outcomes. Semin Surg Oncol 21: 43-52, 2003.
23. Saijo N, Tamura T, Nishio K. Problems in the development of target-based drugs. Cancer Chemother Pharmacol 46 (Suppl): S43-S45, 2000.
24. Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. for the Meta Analysis Group in Cancer. Relation between tumor response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Lancet 356: 373-378, 2000.
25. Di Leo A, Bleiberg H, Buyse M. Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: a critical assessment based on recently reported phase III trials in colorectal and breast cancer. J Clin Oncol 21: 2047-2047, 2003.
26. Hanahan D, Weinberg RA. Rules for making human tumor cells. N Engl J Med 347: 1593-1603, 2002.
27. Fidler IJ. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3: 453-458, 2003.
28. Bernards R, Weinberg RA. Metastasis genes: A progression puzzle. Nature 418: 823, 2002.
29. Schmidt-Kittler O, Ragg T, Daskalakis A. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA 100: 7737-7742, 2003.
30. Hynes RO. Metastatic potential: generic predisposition of the primary tumor or rare, metastatic variants-or both? Cell 113: 821-823, 2003.
31. Liang Y, McDonnell S, and Clynes M. Examining the relationship between cancer invasion/metastasis and drug resistance. Current Cancer Drug Targets 2: 257-277, 2002.
32. De Gruttola VG, Clax P, DeMets DL, Downing GJ, Ellenberg SS, Friedman L, Gail MH, Prentice R, Wittes J, Zeger SL. Considerations in the evaluation of surrogate endpoints in clinical tials: summary of a National Institutes of Health Workshop. Control Clin Trials 22: 485-502, 2001.
33. Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer 2: 210-219, 2000.
34. Davis DW, McConkey DJ, Abbruzzese JL, Herbst RS. Surrogate markers in angiogenesis trials. Brit J Cancer 89: 8-14, 2003.
35. Ramaswamy S, Tamayo P, Rifkin R, Mukherjee S, Yeang CH, Angelo M, Ladd C, Reich M, Latulippe E, Mesirov JP, Poggio T, Gerald W, Loda M, Lander ES, Golub TR. Multiclass cancer diagnosis using tumor gene expression signatures. Proc Natl Acad Sci U S A. 98: 15149-15154, 2001.
36. van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R. A gene expression signature as a predictor of survival in breast cancer. N Eng J Med 347: 1999-2009, 2002.
37. Ramaswamy S, Perou CM. DNA microarrays in breast cancer: the promise of personalized medicine. Lancet 2003; 361: 1576-77.
38. Pusztai L, Ayers M, Stec J, Hortobagyi G. Clinical application of cDNA microarrays in oncology. Oncologist 2003; 8: 252-258.
39. Betensky RA, Louis DN, Cairncross JG. Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol 2002; 20: 2495-2499
40. Nutt CL, Mani DR, Betensky RA, Tamayo P, Cairncross JG, Ladd C, Pobl U, Hartmann C, McLaughlin ME, Batchelor TT, Black PM, von Deimling A, Pomeroy SL, Golub TR, Louis DN. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 63: 1602-1607, 2003
41. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, Lopez-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 346: 1937-1947, 2002.
42. Huang E, Cheng SH, Dressman H, Pittman J, Tsou MH, Horng CF, Bild A, Iversen ES, Liao M, Chen CM, West M, Nevins JR, Huang AT. Gene expression predictors of breast cancer outcomes. Lancet 361: 1590-1596, 2003.
43. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530-536, 2002.
44. Huang E, Ishida S, Pittman J, Dressman H, Bild A, Mark Kloos M, D'Amico M, Pestell RG, West M, Nevins JR. Gene expression phenotypic models that predict the activity of oncogenic pathways. Nat Genet 34: 226-230, 2003.
45. Cheok MH, Yang W, Pui CH, Downing JR, Cheng C, Naeve CW, Relling MV, Evans WE. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genetics 34: 85-90, 2003.
46. Golub TR. Mining the genome for combination therapies. Nat Med 9: 510-511, 2003.
47. Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J, Vingron M. Minimum information about a microarray experiment (MIAME) -toward standards for microarray data. Nature Genetics 29: 365-371, 2001.
48. Amadori D, Silvestrini R. Prognostic and predictive value of thymidine labeling index in breast cancer. Breast Cancer Res and Treatment 51: 267-281, 1998.
49. Daidone MG, Costa A, Silvestrini R. Cell proliferation markers in human solid tumours: assessing their impact in clinical oncology. In: Darzynkiewicz Z, Robinson J, Crissman H, eds. Volume 64 Methods in Cell Biology-Cytometry. New York: Elsevier 359-84, 2001.
50. Silvestrini R, Luisi A, Zambetti M, Cipriani S, Valagussa P, Bonadonna G, Daidone MG. Cell proliferation and outcome following a doxorubicin plus CMF regimens in node-positive breast cancer. Int J Cancer 87: 405-11, 2001.
51. Daidone MG. Prognostic and predictive role of proliferation indices. NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer 25-28, 2000.
52. Gardner SN. Cell cycle phase-specific chemotherapy: computational methods for guiding treatment. Cell Cycle 1: 369-374, 2002.
53. Cameron DA, Ritchie AA, Miller WR. The relative importance of proliferation and cell death in breast cancer growth and response to tamoxifen. Eur J Cancer 37: 1545-1553, 2001.
54. Clare S, Nakhlis F, Panetta JC. Molecular biology of breast cancer metastasis: the use of mathematical models to determine relapse and to predict response to chemotherapy in breast cancer. Breast Cancer Research 2: 430-436, 2000.
55. Gardner SN, Fernandes M. New tools for cancer chemotherapy: computational assistance for tailoring treatments. Molecular Cancer Therapeutics 2: 1079-1084, 2003.
56. Early Breast Cancer Trialists' Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 1-15, 71-85, 1992.
57. Early Breast Cancer Trialists' Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 352: 930-942, 1998.
58. Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185 (HER2/neu) monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16: 2659-2671, 1998.
59. Jordan VC, Murphy CS. Endocrine pharmacology of antiestrogens as antitumour agents. Endoc Rev 11: 578-597, 1990.
60. Abrams JS. Adjuvant therapy for breast cancer - results from the USA consensus conference. Breast Cancer 8: 298-304, 2001.
61. Shah MA, Schwartz GK. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin Cancer Res 7: 2168-2181, 2001.
62. Li Y, Sun X, LaMont JT, Pardee AB, Li CJ. Selective killing of cancer cells by ?-lapachone: direct checkpoint activation as a strategy against cancer. Proc Natl Acad Sci USA 100: 2674-2678, 2003.
63. Gardner SN. Scheduling Chemotherapy: Catch 22 between cell kill and resistance evolution. J Theor Med 2: 215-232, 2000.
64. Shah MA, Schwartz GK. The relevance of drug sequence in combination chemotherapy. Drug Resistance Updates 3: 335-356, 2000.
65. Sebti SM, Hamilton AD. Farnesyltransferase and geranylgeranyl-transferase I inhibitors and cancer therapy: Lessons from mechanism and bench-to-bedside translational studies. Oncogene 19: 6584-6593, 2000.
66. Fox E, Curt GA, Balis FM. Clinical trial design for target-based therapy. Oncologist 7: 401-409, 2002.
67. Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC. Clinical trial design for cytostatic agents: are new approaches needed? J Clin Oncol 19: 265-272, 2001.
68. Schilsky RL. End points in cancer clinical trials and the drug approval process. Clin. Cancer Res. 8: 935-938, 2002.
69. Rosner GL, Stadler W, Ratain MJ. Randomized discontinuation design: application to cytostatic antineoplastic agents. J Clin Oncol 20: 4478-4484, 2002.
70. Seymour L. The design of clinical trials for new molecularly targeted compounds: progress and new initiatives. Current Pharm Des 8: 2279-2284, 2002.
71. Arteaga CL, Baselga J. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implications for drug development and practice. Clin Cancer Res 9: 1579-1589, 2003.
72. Rothenberg MI, Carbone DP, Johnson DH. Improving the evaluation of new cancer treatments: challenges and opportunities. Nat Rev Cancer 3: 303-309, 2003.
73. Hoekstra R, Verweij J, Eskens FA. Clinical trial design for target specific anticancer agents. Invest New Drugs 21, 243-250, 2003
74. Ma BB, Britten CD, Siu LL. Clinical trial designs for targeted agents. Hematol Oncol Clin North Am 16: 1287-1305, 2002.
75. Normanno N, Campiglio M, De Luca A, Somenzi G, Maiello M, Ciardiello F, Gianni L, Salomon DS, Menard S. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 13: 65-72, 2002.
76. Baselga J. Combined anti-EGF receptor and anti-HER2 receptor therapy in breast cancer: a promising strategy for clinical testing. Ann Oncol 13: 8-9, 2002.
77. Hammond MEH, Taube SE. Issues and barriers to development of clinically useful tumor markers: a development pathway proposal. Sem. Oncol. 29: 213-222, 2002.
78. Gutman S. Regulatory issues in tumor marker development. Sem Oncol 29: 294-300, 2002.
79. Kaiser J. NCI goal aims for cancer victory by 2015. Science 299: 1297-1298, 2003.
80. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100: 3983-3988, 2003.
81. Dick JE. Breast stem cells revealed. Proc. Natl. Acad. Sci. USA 100: 3947-3549, 2003.
82. Green DR, Evan GI. A matter of life and death. Cancer Cell 1: 19-30, 2002.
83. Blagosklonny MV. A new science-business paradigm in anticancer drug development. Trends Biotechnol 21: 103-106, 2003.
84. Silvestrini R, Daidone MG, Luisi A, Mastore M, Leutner M, Salvadori B. Cell proliferation in 3,800 node-negative breast cancers: consistency over time of biological and clinical information provided by 3H-thymidine labeling index. Int J Cancer (Pred.Oncol.) 74: 122-27, 1997.
85. Collecchi P, Baldini E, Giannessi P, Naccarato AG, Passoni A, Gardin G, Roncella M, Evangelista O, Bevilacqua G, Conte PF. Primary chemotherapy in locally advanced breast cancer (LABC): Effects on tumour proliferative activity, bcl-2 expression and the relationship between tumour regression and biological markers. Eur J Cancer 34: 1701-1704, 1998.
86. Stapleton AM, Zbell P, Kattan MW, Yang G, Wheeler TM, Scardino PT, Thompson TC. Assessment of the biological markers p53, Ki-67, and apoptotic index as predictive indicators of prostate carcinoma recurrence after surgery. Cancer 82: 168-175, 1998.
87. Sinicrope FA, Hart J, Hsu HA, Lemoine M, Michelassi F, Stephens LC. Apoptotic and mitotic indices predict survival rates in lymph node-negative colon carcinomas. Clin Cancer Res 5: 1793-1804, 1999.
88. Sauer G, Deissler H, Kurzeder C, Kreienberg R. New molecular targets of breast cancer therapy. Strahlenther Onkol 178: 123-133, 2002.
89. Anon. TTP endpoint for cancer drug accelerated approval preferred by FDA. F-D-C Reports - The Pink Sheet 8-9, 21 October 2002.
90. Hirschfeld S, Pazdur R. Oncology drug development: United States Food and Drug Administration perspective. Crit Revi in Hematology/Oncology 42: 137-143, 2002.
91. O'Shaughnessy JA, Kelloff GJ, Gordon GB, Dannenberg AJ, Hong WK, Fabian CJ, Sigman CC, Bertagnolli MM, Stratton SP, Lam S, Nelson WG, Meyskens FL, Alberts DS, Follen M, Rustgi AK, Papadimitrakopoulou V, Scardino PT, Gazdar AF, Wattenberg LW, Sporn MB, Sakr WA, Lippman MS, Von Hoff DD. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Recommendations of the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia. Clin Cancer Res 8: 314-346, 2002.
92. Scher H, Heller G. Clinical states in prostate cancer: toward a dynamic model of disease progression. Urology 55: 323-327, 2000.
93. Cohen, M.H., Marie L. Moses, M.L. and Richard Pazdur, R. FDA Commentary. Gleevec™ for the Treatment of Chronic Myelogenous Leukemia: U.S. Food and Drug Administration Regulatory Mechanisms, Accelerated Approval, and Orphan Drug Status. Oncologist 7, 390-392, 2002.
94. Saijo N, Tamura T, Nishio K. Strategy for the development of novel anticancer drugs. Cancer Chemother Pharmacol 1: 97-101, 2003.
95. Borisy AA, Elliott PJ, Hurst NW, Lee MS, Lehar J, Roydon Price E, Serbedzija G, Zimmermann GR, Foley MA, Stockwell BR, Keith CT. Systematic discovery of multicomponent therapeutics. Proc Natl Acad Sci USA 100: 7977-7982, 2003.
96. Mick R, Crowley JJ, Carroll RJ. Phase II clinical trial design for non-cytotoxic anticancer agents for which time to disease progression is the primary endpoint. Control Clin Trials 21: 343-359, 2000.
97. Mitka M. Accelerated Approval Scrutinized. Confirmatory Phase 4 studies on new drugs languish. JAMA 289: 3227-3229, 2003.
98. Anon. Oncologic confirmatory trial failure not fatal to accelerated approval FDA. F-D-C Reports - The Pink Sheet, 8-9, 17 March 2003.
99. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc?RIIIa gene. Blood 99: 754-758, 2002.
100. Dancey JE, Freidlin B. Targeting epidermal growth factor - are we missing the mark? Lancet 362: 62-64, 2003.
101. Normanno N, Bianco C, De Luca A, Maiello MR, Salomon DS. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocrine-Related Cancer 10: 1-21, 2003.
102. Paterson SC, Smith KD, Holyoake TL, Jorgensen HG. Is there a cloud in the silver lining for imatinib? Brit J Cancer 88: 983-987, 2003.
103. Sausville EA. Imatinib for chronic myelogenous leukemia: 9 or 24 carat gold standard? Lancet 361: 1400-1401, 2003.
104. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukemias. Lancet Oncology 4: 75-85, 2003.
105. Brugarolas J, Clark JW, Chabner B. Using "rationally designed drugs" rationally. Lancet 361: 1758-1759, 2003.
106. Von Hoff DD. There are no bad anticancer agents, only bad clinical trial designs - Twenty-first Richard and Hinda Rosenthal Foundation Award Lecture. Clin Cancer Res 4: 1079-1086, 1998.