Redefining Cancer: A New Paradigm for Better and Faster Treatment Innovation

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David J Stewart
Gerald Batist


Cancer treatment, resistance, orphan drug, innovation, clinical trials, genomic variation


Common cancers may arise from several different mutations, and each causative mutation may require different treatment approaches. There are also several mechanisms by which malignancies may become resistant to therapy, and each mechanism will also require a different therapeutic strategy. Hence, the paradigm of devising therapies based on tumor type is suboptimal. Each common malignancy may now be regarded as a collection of morphologically similar but molecularly distinct orphan diseases, each requiring u nique approaches. Current strategies that employ randomized clinical trials (RCTs) in unselected patients carry a high risk of misleading results. Available data suggest that it is reasonable to grant marketing approval for new anticancer agents based sole ly on high single - agent response rates in small phase I - II studies involving molecularly - defined patient groups where benefit from other therapies is unlikely. This could markedly speed patient access to important therapies while reducing health care costs by slashing drug development costs. Feasible post - approval surveillance procedures could provide ongoing monitoring of drug safety. While assessment of drug combinations would be more complex due to variable contributions of each component, new strategies have been proposed. In addition to savings from more efficient clinical trials methods, it is essential that we also markedly reduce costs of complying with clinical research regulations. Compliance is too cumbersome and expensive, and current regulatory inflexibility markedly slows progress while escalating health care costs. This requires urgent attention. Regulatory approaches intended to enhance safety may instead potentially cost far more life - years than they save by delaying approval of effective the rapies.

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1. Stewart DJ, Kurzrock R. Cancer: the road to Amiens. Journal of C linical O ncology: official journal of the American Society of Clinical Oncology 2009;27:328 - 33.
2. Stewart DJ, Whitney SN, Kurzrock R. Equipoise lost: ethics, costs, and the regulation of cancer clinical research. Journal of C linical O ncology: official journal of the American Society of Clinical Oncology 2010;28:2925 - 35.
3. Stewart DJ, Kurzrock R. Fool's g old, lost treasures, and the randomized clinical trial. BMC C ancer 2013;13:193.
4. Cheng SK, Dietrich MS, Dilts DM. A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of cancer therapy evaluation program (NCI - CTEP) sponsored studies. Clin Cancer Res 2010;16:5557 - 63.
5. Haffner ME, Whitley J, Moses M. Two decades of orphan product development. Nature R eviews Drug D iscovery 2002;1:821 - 5.
6. Cornu C, Kassai B, Fisch R, et al. Experimental designs for small randomised clinical trials: an algorithm for choice. Orphanet Journal of R are D iseases 2013;8:48.
7. Rollet P, Lemoine A, Dunoyer M. Sustainable rare diseases business and drug access: no time for misconceptions. Orphanet J ournal of R are D iseases 2013;8:109.
8. Kesselheim AS, Myers JA, Avorn J. Characteristics of clinical trials to support approval of orphan vs . nonorphan drugs for cancer. JAMA 2011;305:2320 - 6.
9. Horning SJ, Haber DA, Selig WK, et al. Developing standards for breakthrough therapy designation in onc ology. Clin Cancer Res 2013;19:4297 - 304.
10. Abrahamyan L, Diamond IR, Johnson SR, Feldman BM. Clinical trials in rare disorders: C onsidering a toolkit for developing evidence based treatment. J Popul Ther Clin Pharmacol 2014; Vol 21(1):e6 6 - e7 8 .
11. Braiteh F, Kurzrock R. Uncommon tumors and exceptional therapies: paradox or paradigm? Mol Cancer Ther 2007;6:1175 - 9.
12. Cheng L, Alexander RE, Maclennan GT, et al. Molecular pathology of lung cancer: key to personalized medicine. Modern Pathology: an official journal o f the United States and Canadian Academy of Pathology, Inc 2012;25:347 - 69.
13. Matsuura S, Shinmura K, Kamo T, et al. CD74 - ROS1 fusion transcripts in resected non - small cell lung carcinoma. Oncology R eports 2013;30:1675 - 80.
14. Borrelli N, Giannini R, Proietti A, et al. KIF5B/RET fusion gene analysis in a selected series of cytological specimens of EGFR, KRAS and EML4 - ALK wild - type adenocarcinomas of the lung. Lung Cancer 2013;81:377 - 81.
15. Ahmed SM, Salgia R. Epidermal growth factor receptor mutations and susceptibil ity to targeted therapy in lung cancer. Respirology 2006;11:687 - 92. 16. Sequist LV, Waltman BA, Dias - Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science T ranslational M edicine 2011;3:75ra26.
17. Oxnard GR, Zhao B, Sima CS, et al. Variability of lung tumor measur ` ements on repeat computed tomography scans taken within 15 minutes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011;29:3114 - 9.
18. Vidaurre T, Wilkerson J, Simon R, Bates SE, Fojo T. Stable disease is not preferentially observed with targeted therapies and as currently defined has limited value in drug development. Cancer J 2009;15:366 - 73.
19. El - Maraghi RH, Eisenhauer EA. Review of phase II trial d esigns used in studies of molecular targeted agents: outcomes and predictors of success in phase III. Journal of C linical O ncology: official journal of the American Society of Clinical Oncology 2008;26:1346 - 54.
20. Tsimberidou AM, Braiteh F, Stewart DJ, Kurzrock R. Ultimate fate of oncology drugs approved by the us food and drug administration without a randomized t rial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2009; 27:6243 - 50.
21. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507 - 16.
22. Peters S, Michielin O, Zimmermann S. Dramatic r esponse i nduced by v emurafenib in a BRAF V600E - m uta ted l ung a denocarcinoma. Journal of Clinical O ncology: official journal of the American Society of Clinical Oncology 2013;31:e341 - 4.
23. Coffee EM, Faber AC, Roper J, et al. Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V6 00E) colorectal cancer. Clin Cancer Res 2013;19:2688 - 98.
24. Fenstermacher DA, Wenham RM, Rollison DE, Dalton WS. Implementing personalized medicine in a cancer center. Cancer J 2011;17:528 - 36.
25. Mino - Kenudson M, Mark EJ. Reflex testing for epidermal growth factor receptor mutation and anaplastic lymphoma kinase fluorescence in situ hybridization in non - small cell lung cancer. Archives of P athology & L aboratory M edicine 2011;135:655 - 64.
26. O'Leary E, Seow H, Julian J, Levine M, Pond GR. Data collection in cancer clinical trials: Too much of a good thing? Clin Trials 2013.
27. Newell DR, Burtles SS, Fox BW, Jodrell DI, Connors TA. Evaluation of rodent - only toxicology for early clinical trials with novel can cer therapeutics. Br J Cancer 1999;81:760 - 8.
28. Newell DR, Silvester J, McDowell C, Burtles SS. The Cancer Research UK experience of pre - clinical toxicology studies to support early clinical trials with novel cancer therapies. Eur J Cancer 2004;40:899 - 906.
29. An sher SS, Scharf R. The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute: Industry collaborations in new agent development. Annals of the New York Academy of Sciences 2001;949:333 - 40.