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Originally published as JCO Early Release 10.1200/JCO.2008.19.7566 on December 1 2008 © 2009 American Society of Clinical Oncology.
Chemotherapy and Radiotherapy Resistance: Complexity, Reality, and Promise
Departments of Gastrointestinal Medical Oncology, Experimental Therapeutics, and Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX To the Editor: The article by Glynne-Jones and Mawdsley1 discusses the results of the Radiation Therapy Oncology Group 98-11 study and reaches the correct conclusion in the end that mitomycin plus fluorouracil with radiation should remain the standard therapy for anal canal cancer. The authors raise several strategically important issues with regards to resistance to therapy but also express many uncertainties about the value of induction chemotherapy, role of cisplatin, use of taxanes, and about accelerated repopulations. Considerable emphasis is placed on the role of accelerated repopulations. They argue that induction chemotherapy, by inducing accelerated repopulations, makes chemoradiotherapy ineffective. They suggest that induction chemotherapy, not cisplatin, be abandoned. They suggest that a non–cross-resistant cytotoxic (a taxane) could be considered (and cisplatin be abandoned). Later on, the authors change positions by suggesting that "However, we should not be abandoning neoadjuvant chemotherapy...and so on."1 Glynne-Jones and Hoskins2 have previously argued against induction chemotherapy before definitive chemoradiotherapy. We could focus on cancer as a system from a molecular biology angle to find some answers. Cancer, derived from the mutated adult tissue stem cells turned into cancer stem cells (CSCs),3,4 has numerous accumulated genetic and epigenetic alterations.5 Cancer tissue harbors polyclonal subpopulations of cells that acquire more mutations, higher level of heterogeneity, and better survival capabilities with subsequent waves of proliferation.4 The mechanisms by which cancer can survive injury are complex and are partly related to continued evolution of resistance;6 geographic location of certain non-CSCs with regards to access to oxygen and nutrition, phase of cell cycle, number of CSCs;7,8 and yet to be discovered properties. Repopulation after injury is only one component of resistance to therapy and may not be at its root. The majority of the repopulated cancer is composed of progenitors. Proliferating non-CSCs are destined to have finite number of cell cycles, and they eventually die. There is no denying that expanding progenitors cause morbidity and mortality. However, as far as the cure is concerned, one can argue that even though the new crop of cells has a more resistant phenotype than the previous generation, these cells when killed or when they die are not responsible for the cure. Overall resistance is a continuum, an orchestrated survival tactic that begins with CSCs.3,4,6 Besides CSCs, the expanded compartment consists of nonproliferating non-CSCs, contributing microenvironment, strayed non-CSCs, dormant tumor cells that feel no pressure to multiply even in ideal conditions,9 and perhaps another group of cells not yet recognized. Therefore, in order to cure solid tumors, most, if not all, of these populations should be considered. Cancer cells deal with cytotoxics somewhat differently than ionizing radiation. Intrinsic and acquired resistance can affect one specific or multiple classes of cytotoxics and can occur at many levels including drug influx and efflux, drug activation and inactivation, drug targets, cellular DNA repair, cell-cycle arrest, and apoptosis. The recent biotechnological advances have uncovered new pathways.10-13 Appendix Table 1 (online only) shows the representative pathways and biomarkers of drug resistance. Regarding radiation resistance, the models have been developed based on the repopulation hypothesis and methods to overcome resistance by radiosensitization.14 It is stated that repopulation occurs after fractionated radiation.14 Factors that may allow cells to survive radiation injury include hypoxic conditions and cell-cycle status. In the experimental systems and some in clinical trials, repopulation following radiation or chemotherapy has been documented as summarized by Kim and Tannock.14 To argue that altering the dose and/or schedule of cytotoxics or changing the class of cytotoxic could reduce repopulation is entirely speculative and counterintuitive. It has also been suggested that certain agents might sensitize CSCs to chemoradiotherapy therapy; this strategy could be productive but much work remains to be done. Another facet of therapy resistance is the burden of CSCs and this varies from tumor to tumor for the reasons that are not yet clear but suggests that higher the density of CSCs greater the resistance to therapy.15 In addition, CSCs are more resistant to radiation than non-CSCs, as reviewed by Bauman et al.15 This may be due either to dormancy or even dividing CSCs have a more resistant phenotype than non-CSCs. Hypoxic and undernourished noncycling cells and dormant cells, and CSCs (not the accelerated populations) are important. It may be that mutated CSCs, when called on to repopulate the tumor bed, acquire more mutations in the process (of self-renewal), thus we have a next generation of CSCs that have a more resistant phenotype than the previous one and will give rise to more resistant progeny. It would seem that every time we treat a noncurable cancer, we increase the density of CSCs and facilitate cancer to become more resistant. One can always find a report that favors induction therapy before chemoradiotherapy.16 However, it is not the induction chemotherapy or the accelerated repopulations that are responsible for the low cure rates but CSCs and perhaps some nondividing non-CSCs are the obstacles to cancer cure. Anal cancer can be an excellent model for studying resistance to therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. Appendix
ACKNOWLEDGMENTS Supported in part by grants from The University of Texas M. D. Anderson Cancer Center and Cantu, Park, Dallas, and Caporella Families. NOTES published online ahead of print at www.jco.org on December 1, 2008 REFERENCES
1. Glynne-Jones R, Mawdsley S: Anal cancer: The end of the road for neoadjuvant chemoradiotherapy? J Clin Oncol 26:3669-3671, 2008 2. Glynne-Jones R, Hoskin P: Neoadjuvant cisplatin chemotherapy before chemoradiation: A flawed paradigm? J Clin Oncol 25:5281-5286, 2007 3. Boman BM, Wicha MS: Cancer stem cells: A step toward the cure. J Clin Oncol 26:2795-2799, 2008 4. Eyler CE, Rich JN: Survival of the fittest: Cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 26:2839-2845, 2008 5. Chin L, Gray JW: Translating insights from the cancer genome into clinical practice. Nature 452:553-563, 2008[CrossRef][Medline] 6. Dingli D, Michor F: Successful therapy must eradicate cancer stem cells. Stem Cells 24:2603-2610, 2006[CrossRef][Medline] 7. Dewhirst MW, Cao Y, Moeller B: Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8:425-437, 2008[CrossRef][Medline] 8. Moeller BJ, Dreher MR, Rabbani ZN, et al: Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99-110, 2005[CrossRef][Medline] 9. Vessella RL, Pantel K, Mohla S: Tumor cell dormancy: An NCI workshop report. Cancer Biol Ther 6:1496-1504, 2007[Medline] 10. Ruzzo A, Graziano F, Loupakis F, et al: Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy. J Clin Oncol 25:1247-1254, 2007 11. Dressman HK, Berchuck A, Chan G, et al: An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol 25:517-525, 2007 12. Marsh S, McLeod HL: Cancer pharmacogenetics. Br J Cancer 90:8-11, 2004[CrossRef][Medline] 13. Higgins CF: Multiple molecular mechanisms for multidrug resistance transporters. Nature 446:749-757, 2007[CrossRef][Medline] 14. Kim JJ, Tannock IF: Repopulation of cancer cells during therapy: An important cause of treatment failure. Nat Rev Cancer 5:516-525, 2005[CrossRef][Medline] 15. Baumann M, Krause M, Hill R: Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 8:545-554, 2008[CrossRef][Medline] 16. Forastiere AA, Goepfert H, Maor M, et al: Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349:2091-2098, 2003
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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