Originally published as JCO Early Release 10.1200/JCO.2008.21.7570 on April 27 2009

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Ajani, J. A. PubMed PubMed Citation Articles by Ajani, J. A. Related Articles Related Article Social Bookmarking                            What's this?

Chemotherapy and Radiation Resistance: Version 2.0

Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

To the Editor:

The reply by Glynne-Jones et al¹ to our comments is appreciated. Some issues are worthy of further discussion. First, about the Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 trial,² RTOG 98-11's original protocol number was RTOG 95-11, but when it was finally approved for recruitment in late 1998, its number was changed. Thus, it took approximately 2.5 years of multiple discussions including several face-to-face meetings to agree to its final design. As we clearly state on page 1920 of the primary article,² the implemented design was to test one strategy versus another (GI Intergroup recognized from the outset that the experimental arm incorporated two elementary questions: value of induction therapy and cisplatin). We had pilot data on hand from four anal cancer studies (two were reporting on cisplatin as a promising radiosensitizer, and two were reporting on induction chemotherapy followed by chemoradiotherapy). The decision to study the strategy superseded that to studying cisplatin alone. We accepted the fact that if the experimental arm demonstrated superiority, then additional trials would be needed to resolve other questions. Glynne-Jones et al¹ state that RTOG 98-11 was "not designed in the most appropriate fashion," but I argue that it was designed appropriately and consciously to answer the question that was perceived by the GI Intergroup as the higher priority. The results of RTOG 98-11 are clear: the experimental arm resulted in a poorer outcome than the standard arm. These unfavorable results encompass the impact of both induction therapy and cisplatin. Not even a speculative approach can separate the impact of these two elements. Until (and if) the ongoing trial (NCT 00025090; www.clinicaltrials.gov) can clarify the role of cisplatin alone, I can only caution those who suggest that induction chemotherapy is the culprit (what would be the basis for that?). Such speculations, if not sufficiently moderated, could imply to some that cisplatin-based chemoradiotherapy is a substitute for mitomycin-based chemoradiotherapy. RTOG 98-11's conclusions are based on the results and are unambiguous. I urge my colleagues to avoid cisplatin-based therapy for localized anal carcinoma (clinical trials are exempt) because some patients will end up with an unending nightmare of colostomy. Some have raised the issue of radiation dose variability above 45 Gy. RTOG 98-11 provided flexibility to the treating radiation oncologist to increase the dose under specified circumstances. Clearly, this approach may have resulted in radiation dose imbalances. but the median dose in each arm was approximately 55 Gy. This issue is unresolved, but the literature does not support the notion that radiation dose higher than the optimum threshold, in the setting of chemoradiotherapy, influences cure. It all boils down to understanding the mechanisms of chemotherapy and radiation resistance (constituted in the unique make up of each tumor) and knowing which cells are responsible to orchestrate it. I know that if we could give 100+ Gy to anal cancer, we will definitely cause necrotic death of the tumor and everything around it, but that is not what we are arguing here.

Second, about the mechanisms of resistance to improve local cure rate, Glynne-Jones et al¹ remain tethered to their original position of the importance of accelerated repopulations. I remain unconvinced that accelerated repopulations are central. I do not argue against the phenomenon of accelerated repopulations. I argue against their role in local control or lack of it. I urge Glynne-Jones et al to examine Figure 2 of our article³ on this topic. To study chemoradiotherapy resistance in depth, we tested a xenograft model of esophageal cancer and induced chemoradiotherapy injury (to reduce the tumor size), then we made several observations on the temporal relationships on how tumor restores its size (repopulation). After injury, proliferation rates are the first to decline, followed by tumor size; however, repopulation (defined as increase in proliferation followed by increase in tumor size) is preceded by increases in sonic hedgehog ligand and activation of the hedgehog pathway confirmed by nuclear localization of Gli-1 (one of the three transcriptional factors for sonic). Sonic hedgehog is a stem-cell marker and probably a marker for early progenitor cells. Our data are not convincing to argue that cancer stem cells are mediating repopulations (and resistance) because we did not isolate cancer stem cells in this experiment, but there are many elegant experiments already published using a variety of models. A specific population of cells (cancer stem cells or similar cells with stemness) is responsible for repopulation of the tumor bed. The accelerated repopulation phenomenon is a conserved property from the normal adult tissue stem cells and simply an epiphenomenon. Therefore, if an injury (chemotherapy and/or radiation) cannot kill the cells (various populations of cancer stem cells) responsible for repopulation, then you cannot cure cancer. Repopulation is inevitable if the treatment (it does not matter whether the drug is a platinol or taxane, or radiation is used) reduces the volume of cancer. It is natural for tumors to repopulate (think of what happens if you cut your skin—it repopulates). From here onwards, everything becomes more interesting and complicated. Cancer stem cells do exert some degree of inherited regulation on the progenitors and themselves—otherwise, cancer will grow ceaselessly during the first repopulation attempt—but cancer tissue does stop growing (sometimes for a very long time) and yet, overall, cancers know only to grow over time (this may be because cancer stem cells experience some degree of survival pressure mediated by the acquired and evolving mutations even in the absence of a threat [injury from therapy]).

Regarding platinum compounds, Glynne-Jones et al¹ state that "their efficacy is limited by the development of resistance." I agree, but then this nonspecific statement is true for all classes of cytotoxics (and also radiation). Cancer cells use multiple methods to orchestrate resistance to drugs (either by repairing DNA damage, extruding drugs, or both—and there is more). Cell cycle arrest and apoptosis are often the terminal events caused by many classes of cytotoxic (presented in our Appendix Table A1,² available online only) or radiation injury. Their six points of diverse concepts are loosely woven into a framework that does not convincingly articulate their belief that we should seriously focus on accelerated repopulations. If accelerated repopulations are so detrimental then why some metastatic solid tumors given chemotherapy every 3 or 4 weeks are cured and some end up in prolonged remission. We do not fully understand molecular forces that drive clinical biology, but cancer tissue is hierarchically organized, and cancer stem cells may be central to its survival. Unless cancer tissue contains populations of cells that can self-renew (and not only form progenitors), it may not survive. Progenitor cells, by definition, have limited life span, and killing them does not produce cure. I acknowledge that our understanding about cancer stem cells is not without paradoxes, but we do need to shift our attention to modern concepts. I cite only a few of many reports that discuss the immense sophistications and new concepts afoot that we cannot ignore.^4–6

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Glynne-Jones R, Harrison M, Maudsley D: In reply. J Clin Oncol 27:163–164, 2009.[Free Full Text]

2. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 299:1914–1921, 2008.[Abstract/Free Full Text]

3. Sims-Mourtada J, Izzo JG, Apisarnthanarax S, et al: Hedgehog: An attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res 12:6565–6572, 2006.[Abstract/Free Full Text]

4. Hermann PC, Huber SL, Herrler T, et al: Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323, 2007.[CrossRef][Medline]

5. Polyak K, Hahn WC: Roots and stems: Stem cells in cancer. Nat Med 12:296–300, 2006.[CrossRef][Medline]

6. Hambardzumyan D, Becher OJ, Holland EC: Cancer stem cells and survival pathways. Cell Cycle 7:1371–1378, 2008.[Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Reply to J.A. Ajani
  Rob Glynne-Jones, Mark Harrison, and Suzy Mawdsley
  JCO 2009 27: 2737-2738 [Full Text]

This article has been cited by other articles:

				R. Glynne-Jones, M. Harrison, and S. Mawdsley Reply to J.A. Ajani J. Clin. Oncol., June 1, 2009; 27(16): 2737 - 2738. [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Ajani, J. A. PubMed PubMed Citation Articles by Ajani, J. A. Related Articles Related Article Social Bookmarking                            What's this?