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Originally published as JCO Early Release 10.1200/JCO.2008.19.8739 on December 1 2008 © 2009 American Society of Clinical Oncology.
In Reply
Mount Vernon Cancer Centre, Department of Clinical Oncology, Northwood, Middlesex, United Kingdom We thank Dr Ajani for his interest in our commentary on the recently published Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 study in anal cancer. He is critical that we are inconsistent in our views regarding induction chemotherapy with cisplatin. He suggests that our hypothesis to explain the inferiority of the cisplatin arm is both speculative and counterintuitive. We would accept that the alternative explanation offered to explain why the addition of cisplatin was inferior to the combination of fluorouracil (FU) and mitomycin is speculative—as were the conclusions in the original paper that the combination of cisplatin and radiotherapy was ineffective. However, we would challenge the idea that this hypothesis is counterintuitive. We recognize that tumors are heterogeneous and will have multiple strategies of dealing with radiation damage, both on a cellular and tissue level. Although platinum chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin have been used to treat a broad range of cancers (including many squamous cell carcinomas), their efficacy is limited by the development of resistance. These agents work by damaging DNA by the introduction of large, spatially distorting adducts, the removal of which by both nucleotide excision repair and DNA mismatch repair leads to lethal DNA double-strand breaks and potentially mutagenic single-strand breaks. There is data speculating that certain proteins involved in these DNA repair processes may be induced, leading to acquired resistance. Similarly, the lethal effect of radiation is via the induction of double-strand breaks. We wish to clarify our original commentary with six points: (1) When cells are exposed to ionizing radiation or chemical DNA-damaging agents, double-strand DNA breaks are the common lethal mechanism. On a DNA level, both modalities have a similar end-results, and the cellular response to both is similar (ie, cell-cycle arrest and apoptosis). (2) While we acknowledge that there are numerous mechanisms of resistance, repopulation of clonogenic tumor cells during fractionated radiotherapy is recognized as an important factor affecting local control.1 Repopulation has been well documented in squamous cell carcinomas of the head and neck, cervix, lung, and esophagus. Indeed, most radiotherapy departments will have specific protocols to deal with gaps and delays. (3) The 3- to 4-week intervals between cycles of chemotherapy and the extended total duration of treatment are likely to enhance the impact of repopulation when neoadjuvant cisplatin is used.2 (4) The clinical evidence that neoadjuvant cisplatin-based chemotherapy may improve outcome in terms of disease-free or overall survival, when delivered before radiotherapy or chemoradiotherapy, is scant in any squamous cell carcinoma model.3 (5) There is an inverse relationship between platinum and taxane resistance both in cell lines and clinically.4 (6) Recent randomized trials in head and neck cancer have shown that the addition of a taxane to induction chemotherapy significantly improves response rate, time to progression, or survival over FU and cisplatin induction alone before concurrent chemoradiotherapy. In anal cancer, the best partner with radiotherapy appears a combination of FU and mitomycin. In contrast, cisplatin is the standard companion to radiotherapy in head and neck, esophagus, and cervical cancer. In cervical cancer, there has been no agent or combination of agents showing superiority over weekly concurrent cisplatin. Similarly, in head and neck cancer, concurrent cisplatin-based chemotherapy and radiotherapy has proven the most effective strategy for organ preservation in laryngeal and oropharygeal cancers and for the treatment of unresectable disease. Do these different approaches really reflect a distinct biology between squamous cancers in different sites, or have we just not designed the trials in the most appropriate fashion? In our view, the design of the RTOG 98-11 was poor. Concurrent FU/mitomycin was not compared directly with FU/cisplatin because of the confounding factor of neoadjuvant cisplatin and FU, which delayed the radiotherapy and potentially allows resistance mechanisms to radiotherapy and further cisplatin to develop. We still feel the conclusion in the abstract that "these findings do not support the use of cisplatin in place of mitomycin in combination with fluorouracil and radiotherapy in the treatment of anal canal carcinoma"5(p 1914) could be construed as misleading and are not entirely supported by the data. Are there further studies to throw light on this question? The current United Kingdom national Anal Cancer Trial II trial6 uses a 2 x 2 factorial design and randomizes between FU and mitomycin C and FU and cisplatin administered concurrently with radiotherapy (albeit with lower doses of mitomycin than in the RTOG 98-11 study). The second randomization is between control and two further courses of FU/cisplatin consolidation chemotherapy. Hopefully, this trial will clarify in greater detail the role of concurrent radiation FU and cisplatin. In addition the results of the four-arm INTERGROUP/ACCORD 03 randomized study should soon be mature. The concurrent partner with radiation is FU and cisplatin. This study compared moderate dose versus high-dose radiation and induction chemotherapy with FU/cisplatin or immediate chemoradiotherapy.7 Early data on quality of life has already been published.8 The optimal schedule, chemotherapy partners, radiation dose, and techniques in anal cancer continue to be questioned. There may be a role for neoadjuvant chemotherapy but on current evidence the combination of FU and cisplatin is not indicated in the neoadjuvant setting. Because of a lack of cross-resistance, a taxane could be a logical alternative. Many questions remain unanswered and international collaboration will be needed in the future to perform the necessary large prospective clinical studies. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Rob Glynne-Jones, Roche, Sanofi-aventis Research Funding: Rob Glynne-Jones, Roche Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on December 1, 2008 REFERENCES 1. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23:457-467, 1992[Medline] 2. Davis AJ, Tannock JF: Repopulation of tumour cells between cycles of chemotherapy: A neglected factor. Lancet Oncology 1:86-93, 2000[CrossRef][Medline] 3. Glynne-Jones R, Hoskin P: Neoadjuvant cisplatin chemotherapy before chemoradiation: A flawed paradigm? J Clin Oncol 25:5281-5286, 2007 4. Stordal P, Pavlakis N, Davey R: A systematic review of platinum and taxane resistance from bench to clinic: An inverse relationship. Cancer Treat Rev 33:688-703, 2007[CrossRef][Medline] 5. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: A radomized controlled trial. JAMA 299:1914-1921, 2008 6. James R, Meadows H, Wan S: ACT II: The second UK phase III anal cancer trial. Clin Oncol (R Coll Radiol)17:364-366, 2005 7. Peiffert D, Gerard JP, Ducreux M, et al: Induction chemotherapy (ICT) and dose intensification of the radiation boost in locally advanced anal cancer (LAACC): Interim analysis of the 101 first randomised patients (pts) in the Intergroup ACCORD 03 trial (Federation Nacionale des Centres de Lutte Contre le Cancer –Fondation Francaise de Cancerologie Digestive) Eur J Cancer 2:172, 2005 (suppl 3; abstr 614) 8. Tournier-Rangeard L, Mercier M, Peiffert D, et al: Radiochemotherapy of locally advanced anal canal carcinoma: Prospective assessment of early impact on the quality of life (randomized trial ACCORD 03). Radiother Oncol 87:391-397, 2008[CrossRef][Medline]
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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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