Originally published as JCO Early Release 10.1200/JCO.2009.21.8693 on April 27 2009

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Reply to J.A. Ajani

Mount Vernon Cancer Centre, Northwood, Middlesex, United Kingdom

We thank Dr Ajani¹ for his further correspondence, and for the opportunity to elaborate on the rationale of treatment for anal cancer in the light of the Radiation Therapy Oncology Group (RTOG) 98-11 results,² which allows us to propose current and future options.

Dr Ajani¹ defends the design of the RTOG 98-11 study in the context of its time. We recognize that it is easy to make such criticisms about the designs of trials retrospectively. However, it surprises us that the strategy of induction cisplatin tested in the RTOG was interesting to oncologists at the time. The rationale behind induction chemotherapy is usually to deal with micrometastases. Numerous studies in many other sites (cervix, head and neck, and so on) had failed to show convincing evidence of benefit from induction cisplatin in terms of local control. Anal cancer predominantly presents and remains a loco-regional disease. In the United Kingdom Coordinating Committee for Cancer Research Anal Cancer Trial Working Party (UKCCCR ACT) I trial, only 21 (7%) of 285 patients treated with chemoradiotherapy (CRT) developed metastatic disease outside the pelvis in the absence of evidence of pelvic recurrence.³

Our point is that the design does not serve to answer the question whether the CRT component is more effective with either mitomycin or cisplatin, or even whether the schedules are equivalent. The results of the total strategy of induction and CRT cannot be extrapolated and attributed simply to the CRT component.

The ACCORD-03 randomized phase III trial in anal cancer has both similarities and differences to the RTOG 98-11 in that it compared both radiation dose escalation from 60 Gy to 65 to 70 Gy, and the addition of induction chemotherapy with cisplatin in a 2 x 2 factorial design with a standard control arm of cisplatin and fluorouracil CRT alone.⁴ The preliminary results with a median follow-up of 3 years failed to show a benefit from intensification of treatment. In fact, 3-year actuarial local control in the induction and the control cisplatin CRT arm was 88% and 96%, respectively (and was not significantly different). Similarly, the event-free survival was 71% for induction versus 78% for the control cisplatin CRT arm. The actuarial colostomy-free survival rate at 5 years was 83% in the induction arm versus 86% in the control cisplatin CRT arm. Again, these results look if anything worse with the addition of induction cisplatin, even if they are not significantly so.

We therefore agree that there are now two trials which show no obvious advantage to induction cisplatin. But does that necessarily hold for cisplatin CRT? It seems unwise to consign cisplatin-based CRT to history on the basis of the RTOG 98-11 study, when it is so effective in cervical cancer and squamous cell cancer of the head and neck.⁵

The colostomy rate is a good end point in anal cancer because it captures both locoregional failure and also CRT-derived toxicity leading to pain or lack of sphincter function. Hence, in the original ACT I trial, local failure was defined as the determination of residual or recurrent locoregional disease, surgery for treatment-related morbidity, or failure to close a pretreatment colostomy.³ The recent RTOG 98-11 trial report demonstrates that for tumors greater than 5 cm in diameter, there were more colostomies for persistent or recurrent anal cancer in the cisplatin arm (42 of 50; 84%) compared with the mitomycin arm (20 of 30; 66%).⁶ However, this study does not provide sufficient data for us to unpick the reasons for a colostomy (ie, excess toxicity or lack of efficacy) because the dose received for those resorting to a colostomy in each group is not documented. One of the theoretical problems associated with induction chemotherapy is the risk that it compromises the delivery of CRT. Details of the RTOG 98-11 trial confirm adherence to total dose and field size recommendations in the protocol, yet there is no information on the overall duration of CRT treatment and whether total doses were only achieved in the cisplatin arm at the expense of treatment breaks to allow GI or cardiovascular toxicity to settle. Hence it would be useful to know the overall treatment time and the CRT treatment time in each arm, and in particular those resorting to a colostomy.

We would agree with Dr Ajani¹ that the premise that radiation dose escalation within a CRT schedule can increase local control in anal cancer is not substantiated either by the long-term results of the RTOG 92-08 trial or the preliminary results of the ACCORD-03 trial,^4,7 though the small numbers in the latter study mean that the power to detect such differences would have been small.

Dr Ajani¹ maintains that although tumor cell repopulation may occur, it is not relevant to the treatment failure in anal cancer. We would argue the converse and that there is both direct and circumstantial evidence from recent anal cancer trials to support the clinical relevance of repopulation.

Chemotherapy alone in anal cancer is not a curative treatment. It is the radiation component that achieves cure.

A retrospective and unplanned analysis of the data within the randomized ACT I trial³ suggests that the length of the gap between the end of CRT and the boost (mandated at 6 weeks in the protocol) had no impact on outcome in terms of disease-free (DFS), overall (OS), or survival (colostomy-free survival [CFS]; R. Glynne-Jones, personal communication, March 2009). If neither radiation dose nor the overall treatment time in the above studies influences outcome, then either repopulation is completely irrelevant to anal cancer or alternatively it is absolutely critical and we have got it wrong by having any gap at all. The data we have suggests a projected clonogen doubling time of about 4 days,⁸ so repopulation time may be even less than the 3 days identified in head and neck cancer.⁹ Hence, there could be a steep dose response curve beyond the threshold with a large influence from overall treatment duration on locoregional failure.¹⁰

The evidence from the two cohorts on the RTOG 92-08 trial does imply that even a short gap is detrimental to outcome.⁷ When the cohort with a 2-week mandated gap is compared to those with similar initial characteristics in the RTOG 87-04 trial, where a median initial dose of 45 Gy was prescribed,⁵ OS, DFS, and CFS all fared worse.⁷ The 5-year estimates of both DFS and CFS (53% and 58%, respectively) in the mandated gap cohort are lower than those cited in both the European Organisation for Research and Treatment of Cancer study¹¹ and the RTOG 87-04 study. In contrast, patients with no mandated break had similar outcomes to those in the RTOG 87-04 study. Again, patient numbers are small and the comparisons are not randomized. In their discussion, the authors recommend that for optimal local control, treatment interruptions should be kept to a minimum.⁶ Perhaps it is the timing of the gap within the CRT that is critical, or put more clearly the total dose achieved before the gap, which influences local control.

Finally, Dr Ajani¹ points us again in the direction of stem cells and suggests they have a pivotal role in treatment failure—"we do need to shift our attention to modern concepts." We agree that it is more likely that the inherent biology of the tumors themselves is responsible for their curability than the drugs or schedules used. We agree that novel concepts such as stem cells may explain resistance to chemotherapy, but would also point out other aspects such as tumor hypoxia and cell-to-cell signaling. Radiotherapy alone as a strategy can cure solid tumors such as anal cancer and has been used for decades. We have learned a great deal about dose and fractionation because these are central to achieving cure. Our knowledge of the biology of stem cells with regards to DNA damage is extremely limited, but stem cells are unlikely to be any more or less sensitive than other cells within that tumor population. An extrapolation of this is that larger tumors are likely to have greater numbers of stem cells. The recognized way to deal with repopulation is to avoid gaps and use short schedules, concomitant boosts, and hyperfractionation, and deliver concomitant chemotherapy. The principle of a prolonged course of induction cisplatin–based chemotherapy before radical CRT simply ignores what we have learned during the past 80 years.

In conclusion, our understanding of CRT in anal cancer, and hence the schedules used, is almost entirely empirically based. Integration of both different cytotoxics and targeted drugs is attractive both in theory and from preclinical models, but phase III trials often give us answers we do not want to hear.

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

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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 randomised controlled trial. JAMA 199:1914–1921, 2008.

3. United Kingdom Coordinating Committee for Cancer Research Anal Cancer Working Party. Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil and mitomycin C. Lancet 348:1049–1054, 1996.[CrossRef][Medline]

4. Peiffert D, Gerard JP, Ducreux M, et al: Induction chemotherapy (ict) and dose intensification of the radiation boost in locally advanced anal canal carcinoma (laacc): Definitive analysis of the Intergroup Accord 03 trial (Fédération Nationale des centres de lutte contre le cancer) Fondation Française de Cancérologie Digestive. Radiother Oncol 88:S20; 2008 (suppl 2) abstr 65.[CrossRef]

5. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. J Clin Oncol 14:2527–2539, 1996.[Abstract]

6. Ajani JA, Winter KA, Gunderson LL, et al: US Intergroup Anal Carcinoma trial: Tumor diameter predicts for colostomy. J Clin Oncol 27:1116–1121, 2009.[Abstract/Free Full Text]

7. Konski A, Garcia M, John M, et al: Evaluation of planned treatment breaks during radiation therapy for anal cancer: Update of RTOG 92-08. Int J Radiat Oncol Biol Phys 72:114–118, 2008.[Medline]

8. Wong CS, Tsang RW, Cummings BJ, et al: Proliferation parameters in epidermoid carcinomas of the anal canal. Radiother Oncol 56:349–353, 2000.[CrossRef][Medline]

9. Withers HR, Taylor JMG, Maciejewsski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131–146, 1988.[Medline]

10. Fowler JF: Is there an optimum overall time for head and neck radiotherapy? A review, with new modeling. Clin Oncol (R Coll Radiol) 20:124–126, 2008.

11. Bartelink H, Roelofsen F, Eschwege F, et al: Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal cooperative groups. J Clin Oncol 15:2040–2049, 1997.[Abstract/Free Full Text]

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