Originally published as JCO Early Release 10.1200/JCO.2008.20.7183 on December 8 2008

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In Reply

Jaffer A. Ajani

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

I thank Adenis and Conroy for their interest in the results of the Radiation Therapy Oncology Group (RTOG) 0113 trial and for agreeing with some of the conclusions stated in the report.¹ Discussions during trial conception/finalization focused on mucosal toxicity (in particular, esophagitis) as a result of fluorouracil, and on exploring a then-new radiosensitizer (a taxane). With regard to mucosal toxicity, fluorouracil was considered an unfavorable agent (something to be avoided), and some members passionately related anecdotes of many patients experiencing severe esophagitis, whereas others did not believe this toxicity to be frequent. The results of the RTOG 0113 trial have demonstrated that mucosal toxicity of fluorouracil is hardly an issue, reflecting a decided benefit of the randomization strategy. Adenis and Conroy suggest, with caution, that the high rate of grade 3 or 4 toxic effects we observed in each arm of our trial could have been anticipated. We are all too familiar with the phenomenon of high-efficacy results with "excellent" safety in phase II trials conducted at individual institutions (I dare not cite any references). Many such studies have resulted in considerable toxicities when tested in multicenter trials. The reasons for this disparity are many: research infrastructure, investigators’ experience, patient selection, familiarity with multimodality approaches, and other unknown factors. The common assumption (in multinational and/or multi-institutional trials) that all infrastructures and investigators’ experience are equal is totally wrong. Nevertheless, the emphasis of Adenis and Conroy on developing a chemoradiotherapy regimen with an acceptable safety profile (would it be < 50% grade 3 or 4 toxicities, or < 30% grade 3 or 4 toxicities in a multi-institutional setting?) is laudable, and we could aspire to achieve this. However, it is a challenge, because among many other aspects, first, radiation fields vary considerably with geographic distribution of the cancer, and simulation techniques also vary among different institutions, and second, practice patterns in managing patients undergoing chemoradiotherapy differ. The National Comprehensive Cancer Network gastroesophageal cancer guidelines now describe principles of chemotherapy, combined-modality therapy, and radiation therapy (and surgery).² Many ancillary aspects (nutritional condition and its improvement/maintenance, social support, patient understanding and commitment, and treating individuals’ awareness of what can go wrong, and when, during chemoradiotherapy) are critical in managing these patients. For example, dehydration should be anticipated between weeks 3.5 and 5.5. Sometimes, one must proactively hydrate patients three or more times per week to avert hospitalization for toxicity management (a grade 4 event).

Finally, which classes of cytotoxic agents should be administered with radiation remains somewhat unclear. The results of the RTOG 0113 trial (we did not compare the efficacy of the two arms directly, but the two curves are different) suggest that fluorouracil should be used routinely (here again, I agree with Adenis and Conroy completely). However, it is unclear which one of the other cytotoxic agents, at least on the basis of these retrospective studies,^3-6 should be added to fluorouracil to improve efficacy. I note that the safety profile of fluorouracil and oxaliplatin with concurrent radiation described by Adenis and Conroy is favorable, but is it transportable? In one esophageal cancer trial at The University of Texas M. D. Anderson Cancer Center (Houston, TX), we have already treated more than 75 patients with fluorouracil, oxaliplatin, and concurrent radiation, and the toxicity profile is not impressively better or worse (it will be worse than it is currently, if the combination is adopted in a multicenter strategy) than we have reported/observed previously in most trials. Clearly, the idea that one chemoradiotherapy regimen is right for all patients is not a solution for the future. We need to garner resources to develop strategies that will allow us to optimize therapy for each esophageal patient; this is the ultimate and exciting frontier.⁷

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

NOTES

published online ahead of print at www.jco.org on December 8, 2008

REFERENCES

1. Ajani JA, Winter K, Komaki R, et al: Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by chemoradiation in patients with localized carcinoma of the esophagus: RTOG 0113. J Clin Oncol 26:4551-4556, 2008[Abstract/Free Full Text]

2. Ajani JA, Barthel JS, Bekaii-Saab T, et al: Esophageal cancer. J Natl Compr Canc Netw 6:818-849, 2008[Medline]

3. Chirieac LR, Swisher SG, Ajani JA, et al: Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 103:1347-1355, 2005[CrossRef][Medline]

4. Javeri H, Arora R, Correa AM, et al: Influence of induction chemotherapy and class of cytotoxics on pathologic response and survival after preoperative chemoradiation in patients with carcinoma of the esophagus. Cancer 113:1308-1308, 2008

5. Kelsey CR, Chino JP, Willett CG, et al: Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer. Int J Radiat Oncol Biol Phys 69:770-776, 2007[Medline]

6. Bader FG, Lordick F, Fink U, et al: Paclitaxel in the neoadjuvant treatment for adeno carcinoma of the distal esophagus (AEG I): A comparison of two phase II trials with long-term follow-up. Onkologie 31:366-372, 2008[CrossRef][Medline]

7. Ajani J: Therapy of localized esophageal cancer: It is time to reengineer our investigative strategies. Onkologie 31:360-361, 2008[Medline]

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• Fluorouracil Should Continue to Be Incorporated in the Treatment of Localized Esophageal Cancer
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