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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. 4665-4666 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.2206
In ReplyRoyal Marsden Hospital, London and Surrey, United Kingdom The letter by Drs Glynne-Jones and Sebag-Montefiore outlines their view on our A Phase II Study of Oxaliplatin (Eloxatin), Capecitabine (Xeloda), and Preoperative Radiotherapy for Patients With Locally Advanced and Inoperable Rectal Cancer (EXPERT) study1 and includes some helpful comments. However, we would like to clarify some misunderstandings of our trial design and results. Our treatment program comprised neoadjuvant chemotherapy, synchronous chemoradiotherapy, total mesorectal excision, and postoperatative chemotherapy. We have attributed our early promising results to the whole EXPERT program, rather than individual components. It is important to note that our treatment consisted of both pre- and postoperative chemotherapy for a total duration of 6 months and not merely neoadjuvant chemotherapy. Moreover, whereas neoadjuvant chemotherapy achieved a significant amount of treatment benefit, there was no doubt that radiotherapy (RT) added further to this promising efficacy in our study. In relation to RT, the authors made a contradictory comment that our promising results might simply reflect a high dose of pelvic RT (54 Gy) used (although this could be true), then commented that similar results were indeed achieved by lower dose RT (45 to 50.4 Gy). Data on whether RT dose escalation above 45 Gy would lead to improved efficacy are currently conflicting.2-4 In the future, we could potentially, at least in part, address this issue because our current randomized study of this EXPERT program with or without cetuximab (EXPERT-C study) is using a lower dose of RT (50.4 Gy) in both arms due to concurrent cetuximab during chemoradiotherapy. Nevertheless, there is no evidence that the incidence of acute pelvic morbidity was higher in our study using a higher dose of RT compared with other published studies,2,5,6 except RT field erythema which is subjective and prone to under-reporting in published studies. Neoadjuvant or perioperative chemotherapy followed by definitive local treatment is now standard of care in several tumor types including esophagus,7 stomach,8 and breast9 cancers. With more effective cytotoxic drugs now available, induction platinum-based chemotherapy followed by (chemo)radiation is an actively pursued treatment strategy and have proven efficacy in recently reported large randomized studies of non–small-cell lung cancer10,11 and head and neck cancer.12 As stated in our article, neoadjuvant chemotherapy administered at full systemic dose is more likely to address the current major hurdle of controlling distant metastasis in rectal cancer and giving these cytotoxic agents in conjunction with RT at lower doses might potentially compromised the systemic effect of these drugs. Moreover, the pathological complete response (pCR) rates in reported phase II studies utilizing synchronous oxaliplatin, capecitabine, and RT were somewhat lower than in our EXPERT study.5,13,14 In addition, the rapid symptomatic improvement accompanied by significant tumor regression resulting from neoadjuvant oxaliplatin plus capecitabine is a particularly valuable treatment outcome for our patients. We used pCR rate as our primary end point, in line with other cooperative groups' and multi-institutional phase II studies.2,5,6,13 Because pCR was our primary end point, we have therefore reported this end point in both intention-to-treat and assessable population. However, we feel it is adequate to report all other secondary end points in the assessable population only. Furthermore, we did not intend to compare our study results with the other studies cited by the authors, both of which were analyses of prospectively acquired databases rather than formal clinical trials. The authors refer to a toxic death rate of 5% (four of 77 patients) in our study. However, it should be emphasized that three of these deaths were cardiac and thromboembolic (CTE) events; one patient died from pulmonary embolism, one patient died from ischemic heart disease, and one patient experienced sudden death with a history of chest pain. Although these events may be related to chemotherapy, the causal associations are by no means definite. The dose schedule used in our study was identical to those used in several phase III studies in both adjuvant and advanced disease settings without any safety concerns.15,16 In the adjuvant trial of 1,886 patients, capecitabine and oxaliplatin were associated with less than 1% of grade 3 or 4 cardiotoxicity and 0.6% of treatment-related deaths.15 In the advanced disease setting, this combination was associated with 4% of thromboemobilic events.16 In both studies, the incidences of CTE were similar to control arms. We had amended our protocol during the study to exclude patients with significant cardiac history, in line with other randomized studies. Indeed in our current EXPERT-C study, we have not encountered any deaths from CTE events. Nevertheless, one patient died from neutropenic colitis in EXPERT study and this was likely to be the results of the study drugs. In view of the recent safety results from the TREE 1 and TREE 2 studies,17 we are reducing the capecitabine dose to 850mg/m2 twice daily in the EXPERT-C study. In conclusion, this is the first report of the use of neoadjuvant chemotherapy, synchronous chemoradiotherapy, surgery, and adjuvant chemotherapy in patients with magnetic resonance imaging-defined poor-risk rectal cancer. The rapid improvement in tumor-related symptoms and high rate of tumor regression from neoadjuvant chemotherapy is an important and encouraging finding and highlights the potential relevance of this approach as a prelude to definitive chemoradiotherapy and surgery. This treatment approach should be rigorously tested in future phase III studies. Our current study integrates cetuximab into this treatment approach, as we believe this could represent a more active treatment program to be evaluated in phase III studies. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Chau I, Brown G, Cunningham D, et al: Neoadjuvant capecitabine and oxaliplatin followed by synchronous chemoradiation and total mesorectal excision in magnetic resonance imaging-defined poor-risk rectal cancer. J Clin Oncol 24:668-674, 2006 2. Mohiuddin M, Winter K, Mitchell E, et al: Randomized phase II study of neoadjuvant combined-modality chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. J Clin Oncol 24:650-655, 2006 3. Mohiuddin M, Regine WF, John WJ, et al: Preoperative chemoradiation in fixed distal rectal cancer: Dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 46:883-888, 2000[CrossRef][Medline] 4. Hartley A, Ho KF, McConkey C, et al: Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: Analysis of phase II/III trials. Br J Radiol 78:934-938, 2005 5. Machiels JP, Duck L, Honhon B, et al: Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: The RadiOxCape study. Ann Oncol 16:1898-1905, 2005 6. Ryan DP, Niedzwiecki D, Hollis D, et al: Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: Cancer and Leukemia Group B 89901. J Clin Oncol 24:2557-2562, 2006 7. Medical Research Council Oesophageal Cancer Working Party: Surgical resection with or without preoperative chemotherapy in oesophageal cancer: A randomised controlled trial. Lancet 359:1727-1733, 2002[CrossRef][Medline] 8. Cunningham D, Allum WH, Stenning SP, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 355:11-20, 2006 9. Bear HD, Anderson S, Smith RE et al: A randomized trial comparing preoperative doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative T in patients wit operable carcinoma of the breast: Results of NSABP B-27. Breast Cancer Res Treat 88:S16, 2004 (abstr 26) 10. van Meerbeeck JP, Kramer G, van Schil PE et al: A randomized trial of radical surgery (S) versus thoracic radiotherapy (TRT) in patients (pts) with stage IIIA-N2 non-small cell lung cancer (NSCLC) after response to induction chemotherapy (ICT) (EORTC 08941). J Clin Oncol 23:624s, 2005 (abstr 7015) 11. Gervais R, Ducolone A, Lechevalier T et al: Conventional radiation (RT) with daily carboplatin (Cb) compared to RT alone after induction chemotherapy (ICT) vinorelbine (Vr)-cisplatine (P): Final results of a randomized phase III trial in stage III unresectable non small cell lung (NSCLC) cancer: Study CRG/BMS/NPC/96 of the French Lung Cancer Study Group FNCLCC and IFCT. J Clin Oncol 23:625s, 2005 (abstr 7016) 12. Calais G, Pointreau Y, Alfonsi M et al: Randomized phase III trial comparing induction chemotherapy using cisplatin (P) fluorouracil (F) with or without docetaxel (T) for organ preservation in hypopharynx and larynx cancer: Preliminary results of GORTEC 2000-01. J Clin Oncol 24:281s, 2006 (abstr 5506) 13. Rutten H, Sebag-Montefiore D, Glynne-Jones R, et al: Capecitabine, oxaliplatin, radiotherapy, and excision (CORE) in patients with MRI-defined locally advanced rectal adenocarcinoma: Results of an international multicenter phase II study. J Clin Oncol 24: 2006 (abstr 3528) 14. Glynne-Jones R, Sebag-Montefiore D, Samuel L, et al: Socrates phase II study results: Capecitabine (CAP) combined with oxaliplatin (OX) and preoperative radiation (RT) in patients (pts) with locally advanced rectal cancer (LARC). J Clin Oncol 23:252s, 2005 (abstr 3527) 15. Schmoll HJ, Tabernero J, Nowacki M, et al: Final safety findings from a randomized phase III trial of capecitabine + oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer. J Clin Oncol 24:163s, 2006 (abstr 3569) 16. Massuti B, Gomez A, Sastre J et al: Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first line treatment in advanced or metastatic colorectal cancer (CRC). J Clin Oncol 24:165s, 2006 (abstr 3580) 17. Hochster HS, Hart LL, Ramanathan RK et al: Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): Final analysis of the TREE-Study. J Clin Oncol 24:148s, 2006 (abstr 3510) Related Correspondence
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
