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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 668-674 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.4875 Neoadjuvant Capecitabine and Oxaliplatin Followed by Synchronous Chemoradiation and Total Mesorectal Excision in Magnetic Resonance Imaging–Defined Poor-Risk Rectal CancerFrom the Departments of Medicine, Diagnostic Imaging, Radiotherapy, Histopathology, and Computing and Information, Royal Marsden Hospital, London and Surrey, United Kingdom. Address reprint requests to David Cunningham, MD, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey, United Kingdom SM2 5PT; e-mail: david.cunningham{at}icr.ac.uk
PURPOSE: To evaluate neoadjuvant capecitabine/oxaliplatin before chemoradiotherapy (CRT) and total mesorectal excision (TME) in newly diagnosed patients with magnetic resonance imaging (MRI) –defined poor-risk rectal cancer.
PATIENTS AND METHODS: MRI criteria for poor-risk rectal cancer were tumors within 1 mm of mesorectal fascia (ie, circumferential resection margin threatened), T3 tumors at or below levators, tumors extending RESULTS: Between November 2001 and August 2004, 77 eligible patients were recruited. After neoadjuvant capecitabine/oxaliplatin, the radiologic response rate was 88%. In addition, 86% of patients had symptomatic responses in a median of 32 days (ie, just over one cycle of capecitabine/oxaliplatin). After CRT, the tumor response rate was increased to 97%. Three patients remained inoperable. Sixty-seven patients proceeded to TME, and all but one patient had R0 resection. Pathologic complete response was observed in 16 patients (24%; 95% CI, 14% to 36%), and in an additional 32 patients (48%), only microscopic tumor foci were found on surgical specimens. Four deaths occurred during neoadjuvant capecitabine/oxaliplatin therapy as a result of pulmonary embolism, ischemic heart disease, sudden death with history of chest pain, and neutropenic colitis. CONCLUSION: Capecitabine/oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection.
Surgery is the primary modality for cure in rectal cancer. However, local recurrence rates of 25% to 40% have been reported after conventional resection.1,2 Despite a lack of randomized data comparing total mesorectal excision (TME) with conventional surgery, recurrence rates of less than 10%1,3-5 and superior survival1,6 have been reported with TME. In rectal cancer, involvement of the histologic circumferential resection margin (CRM), which is defined as tumor  1 mm from the resection margin, has been shown to be an important prognostic factor, resulting in both higher rates of local recurrence4,5,7-10 and poorer survival,4,7,8 even after TME surgery.11 In the Dutch study comparing TME with or without preoperative short-course (25 Gy in 5 fractions) radiotherapy (RT), preoperative RT significantly improved local control compared with TME alone without impacting on survival.12 More recently, preoperative long-course fluorouracil (FU) -based chemoradiotherapy (CRT) has been shown to significantly improve local control compared with either postoperative CRT13 or preoperative long-course RT (45 Gy in 25 fractions).14,15 We have previously demonstrated that neoadjuvant protracted venous infusion (PVI) FU and mitomycin (MMC) as a prelude to synchronous CRT can be administered with negligible risk of disease progression and low risk of systemic spread.16 This treatment strategy allowed R0 resection in 82% of patients with locally advanced rectal cancer, including patients with initial CRM involvement. Oxaliplatin and infused FU/leucovorin (LV) is now considered as one of the standards of care in advanced colorectal cancer.17,18 The substitution of infused FU/LV by capecitabine has also been shown recently to be as efficacious when combined with oxaliplatin.19 Concomitant RT and oxaliplatin with either FU/LV or capecitabine can achieve pathologic complete response (pCR) rates of 15% to 28% in locally advanced rectal cancer.20-23 Therefore, in our current protocol, we substituted MMC and PVI FU with oxaliplatin and capecitabine during neoadjuvant chemotherapy and used capecitabine during CRT. This study represents, for the first time, the implementation of a preoperative treatment strategy based on magnetic resonance imaging (MRI) assessment on the potential resection margin and, in addition, a prolonged block of systemic-dose chemotherapy before synchronous CRT.
This study was approved by the local scientific and research ethics committee (Local Research Ethics Committee No. 1973). Signed written informed consent was obtained from each patient.
Patient Selection Before entry onto the study, all patients were assessed by a multidisciplinary team comprising medical, radiation, and surgical oncologists, gastroenterologists, and radiologists. Patients were considered to have poor-risk disease on the basis of high-resolution, thin-slice (3 mm) MRIs of the pelvis, which were performed as previously described (Appendix).24,25 MRI criteria for poor-risk disease were as follows: tumor extending to within 1 mm of or beyond the mesorectal fascia (ie, CRM involved or threatened), T3 low-lying tumor at or below the levators, tumor extending 5 mm or more into perirectal fat, tumor invading surrounding structures or peritoneum (T4), and T1-4N2 tumors. Apart from MRI of the pelvis, all patients were required to have a CT scan of the chest, abdomen, and pelvis and carcinoembryonic antigen measurement.
Treatment Synchronous CRT. On completion of 12 weeks of neoadjuvant chemotherapy, patients began CRT. RT was delivered by a two-phase technique; both phases were conformally (CT) planned. Phase 1 delivered a total of 45 Gy in 25 daily fractions and encompassed the primary tumor and pelvic lymph nodes. During phase 2, the protocol aim was to deliver 9 Gy in 5 fractions covering the tumor, either clinically palpable or visible on imaging, with a 2-cm margin in all directions. Patients received concomitant capecitabine at a reduced dose of 1,650 mg/m2/d continuously without interruption. If patients already had dose reduction to capecitabine during neoadjuvant chemotherapy, the same proportional dose reduction was made during synchronous CRT. Surgery. TME was performed 6 weeks after the completion of CRT. The final choice of surgical procedure (abdominoperineal [AP] or anterior resection) was at the surgeons' discretion, although a recommendation was suggested by the multidisciplinary team. Postoperative adjuvant chemotherapy. After recovery from surgery, patients were to receive another 12 weeks of capecitabine at a dose of 2,500 mg/m2/d for 14 days followed by 7 days of rest.
Evaluation of Response During neoadjuvant chemotherapy, particular inquiry was made regarding symptoms of rectal bleeding, pelvic pain/tenesmus, and diarrhea/constipation. Disappearance or attenuation of these tumor-related symptoms was recorded at each hospital visit. Data regarding the time between commencement of treatment and resolution of symptoms were collected weekly. pCR was defined as the absence of any residual tumor cells detected in the resected specimen, and pCR was used as the primary end point in the study. Carefully matched whole-mount sections of the surgical specimen were made to correlate with the MRI findings and aid histologic interpretation (Appendix). Tumor specimens were examined for resection margin involvement. Tumor downstaging was defined as a reduction of at least one level in T or N staging (eg, T3 to T2 or N2 to N0).
Statistical Considerations Failure-free survival (FFS) was calculated from the date of trial entry until disease progression, relapse, or death from any cause. Overall survival (OS) was calculated from the date of trial entry until death from any cause or censored at last follow-up. Both FFS and OS were estimated using the Kaplan-Meier method.29 All end points were updated in August 2005, and analyses were performed using SPSS package version 12 (SPSS Inc, Chicago, IL).
Between November 2001 and August 2004, 79 patients were recruited onto the study. Two patients were ineligible; one patient was ineligible because of metastatic bone disease at presentation demonstrated at radiology review, and the other patient could not receive protocol treatment as a result of deterioration in renal function. Table 1 lists the baseline characteristics.
Figure 1 shows the progress of all patients during the trial. Of the 77 eligible patients who commenced neoadjuvant oxaliplatin and capecitabine, nine patients did not finish the entire course of neoadjuvant chemotherapy. Three patients, who received neoadjuvant chemotherapy, omitted CRT and proceeded directly to surgery. Of these patients, one patient had a major response and developed bowel perforation after only one course of treatment. At surgery, no primary tumor could be identified, and histology showed residual focus in one lymph node only. Two other patients had favorable response to neoadjuvant chemotherapy and declined CRT. After CRT, two further patients declined AP resection, whereas another patient, who had a stroke and myocardial infarction during treatment, was considered unfit to undergo general anesthesia.
Table 2 lists the radiologic tumor responses. After neoadjuvant chemotherapy, the objective response rate was 88% (95% CI, 78% to 95%). After CRT, the objective response rate increased to 97% (95% CI, 90% to 100%). Overall, 86% of patients had an improvement in symptoms. Of the patients with symptoms, 71% had diminished pelvic pain/tenesmus, 90% had improvement in diarrhea/constipation, 100% had reduced rectal bleeding, and 93% had weight stabilization or weight gain. Table 3 lists the symptomatic improvement and time to complete resolution of symptoms. The median time to complete resolution of symptoms was 32 days (interquartile range, 21 to 68 days).
Forty-three patients underwent an anterior resection, and 24 underwent an AP resection. Three patients were still considered inoperable at laparotomy. Of the 67 patients who underwent TME, R0 resections were achieved in all but one patient (99%). pCR was observed in 16 patients (24%; 95% CI, 14% to 36%). In a further 32 patients (48%), only microscopic tumor foci were found. On an intent-to-treat basis, pCR was achieved in 16 (21%; 95% CI, 12% to 32%) of 77 patients. Compared with baseline MRI, 51 (76%) of 67 patients had downstaging of their primary tumor in T only (n = 13), N only (n = 14), or both T+N (n = 24) staging. Table 4 shows the comparison between baseline MRI and post-treatment histologic staging. In 16 (62%) of 26 patients, T3 tumors corresponded to only microscopic foci that were still through the muscularis propria. Thirty-two patients had low-lying tumors below the levator; 12 (38%) of these 32 patients had sphincter-saving surgery after our treatment program. Of the 18 patients who underwent AP resection, four were found to have pCR.
Table 5 lists the incidences of grade 3 to 5 toxicities during neoadjuvant chemotherapy and during CRT. Four deaths occurred during neoadjuvant chemotherapy. We observed a clinically significant occurrence of cardiac/thromboembolic (CTE) toxicity during neoadjuvant oxaliplatin/capecitabine, which led to three mortalities. This prompted our protocol amendment in January 2004 (see Patients and Methods). Table 6 shows an account of these CTE toxicities. Nine patients did not finish neoadjuvant chemotherapy; six patients did not finish because of CTE toxicity, one patient had neutropenic colitis leading to multiorgan failure and death, one patient had grade 4 diarrhea requiring defunctioning colostomy, and one patient had dramatic tumor response leading to bowel perforation, as mentioned previously.
With a median follow-up time of 23 months, the 1-year FFS rate was 87% (95% CI, 77% to 93%). Two local and eight distant recurrences (liver, n = 4; lung, n = 3; and peritoneum, n = 1) have been observed so far. The 1-year OS rate was 95% (95% CI, 87% to 98%). Figure 2 shows the FFS and OS for all eligible patients.
In this study, objective tumor responses were seen in 88% of patients after neoadjuvant oxaliplatin and capecitabine. Moreover, this was accompanied by rapid symptomatic relief occurring within a median of 32 days after commencement of neoadjuvant chemotherapy (ie, just over one cycle of treatment). The radiologic response rate further improved to 97% after synchronous CRT. R0 resection was achieved in 99% of patients. The pCR rate of 24% was encouraging considering the advanced nature of most patients' rectal cancer. With a prolonged 12-week block of full systemic-dose neoadjuvant chemotherapy before CRT, no disease progression was seen during preoperative treatment. Furthermore, preliminary survival data were encouraging, although further follow-up would be required to see whether reduction of distant metastasis and, thereby, improvement of OS can be achieved with this approach. Our definition of poor-risk rectal cancer was based on several lines of evidence. First, CRM involvement in rectal cancer has been found to be a poor prognostic factor for both local recurrence and survival in patients who have TME.4,6,11 Second, T3 tumors extending more than 5 mm beyond the muscularis propria were shown to have a significantly higher locoregional recurrence rate and poorer 5-year cancer-specific survival.30 Third, patients with low-lying tumors requiring AP resections had higher rates of CRM involvement, more local recurrence, and poorer survival rates compared with patients undergoing anterior resection despite the use of TME.31 Finally, in a recent pooled analysis of five randomized rectal adjuvant studies, patients with T4 and N2 tumors had poorer survival despite the use of triple-modality (surgery, chemotherapy, and RT) treatment compared with patients with lower T and N staging.32 Therefore, our cohort of patients represented a group with particularly adverse outcomes who would require an aggressive preoperative treatment strategy. In our recent audit of new rectal cancer patients presenting to our cancer network,33 60% of patients with T3 tumors had tumors that extended less than 5 mm beyond the muscularis propria on baseline MRI. In addition, a third of patients with T1-2 tumors had N1 disease. All of these early T3 and N1 patients would have been included in other preoperative CRT trials, again illustrating our stringent criteria for distinctively poor-risk patients. The use of MRI has been validated in previous studies,34,35 and the reproducibility and generalizability of this technique have been shown in a recent, multicenter, prospective magnetic resonance imaging and rectal cancer European equivalence study (MERCURY), which demonstrated statistical equivalence in measurement of tumor spread compared with the histopathologic gold standard.36 Moreover, there was good agreement between the central radiologist and the participating radiologists in our trial, reinforcing the fact that the MRI entry criteria used in our study can be adequately and reproducibly assessed by radiologists. Several randomized studies have recently been reported evaluating the use of preoperative FU-based CRT. A German trial compared preoperative CRT with postoperative CRT.13 Although no disease-free survival (DFS) or OS differences were seen between the two arms, a significant reduction in local recurrence was seen with preoperative CRT. Two other studies performed by the European Organisation for Research and Treatment of Cancer14 and Fédération Francophone de Cancérologie Digestive15 compared preoperative CRT with preoperative RT alone. Preoperative CRT again resulted in lower local recurrence without any survival benefit. Interestingly, in all three studies, no impact was seen on distant metastasis with preoperative CRT. Two possible explanations for this observation were that the chemotherapeutic agents used in these studies (FU/LV) were administered at doses adequate only for radiosensitizing local effect but not adequate to have a systemic effect and that FU and LV were suboptimal chemotherapeutic agents. In the adjuvant setting for colon cancer, both capecitabine and oxaliplatin have been shown to be equivalent or superior in DFS compared with bolus and/or infused FU/LV, respectively, although no significant OS improvement has been observed yet.37-39 The combination of oxaliplatin and capecitabine has shown promising clinical activity in advanced colorectal cancer40 and was noninferior compared with oxaliplatin/infused FU.19 Therefore, it was rational for us to investigate oxaliplatin and capecitabine as neoadjuvant chemotherapy. In our study, all patients underwent repeat MRI scans after neoadjuvant oxaliplatin/capecitabine and after synchronous CRT to assess response in the primary tumor. In our previous study, neoadjuvant PVI FU and MMC produced a response rate of 28% (95% CI, 14% to 45%),16 whereas oxaliplatin and capecitabine in this study produced a response rate of 88% (95% CI, 78% to 95%). The pCR rate of 24% in this study was encouraging, and furthermore, another 48% of patients had only microscopic tumor foci seen on resected specimen, with clear pathologic CRM observed in all but one patient. The pathologic downstaging rate was 76%, probably understating the dramatic downsizing effect of our treatment program considering many patients had bulky disease before treatment. The degree of histologic tumor regression after preoperative CRT has been assessed in the German study.41 Complete and intermediate primary tumor (not including nodal) response was associated with improved DFS (P = .006), although in multivariate analyses, only pathologic nodal staging predicted DFS, local recurrence, and distant metastasis rates. Further follow-up in our group of patients with microscopic tumor foci might elucidate whether their outcome is similar to patients achieving pCR. Nevertheless, three patients remained inoperable after our treatment program. The majority of our patients had tumor involving the CRM before treatment, rendering curative resections precarious. Indeed, two of these three patients had good responses, leading to extensive extramural fibrosis on post-CRT MRI with loss of conventional resection planes. This resulted in fixation of pelvic structures, and surgical resection was not attempted. Several phase I and II studies have evaluated oxaliplatin, FU/LV, and capecitabine in rectal cancer, with pCR rates of 15% to 28% found in larger phase II studies.20-23,42-50 These results were promising considering that preoperative FU-based CRT resulted in pCR rates of only 8% and 11.7% in the German13 and Fédération Francophone de Cancérologie Digestive15 studies, respectively. With the use of preoperative FU-based CRT and TME, 5-year local recurrence rates of 6% to 8% are now reported.13-15 The next big hurdle would be the reduction of distant metastasis and prolongation of survival. In our previous study assessing MMC and FU, distant metastasis occurred in 28% of patients after only 15 months, whereas in this study, distant metastasis was seen in 10% of patients with a follow-up time of 23 months.
We observed a clinically significant frequency of CTE toxicity during neoadjuvant chemotherapy, which resulted in three deaths, although we used the same dose schedule as a large, multicenter, phase II study that reported no increased CTE toxicity.40 At the start of our study, we included patients with medically controlled ischemic heart disease who would have been excluded in other phase III studies. Many of our patients had bulky pelvic tumor, increasing the risk for venous thromboembolism. However, there might also be under-reporting of CTE toxicities in other advanced colorectal cancer trials because investigators might attribute these events to the underlying disease rather than trial treatment. We have pooled the data from this study and another phase II study that used the same dose schedule of oxaliplatin/capecitabine in advanced colorectal cancer.51 Cardiotoxicity was observed in 6.5% of a cohort of 153 patients. The majority of these events occurred during the first cycle of treatment; thus, physicians and patients need to be aware of these complications so that discontinuation of treatment and the appropriate intervention may be instituted without delay. A further patient died from neutropenic colitis, again highlighting the need for initiating immediate supportive measures when diarrhea occurs, especially around the time of anticipated neutropenia. Neoadjuvant oxaliplatin and capecitabine therapy was not associated with any other unexpected increased incidence of toxicity, and it did not increase the frequency of severe adverse events during CRT in our study. Because of the low cumulative dose of oxaliplatin (520 mg/m2) used in our study, no grade In conclusion, capecitabine and oxaliplatin before synchronous CRT and TME results in substantial tumor regression, rapid symptomatic response, and achievement of R0 resection. In view of this promising activity, we are now conducting a multicenter randomized study using this treatment approach with or without cetuximab, which is a monoclonal antibody against the epidermal growth factor receptor.
MRI protocol. Scans were performed using 1.5T MRI scanners. The protocol used a thin 3-mm section turbo spin-echo T2-weighted technique using a surface pelvic phased-array coil. For all tumors, scans were performed perpendicular to the long axis of the tumor. Coronal imaging was performed for all tumors arising at or below the levator muscle origins. Images were stored in digital imaging and communications in medicine (DICOM) format on compact disc. No bowel preparation, air insufflation or intravenous antispasmodic agents were used. For a 1.5T MRI scanner, four sequences were used. After a coronal localizer, sagittal scans were required from inner pelvic sidewall to sidewall using a 24-cm field of view, 5-mm contiguous/interleaved slices (no gap), and repetition time more than 2,500ms and less than 5,000ms (ms = 85). These acquisitions were used to plan thin-section oblique axial images. Axial T2FSE acquisitions of the anatomic pelvis were made by using a 24-cm field of view, a 5-mm contiguous section thickness, 4,000/85, 512 x 256 matrix, an echo train length of eight, no fat saturation, a 32 kHz bandwidth, and two signals acquisitions (2NEX). The sagittal T2-weighted images obtained were then used to plan T2-weighted thin-section axial images through the rectal cancer and adjacent perirectal tissues. These images were performed perpendicular to the long axis of the rectum. These were obtained by using a 16-cm field of view, a 3-mm section thickness, no intersection gap, 4,000/85, a 256 x 256 matrix, an echo train length of eight, no fat saturation, a 32 kHz bandwidth, and four acquisitions (4NEX). Histologic examination. The surgical specimens were fixed by instilling formalin into the lumen of the intact rectum and floating the specimen in a vat of formalin. The specimen was serially sectioned transversely to retain the relationships between rectum and mesorectal surgical margins. The slices that included the area covering the location of the pretreatment tumor were selected for preparation of whole-mount sections.
Althoguh all authors completed the disclosure declaration, the following authors or their immediate family members have 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)
We express special thanks to all members of the Royal Marsden Hospital Rectal Cancer Study Group (in alphabetical order): Medical oncologists: D. Cunningham (Royal Marsden Hospital, London and Surrey), M. Hill (Royal Marsden Hospital, Surrey), and P. Ross (Royal Marsden Hospital, Surrey); Radiation oncologist: D. Tait (Royal Marsden Hospital, London and Surrey); Surgeons: M. Abulafi (Mayday University Hospital, Croydon), N. Bett (St Helier Hospital, Cashalton), I. Daniels (Pelican Cancer Foundation), R.J. Heald (Pelican Cancer Foundation), M. Henry (Royal Marsden Hospital, London), S. Fahrat (St Helier Hospital, Cashalton), D. Kumar (St George's Hospital, London), R. Leicester (St George's Hospital, London), M.A. Raja (Epsom General Hospital, Epsom), I. Swift (Mayday University Hospital, Croydon), and P. Toomey (Epsom General Hospital, Epsom); Pathologists: A. Arnaout (Mayday University Hospital, Croydon), L. Temple (Epsom General Hospital, Epsom), S. Sampson (St Helier Hospital, Cashalton), and A. Wotherspoon (Royal Marsden Hospital, London); Radiologists: N. Bees (Mayday University Hospital, Croydon), H. Blake (Mayday University Hospital, Croydon), G. Brown (Royal Marsden Hospital, London and Surrey), P. Bryne (Epsom and St Helier National Health Service Trust), C. George (Epsom and St Helier National Health Service Trust), N. Jeyadevan (Mayday University Hospital, Croydon), and M. Koh (Royal Marsden Hospital, London and Surrey); Gastroenterologists: J. Andreyev (Chelsea and Westminster Hospital, London) and M. Benson (St Helier Hospital, Carshalton).
Supported by an education grant from Sanofi-Aventis. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; and the 2nd Annual Gastrointestinal Cancers Symposium, Miami, FL, January 27-29, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Havenga K, Enker WE, Norstein J, et al: Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: An international analysis of 1411 patients. Eur J Surg Oncol 25:368-374, 1999[CrossRef][Medline] 2. Nesbakken A, Nygaard K, Westerheim O, et al: Local recurrence after mesorectal excision for rectal cancer. Eur J Surg Oncol 28:126-134, 2002[CrossRef][Medline] 3. Heald RJ, Moran BJ, Ryall RD, et al: Rectal cancer: The Basingstoke experience of total mesorectal excision, 1978-1997. Arch Surg 133:894-899, 1998 4. Wibe A, Rendedal PR, Svensson E, et al: Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer. Br J Surg 89:327-334, 2002[CrossRef][Medline] 5. Nagtegaal ID, Marijnen CA, Kranenbarg EK, et al: Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma: Not one millimeter but two millimeters is the limit. Am J Surg Pathol 26:350-357, 2002[CrossRef][Medline] 6. Kapiteijn E, Putter H, Van de Velde CJ: Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in the Netherlands. Br J Surg 89:1142-1149, 2002[CrossRef][Medline] 7. Adam IJ, Mohamdee MO, Martin IG, et al: Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet 344:707-711, 1994[CrossRef][Medline] 8. Birbeck KF, Macklin CP, Tiffin NJ, et al: Rates of circumferential resection margin involvement vary between surgeons and predict outcomes in rectal cancer surgery. Ann Surg 235:449-457, 2002[CrossRef][Medline] 9. Quirke P, Durdey P, Dixon MF, et al: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histopathological study of lateral tumour spread and surgical excision. Lancet 2:996-999, 1986[CrossRef][Medline] 10. Stocchi L, Nelson H, Sargent DJ, et al: Impact of surgical and pathologic variables in rectal cancer: A United States community and cooperative group report. J Clin Oncol 19:3895-3902, 2001 11. Marijnen CA, Nagtegaal ID, Kapiteijn E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients: Report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55:1311-1320, 2003[CrossRef][Medline] 12. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345:638-646, 2001 13. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 14. Bosset JF, Calais G, Mineur L, et al: Preoperative radiation (Preop RT) in rectal cancer: Effect and timing of additional chemotherapy (CT) 5-year results of the EORTC 22921 trial. J Clin Oncol 23:247s, 2005 (suppl; abstr 3505)[CrossRef] 15. Gerard JP, Bonnetain F, Conroy T, et al: Preoperative (preop) radiotherapy (RT) {+/–} 5 FU/folinic acid (FA) in T3-4 rectal cancers: Results of the FFCD 9203 randomized trial. J Clin Oncol 23:247s, 2005 (suppl; abstr 3504)[CrossRef] 16. Chau I, Allen M, Cunningham D, et al: Neoadjuvant systemic fluorouracil and mitomycin C prior to synchronous chemoradiation is an effective strategy in locally advanced rectal cancer. Br J Cancer 88:1017-1024, 2003[CrossRef][Medline] 17. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 18. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 19. Arkenau HT, Schmoll H, Kubicka S, et al: Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): Results of the safety and efficacy analysis. J Clin Oncol 23:247s, 2005 (suppl; abstr 3507)[CrossRef] 20. Aschele C, Friso ML, Pucciarelli S, et al: A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol 16:1140-1146, 2005 21. Gerard JP, Chapet O, Nemoz C, et al: Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: The Lyon R0-04 phase II trial. J Clin Oncol 21:1119-1124, 2003 22. 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 (suppl; abstr 3527) 23. Rodel C, Grabenbauer GG, Papadopoulos T, et al: Phase I/II trial of capecitabine, oxaliplatin, and radiation for rectal cancer. J Clin Oncol 21:3098-3104, 2003 24. Brown G, Richards CJ, Newcombe RG, et al: Rectal carcinoma: Thin-section MR imaging for staging in 28 patients. Radiology 211:215-222, 1999 25. Brown G, Daniels IR, Richardson C, et al: Techniques and trouble-shooting in high spatial resolution thin slice MRI for rectal cancer. Br J Radiol 78:245-251, 2005 26. National Cancer Institute: National Cancer Institute Common Toxicity Criteria. Bethesda, MD, National Cancer Institute, 1998 27. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 28. A'Hern RP: Sample size tables for exact single-stage phase II designs. Stat Med 20:859-866, 2001[CrossRef][Medline] 29. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 30. Merkel S, Mansmann U, Siassi M, et al: The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 16:298-304, 2001[CrossRef][Medline] 31. Marr R, Birbeck K, Garvican J, et al: The modern abdominoperineal excision: The next challenge after total mesorectal excision. Ann Surg 242:74-82, 2005[CrossRef][Medline] 32. Gunderson LL, Sargent DJ, Tepper JE, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004 33. Burton S, Daniels I, Brown G, et al: Evaluation of the role of MRI in staging rectal cancer within the multidisciplinary team setting. J Clin Oncol 22:272s, 2004 (suppl; abstr 3611) 34. Brown G, Radcliffe AG, Newcombe RG, et al: Preoperative assessment of prognostic factors in rectal cancer using high-resolution magnetic resonance imaging. Br J Surg 90:355-364, 2003[CrossRef][Medline] 35. Brown G, Davies S, Williams GT, et al: Effectiveness of preoperative staging in rectal cancer: Digital rectal examination, endoluminal ultrasound or magnetic resonance imaging? Br J Cancer 91:23-29, 2004[CrossRef][Medline] 36. Brown G, Daniels IR: Preoperative staging of rectal cancer: The MERCURY research project. Recent Results Cancer Res 165:58-74, 2005[Medline] 37. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004 38. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696-2704, 2005 39. Wolmark N, Wieand S, Kuebler JP, et al: A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol 23:246s, 2005 (suppl, abstr LBA3500)[CrossRef] 40. Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004 41. Rodel C, Martus P, Papadoupolos T, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688-8696, 2005 42. Carraro S, Roca EL, Cartelli C, et al: Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3–T4 unresectable rectal cancer: A phase II IATTGI study. Int J Radiat Oncol Biol Phys 54:397-402, 2002[CrossRef][Medline] 43. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983-3991, 2002 44. Dunst J, Reese T, Debus J, et al: Phase-II study of preoperative chemoradiation with capecitabine in rectal cancer. J Clin Oncol 22:259s, 2004 (suppl; abstr 3559) 45. Freyer G, Bossard N, Romestaing P, et al: Addition of oxaliplatin to continuous fluorouracil, L-folinic acid, and concomitant radiotherapy in rectal cancer: The Lyon R 97-03 phase I trial. J Clin Oncol 19:2433-2438, 2001 46. Kim JC, Kim TW, Kim JH, et al: Preoperative concurrent radiotherapy with capecitabine before total mesorectal excision in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 63:346-353, 2005[CrossRef][Medline] 47. Kim JS, Kim JS, Cho MJ, et al: Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 54:403-408, 2002[CrossRef][Medline] 48. Loi S, Ngan SY, Hicks RJ, et al: Oxaliplatin combined with infusional 5-fluorouracil and concomitant radiotherapy in inoperable and metastatic rectal cancer: A phase I trial. Br J Cancer 92:655-661, 2005[CrossRef][Medline] 49. Ngan SY, Michael M, MacKay J, et al: A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br J Cancer 91:1019-1024, 2004[CrossRef][Medline] 50. Reerink O, Mulder NH, Verschueren RC, et al: Addition of oxaliplatin to neo-adjuvant radiochemotherapy for irresectable rectal cancer, a phase I study. Anticancer Res 25:629-633, 2005[Medline] 51. Ng M, Cunningham D, Norman AR: The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC). Eur J Cancer 41:1542-1546, 2005[CrossRef][Medline] Submitted October 13, 2005; accepted November 21, 2005. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
5 mm into perirectal fat, T4 tumors, and T1-4N2 tumors. Patients received 12 weeks of neoadjuvant capecitabine/oxaliplatin followed by concomitant capecitabine and radiotherapy. TME was planned 6 weeks after CRT. Postoperatively, patients received another 12 weeks of capecitabine. 
= .05, 90% power). At the end of the first stage, five patients had already achieved pCR, and therefore, this study was expanded using the Simon one-stage design with the Ahern exact P value
