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Journal of Clinical Oncology, Vol 25, No 28 (October 1), 2007: pp. 4379-4386 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9685 Patients With Curative Resection of cT3-4 Rectal Cancer After Preoperative Radiotherapy or Radiochemotherapy: Does Anybody Benefit From Adjuvant Fluorouracil-Based Chemotherapy? A Trial of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group
From the Statistics Department, European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; Department of Radiation Therapy, University of Franche-Comté, Besançon; Department of Radiation Therapy, Clinic Sainte-Catherine, Avignon; Department of Radiation Therapy, Cancer Center Dijon, Dijon; Department of Radiation Therapy, University François Rabelais, Tours, France; Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands; and Institute for Oncology and Radiology, Belgrad, Serbia Address reprint requests to Laurence Collette, MSc, PhD, European Organisation for Research and Treatment of Cancer (EORTC), Department of Statistics, Avenue E. Mounier 83/11, B-1200 Bruxelles, Belgium; e-mail: laurence.collette{at}eortc.be
Purpose European Organisation for Research and Treatment of Cancer (EORTC) trial 22921 compared adjuvant fluorouracil-based chemotherapy (CT) to no adjuvant treatment in a 2 x 2 factorial trial with randomization for preoperative (chemo)radiotherapy in patients with resectable T3-4 rectal cancer. The results showed no significant impact of adjuvant CT on progression-free or overall survival, although a difference seemed to emerge at approximately, respectively, 2 and 5 years after the start of preoperative treatment. We further explored the data with the aim of refining our understanding of the long-term results. Patients and Methods Data of 785 of the 1,011 randomly assigned patients who whose disease was M0 at curative surgery were used. Using meta-analytic methods, we investigated the homogeneity of the effect of adjuvant CT on the time to relapse or death after surgery (disease-free survival [DFS]) and survival in patient subgroups. Results Although there was no statistically significant impact of adjuvant CT on DFS for the whole group (P > .5), the treatment effect differed significantly between the ypT0-2 and the ypT3-4 patients (heterogeneity P = .009): only the ypT0-2 patients seemed to benefit from adjuvant CT (P = .011). The same pattern was observed for overall survival. Conclusion Exploratory analyses suggest that only good-prognosis patients (ypT0-2) benefit from adjuvant CT. This could explain why, in the whole group, the progression-free and overall survival diverged only after the poor-prognosis patients (ypT3-4) had experienced treatment failure. Patients in whom no downstaging was achieved did not benefit. This also suggests that the same prognostic factors may drive both tumor sensitivity for the primary treatment and long-term clinical benefit from further adjuvant CT.
The European Organisation for Research and Treatment of Cancer (EORTC) 22921 trial was a 2 x 2 factorial plan, four-arm, randomized trial that questioned the value of preoperative chemoradiotherapy (RT-CT) versus preoperative radiotherapy (RT) alone and the value of adjuvant chemotherapy (CT) versus none with respect to overall and progression-free survival in patients with potentially resectable cT3-4 M0 rectal cancer. From April 1993 to March 2003, 1,011 patients were allocated to one of the following treatment arms: arm 1, preoperative RT; arm 2, preoperative RT-CT; arm 3, preoperative RT and adjuvant CT; and arm 4, preoperative RT-CT and adjuvant CT. The main trial results were recently published with a median follow-up of 5.4 years.1 A first analysis showed that the addition of CT to preoperative RT induced a significant increase of the downstaging rate.2 The long-term results1 failed to demonstrate a significant impact of CT (either before or after surgery) on progression-free or overall survival, the primary trial end points. The 5-year overall survival rate was 63.2% in the no–adjuvant CT and 67.2% in the adjuvant-CT arms (P = .12) with a hazard ratio (HR) of 0.85 for adjuvant CT (95% CI, 0.68 to 1.04). The 5-year progression-free survival rates were 52.2% and 58.2% in the no-adjuvant and adjuvant arms, respectively (P = .132; HR = 0.87; 95% CI, 0.72 to 1.04). However, the progression-free and overall survival curves started to diverge at approximately, respectively, 2 and 5 years after entry onto study, suggesting that a subset of patients of better prognosis who survive 2 to 5 years after the initiation of the first treatment might benefit from the adjuvant treatment in the long-term. We now further explore the data with the aim of refining our understanding of the long-term results. For that purpose, we will focus on the group of eligible patients whose disease had not spread to distant sites before or at surgery and in whom a complete resection was performed. This subgroup should be disease free after surgery. We will then investigate whether we can identify, on the basis of baseline patient and treatment factors as well as preoperative and surgical treatment and outcome characteristics, a subgroup of patients who benefit significantly from the adjuvant treatment in the long term.
Trial Design The trial design and eligibility criteria have been reported previously,1 and we will summarize only the main features herein. Patients age up to 80 years with resectable T3 or T4 M0 (1987 International Union Against Cancer [UICC] staging) adenocarcinoma of the rectum,3 located within 15 cm of the anal margin, with a WHO performance status of 0 or 1, and without previous history of cancer, angina pectoris, or inflammatory disease of the ileum or colon were eligible for the trial. Disease staging was by clinical examination, rigid sigmoidoscopy, chest x-ray, and abdominopelvic computed tomography scan. Endorectal ultrasonography was optional. The trial was approved by the medical ethics committees of all participating centers. Informed consent was obtained from all patients before random assignment. The patients were centrally randomized at the EORTC Data Center to RT or RT-CT as preoperative treatment and to CT or nil as adjuvant treatment. RT consisted of a 45-Gy dose delivered in 25 fractions of 1.8 Gy to the posterior pelvis.2,4 Irradiation techniques and treatment volumes have been reported previously.2,4 Preoperative CT was delivered in two 5-day courses during the first and fifth weeks of RT. Surgery was planned 3 to 10 weeks thereafter, and total mesorectal excision was recommended from 1999 onwards. When allocated, the four 3-week courses of adjuvant CT had to start 3 to 10 weeks after surgery. Preoperative and adjuvant CT consisted of fluorouracil (350 mg/m2/d) and leucovorin (20 mg/m2/d) administered as a short intravenous infusion. The toxicity was monitored during treatment.4 Patients were then followed at 6-month intervals for at least 5 years by clinical examination, abdominal ultrasound, and chest x-ray; coloscopy was performed annually. Recurrences were confirmed radiologically or histologically. Local recurrence was defined as a tumor regrowth within the pelvis or perineum.
Analysis Set and End Points
Statistical Methods
A total of 226 patients were excluded from the analysis (102 initially allocated to no adjuvant CT and 124 to adjuvant CT): 15 were ineligible, 45 had metastatic progression before surgery, 57 have unknown metastatic status, 10 were not resected despite disease being M0, and 78 had an incomplete resection; in 21, the information regarding completeness of the resection was unknown. Of the 785 patients included in the analysis, 199 had been randomly assigned to the RT arm without adjuvant CT, 204 to RT-CT arm without adjuvant CT, 190 to the RT arm with adjuvant CT, and 192 to the RT-CT arm with adjuvant CT. In the analyzed set, all patients allocated adjuvant CT received at least one adjuvant CT cycle. The four adjuvant CT cycles were delivered to 140 (73.7%) of 190 patients and 142 (73.9%) of 192 patients allocated adjuvant CT in the RT and RT-CT arms, respectively. Of the patients in the RT arm, 233 (57.8%) were alive and free of disease at a median follow-up of 5.2 years from surgery, compared with 237 (62.0%) in the RT-CT arm (Fig 1). The first relapse was locoregional in 37 patients receiving RT versus 19 patients receiving RT-CT, distant relapse occurred in 98 v 91 patients, the two types of events occurred concurrently in five versus eight patients, a death without relapse occurred in 28 v 25 patients, and relapse at unspecified localization occurred in two patients in each arm.
The patients and the potential predictors considered in the analysis are described in Table 1. Because only 5.2% of the cases had mucinous tumors, this variable was not analyzed. Although the treatments were randomly assigned, some factors were slightly imbalanced between the two adjuvant treatment groups: WHO performance status more than 1 was more frequent in the adjuvant treatment group (32.2% v 25%), whereas in the no-adjuvant group, treatment downstaging to ypT0-2 was less frequent (51.8% v 55.8%) and pN+ cases were less common (25.4% v 29.5%). The imbalances in prognostic factors seemed to average out: The adjuvant treatment HR for DFS was very similar with (HR = 0.94; 95% CI, 0.73 to 1.20; P = .262) or without (HR = 0.92; 95% CI, 0.73 to 1.14; P = .443) adjustment for the covariates; as was the adjuvant treatment HR for overall survival with (HR = 0.93; 95% CI, 0.69 to 1.25; P = .623) or without adjustment for the covariates (HR = 0.92; 95% CI, 0.70 to 1.19; P = .514).
The univariate interaction tests for DFS and overall survival are also presented in Table 1 with the HRs and CIs. Only the downstaging (ypT0-2 v ypT3-4) statistically significantly influenced the magnitude of the adjuvant treatment effect (P = .008; Fig 2), with an interaction HR of 1.87 (95% CI, 1.18 to 2.98) indicating a significantly larger treatment benefit for the group with downstaging. In the group of patients with downstaging to ypT0-2 at the time of surgery, the treatment HR for DFS was 0.64 (95% CI, 0.45 to 0.91) in favor of adjuvant CT (P = .013); the DFS rate was 65.6% (95% CI, 58.3% to 72.0%) without CT and 76.7% (95% CI, 69.4% to 82.5%) with CT (Fig 3). In patients without downstaging, there was no statistically significant benefit of adjuvant CT (HR = 1.18; 95% CI, 0.89 to 1.57; P = .244). For that group, the 5-year DFS rate was 48.9% without CT (95% CI, 40.8% to 56.5%) and 45.1% with adjuvant CT (95% CI, 37.3% to 52.5%; Fig 3).
For survival, the downstaging also significantly influenced the effect of the adjuvant treatment (heterogeneity test P = .024; Fig 4), with an interaction HR of 1.89 (95% CI, 1.09 to 3.27; Table 1). In the group with downstaging, adjuvant CT significantly prolonged survival time after surgery (P = .030; HR = 0.64; 95% CI, 0.42 to 0.96), whereas the group without downstaging did not seem to benefit (P = .337; HR = 1.19; 95% CI, 0.84 to 1.68). Unlike for DFS, the benefit from adjuvant CT was significantly increased in patients with tumor located more than 5 cm from the anal verge compared with the benefit seen in patients with a tumor located 5 cm or less from the anal verge (low rectum; heterogeneity test P = .026; interaction HR = 0.54; 95% CI, 0.31 to 0.98; Fig 4). For tumors in the low rectum, adjuvant CT was not beneficial (P = .353; HR = 1.18; 95% CI, 0.83 to 1.66), whereas it was beneficial in patients with tumors located higher up in the rectum (P = .033), with a treatment HR of 0.64 (95% CI, 0.42 to 0.96) indicating prolonged survival with adjuvant treatment. Similarly, the type of surgical procedure also influenced the effect of adjuvant chemotherapy (interaction HR = 0.54; 95% CI, 0.31 to 0.93; P = .026). Patients who had undergone an abdominoperineal resection (APR) did not seem to benefit from adjuvant CT (HR = 1.26; P = .222), whereas those with another type of surgical procedure did (HR = 0.68; P = .046; Fig 4). This is not surprising, because tumor localization in the rectum is the major driver of choice of the surgical procedure, and 68% of the patients with a tumor in the low rectum underwent APR, compared with only 12% in those with tumors located higher in the rectum.
Because the type of surgical procedure and the tumor localization in the rectum are strongly correlated,9,10 only the tumor localization was combined with tumor downstaging for a multivariate predictive factor analysis of overall survival. The four-group classification combining tumor downstaging (ypT0-2 v ypT3-4) and tumor localization (  5 cm v >5 cm from the anal verge) statistically significantly influenced the treatment effect (heterogeneity test P = .012; 3 df; Fig 5A). However, within the subgroup with ypT0-2, the treatment effect seemed not to significantly vary according to tumor localization (heterogeneity P = .255) whereas it seemed to differ more within the subgroup with ypT3-4, although not statistically significantly (heterogeneity P = .071). Nevertheless, the three-way interaction among ypT, tumor localization, and treatment was not statistically significant (P = .731). In the patients with ypT0-2, the HR favored adjuvant CT (HR = 0.73; 95% CI, 0.43 to 1.26; and HR = 0.45; 95% CI, 0.24 to 0.85 for low and middle/high rectum, respectively). In the patients with ypT3-4 disease, the treatment HRs were not in favor of adjuvant CT: The treatment HR was 1.55, pointing against adjuvant CT for patients with a tumor in the low rectum (95% CI, 0.99 to 2.44; P = .053), and it was 0.81 for patients with tumors located in the middle or high rectum (95% CI, 0.47 to 1.41).
The impact of this classification on DFS after surgery is represented in Figure 5B and shows that only the classification by ypT influences the treatment effect on this end point. The study could not demonstrate a statistically significant behavior according to the type of preoperative treatment administered, but the predictive effect remained significant even if patients had no preoperative CT.
Overall, the EORTC trial 22921 could not demonstrate that delivering adjuvant CT to all patients with resectable T3-T4 rectal cancer would prolong progression-free or overall survival.1 In the present analysis, we focused on those patients whose tumor could be resected completely and whose disease had not extended to metastatic sites by the time of the surgery. We then showed that, in the subgroup of patients whose disease had been downstaged to ypT0-2 by preoperative treatment, the delivery of adjuvant CT prolonged both the time to relapse and the survival time. These findings should not, however, be misinterpreted: It is a common mistake to conclude causality when only associations have been demonstrated. We did not show that it is because tumor downstaging was achieved that these patients also benefited of further CT, but rather that those same patients who achieved downstaging have a disease that is responsive to both the preoperative and the adjuvant treatment. This suggests that the same good prognostic factors induce both an increased likelihood of downstaging from preoperative treatment and increased likelihood of a benefit from adjuvant CT. These findings are no proof of surrogacy of the downstaging for the long-term end points,10 but are in line with Valicenti et al's11 statement that heterogeneity of tumor behavior exists, which identification may be promoted by preoperative treatment. One could then ask which factors drive the sensitivity to pre- and postoperative treatment. In this database, the factors predicting an increased likelihood of downstaging were preoperative treatment,4 along with tumor length and the use of modern staging by endorectal ultrasonography (data not shown). The factors predicting progression-free survival after surgery were type of surgical procedure, pN status, and microscopic surgical margin status and tumor downstaging by preoperative treatment.9 We therefore focused on curatively resected patients. We believe, however, that other factors more closely related to sensitivity to RT and/or CT and to the biology of the disease are probably more relevant to the definition of the "good prognostic" patient group. However, these factors are not known from the data collected in the trial. We can therefore only identify this subgroup a posteriori, on the basis of the pathologic downstaging after preoperative treatment. The other factors that seemed to influence the effect of the adjuvant treatment on overall survival (tumor localization and type of surgery) were not confirmed to influence the effect of the treatment on progression-free survival. These factors are known prognostic factors of outcome,8,9 but in our study, they were not confirmed to be predictive for a benefit from adjuvant treatment regarding progression-free survival. This analysis is exploratory in nature: Neither the end point nor the hypotheses studied were planned in the study protocol. The hypothesis that a subgroup might benefit from adjuvant treatment emerged from the first trial results that were suggestive of mixture of patients in the sample, with varying sensitivity to and potential benefit from the tested adjuvant treatment. These findings must, therefore, be validated on an independent set of patients with cT3-4 rectal cancer who received preoperative treatment, were operated on, and were downstaged to pT0-2 and then randomly assigned to receive or not receive fluorouracil-based adjuvant CT. Despite the lack of evidence to support the routine use of adjuvant CT for all patients with resectable T3-T4 rectal cancer after preoperative treatment,1 adjuvant chemotherapy is regarded by some as standard adjuvant treatment.12-16 The present report, however, confirms that, at least in patients presenting with poorer risk features (ie, without tumor downstaging after preoperative radiotherapy or radiochemotherapy), adjuvant chemotherapy with fluorouracil and leucovorin may be an ineffective treatment, causing extra burden and toxicity to the patients without evidence, so far, of any clinical benefit. Our findings contrast with the recommendations by Das et al,14 who suggest, rather, that adjuvant chemotherapy might benefit more higher-risk patients but are in line with those of Janjan et al,17 who report higher rates of relapse despite adjuvant chemotherapy in patients showing no response to preoperative treatment. However, they suggest the use of FOLFOX for high-risk patients, which includes oxaliplatin in addition to the fluorouracil and leucovorin used in EORTC trial 22921. In a study of 95 rectal cancer patients who all underwent preoperative chemoradiotherapy and a microscopically complete resection, Fietkau et al13 concluded that postoperative chemotherapy may not be necessary in patients with ypN0. Their conclusions are based on the observation that ypN was the most important and sole independent prognostic factor for disease-free survival in their study and that there was no significant impact of the type if any, of postoperative treatment on outcome. EORTC trial 22921 confirmed that ypN was a strong independent prognostic factor for overall survival and DFS9; however, we demonstrated in the present report that ypN status after preoperative treatment did not show an interaction with the benefit from postoperative CT. The findings reported by Frietkaut may well have resulted from lack of power in their analyses, in relation to the limited number of patients in their study. We can therefore conclude that newer agents are worth investigating either alone or in combination as (neo)adjuvant treatment of rectal cancer, but predictive factors such as tumor responsiveness to preoperative treatment must be taken into account in the design of future phase III trials. Separate treatment strategies may be devised for patients with differing sensitivity to classical chemotherapeutic agents. Finally, the analysis of gene expression profiles of the primary tumor may be relevant to identify patients who may benefit from preoperative chemoradiotherapy16 and adjuvant fluouracil-based chemotherapy.18,19
The author(s) indicated no potential conflicts of interest.
Conception and design: Laurence Collette, Jean-François Bosset, Gilles Calais Administrative support: Marianne Piérart Provision of study materials or patients: Jean-François Bosset, Laurent Mineur, Philippe Maingon, Ljiljana Radosevic-Jelic, Gilles Calais Collection and assembly of data: Marianne Piérart Data analysis and interpretation: Laurence Collette, Marcel den Dulk, France Nguyen Manuscript writing: Laurence Collette, Jean-François Bosset, Marcel den Dulk Final approval of manuscript: Laurence Collette, Jean-François Bosset, Marcel den Dulk, France Nguyen, Laurent Mineur, Philippe Maingon, Ljiljana Radosevic-Jelic, Marianne Piérart, Gilles Calais
We thank all institutions that participated in the EORTC Radiotherapy Group Trial 22921 and the EORTC Data Center for its methodologic support to the trial and data analyses. Participating institutions: France—CHU de Besançon, Besançon; CHU de Tours –Hopital Bretonneau, Tours; Clinique Sainte Catherine, Avignon; Centre Georges-François Leclerc, Dijon; Hôpital Jean Bernard, Poitiers; Centre René Gauducheau, Nantes; Centre Paul Strauss, Strasbourg; CHU de Grenoble-la-Tronche, Grenoble; Centre Saint-Yves, Vannes; CHRU de Limoges; Polyclinique Clairval, Marseille; Clinique du Valdegour, Nîmes and Clinique de la Rochebelle, Alès; Centre Hospitalier Général de Belfort; Centre Paul Papin, Angers; CHU Henri Mondor, Créteil; Clinique Sainte Clotilde, La Réunion; CHU de Brest, Brest; Centre Oscar Lambret, Lille; CRHU Caen. Belgium—Hôpital Universitaire Erasme, Brussels; Intercommunale de Santé Publique du Pays de Charleroi; Hopital de Jolimont; Centre Hospitalier de Tivoli, La Louvière; Clinique Sainte Elisabeth, Namur; Institut Jules Bordet, Brussels. Israel—Rambam Medical Center, Haifa. Germany—Heinrich-Heine universitaetsklintk Dusseldorf, Allgemeines Krankenhaus Hagen. The Netherlands—University Medical Centre Nijmegen; Dr Bernard Verbeeten Instituut, Tilburg; Arnhem's radiotherapeutisch Instituut. Poland—Medical University of Gdansk. Serbia—Institute of Oncology & Radiology, Belgrade. Spain—Hopital General Vall d'Hebron, Barcelona; CSU de Bellvitge-Hospital Princeps d'Espanya now Institut Catala d'Oncologia, Hospital General Gregorio Maranon. Switzerland—Universitaetspital Zurich, Kantonsspital Winterthur. Turkey—Dokuz Eylul University School of Medicine, Izmir.
Supported by Grant Nos. 2U10-CA11488-21 through 5U10 CA11488-35 from the National Cancer Institute, by Programme Hospitalier de Recherche Clinique (PHRC 1992-France) and by the Ligue Contre le Cancer Comité du Doubs. M.D. is supported by a Quality Assurance Fellowship of the European Society of Surgical Oncology. Presented in an oral session of the 13th European Cancer Conference, October 30-November 3, 2005, Paris, France. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Bosset JF, Collette L, Calais G, et al: Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114-1123, 2006 2. Bosset JF, Calais G, Mineur L, et al: Enhanced tumorocidal effect of preoperative radiotherapy on rectal cancer by adding chemotherapy: Results from the 22921 EORTC randomized trial. J Clin Oncol 23:5620-5627, 2005 3. Sobin LH, Witteking C: TNM Classification of Malignant Tumours. Geneva, Switzerland, International Union Against Cancer, 1987 4. Bosset JF, Calais G, Daban A, et al: Preoperative chemo radiotherapy versus preoperative radiotherapy in rectal cancer patients: Assessment of acute toxicity and treatment compliance—Report of the 22921 randomized trial conducted by the EORTC Radiotherapy Group. Eur J Cancer 40:219-224, 2004[CrossRef][Medline] 5. Early Breast Cancer Trialists' Collaborative Group.Treatment of Early Breast Cancer, Worldwide Evidence 1985-1990, Vol 1. Oxford, United Kingdom, Oxford University Press, 1990 6. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 7. Peterson B, George SL: Sample size requirements and length of study for testing interactions in 2xk factorial design with time-to-failure outcome. Control Clin Trials 14:511-522, 1993[CrossRef][Medline] 8. Nagtegaal ID, van de Velde CJH, Marijnen CAM, et al: Low rectal cancer: A call for a change of approach in abdominoperineal resection. J Clin Oncol 23:9257-9264, 2005 9. Den dulk M, Collette L, Van de Velde CJH, et al: Quality of surgery in T3–T4 rectal cancer: Involvement of circumferential resection margin not influenced by preoperative treatment—Results from EORTC trial 22921. Eur J Cancer 43:1821-1828, 2007 (suppl; abstr 370)[CrossRef][Medline] 10. Baker SG, Kramer BS: A perfect correlate dose not a surrogate make. BMC Medical Research Methodology 3:16, 2003[CrossRef][Medline] 11. Valentini V, Coco C, Picciocchi A, et al: Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients. Int J Radiat Oncol Biol Phys 53:664-674, 2002[CrossRef][Medline] 12. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus adjuvant chemotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 13. Fietkau R, Barten M, Klautke G, et al: Adjuvant chemotherapy may not be necessary for patients with ypN0-category after neoadjuvant chemoradiotherapy of rectal cancer. Dis Colon Rectum 49:1284-1292, 2006[CrossRef][Medline] 14. Das P, Skibber JM, Rodriguez-Bigas MA, et al: Clinical and pathologic predictors of locoregional recurrence, distant metastasis and overall survival in patients treated with chemoradiation and mesorectal excision for rectal cancer. Am J Clin Oncol 29:219-224, 2006[CrossRef][Medline] 15. Gérard JP, Conroy T, Bonnetain F, et al: Preoperative radiotherapy with or without concurrent flurouracil and Leucovorin in T3-4 rectal cancers: Results of FFCD 9203. J Clin Oncol 24:4620-4625, 2006 16. Ghadimi BM, Grade M, Difilippantonio MJ, et al: Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. J Clin Oncol 23:1826-1838, 2005 17. Janjan NA, Crane C, Feig BW, et al: Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 24:107-112, 2001[CrossRef][Medline] 18. Liersch T, Langer C, Ghadimi MB, et al: Lymph node status and TS gene expression are prognostic markers in stage II/III rectal cancer after neoajduvant fluorouracil-based chemoradiotherapy. J Clin Oncol 24:4062-4068, 2006 19. Johnston PG: Prognostic markers of local relapse in rectal cancer: are we any further forward? J Clin Oncol 24:4049-4050, 2006 Submitted April 2, 2007; accepted June 12, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
