Enhanced Tumorocidal Effect of Chemotherapy With Preoperative Radiotherapy for Rectal Cancer: Preliminary Results—EORTC 22921
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《临床肿瘤学》
the Centre Hospitalier Universitaire (CHU) Besan?on, Besan?on
CHU Tours, Tours
Clinic Avignon, Avignon
Cancer Center Dijon, Dijon
CHU Poitiers, Poitiers
Cancer Center Nantes, Nantes, France
Institut for Oncology and Radiology, Belgrad, Serbia
Rambam Medical Center Ha?fa, Ha?fa, Isra?l
European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium
ABSTRACT
PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) trial evaluated the addition of chemotherapy (CT) to preoperative radiation (preop RT) and the value of postoperative CT for improving the survival in patients with T3-4 resectable rectal cancer. Patients were allocated to the following four arms: arm 1, preop RT 45 Gy in 5 weeks; arm 2, preop RT plus two 5-day CT courses (fluorouracil 350 mg/m2/d and leucovorin 20 mg/m2/d) in the first and fifth week of RT; arm 3, preop RT plus four postoperative CT courses; and arm 4, preop RT and CT plus postoperative CT. We investigated the effect of adding CT on the pathologic parameters.
PATIENTS AND METHODS: One thousand eleven patients were entered onto the trial; 505 received preop RT (arms 1 and 3), and 506 received preop RT-CT (arms 2 and 4). We analyzed the differences in tumor size, tumor node stage, number of retrieved nodes, and histologic features such as lymphatic, venous, and perineural invasions, tumor differentiation, and tumor type.
RESULTS: After preop RT-CT, tumors were smaller (P < .0001), had less advanced pT (P < .001) and pN stages (P < .001), had small numbers of examined nodes (P = .046), and less frequent LVN invasions (P .008). Mucinous tumors increased after preop RT-CT (P < .001).
CONCLUSION: In patients with rectal cancer, preliminary results of EORTC Trial 22921 indicate that the addition of CT to preop RT induces downsizing, downstaging, and significant changes in histologic characteristics. Longer follow-up is needed to assess the impact on local control and survival.
INTRODUCTION
More than 30 years ago, Moertel et al1 demonstrated that radiotherapy (RT) combined with fluorouracil (FU) significantly increased the overall survival of patients with locally advanced GI tumors compared with the same RT plus a placebo. From 1975 to 1989, postoperative pelvic RT combined with FU-based chemotherapy (CT) was evaluated in the United States in patients with Dukes' B and C rectal cancer. The combined therapy resulted in a significant benefit for local control, distant metastases, and survival compared with surgery alone.2-4 In 1989, a National Institutes of Health Consensus Conference stated that postoperative chemoradiotherapy (RT-CT) should be regarded as standard treatment for patients with stage II and III rectal cancer.5 Conversely, preoperative (preop) RT alone, which was mainly developed in Europe during the same period, demonstrated its value on local control6 and, more recently, on survival.7 Two RT schemes were explored; the so-called Swedish scheme delivered 25 Gy in 5 fractions over 1 week immediately followed by surgery, and conventional schemes delivered 40 to 50 Gy in 20 to 25 fractions over 4 to 5 weeks followed 3 to 4 weeks later by surgery. Compared with surgery alone, preop RT halved the local failure rates, irrespective of the scheme. Therefore, at the beginning of the 1990s, it became clear that preop RT-CT was a relevant issue for clinical research in Europe. The European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy Group demonstrated that an FU dose of 350 mg/m2/d could be safely administrated in combination with a leucovorin (LV) dose of 20 mg/m2/d delivered the first and fifth weeks of a 45-Gy dose of pelvic RT in patients with unresectable or locally recurrent rectal cancer.8 Then, in 1993, the EORTC initiated a four-arm randomized trial (EORTC 22921) to examine the value of preop RT-CT versus preop RT alone and the value of additional CT versus none with respect to overall survival and progression-free survival in the same patient group (Fig 1). A separate study was conducted in France by the Fondation Francaise de Cancérologie Digestive, which adopted strictly the EORTC protocol for its two-arm rectal study (Fondation Francaise de Cancérologie Digestive trial 9203), but all patients received postoperative CT. In this article, we report on the impact of the addition of the FU-LV combination to preop RT on the pathologic parameters in patients who entered the EORTC trial.
PATIENTS AND METHODS
Study Population
Between April 1993 and March 2003, 1,011 patients with rectal cancer were allocated to one of the following treatment arms: arm 1, preop RT; arm 2, preop RT-CT; arm 3, preop RT and postoperative CT; and arm 4, preop RT-CT and postoperative CT. Preop RT was considered the standard arm.
Patients were included in the study if they presented with all of the following: T3 or resectable T4 M0 adenocarcinoma of the rectum, according to the 1987 International Union Against Cancer (UICC) criteria9; WHO performance status of 0 or 1; age 80 years or less; and tumor located within 15 cm from the anal margin. Other criteria included leukocyte count greater than 4 x 109/L, platelet count greater than 130 x 109/L, and serum creatinine level less than 120 μmol/L. Patients were excluded if they had previously undergone treatment for this disease, except for a diverting colostomy; had a history of any other cancer, except basal cell carcinoma of the skin or in situ carcinoma of the cervix; or had angina pectoris or a chronic inflammatory disease of the ileum or the colon.
The extent of the tumor was evaluated by clinical examination, rigid rectoscopy, abdomino-pelvic computed tomography scan and chest x-ray. Endorectal ultrasonography (EUS) was optional. Tumor stage was obtained either clinically or with EUS. A clinical T3 had to have at least one of the following characteristics at digital rectal examination: a circular extension, a lateral or posterior fixity, and an anterior adhesion to the prostate or invasion of the recto-vaginal wall. Tumors with invasion of any neighboring structure or organ were classified as T4. Tumors not accessible to digital rectal examination were considered as T3 if they were circular or were classified using EUS. Before entry, the surgeon had to declare the tumor resectable. Tumor location within the rectum was defined with rigid rectoscopy and classified to be within the lower rectum if the inferior tumor margin was within 5 cm from the anal verge, to be in the middle rectum if the margin was 6 to 10 cm from the anal verge, and to be in the upper rectum if the margin was beyond 10 cm from the anal verge.
This study was approved by the ethics committees of the participating centers. Informed consent was obtained from all patients before their inclusion. Treatment allocation was performed centrally using the minimization technique, with stratification for institution, sex, clinical tumor stage, and distance from the tumor to the anal verge.
Treatment
RT. The target volume of RT was not a classical pelvic volume but was limited to the main field of tumor spread and to the perirectal nodes, which were both located within the mesorectum area below the S2-S3 interval.10 This limited volume is consistent with 5-year local failure reduction rates from 30% after incomplete dissection of the mesorectum to 4% after careful dissection of the fascial planes confining the mesorectum.11,12 For tumors located in the upper rectum, the target volume included 3 cm above the tumor and excluded the anal canal. For tumors located in the lower rectum, the target volume included the perineum and the anal canal. Posteriorly, the target included the sacrum. Anteriorly and laterally, the target extended at least 3 cm beyond the macroscopic extension of the tumor. These recommendations for two-dimensional simulation translate into the inclusion of the whole mesorectum area in a three-dimensional simulation but exclude the lateral pelvic lymph nodes.13 The prescribed RT dose was specified according to the guidelines of the International Commission on Radiation Units and Measurements Report 29.14 Figure 2 shows the target delineations of a tumor located in the middle rectum.
CT. The FU-LV combination was delivered in 5-day courses. FU was administered as a short intravenous infusion at a dose of 350 mg/m2/d; LV was administered as an intravenous push just before FU at a dose of 20 mg/m2/d. Preop CT was delivered during the first and fifth weeks of preop RT. Four courses of CT were planned in the postoperative CT arms.
Surgery. Surgery was planned 3 to 10 weeks after the end of the preop treatment. The surgical technique (anterior resection or abdomino-perineal resection) was decided upfront. Increasing sphincter-sparing surgery by adding CT to preop RT was not an objective of the trial. A total mesorectal resection was always recommended.
Pathology Procedures
Macroscopic and microscopic characteristics of the resected specimen were recorded prospectively by the pathologists on a standard pathology case report form. Macroscopic examination was registered on the fixed specimen. Lymph nodes were registered as total number of nodes examined, total nodes involved, and site of the nodes (perirectal, intermediate, and central). Tumor staging was performed according to the UICC 1987 classification.9 Histologic differentiation was determined according to WHO criteria.15 A tumor was considered to be of the mucinous type when at least 50% of the tumor was mucinous, as recommended by Symonds and Vickery.16 For tumors invading beyond the muscularis propria, the status of radial margin was defined according to the recommendations by Quirke et al.17 Lymphatic invasion was defined as tumor cells within an endothelial-lined space.18 Venous invasion was defined according to the recommendations by Talbot et al.19 Perineural invasion was recorded when tumor cells were identified in the perineural spaces.20
Data Management
All case report forms were centralized at the EORTC Data Center in Brussels, Belgium, and reviewed by the Data Manager and the Study Coordinator.
Statistics
The primary objective of this 2 x 2 factorial trial was to compare overall survival between the two preop treatments and between the postoperative treatments. A total of 340 recorded deaths were needed to ensure 80% statistical power of detecting a target improvement of 10% survival at 5 years. The public release of the pathologic and surgical data was authorized by an Independent Data Monitoring Committee in December 2003. Complete pathologic response was regarded as the primary parameter. Statistical significance for all analyses in the present report is considered at the two-sided 5% level. The Wilcoxon rank sum test was used for comparing numeric variables, and the 2 test and odds ratios were used to compare classes. Patient population and treatment characteristics were described for all patients who were entered onto the trial. Pathologic results were analyzed in patients whose tumor was actually resected.
RESULTS
Patient, Tumor, and Treatment Characteristics
Of the 1,011 patients who entered the trial, 505 were assigned to receive preop RT (RT group), and 506 were assigned to receive preop RT-CT (RT-CT group). Table 1 lists the well-balanced patient and tumor characteristics in both groups. Tumors were located within 10 cm from the anal margin in 938 patients (92.8%). Tumor stage was identified by EUS in 655 patients (64.8%). A T3 stage was observed in 905 patients (89.5%). Nine patients (0.9%) presented with a mucinous tumor. Table 2 lists treatment characteristics. The planned RT dose was received by 498 patients in the RT group and 486 patients in the RT-CT group. A quality assurance audit of RT showed that the recommendations on target volume definitions and treatment delivery were correctly applied.21 In the RT-CT group, 484 (95.7%) of 506 patients received CT, and 405 patients (83.7%) received all of the planned FU doses. The median time interval between the end of the preop treatment and surgery was 5.4 weeks in both groups. Overt liver metastases were uncovered in 20 and 22 patients in the RT and RT-CT groups, respectively. The tumor was resected in 949 patients (93.9%). In the RT and RT-CT groups, 21 and 10 patients had an incomplete (R2) resection, respectively. An anterior resection was performed in 249 patients (52.4%) in the RT group and in 263 patients (55.6%) in the RT-CT group (P = .05).
Pathologic Characteristics
The tumor was resected in 476 and 473 patients in the RT and RT-CT groups, respectively (Table 3). Comparison of the two groups indicated a significant reduction of the mean tumor size in the RT-CT group.
A lower pathologic disease stage was also observed in the RT-CT group. This was true for both the tumor (pT) substage and the nodal (pN) substage. A complete pathologic tumor response (pT0) was observed in 25 (5.3%) and 65 patients (13.7%) in the RT and RT-CT groups, respectively (odds ratio, 2.84; 95% CI, 1.75 to 4.59; P < .0001). Tumors less than pT3 were observed in 202 (42.4%) and 270 patients (57.1%) in the RT and RT-CT groups, respectively (odds ratio, 1.79; 95% CI, 1.38 to 2.32; P < .0001). Effects were unchanged when adjusting for baseline factors. The mean number of retrieved lymph nodes was nine and seven in the RT and RT-CT groups, respectively. The mean number of involved nodes was 0.86 in the RT-CT group and 1.52 in the RT group. There were less N1 and N2 tumors in the RT-CT group. Nodal involvement was observed in three (12%) of 25 patients with a pT0 in the RT group and in six (9%) of 65 patients with a pT0 in the RT-CT group. Figure 3 depicts the respective disease stages of the two treatment groups according to the 1987 UICC pathologic staging system.
Histologic Characteristics
There were significantly more mucinous tumors after preop RT-CT than after preop RT (Table 4). The proportion of venous, perineural, and lymphatic invasions was significantly reduced in the preop RT-CT group compared with the preop RT group. A tumor extension at the circumferential margin was observed in 8.5% of the patients in both groups.
DISCUSSION
Despite the absence of a central review of pathologic specimens, which was impossible to plan for this large multicenter study, the precise description of the pathologic procedures and the large number of specimen analyzed make consistent the results observed. Adding FU-LV to preop RT significantly decreases tumor size, pTN stage, number of recovered lymph nodes, and lymphatic, venous, and perineural invasion. It also increases the tumor sterilization rate and tumor of the mucinous type.
In their report of the pathologic results observed in the Dutch total mesorectal excision trial, Marijnen et al22 made an extensive analysis of the data from randomized trials that compared preop RT to surgery alone. These trials used either short treatment schemes (25-Gy RT dose in 5 fractions over 1 week, followed by immediate surgery) or longer treatment schemes (34.5 to 40 Gy over 3 or 4 weeks, with surgery delayed from 1 to 4 weeks). Tumor size reduction was observed after both schemes. Adding CT to RT in the comparatively longer treatment schemes further decreased the tumor size. Tumor size reduction is suggested to be related to intratumoral lymphocytic cell death by apoptosis after short schemes.22 An additional tumor cell death effect is likely after long schemes. Increasing the downsizing effect by adding concurrent CT or other radiopotentiators is one aim of preop treatment, with the purpose of increasing sphincter-sparing surgery. Although it was not an objective of this trial, the addition of CT translated into a marginally increased rate of anterior resection from 52.4% to 55.6% in the RT and RT-CT groups, respectively.
The 5% tumor sterilization rate observed in the RT group is in line with reports from previous trials that used long treatment schemes.23,24 The addition of CT resulted in a 2.5-fold increase of the pT0 rate. However, it did not decrease the risk of nodal involvement in this subgroup, which was near 10% in both treatment groups.
A downstaging effect has been observed after long preop schemes, especially if surgery was delayed by several weeks after RT. In a randomized Medical Research Council study that compared surgery alone versus preop RT (40 Gy over 4 weeks) and surgery performed after 4 weeks or later, the rate of stage III disease decreased from 59% in the surgery group to 30% in the RT group.24 The addition of CT further increased the downstaging effect, with 14.6% and 11.4% more patients in the pT0-2 and pN0 substages. The rate of pathologic stage III disease decreased from 31.7% in the RT group to 22.8% in the RT-CT group.
This stage migration in rectal cancer patients should be considered in trials that involve both upfront and adjuvant treatment. In addition to its effect on nodal involvement, preop RT-CT also reduces the number of retrieved lymph nodes. The outcome of rectal cancer is strongly related to lymph node involvement and to the number of involved nodes.25-28 Altering these components may confound the correct prognostic assessment of the patients. Preop RT has been shown to reduce the volume of lymph nodes that may not be identified with gross dissection technique.29 Therefore, it cannot be excluded that preop RT-CT increases this phenomenon and that part of the downstaging effect may, in fact, be a result of the masking of pretreatment lymph node involvement. The lymph node clearing technique that can detect more small lymph nodes should be introduced into the pathologic work-up of new trials.30,31 Tumors of the mucinous type have been observed in less than 10% of the specimens after surgery alone.32 In the Dutch trial, mucinous tumors significantly increased from 7% in the surgery group to 13% in the group treated with short-course RT.22 After long-course RT, mucinous tumors have been observed in up to 30% of patients.33 Adding CT to preop long-course RT further increases the frequency of mucinous tumors. The consensus of the College of American Pathologists stated that mucin production after preop treatment should be considered as a mode of response to preop treatment.34 Its explanation and impact on prognosis are not determined. We suggest that it may be explained by a greater effect of RT-CT on the adenocarcinoma component.
Lymphatic, venous, and perineural invasions have been shown to impact negatively on the outcome of rectal cancer.35-38 Adding CT significantly reduces these specific features.
Preop RT-CT has been previously recommended after the observation that patients with a pathologic tumor response had a favorable outcome.39-42 However, this statement was only supported by evidence from nonrandomized studies in a limited number of patients in whom the downstaging effect was assessed in relation to the pretreatment clinical stage. This recommendation may now be adopted after the results of the randomized German study showed improved local control and reduced toxicity with preop RT-CT compared with postoperative RT-CT.43 The long-term results of the present EORTC trial will provide definitive arguments to validate preop RT-CT over preop RT alone. At present, the observed enhanced tumorocidal effects of RT-CT as judged on the resected specimen should be viewed critically, and they should in no case be regarded as a surrogate indication for a longer term treatment effect on locoregional control or survival.
Appendix
The following institutions of the European Organisation for Research and Treatment of Cancer Radiotherapy Group participated in this study: In France: Centre Hospitalier Universitaire (CHU) de Besan?on, Besan?on; CHU de Tours, Hopital Bretonneau, Tours; Clinique Sainte Catherine, Avignon; Centre Georges-Fran?ois Leclerc, Dijon; H?pital Jean Bernard, Poitiers; Centre René Gauducheau, Nantes; Centre Paul Strauss, Strasbourg; CHU de Grenoble-la-Tronche, Grenoble; Centre Saint-Yves, Vannes; Centre Hospitalier Régional Universitaire de Limoges, Limoges; Polyclinique Clairval, Marseille; Clinique du Valdegour, N?mes; Clinique de la Rochebelle, Alès; Centre Hospitalier Général de Belfort, Belfort; Centre Paul Papin, Angers; CHU Henri Mondor, Créteil; Clinique Sainte Clotilde, La Réunion; CHU de Brest, Brest; Centre Oscar Lambret, Lille; Centre Hospitalier Régional Universitaire, Caen; in Belgium: H?pital Universitaire Erasme, Brussels; Intercommunale de Santé Publique du Pays de Charleroi, Charleroi; Hopital de Jolimont, Jolimont; Centre Hospitalier de Tivoli, La Louvière; Clinique Sainte Elisabeth, Namur; Institut Jules Bordet, Brussels; in the Netherlands: University Medical Centre Nijmegen, Nijmegen; Dr Bernard Verbeeten Instituut, Tilburg; Arnhem's Radiotherapeutisch Instituut, Arnhem; in Spain: Hopital General Vall d'Hebron, Barcelona; CSU de Bellvitge-Hospital Princeps d'Espanya now Institut Catala d'Oncologia, Hospital General Gregorio Maranon, Madrid; in Germany: Heinrich-Heine Universitaetsklintk, Dusseldorf; Allgemeines Krankenhaus, Hagen; in Poland: Medical University of Gdansk, Gdansk; in Isra?l: Rambam Medical Center, Haifa; in Serbia: Institute of Oncology and Radiology, Belgrade; in Turkey: Dokuz Eylul University School of Medicine, Izmir; in Switzerland: Universitaetspital Zurich, Kantonsspital Winterthur, Zurich.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant Nos. 2U10 CA11488-21 through 5U10 CA11488-34 from the National Cancer Institute (Bethesda, MD) and by Programme Hospitalier de Recherche Clinique (PHRC 1992-France).
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the National Cancer Institute.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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CHU Tours, Tours
Clinic Avignon, Avignon
Cancer Center Dijon, Dijon
CHU Poitiers, Poitiers
Cancer Center Nantes, Nantes, France
Institut for Oncology and Radiology, Belgrad, Serbia
Rambam Medical Center Ha?fa, Ha?fa, Isra?l
European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium
ABSTRACT
PURPOSE: The European Organisation for Research and Treatment of Cancer (EORTC) trial evaluated the addition of chemotherapy (CT) to preoperative radiation (preop RT) and the value of postoperative CT for improving the survival in patients with T3-4 resectable rectal cancer. Patients were allocated to the following four arms: arm 1, preop RT 45 Gy in 5 weeks; arm 2, preop RT plus two 5-day CT courses (fluorouracil 350 mg/m2/d and leucovorin 20 mg/m2/d) in the first and fifth week of RT; arm 3, preop RT plus four postoperative CT courses; and arm 4, preop RT and CT plus postoperative CT. We investigated the effect of adding CT on the pathologic parameters.
PATIENTS AND METHODS: One thousand eleven patients were entered onto the trial; 505 received preop RT (arms 1 and 3), and 506 received preop RT-CT (arms 2 and 4). We analyzed the differences in tumor size, tumor node stage, number of retrieved nodes, and histologic features such as lymphatic, venous, and perineural invasions, tumor differentiation, and tumor type.
RESULTS: After preop RT-CT, tumors were smaller (P < .0001), had less advanced pT (P < .001) and pN stages (P < .001), had small numbers of examined nodes (P = .046), and less frequent LVN invasions (P .008). Mucinous tumors increased after preop RT-CT (P < .001).
CONCLUSION: In patients with rectal cancer, preliminary results of EORTC Trial 22921 indicate that the addition of CT to preop RT induces downsizing, downstaging, and significant changes in histologic characteristics. Longer follow-up is needed to assess the impact on local control and survival.
INTRODUCTION
More than 30 years ago, Moertel et al1 demonstrated that radiotherapy (RT) combined with fluorouracil (FU) significantly increased the overall survival of patients with locally advanced GI tumors compared with the same RT plus a placebo. From 1975 to 1989, postoperative pelvic RT combined with FU-based chemotherapy (CT) was evaluated in the United States in patients with Dukes' B and C rectal cancer. The combined therapy resulted in a significant benefit for local control, distant metastases, and survival compared with surgery alone.2-4 In 1989, a National Institutes of Health Consensus Conference stated that postoperative chemoradiotherapy (RT-CT) should be regarded as standard treatment for patients with stage II and III rectal cancer.5 Conversely, preoperative (preop) RT alone, which was mainly developed in Europe during the same period, demonstrated its value on local control6 and, more recently, on survival.7 Two RT schemes were explored; the so-called Swedish scheme delivered 25 Gy in 5 fractions over 1 week immediately followed by surgery, and conventional schemes delivered 40 to 50 Gy in 20 to 25 fractions over 4 to 5 weeks followed 3 to 4 weeks later by surgery. Compared with surgery alone, preop RT halved the local failure rates, irrespective of the scheme. Therefore, at the beginning of the 1990s, it became clear that preop RT-CT was a relevant issue for clinical research in Europe. The European Organisation for Research and Treatment of Cancer (EORTC) Radiotherapy Group demonstrated that an FU dose of 350 mg/m2/d could be safely administrated in combination with a leucovorin (LV) dose of 20 mg/m2/d delivered the first and fifth weeks of a 45-Gy dose of pelvic RT in patients with unresectable or locally recurrent rectal cancer.8 Then, in 1993, the EORTC initiated a four-arm randomized trial (EORTC 22921) to examine the value of preop RT-CT versus preop RT alone and the value of additional CT versus none with respect to overall survival and progression-free survival in the same patient group (Fig 1). A separate study was conducted in France by the Fondation Francaise de Cancérologie Digestive, which adopted strictly the EORTC protocol for its two-arm rectal study (Fondation Francaise de Cancérologie Digestive trial 9203), but all patients received postoperative CT. In this article, we report on the impact of the addition of the FU-LV combination to preop RT on the pathologic parameters in patients who entered the EORTC trial.
PATIENTS AND METHODS
Study Population
Between April 1993 and March 2003, 1,011 patients with rectal cancer were allocated to one of the following treatment arms: arm 1, preop RT; arm 2, preop RT-CT; arm 3, preop RT and postoperative CT; and arm 4, preop RT-CT and postoperative CT. Preop RT was considered the standard arm.
Patients were included in the study if they presented with all of the following: T3 or resectable T4 M0 adenocarcinoma of the rectum, according to the 1987 International Union Against Cancer (UICC) criteria9; WHO performance status of 0 or 1; age 80 years or less; and tumor located within 15 cm from the anal margin. Other criteria included leukocyte count greater than 4 x 109/L, platelet count greater than 130 x 109/L, and serum creatinine level less than 120 μmol/L. Patients were excluded if they had previously undergone treatment for this disease, except for a diverting colostomy; had a history of any other cancer, except basal cell carcinoma of the skin or in situ carcinoma of the cervix; or had angina pectoris or a chronic inflammatory disease of the ileum or the colon.
The extent of the tumor was evaluated by clinical examination, rigid rectoscopy, abdomino-pelvic computed tomography scan and chest x-ray. Endorectal ultrasonography (EUS) was optional. Tumor stage was obtained either clinically or with EUS. A clinical T3 had to have at least one of the following characteristics at digital rectal examination: a circular extension, a lateral or posterior fixity, and an anterior adhesion to the prostate or invasion of the recto-vaginal wall. Tumors with invasion of any neighboring structure or organ were classified as T4. Tumors not accessible to digital rectal examination were considered as T3 if they were circular or were classified using EUS. Before entry, the surgeon had to declare the tumor resectable. Tumor location within the rectum was defined with rigid rectoscopy and classified to be within the lower rectum if the inferior tumor margin was within 5 cm from the anal verge, to be in the middle rectum if the margin was 6 to 10 cm from the anal verge, and to be in the upper rectum if the margin was beyond 10 cm from the anal verge.
This study was approved by the ethics committees of the participating centers. Informed consent was obtained from all patients before their inclusion. Treatment allocation was performed centrally using the minimization technique, with stratification for institution, sex, clinical tumor stage, and distance from the tumor to the anal verge.
Treatment
RT. The target volume of RT was not a classical pelvic volume but was limited to the main field of tumor spread and to the perirectal nodes, which were both located within the mesorectum area below the S2-S3 interval.10 This limited volume is consistent with 5-year local failure reduction rates from 30% after incomplete dissection of the mesorectum to 4% after careful dissection of the fascial planes confining the mesorectum.11,12 For tumors located in the upper rectum, the target volume included 3 cm above the tumor and excluded the anal canal. For tumors located in the lower rectum, the target volume included the perineum and the anal canal. Posteriorly, the target included the sacrum. Anteriorly and laterally, the target extended at least 3 cm beyond the macroscopic extension of the tumor. These recommendations for two-dimensional simulation translate into the inclusion of the whole mesorectum area in a three-dimensional simulation but exclude the lateral pelvic lymph nodes.13 The prescribed RT dose was specified according to the guidelines of the International Commission on Radiation Units and Measurements Report 29.14 Figure 2 shows the target delineations of a tumor located in the middle rectum.
CT. The FU-LV combination was delivered in 5-day courses. FU was administered as a short intravenous infusion at a dose of 350 mg/m2/d; LV was administered as an intravenous push just before FU at a dose of 20 mg/m2/d. Preop CT was delivered during the first and fifth weeks of preop RT. Four courses of CT were planned in the postoperative CT arms.
Surgery. Surgery was planned 3 to 10 weeks after the end of the preop treatment. The surgical technique (anterior resection or abdomino-perineal resection) was decided upfront. Increasing sphincter-sparing surgery by adding CT to preop RT was not an objective of the trial. A total mesorectal resection was always recommended.
Pathology Procedures
Macroscopic and microscopic characteristics of the resected specimen were recorded prospectively by the pathologists on a standard pathology case report form. Macroscopic examination was registered on the fixed specimen. Lymph nodes were registered as total number of nodes examined, total nodes involved, and site of the nodes (perirectal, intermediate, and central). Tumor staging was performed according to the UICC 1987 classification.9 Histologic differentiation was determined according to WHO criteria.15 A tumor was considered to be of the mucinous type when at least 50% of the tumor was mucinous, as recommended by Symonds and Vickery.16 For tumors invading beyond the muscularis propria, the status of radial margin was defined according to the recommendations by Quirke et al.17 Lymphatic invasion was defined as tumor cells within an endothelial-lined space.18 Venous invasion was defined according to the recommendations by Talbot et al.19 Perineural invasion was recorded when tumor cells were identified in the perineural spaces.20
Data Management
All case report forms were centralized at the EORTC Data Center in Brussels, Belgium, and reviewed by the Data Manager and the Study Coordinator.
Statistics
The primary objective of this 2 x 2 factorial trial was to compare overall survival between the two preop treatments and between the postoperative treatments. A total of 340 recorded deaths were needed to ensure 80% statistical power of detecting a target improvement of 10% survival at 5 years. The public release of the pathologic and surgical data was authorized by an Independent Data Monitoring Committee in December 2003. Complete pathologic response was regarded as the primary parameter. Statistical significance for all analyses in the present report is considered at the two-sided 5% level. The Wilcoxon rank sum test was used for comparing numeric variables, and the 2 test and odds ratios were used to compare classes. Patient population and treatment characteristics were described for all patients who were entered onto the trial. Pathologic results were analyzed in patients whose tumor was actually resected.
RESULTS
Patient, Tumor, and Treatment Characteristics
Of the 1,011 patients who entered the trial, 505 were assigned to receive preop RT (RT group), and 506 were assigned to receive preop RT-CT (RT-CT group). Table 1 lists the well-balanced patient and tumor characteristics in both groups. Tumors were located within 10 cm from the anal margin in 938 patients (92.8%). Tumor stage was identified by EUS in 655 patients (64.8%). A T3 stage was observed in 905 patients (89.5%). Nine patients (0.9%) presented with a mucinous tumor. Table 2 lists treatment characteristics. The planned RT dose was received by 498 patients in the RT group and 486 patients in the RT-CT group. A quality assurance audit of RT showed that the recommendations on target volume definitions and treatment delivery were correctly applied.21 In the RT-CT group, 484 (95.7%) of 506 patients received CT, and 405 patients (83.7%) received all of the planned FU doses. The median time interval between the end of the preop treatment and surgery was 5.4 weeks in both groups. Overt liver metastases were uncovered in 20 and 22 patients in the RT and RT-CT groups, respectively. The tumor was resected in 949 patients (93.9%). In the RT and RT-CT groups, 21 and 10 patients had an incomplete (R2) resection, respectively. An anterior resection was performed in 249 patients (52.4%) in the RT group and in 263 patients (55.6%) in the RT-CT group (P = .05).
Pathologic Characteristics
The tumor was resected in 476 and 473 patients in the RT and RT-CT groups, respectively (Table 3). Comparison of the two groups indicated a significant reduction of the mean tumor size in the RT-CT group.
A lower pathologic disease stage was also observed in the RT-CT group. This was true for both the tumor (pT) substage and the nodal (pN) substage. A complete pathologic tumor response (pT0) was observed in 25 (5.3%) and 65 patients (13.7%) in the RT and RT-CT groups, respectively (odds ratio, 2.84; 95% CI, 1.75 to 4.59; P < .0001). Tumors less than pT3 were observed in 202 (42.4%) and 270 patients (57.1%) in the RT and RT-CT groups, respectively (odds ratio, 1.79; 95% CI, 1.38 to 2.32; P < .0001). Effects were unchanged when adjusting for baseline factors. The mean number of retrieved lymph nodes was nine and seven in the RT and RT-CT groups, respectively. The mean number of involved nodes was 0.86 in the RT-CT group and 1.52 in the RT group. There were less N1 and N2 tumors in the RT-CT group. Nodal involvement was observed in three (12%) of 25 patients with a pT0 in the RT group and in six (9%) of 65 patients with a pT0 in the RT-CT group. Figure 3 depicts the respective disease stages of the two treatment groups according to the 1987 UICC pathologic staging system.
Histologic Characteristics
There were significantly more mucinous tumors after preop RT-CT than after preop RT (Table 4). The proportion of venous, perineural, and lymphatic invasions was significantly reduced in the preop RT-CT group compared with the preop RT group. A tumor extension at the circumferential margin was observed in 8.5% of the patients in both groups.
DISCUSSION
Despite the absence of a central review of pathologic specimens, which was impossible to plan for this large multicenter study, the precise description of the pathologic procedures and the large number of specimen analyzed make consistent the results observed. Adding FU-LV to preop RT significantly decreases tumor size, pTN stage, number of recovered lymph nodes, and lymphatic, venous, and perineural invasion. It also increases the tumor sterilization rate and tumor of the mucinous type.
In their report of the pathologic results observed in the Dutch total mesorectal excision trial, Marijnen et al22 made an extensive analysis of the data from randomized trials that compared preop RT to surgery alone. These trials used either short treatment schemes (25-Gy RT dose in 5 fractions over 1 week, followed by immediate surgery) or longer treatment schemes (34.5 to 40 Gy over 3 or 4 weeks, with surgery delayed from 1 to 4 weeks). Tumor size reduction was observed after both schemes. Adding CT to RT in the comparatively longer treatment schemes further decreased the tumor size. Tumor size reduction is suggested to be related to intratumoral lymphocytic cell death by apoptosis after short schemes.22 An additional tumor cell death effect is likely after long schemes. Increasing the downsizing effect by adding concurrent CT or other radiopotentiators is one aim of preop treatment, with the purpose of increasing sphincter-sparing surgery. Although it was not an objective of this trial, the addition of CT translated into a marginally increased rate of anterior resection from 52.4% to 55.6% in the RT and RT-CT groups, respectively.
The 5% tumor sterilization rate observed in the RT group is in line with reports from previous trials that used long treatment schemes.23,24 The addition of CT resulted in a 2.5-fold increase of the pT0 rate. However, it did not decrease the risk of nodal involvement in this subgroup, which was near 10% in both treatment groups.
A downstaging effect has been observed after long preop schemes, especially if surgery was delayed by several weeks after RT. In a randomized Medical Research Council study that compared surgery alone versus preop RT (40 Gy over 4 weeks) and surgery performed after 4 weeks or later, the rate of stage III disease decreased from 59% in the surgery group to 30% in the RT group.24 The addition of CT further increased the downstaging effect, with 14.6% and 11.4% more patients in the pT0-2 and pN0 substages. The rate of pathologic stage III disease decreased from 31.7% in the RT group to 22.8% in the RT-CT group.
This stage migration in rectal cancer patients should be considered in trials that involve both upfront and adjuvant treatment. In addition to its effect on nodal involvement, preop RT-CT also reduces the number of retrieved lymph nodes. The outcome of rectal cancer is strongly related to lymph node involvement and to the number of involved nodes.25-28 Altering these components may confound the correct prognostic assessment of the patients. Preop RT has been shown to reduce the volume of lymph nodes that may not be identified with gross dissection technique.29 Therefore, it cannot be excluded that preop RT-CT increases this phenomenon and that part of the downstaging effect may, in fact, be a result of the masking of pretreatment lymph node involvement. The lymph node clearing technique that can detect more small lymph nodes should be introduced into the pathologic work-up of new trials.30,31 Tumors of the mucinous type have been observed in less than 10% of the specimens after surgery alone.32 In the Dutch trial, mucinous tumors significantly increased from 7% in the surgery group to 13% in the group treated with short-course RT.22 After long-course RT, mucinous tumors have been observed in up to 30% of patients.33 Adding CT to preop long-course RT further increases the frequency of mucinous tumors. The consensus of the College of American Pathologists stated that mucin production after preop treatment should be considered as a mode of response to preop treatment.34 Its explanation and impact on prognosis are not determined. We suggest that it may be explained by a greater effect of RT-CT on the adenocarcinoma component.
Lymphatic, venous, and perineural invasions have been shown to impact negatively on the outcome of rectal cancer.35-38 Adding CT significantly reduces these specific features.
Preop RT-CT has been previously recommended after the observation that patients with a pathologic tumor response had a favorable outcome.39-42 However, this statement was only supported by evidence from nonrandomized studies in a limited number of patients in whom the downstaging effect was assessed in relation to the pretreatment clinical stage. This recommendation may now be adopted after the results of the randomized German study showed improved local control and reduced toxicity with preop RT-CT compared with postoperative RT-CT.43 The long-term results of the present EORTC trial will provide definitive arguments to validate preop RT-CT over preop RT alone. At present, the observed enhanced tumorocidal effects of RT-CT as judged on the resected specimen should be viewed critically, and they should in no case be regarded as a surrogate indication for a longer term treatment effect on locoregional control or survival.
Appendix
The following institutions of the European Organisation for Research and Treatment of Cancer Radiotherapy Group participated in this study: In France: Centre Hospitalier Universitaire (CHU) de Besan?on, Besan?on; CHU de Tours, Hopital Bretonneau, Tours; Clinique Sainte Catherine, Avignon; Centre Georges-Fran?ois Leclerc, Dijon; H?pital Jean Bernard, Poitiers; Centre René Gauducheau, Nantes; Centre Paul Strauss, Strasbourg; CHU de Grenoble-la-Tronche, Grenoble; Centre Saint-Yves, Vannes; Centre Hospitalier Régional Universitaire de Limoges, Limoges; Polyclinique Clairval, Marseille; Clinique du Valdegour, N?mes; Clinique de la Rochebelle, Alès; Centre Hospitalier Général de Belfort, Belfort; Centre Paul Papin, Angers; CHU Henri Mondor, Créteil; Clinique Sainte Clotilde, La Réunion; CHU de Brest, Brest; Centre Oscar Lambret, Lille; Centre Hospitalier Régional Universitaire, Caen; in Belgium: H?pital Universitaire Erasme, Brussels; Intercommunale de Santé Publique du Pays de Charleroi, Charleroi; Hopital de Jolimont, Jolimont; Centre Hospitalier de Tivoli, La Louvière; Clinique Sainte Elisabeth, Namur; Institut Jules Bordet, Brussels; in the Netherlands: University Medical Centre Nijmegen, Nijmegen; Dr Bernard Verbeeten Instituut, Tilburg; Arnhem's Radiotherapeutisch Instituut, Arnhem; in Spain: Hopital General Vall d'Hebron, Barcelona; CSU de Bellvitge-Hospital Princeps d'Espanya now Institut Catala d'Oncologia, Hospital General Gregorio Maranon, Madrid; in Germany: Heinrich-Heine Universitaetsklintk, Dusseldorf; Allgemeines Krankenhaus, Hagen; in Poland: Medical University of Gdansk, Gdansk; in Isra?l: Rambam Medical Center, Haifa; in Serbia: Institute of Oncology and Radiology, Belgrade; in Turkey: Dokuz Eylul University School of Medicine, Izmir; in Switzerland: Universitaetspital Zurich, Kantonsspital Winterthur, Zurich.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported by grant Nos. 2U10 CA11488-21 through 5U10 CA11488-34 from the National Cancer Institute (Bethesda, MD) and by Programme Hospitalier de Recherche Clinique (PHRC 1992-France).
Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the National Cancer Institute.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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