Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer
Rolf Sauer, M.D., Heinz Becker, M.D., Werner Hohenberger, M.D., Claus Rödel, M.D., Christian Wittekind, M.D., Rainer Fietkau, M.D., Peter Martus, Ph.D., Jörg Tschmelitsch, M.D., Eva Hager, M.D., Clemens F. Hess, M.D., Johann-H. Karstens, M.D., Torsten Liersch, M.D., Heinz Schmidberger, M.D., Rudolf Raab, M.D., for the German Rectal Cancer Study Group
Background Postoperative chemoradiotherapy is the recommendedstandard therapy for patients with locally advanced rectal cancer.In recent years, encouraging results with preoperative radiotherapyhave been reported. We compared preoperative chemoradiotherapywith postoperative chemoradiotherapy for locally advanced rectalcancer.
Methods We randomly assigned patients with clinical stage T3or T4 or node-positive disease to receive either preoperativeor postoperative chemoradiotherapy. The preoperative treatmentconsisted of 5040 cGy delivered in fractions of 180 cGy perday, five days per week, and fluorouracil, given in a 120-hourcontinuous intravenous infusion at a dose of 1000 mg per squaremeter of body-surface area per day during the first and fifthweeks of radiotherapy. Surgery was performed six weeks afterthe completion of chemoradiotherapy. One month after surgery,four five-day cycles of fluorouracil (500 mg per square meterper day) were given. Chemoradiotherapy was identical in thepostoperative-treatment group, except for the delivery of aboost of 540 cGy. The primary end point was overall survival.
Conclusions Preoperative chemoradiotherapy, as compared withpostoperative chemoradiotherapy, improved local control andwas associated with reduced toxicity but did not improve overallsurvival.
Adjuvant radiotherapy with or without chemotherapy has beenused widely to improve outcomes in patients with rectal cancer.For locally advanced disease, postoperative chemoradiotherapysignificantly improves both local control and overall survivalas compared with surgery alone or surgery plus irradiation.1,2This information prompted a National Institutes of Health consensusconference, convened in 1990, to recommend postoperative adjuvantchemoradiotherapy as standard treatment for patients with rectalcancer classified as tumor–node–metastasis (TNM)stage II (i.e., a tumor penetrating the rectal wall, withoutregional lymph-node involvement) or stage III (i.e., any tumorwith regional lymph-node involvement).3
Several randomized studies have found lower rates of local failurewith preoperative radiotherapy than with surgery alone. However,only the Swedish Rectal Cancer Trial, which evaluated a shortcourse of preoperative irradiation (25 Gy, delivered in fivefractions), found an advantage in overall survival.4 The authorsof a subsequent meta-analysis also concluded that the combinationof preoperative radiotherapy and surgery, as compared with surgeryalone, significantly improves local control and overall survival.5The Dutch Colorectal Cancer Group reported that the additionof short-course preoperative radiotherapy to optimal surgerywith total mesorectal excision reduced the rate of local recurrencebut did not improve two-year survival.6
Given the potential advantages of preoperative radiotherapyand the finding that the addition of chemotherapy to radiotherapyimproves survival in the adjuvant setting, we conducted a trialto compare preoperative conventionally fractionated radiotherapyand concurrent fluorouracil chemotherapy with the same treatmentgiven postoperatively in patients with locally advanced rectalcancer. We present the results after a median follow-up of 45.8months.
Methods
Eligibility for Enrollment
We initiated the trial in 1994; patients were enrolled beginningin February 1995, and enrollment was extended through September2002. Eligibility criteria included histopathologically confirmed,resectable adenocarcinoma with the inferior margin within 16cm from the anal verge. Endorectal ultrasonography and computedtomographic (CT) scanning of the abdomen and pelvis were performedto rule out TNM stage I tumors and distant metastases. Patientswere excluded if they were older than 75 years of age, had previouslyhad cancer other than nonmelanoma skin cancer, had previouslyreceived chemotherapy, had previously received radiotherapyto the pelvis, or had contraindications to chemoradiotherapy.The trial was approved by the medical ethics committees of allthe participating hospitals.
Randomization and Treatment
After written informed consent had been obtained, eligible patientswere randomly assigned to receive either postoperative chemoradiotherapyor preoperative chemoradiotherapy. Randomization was performedby the study center in Erlangen, Germany, and was based on permutedblocks of 14, with stratification according to surgeon. Beginningin October 1998, prerandomization according to the double-consentdesign of Zelen7 was permitted at the request of 16 of the 26participating centers. According to this design, informed consentis sought after the patient is told the result of randomizationand, as suggested by the term "double," the result is disclosedto patients in both groups. According to this design, data mustbe analyzed according to the result of randomization and anydecisions made by patients to receive the alternative treatmentmust be disregarded with respect to the analysis.
Radiotherapy consisted of a total of 5040 cGy delivered (asat least 6-MV photons) in 28 fractions of 180 cGy, five timesweekly, to the pelvis with individually shaped portals and theuse of a three-field or four-field box technique. During thefirst and fifth weeks of radiotherapy, fluorouracil was givenas a 120-hour continuous infusion at a dose of 1000 mg per squaremeter per day. Treatment was identical in both groups exceptfor a 540-cGy boost delivered to the tumor bed in the postoperative-treatmentgroup. In patients who were assigned to preoperative treatment,surgery was scheduled to take place six weeks after the completionof chemoradiotherapy. Four cycles of bolus fluorouracil (500mg per square meter per day, five times weekly, every four weeks)were started four weeks after surgery (in the preoperative-treatmentgroup) or four weeks after chemoradiotherapy (in the postoperative-treatmentgroup). Irradiation techniques and treatment volumes have beendescribed in detail elsewhere.8
Surgery
Total mesorectal excision was performed in all the patientsaccording to a standardized technique. To rule out potentialbias with respect to the quality of surgery and the commitmentto sphincter preservation, patients were stratified accordingto surgeon. Assessment of the intended surgical procedure beforerandomization (i.e., whether sphincter preservation was deemedpossible or not) was included to evaluate the efficacy of preoperativechemoradiotherapy in permitting sphincter-sparing surgery inpatients with low-lying tumors.
Follow-up
During therapy, patients were monitored weekly for signs ofacute toxic effects, with appropriate adjustments in chemotherapyand radiotherapy made as necessary; long-term toxic effectswere assessed at one, three, and five years. Acute and long-termtoxic effects were graded according to a German classificationsystem9 that corresponds to the World Health Organization criteriafor assessing the toxicity of chemotherapy and that is compatiblewith the criteria of the Radiation Therapy Oncology Group (RTOG)and the European Organization for Research and Treatment ofCancer with respect to the acute and late adverse effects ofradiotherapy. Perioperative and 30-day postoperative complicationsassessed included anastomotic leakage, perineal complications,bleeding, ileus, fistulas, and death.
Patients were followed at three-month intervals for two yearsand then at six-month intervals for three years. Evaluationsconsisted of physical examination, a complete blood count, andblood chemical analysis. Proctoscopy, abdominal ultrasonography,CT of the abdomen, and chest radiography were also used, accordingto guidelines of the German Cancer Society.10 Histopathologicalconfirmation of local recurrence (defined as a tumor withinthe pelvis or the perineal scar) and of distant recurrence wasencouraged; acceptable alternative approaches included sequentialradiologic studies to detect the enlargement of a mass. Thephysicians evaluating patients' relapse status were aware ofthe treatment assignments.
Quality Control
A quality-assurance program controlled the information submittedon enrollment forms. Reference institutions for surgery (theDepartment of Surgery, Medizinische Hochschule Hannover), chemotherapyand radiotherapy (the Departments of Radiation Therapy, Universityof Erlangen and University of Rostock), and pathology (Instituteof Pathology, University of Leipzig) obtained copies of originaltreatment records and could request any other information toconfirm compliance with the protocol. All resection specimenswere examined according to a standardized protocol that includedUnion Internationale contre le Cancer TNM categories and staginggroups, the number of examined and involved lymph nodes, andthe status of oral, aboral, and circumferential resection margins.11The quality of each specimen obtained by total mesorectal excisionwas not formally assessed; however, the distance from the tumorto the resection margins was recorded.
Statistical Analysis
The primary end point was overall survival. The study was designedto have 80 percent power to detect an absolute difference of10 percentage points in the five-year overall survival rate,with a two-sided alpha level of 0.05. The sample size requiredto detect this difference was 340 patients per group. Becausean estimated 15 percent dropout rate was expected, the enrollmentperiod was extended to the end of September 2002, at which point823 patients had been enrolled. Secondary end points were disease-freesurvival, local and distant recurrences, postoperative complications,acute and long-term toxic effects, and sphincter preservation.All eligible and consenting patients (the full analysis population)were included in the analyses of overall and disease-free survivaland the cumulative incidence rates of local and distant recurrences,according to the intention-to-treat principle. End points weremeasured beginning at the time of randomization. Patients whoreceived any neoadjuvant or adjuvant radiotherapy were assessedfor acute and delayed toxic effects according to their actualtreatment group.
Chi-square tests were used to compare proportions. Mann–Whitneytests were used to compare quantitative and ordinal variables.Univariate analyses of survival were carried out by the Kaplan–Meiermethod, and the evaluation of differences was performed withthe log-rank test. Data from patients who where alive and freeof recurrence or who died without having had a recurrence werecensored in the analyses of disease-free survival and recurrence.
The Cox proportional-hazards model was used to calculate hazardratios and 95 percent confidence intervals. Cumulative incidencewas determined according to the method proposed by Breslow andDay.12 Statistical comparisons of cumulative incidence rateswere performed with the use of a Poisson regression model, withthe assigned treatment group (according to the intention totreat) as a categorical covariate. A two-sided P value of lessthan or equal to 0.05 was considered to indicate statisticalsignificance. No interim analyses of efficacy end points wereperformed.
Results
Patients
A total of 823 patients from 26 hospitals were randomly assignedto one of the two treatment groups. Randomization was performedaccording to the double-consent design in the cases of 146 ofthe 823 patients. Of the 421 patients randomly assigned to preoperativechemoradiotherapy and the 402 randomly assigned to postoperativechemoradiotherapy, 16 and 8 patients, respectively, were notincluded in the full analysis population because they withdrewconsent to participate (5 and 4 patients, respectively) or because,as a result of institutional errors, they did not meet the inclusioncriteria: 2 patients in each group had distant metastases atthe time of randomization, 1 patient in each group did not haveadenocarcinoma, 2 patients in the preoperative-treatment groupand 1 in the postoperative-treatment group presented with fixed,inoperable tumors, and 6 patients in the preoperative-treatmentgroup either had a contraindication to fluorouracil or had previouslyhad cancer. For the most part, the baseline characteristicsof the 799 patients in the full analysis population were similarin the two groups (Table 1). Significantly more patients inthe preoperative-treatment group than in the postoperative-treatmentgroup had tumors located 5 cm or less from the anal verge.
Table 1. Baseline Characteristics of the 799 Eligible Patients, According to Randomly Assigned Treatment Group.
Treatment
Of the 405 patients randomly assigned to preoperative chemoradiotherapyand the 394 randomly assigned to postoperative chemoradiotherapy(i.e., the full analysis population), 9 and 19 patients, respectively,requested a change in treatment group (Table 2). Thus, 415 patientswere treated according to the preoperative protocol and 384patients according to the postoperative protocol. In the preoperative-treatmentgroup, 92 percent received the prescribed radiotherapy and 89percent completed preoperative chemoradiotherapy as planned.In the postoperative-treatment group, 28 percent were excludedfrom receiving postoperative chemoradiotherapy according tothe protocol specifications, either because of stage I disease(18 percent) or because of intraoperatively detected distantmetastases or postoperative complications or death (10 percent).Overall, there were modifications in the radiotherapy or chemotherapyregimens, mainly due to toxic effects, in 5 to 8 percent ofthe patients. Protocol violations occurred more frequently inthe postoperative-treatment group and were mainly due to patients'refusal to receive radiotherapy or chemotherapy (Table 2).
Table 2. Compliance with the Protocol and Protocol Violations.
Histopathological Tumor Staging and Surgical Procedures
After preoperative chemoradiotherapy, there was a significantshift toward earlier TNM stages (P<0.001): 8 percent of thepatients in this group had a complete response, according tohistopathological examination of the tumor specimen, and only25 percent (as compared with 40 percent in the postoperative-treatmentgroup) had positive lymph nodes (TNM stage III) (Table 3). Eighteenpercent of the patients in the postoperative-treatment grouphad TNM stage I disease on histopathological examination oftheir resected specimen; all 18 percent had previously beenfound to have stage T3 or T4 or node-positive disease on endorectalultrasonography.
Table 3. Postoperative Pathological Tumor Stage, Type of Surgery, and Completeness of Resection, According to Actual Treatment Given.
The rates of complete resection and sphincter-sparing surgerydid not differ between the groups when the 799 patients in thefull analysis population were considered (Table 3). However,among the 194 patients with tumors that were determined by thesurgeon before randomization to require an abdominoperinealexcision, a statistically significant increase in sphincterpreservation was achieved among patients who received preoperativechemoradiotherapy (Table 4).
Table 4. Rates of Sphincter-Sparing Surgery in 194 Patients Determined by the Surgeon before Randomization to Require Abdominoperineal Resection, According to Actual Treatment Given.
Postoperative Morbidity and Toxicity of Chemoradiotherapy
In-hospital mortality was 0.7 percent in the preoperative chemoradiotherapygroup (3 of the 415 treated patients died while hospitalized)and 1.3 percent in the postoperative-treatment group (5 of the384 treated patients died while hospitalized; P=0.41). The overallrate of postoperative complications was 36 percent in the preoperative-treatmentgroup and 34 percent in the postoperative-treatment group (P=0.68).The rate of anastomotic leakage of any grade was 11 percentin the preoperative-treatment group and 12 percent in the postoperative-treatmentgroup (P=0.77). The rates of delayed sacral-wound healing (10percent in the preoperative-treatment group vs. 8 percent inthe postoperative-treatment group, P=0.10), postoperative bleeding(3 percent vs. 2 percent, respectively; P=0.50), and ileus (2percent vs. 1 percent, respectively; P=0.26) did not differsignificantly between the groups.
Grade 3 or 4 acute and long-term toxic effects that occurredamong patients who received preoperative or postoperative radiotherapyare summarized in Table 5. The overall rates of acute and long-termside effects were lower with the preoperative approach thanwith the postoperative approach, especially with respect toacute and chronic diarrhea and the development of stricturesat the anastomotic site. When the toxicity analyses were performedfor all patients, including the 110 patients in the postoperative-treatmentgroup who, for various reasons, received no radiotherapy (Table 2),no significant differences between the two groups were noted(overall rate of acute toxic effects, 25 percent in the preoperative-treatmentgroup vs. 24 percent in the postoperative-treatment group; P=0.78;overall rate of long-term toxic effects, 14 percent vs. 15 percent,respectively; P=0.85).
Table 5. Grade 3 or 4 Toxic Effects of Chemoradiotherapy, According to Actual Treatment Given.
Events during Follow-up
As of November 2003, surviving patients had been followed fora median of 46 months (range, 3 to 102). Of these 642 patients,67 percent were followed for at least three years, 48 percentfor at least four years, and 32 percent for at least five years.The median follow-up time was 45 months (range, 5 to 101) amongthe patients assigned to preoperative chemoradiotherapy and49 months (range, 3 to 102) among those assigned to postoperativechemoradiotherapy; no follow-up data were available for 8 and10 patients, respectively. Of the 157 deaths that occurred duringfollow-up, 109 were related to rectal cancer and 35 to othercauses; in 13 cases the cause of death was unknown. Local recurrenceoccurred in 53 patients: 15 (28 percent) had local recurrencealone, and 38 (72 percent) also had distant recurrences. A totalof 160 patients had only distant recurrences.
Overall and Disease-free Survival
In the full analysis population, 102 of the 405 patients assignedto preoperative chemoradiotherapy had a relapse and 77 died.The corresponding outcomes among the 394 patients assigned topostoperative chemoradiotherapy were 111 relapses and 80 deaths.The overall survival at five years was 76 percent in the preoperative-treatmentgroup and 74 percent in the postoperative-treatment group (P=0.80)(Figure 1A). The hazard ratio for death in the preoperative-treatmentgroup, as compared with the postoperative-treatment group, was0.96 (95 percent confidence interval, 0.70 to 1.31). The five-yearrate of disease-free survival was 68 percent in the preoperative-treatmentgroup and 65 percent in the postoperative-treatment group (P=0.32)(Figure 1B), and the hazard ratio for disease-free survivalin the former group, as compared with the latter, was 0.87 (95percent confidence interval, 0.67 to 1.14).
Figure 1. Overall Survival (Panel A) and Disease-free Survival (Panel B) among the 799 Patients Randomly Assigned to Preoperative or Postoperative Chemoradiotherapy, According to an Intention-to-Treat Analysis.
Figure 2. Cumulative Incidence of Local Recurrences (Panel A) and Distant Recurrences (Panel B) among the 799 Patients Randomly Assigned to Preoperative or Postoperative Chemoradiotherapy, According to an Intention-to-Treat Analysis.
Follow-up data were available for 781 patients.
Discussion
Interest in preoperative chemoradiotherapy for patients withresectable rectal cancer is based not only on the expected survivalbenefit achieved with this treatment, but also on the potentialadvantages of delivering both agents preoperatively. These advantagesinclude improved compliance with the chemoradiotherapy regimenif it is given before major surgery, as well as down-staging,which may enhance the rate of curative surgery and permit sphincterpreservation in patients with low-lying tumors. In addition,because tumor oxygenation is better with preoperative treatmentthan with postoperative treatment, irradiation seems to be moreeffective with the former approach.13 Retrospective, nonrandomizedstudies have also found reduced toxicity with preoperative treatment.14
Prospective, randomized trials comparing the efficacy of preoperativechemoradiotherapy with that of standard, postoperative chemoradiotherapyfor rectal cancer were initiated in the United States by theRTOG (trial 94-01) and the National Surgical Adjuvant Breastand Bowel Project (protocol R-03).15 Unfortunately, both studiessuffered from low enrollment and were closed prematurely.
In our study, we confirmed that preoperative chemoradiotherapy,given as planned (i.e., without any modification or dose reduction)in most of the patients assigned to this group (89 percent),significantly reduced rates of local failure and acute and long-termtoxic effects. Among patients with tumors judged by the surgeonto require an abdominoperineal excision, the rate of sphincter-preservingsurgery was more than doubled after preoperative chemoradiotherapy.Postponing surgery for a six-week course of neoadjuvant treatmentplus a six-week interval to allow tumor shrinkage and recoveryfrom side effects did not result in an increased rate of surgicalcomplications or an increased incidence of tumor progression.
Our trial was designed to show an absolute difference of 10percentage points in overall survival between standard postoperativeand preoperative chemoradiotherapy. It was based on the hypothesesthat starting systemic treatment as early as possible mighteffectively treat systemic micrometastases and that the combinationof chemotherapy and radiotherapy given preoperatively reducesrates of local failure. Although the latter hypothesis was clearlyconfirmed, no statistically significant difference in the incidenceof distant recurrence or in the rates of disease-free or overallsurvival could be demonstrated. Given that the rate of localrecurrence with preoperative chemoradiotherapy and total mesorectalexcision was only 6 percent, it is possible that further progressin the prevention of distant recurrences might be accomplishedwith more effective chemotherapy. Phase 1 and 2 trials of preoperativeradiotherapy with concurrent capecitabine and oxaliplatin havebeen completed by our group.16 This combination regimen shouldbe tested against standard fluorouracil-based chemoradiotherapyin subsequent trials.
With the increasing use of preoperative treatment in patientswith rectal cancer, accurate staging is needed to avoid unnecessarytreatment of early-stage tumors. The accuracy of endorectalultrasonography is reported to be 67 to 93 percent for the assessmentof rectal-wall penetration and 62 to 83 percent for the determinationof nodal status.17 In our study, endorectal ultrasonographywas mandatory for pretreatment evaluation of the tumor. Eighteenpercent of patients in the postoperative-treatment group, determinedpreoperatively to have tumor penetration through the bowel wall(stage T3 or T4 disease) or lymph-node metastasis, were foundto have stage T1 or T2, node-negative tumors (i.e., TNM stageI disease) on pathological examination of the resected specimen.As experience with this technique increases, the accuracy ofstaging should improve. Moreover, innovative approaches, includingthree-dimensional endosonography and magnetic resonance imaging,may further improve the accuracy of staging.18,19
In conclusion, although no survival benefit was achieved withpreoperative as compared with postoperative chemoradiotherapy,we suggest that preoperative chemoradiotherapy is the preferredtreatment for patients with locally advanced rectal cancer,given that it is associated with a superior overall compliancerate, an improved rate of local control, reduced toxicity, andan increased rate of sphincter preservation in patients withlow-lying tumors.
Supported by a grant (70-587) from Deutsche Krebshilfe.
Dr. Rödel reports having received consulting fees fromRoche, Sanofi-Synthelabo, and Merck and lecture fees from Roche.
We are indebted to Petra Lietzau, Karin Zecho, and Sabrina Petsch(all of the Erlangen Tumor Center) for data monitoring and documentationand to Richard Herrmann (Basel) for helpful discussions.
* Other participating investigators are listed in the Appendix.
Source Information
From the Departments of Radiation Therapy (R.S., C.R.) and Surgery (W.H.), University of Erlangen, Erlangen, Germany; the Departments of Surgery (H.B., T.L.) and Radiation Therapy (C.F.H., H.S.), University of Göttingen, Göttingen, Germany; the Institute of Pathology, University of Leipzig, Leipzig, Germany (C.W.); the Department of Radiation Therapy, University of Rostock, Rostock, Germany (R.F.); the Institute of Medical Informatics, Biometry, and Epidemiology, Charité University Medicine Berlin, Berlin (P.M.); the Department of Surgery, Krankenhaus der Barmherzigen Brüder, St. Veit an der Glan, Austria (J.T.); the Institute of Radiotherapy, Landeskrankenhaus Klagenfurt, Austria (E.H.); the Department of Radiation Therapy, Medizinische Hochschule Hannover, Hannover, Germany (J.-H.K.); and the Department of Surgery, Klinikum Oldenburg, Oldenburg, Germany (R.R.).
Address reprint requests to Dr. Sauer at the Department of Radiation Therapy, University of Erlangen, Universitätsstr. 27 91054, Erlangen, Germany, or at sekretariat{at}strahlen.med.uni-erlangen.de.
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Appendix
Other members of the German Rectal Cancer Study Group who participatedin this study are as follows: Germany — F. Lindemann,G. Schlimok, M. Küffner, A.-C. Voss, F. M. Meyer, H. Arnholdt,and T. Wagner (Zentralklinikum Augsburg, Augsburg); K.-H. Pflüger,T. Wolff, C. Schreiber, and A. Franke (DIAKO Ev. Diakonie-Krankenhaus,Bremen); S. Staar, W. Horn, U. Bonk, and P. Hanisch (ZentralkrankenhausBremen, Bremen); P. Klaue, R. Mewes, W. Matek, D. Eichmann,H.-J. Romahn, G. Brinster, D. Latz, M. Alfrink, and H.-D. Zimmermann(Klinikum Coburg, Coburg); H.D. Saeger, D. Ockert, T. Jacobi,C. Petersen, S. Friedrich, M. Dawel, and G. Baretton (Carl GustavCarus Universität Dresden, Dresden); K. Ludwig, G. Hellmich,S. Petersen, J. Schorcht, N. Christen, H. Wolf, A. Freidt, G.Haroske, and J. Hensel (Städt. Klinikum Dresden-Friedrichstadt,Dresden); C. Schick and T. Papadopoulos (Universität Erlangen-Nürnberg,Erlangen); H. Bockhorn, B.H. Görge, S. Steigerwald, M.van Kampen, M. Hutter, M. Altmannsberger, and B. Gollnick (KrankenhausNordwest, Frankfurt am Main); C. Gog, E. Staib-Sebler, M. Lorenz(deceased), H.D. Böttcher, S. Schäfer, K. Engels,and C. Fellbaum (Klinikum der Johann Wolfgang Goethe Universität,Frankfurt); C. Burfeind, J. Kreutzer, C. Heuermann, L. Füzesi,B. Sattler, and C. Jakob (Georg August Universität Göttingen,Göttingen); H. Dralle and T. Sutter (Klinikum Kröllwitz,Halle an der Saale); H.-J. Schmoll, D. Arnold, J. Dunst, T.Reese, H.-J. Holzhausen, and U. Krause (Martin-Luther-UniversitätHalle Wittenberg, Halle/Saale); J. Klempnauer, P. Piso, A. Warszawski,A. Ganser, P. Schöffski, M. Manns, H.H. Kreipe, and S.Vornhusen (Medizinische Hochschule Hannover, Hannover); F. Köckerling,J. Rose, and H. Kirchner (Klinikum Hannover–Siloah, Hannover);H. Ostertag and C. Brüschke (Städt. Krankenhaus Hannover–Nordstadt,Hannover); B. Kremer, I. Vogel, J. Tepel, B. Kimmig, H. Ewald,W. Kloss, G. Klöppel, A. Solterbeck, and U. Solterbeck(Universitätsklinikum Schleswig-Holstein, Campus Kiel,Kiel); B. Feyerabend (Klinikum der Christian-Albrechts-Universitätzu Kiel, Kiel); R.-D. Filler, L. Woidy, M. Rath, H.-J. Wypior,A. Holstege, W. Permanetter, H. Joswig-Priewe, and F. Leitl(Klinikum Landshut, Landshut); J. Hauss, H. Witzigmann, F.-H.Kamprad, S. Miethe, and A. Tannapfel (UniversitätsklinikumLeipzig AöR, Leipzig); E. Deltz, M. Völz, E. Mroczek,H. Held, T. Thomsen, M. Beck, and S. Brackrock (Friedrich-Ebert-Krankenhaus,Neumünster); H. J. Schlitt, A. Fürst, I. Iesalnieks,M. Herbst, C. Schäfer, F. Hofstädter, and F. Bataille(Universität Regensburg, Regensburg); W. Schumm (KKH Rendsburg,Rendsburg); P. Decker and W. Dornoff (Krankenanstalt Mutterhausder Borromäerinnen, Trier); J. Kriegsmann, K. Hinkeldey,and M. Otto (Pathologisches Institut, Trier); H. Zühlke,W. Janus, A. Gabler, and S. Kobylinski (Paul-Gerhardt-Stiftung,Lutherstadt Wittenberg); Austria — M. Jagoditsch and D.Schlapper (Krankenhaus der Barmherzigen Brüder, St. Veitan der Glan); H. Sabitzer (Landeskrankenhaus Klagenfurt, Klagenfurt);and M. Klimpfinger (Kaiser-Franz-Josef-Spital, Wien).
Chemoradiotherapy for Rectal Cancer
Gaur S., Shukla V., Julianov A., Ferretti G., Bria E., Mandalà M., Bujko K., Nowacki M. P., Kepka L., Unnikrishnan G., Dhar P., Sudhindran S., Sauer R., Rödel C.
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