Heinz Becker

Preoperative Versus Postoperative Chemoradiotherapy for Locally Advanced Rectal Cancer: Results of the German CAO/ARO/AIO-94 Randomized Phase III Trial After a Median Follow-Up of 11 Years

PURPOSE Preoperative chemoradiotherapy (CRT) has been established as standard treatment for locally advanced rectal cancer after first results of the CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] trial, published in 2004, showed an improved local control rate. However, after a median follow-up of 46 months, no survival benefit could be shown. Here, we report long-term results with a median follow-up of 134 months. PATIENTS AND METHODS A total of 823 patients with stage II to III rectal cancer were randomly assigned to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or the same schedule of CRT used postoperatively. The study was designed to have 80% power to detect a difference of 10% in 5-year overall survival as the primary end point. Secondary end points included the cumulative incidence of local and distant relapses and disease-free survival. RESULTS Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT. According to intention-to-treat analysis, overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P = .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P = .048). No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P = .9) and disease-free survival. CONCLUSION There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. Integrating more effective systemic treatment into the multimodal therapy has been adopted in the CAO/ARO/AIO-04 trial to possibly reduce distant metastases and improve survival.3516 Background: CAO/ARO/AIO-94 was published in 2004 with a median follow-up of 46 months (Sauer et al., N Engl J Med 2004). This trial established preoperative CRT as standard treatment for rectal cancer based on an improved local control rate at 5 years, however, no survival benefit could be shown. We here report results with a median follow-up of 134 months. METHODS We randomly assigned 823 patients with stage II or III rectal cancer to preoperative CRT (50.4 Gy) with 5-FU (1 g/msq/days 1-5, 29-33), surgery, and adjuvant 5-FU (500 mg/msq/days 1-5, 4 cycles), or the same schedule applied postoperatively. The study was designed to have 80% power to detect a difference of 10% in the 5-year overall survival as primary endpoint. Secondary endpoints included the cumulative incidence of local and distant relapses and disease-free survival. RESULTS Of 823 patients, 404 and 395 were randomized to preoperative and postoperative CRT, respectively; 24 were ineligible, and 38 requested a change in treatment group. Thus, 406 patients received preoperative CRT, 393 were treated in the postoperative arm. As of 12/2010, updated data for life and tumor status were available for 791 and 783 of 799 eligible patients, respectively. Overall survival at 10 years was 59.9 years (95% CI, 55.0-64.8%) in the preoperative arm, and 59.5% (95% CI, 54.6-64.4%) in the postoperative arm (p=0.86, log-rank test, according to intention to treat). The 10-year cumulative incidence of local relapse after macroscopically complete resection was 5.7% (95% CI, 3.2-8.2%) and 10.4% (95% CI, 7.1-13.4%) in the pre- and postoperative arms, respectively (p=0.009, log-rank test, according to actual treatment). No significant differences were detected for 10-year cumulative incidence of distant metastases (25.5% both, p=0.88) and DFS. CONCLUSIONS There is a persisting significant improvement of pre- vs. postoperative CRT on local control, however, no effect on overall survival. Integrating more effective systemic treatment into the combined modality treatment has been adopted in trial CAO/ARO/AIO-04 to possibly reduce distant metastases and improve survival.

Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial

BACKGROUND Preoperative chemoradiotherapy, total mesorectal excision surgery, and adjuvant chemotherapy with fluorouracil is the standard combined modality treatment for rectal cancer. With the aim of improving disease-free survival (DFS), this phase 3 study (CAO/ARO/AIO-04) integrated oxaliplatin into standard treatment. METHODS This was a multicentre, open-label, randomised, phase 3 study in patients with histologically proven carcinoma of the rectum with clinically staged T3-4 or any node-positive disease. Between July 25, 2006, and Feb 26, 2010, patients were randomly assigned to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (1000 mg/m(2) days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) days 1-5 and 29; fluorouracil group); and an experimental group receiving preoperative radiotherapy of 50·4 Gy plus infusional fluorouracil (250 mg/m(2) days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) days 1, 8, 22, and 29), followed by surgery and eight cycles of adjuvant chemotherapy with oxaliplatin (100 mg/m(2) days 1 and 15), leucovorin (400 mg/m(2) days 1 and 15), and infusional fluorouracil (2400 mg/m(2) days 1-2 and 15-16; fluorouracil plus oxaliplatin group). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-4 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. DFS is the primary endpoint. Secondary endpoints, including toxicity, compliance, and histopathological response are reported here. Safety and compliance analyses included patients as treated, efficacy endpoints were analysed according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS Of the 1265 patients initially enrolled, 1236 were evaluable (613 in the fluorouracil plus oxaliplatin group and 623 in the fluorouracil group). Preoperative grade 3-4 toxic effects occurred in 140 (23%) of 606 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 127 (20%) of 624 patients who actually received fluorouracil chemoradiotherapy. Grade 3-4 diarrhoea was more common in those who received fluorouracil and oxaliplatin during chemoradiotherapy than in those who received fluorouracil during chemoradiotherapy (73 patients [12%] vs 52 patients [8%]), as was grade 3-4 nausea or vomiting (23 [4%] vs nine [1%]). 516 (85%) of the 606 patients who received fluorouracil and oxaliplatin-based chemoradiotherapy had the full dose of chemotherapy, and 571 (94%) had the full dose of radiotherapy; as did 495 (79%) and 601 (96%) of 624 patients who received fluorouracil-based chemoradiotherapy, respectively. A pathological complete response was achieved in 103 (17%) of 591 patients who underwent surgery in the fluorouracil and oxaliplatin group and in 81 (13%) of 606 patients who underwent surgery in the fluorouracil group (odds ratio 1·40, 95% CI 1·02-1·92; p=0·038). In the fluorouracil and oxaliplatin group, 352 (81%) of 435 patients who began adjuvant chemotherapy completed all cycles (with or without dose reduction), as did 386 (83%) of 463 patients in the fluorouracil group. INTERPRETATION Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS. FUNDING German Cancer Aid (Deutsche Krebshilfe).

Effectiveness of Gene Expression Profiling for Response Prediction of Rectal Adenocarcinomas to Preoperative Chemoradiotherapy

PURPOSE There is a wide spectrum of tumor responsiveness of rectal adenocarcinomas to preoperative chemoradiotherapy ranging from complete response to complete resistance. This study aimed to investigate whether parallel gene expression profiling of the primary tumor can contribute to stratification of patients into groups of responders or nonresponders. PATIENTS AND METHODS Pretherapeutic biopsies from 30 locally advanced rectal carcinomas were analyzed for gene expression signatures using microarrays. All patients were participants of a phase III clinical trial (CAO/ARO/AIO-94, German Rectal Cancer Trial) and were randomized to receive a preoperative combined-modality therapy including fluorouracil and radiation. Class comparison was used to identify a set of genes that were differentially expressed between responders and nonresponders as measured by T level downsizing and histopathologic tumor regression grading. RESULTS In an initial set of 23 patients, responders and nonresponders showed significantly different expression levels for 54 genes (P < .001). The ability to predict response to therapy using gene expression profiles was rigorously evaluated using leave-one-out cross-validation. Tumor behavior was correctly predicted in 83% of patients (P = .02). Sensitivity (correct prediction of response) was 78%, and specificity (correct prediction of nonresponse) was 86%, with a positive and negative predictive value of 78% and 86%, respectively. CONCLUSION Our results suggest that pretherapeutic gene expression profiling may assist in response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. The implementation of gene expression profiles for treatment stratification and clinical management of cancer patients requires validation in large, independent studies, which are now warranted.

Prognostic factors influencing surgical management and outcome of gastrointestinal stromal tumours

The purpose of this study was to review surgical experience with gastrointestinal stromal tumours (GISTs) at a single tertiary university hospital, and to identify morphological and genetic prognostic markers of tumour progression.

Surgical cure for early rectal carcinoma and large adenoma: transanal endoscopic microsurgery (using ultrasound or electrosurgery) compared to conventional local and radical resection.

Abstract Background and aims. The minimally invasive technique of transanal endoscopic microsurgery (TEM) combines the benefits of local resections, a low complication rate and high patient comfort, with low recurrence rate and excellent survival rate after radical surgery (RS). The use of an ultrasonically activated scalpel rather than electrosurgery further improves the results of TEM. Patients and methods. A retrospective study was performed of 182 operations on 162 patients with early rectal carcinoma (pT1, G1/2) or adenoma to compare the outcome following four different kinds of surgical resection techniques: RS (anterior or abdominoperineal resection; n=27), conventional transanal resection using Parks retractor (TP; n=76), transanal endoscopic microsurgery (TEM) with electrosurgery (TEM-ES; n=45), and TEM with UltraCision (TEM-UC; n=34). One-third of the patients with RS (33%) received either a colostomy or a protective loop-ileostomy. Results. Operation time with TEM-UC was significantly shorter than with TEM-ES or RS. Hospitalization was significantly longer with RS than for TEM or TP. Complication rate with TEM was significantly lower than with RS. Recurrence rate with RS and TEM was significantly lower than with TP, with a trend to TEM-UC being better than TEM-ES. Mortality rate was 3.7% with RS and 0 with TP and TEM. The 2-year survival rate was 96.3% with RS and 100% each with TP and TEM. Conclusion. TEM using UC seems to be the technique of choice. TP leads to an unacceptable recurrence rate, and RS results in a higher incidence of complication and impairment of life quality.

Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited: Updated Results of the CAO/ARO/AIO-94 Trial

PURPOSE We previously described the prognostic impact of tumor regression grading (TRG) on the outcome of patients with rectal carcinoma treated with preoperative chemoradiotherapy (CRT) in the CAO/ARO/AIO-94 trial. Here we report long-term results after a median follow-up of 132 months. PATIENTS AND METHODS TRG after preoperative CRT was determined in 386 surgical specimens by the amount of viable tumor cells versus fibrosis, ranging from TRG 4 (no viable tumor cells) to TRG 0 (no signs of regression). Clinicopathologic parameters and TRG were correlated to the cumulative incidence of local recurrence, distant metastasis, and disease-free survival (DFS). RESULTS Ten-year cumulative incidence of distant metastasis and DFS were 10.5% and 89.5% for patients with TRG 4 (complete regression), 29.3% and 73.6% for TRG 2 and 3 (intermediate regression), and 39.6% and 63% for TRG 0 and 1 (poor regression), respectively (P = .005 and P = .008, respectively). On multivariable analysis, residual lymph node metastasis (ypN+) and TRG were the only independent prognostic factors for cumulative incidence of distant metastasis (P < .001 and P = .035, respectively) and DFS (P < .001 and P = .039, respectively), whereas local recurrence was significantly affected by ypN status (P < .001) and lymphatic invasion (P = .026). CONCLUSION Complete and intermediate tumor regressions were associated with improved long-term outcome in patients with rectal carcinoma after preoperative CRT independent of clinicopathologic parameters. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting.

Adjuvant versus neoadjuvant radiochemotherapy for locally advanced rectal cancer. A progress report of a phase-III randomized trial (protocol CAO/ARO/AIO-94).

Aim: The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy is recommended for patients with advanced disease (pT3/4 or pN+). In recent years, encouraging results of preoperative radiotherapy have been reported. This prospective randomized phase-III trial (CAO/ARO/AIO-94) compares the efficacy of neoadjuvant radiochemotherapy to standard postoperative radiochemotherapy. We report on the design of the study and first results with regard to toxicity of radiochemotherapy and postoperative morbidity. Patients and Methods: Patients with locally advanced operable rectal cancer (uT3/4 or uN+, Mason CS III/IV) were randomly assigned to pre- or postoperative radiochemotherapy: A total dose of 50.4 Gy (single dose 1.8 Gy) was applied to the tumor and the pelvic lymph nodes. 5-FU (1,000 mg/m2/d) was administered concomitantly in the first and fifth week of radiation as 120-h continuous infusion. Four additional cycles of 5-FU chemotherapy (500 mg/m2/d, iv bolus) were applied. Radiochemotherapy was identical in both arms except for a small-volume boost of 5.4 Gy in the postoperative setting. Time interval between radiochemotherapy and surgery was 4–6 weeks in both arms. Techniques of surgery were standardized and included total mesorectal excision. In addition, stratification according to surgeons involved has been provided for. Primary endpoints of the study are 5-year overall-survival, local and distant control, secondary endpoints include rate of curative (R0) resections and sphincter saving procedures, toxicity of radiochemotherapy, surgical complications and quality of life. Results: As of 15th November 2000, 628 patients were randomized from 26 participating institutions: 310 patients were randomized to postoperative radiochemotherapy, 318 patients to preoperative radiochemotherapy. Acute toxicity (WHO) of radiochemotherapy was low, with less than 15% of patients experiencing Grade 3 or higher toxicity: The principal toxicity was diarrhea, with 12% in the postoperative radiochemotherapy arm and 10% in the preoperative radiochemotherapy arm having Grade-3, and 1% in either arm having Grade 4 diarrhea. Erythema, nausea and leukopenia were the next common toxicities, with less than 3% of patients in either arm suffering Grade 3 or greater leukopenia or nausea. Postoperative complication rates were similar in both arms, with 12% (postoperative radiochemotherapy) and 13% (preoperative radiochemotherapy) of patients, respectively, suffering from anastomotic teakage, 4% (postoperative radiochemotherapy) and 3% (preoperative radiochemotherapy) from postoperative bleeding, and 6% (postoperative radiochemotherapy) and 5% (preoperative radiochemotherapy) from delayed wound healing. Conclusion: The patient accrual of our trial is satisfactory, neoadjuvant radiochemotherapy is well tolerated and bears no higher risk for postoperative morbidity.Ziel: Die Standardbehandlung des operablen Rektumkarzinoms ist die sofortige Operation. Eine postoperative Radiochemotherapie wird für Patienten mit fortgeschrittenen Tumoren (pT3/4 oder pN+) empfohlen. In den letzten Jahren wurden vielversprechende Ergebnisse durch eine präoperative Bestrahlung erzielt. Wir beschreiben das Design einer prospektiv randomisierten Phase-III-Studie (CAO/ARO/AIO-94), die die Wirksamkeit einer neoadjuvanten Radiochemotherapie mit der postoperativen Standardbehandlung vergleicht, und berichten über erste Ergebnisse zur Toxizität der Radiochemotherapie und zur postoperativen Komplikationsrate. Patienten und Methoden: Patienten mit lokal fortgeschrittenem operablen Rektumkarzinom (uT3/4 oder uN+, Mason CS III/IV) wurden auf den prä- oder postoperativen Radiochemotherapiearm randomisiert: Tumor(-bett) und pelvines Lymphabflussgebiet erhielten 50,4 Gy (Einzeldosis: 1,8 Gy). In der ersten und fünften Bestrahlungswoche erfolgte eine simultane 5-FU-Chemotherapie in einer Dosierung von 1000 mg/m2/Tag, appliziert als 120-stündige Dauerinfusion. Vier weitere Zyklen 5-FU (500 mg/m2/Tag, appliziert als Bolusgabe) schlossen sich an. Das Radiochemotherapieregime war in beiden Armen (bis auf einen Boost von 5,4 Gy im postoperativen Radiochemotherapiearm) identisch. Das Intervall zwischen Radiochemotherapie und Operation betrug in beiden Armen 4–6 Wochen. Die Operationstechnik war standardisiert und beinhaltete die totale Entfernung des Mesorektums. Außerdem erfolgte eine Stratifizierung nach beteiligten Chirurgen. Primäre Endpunkte der Studie sind das 5-Jahres-Überleben, die lokale und systemische Tumorkontrolle; sekundäre Endpunkte umfassen die Rate an R0-Operationen und kontinenzerhaltenden Verfahren, die Toxizität der Radiochemotherapie, die postoperative Komplikationsrate und die Lebensqualität. Ergebnisse: Bis 15. November 2000 wurden 628 Patienten in 26 beteiligten Zentren randomisiert: 310 Patienten in den postoperativen Radiochemotherapiearm, 318 Patienten in den präoperativen Radiochemotherapiearm. Die Akuttoxizität war insgesamt gering; bei weniger als 15% der Patienten trat eine Grad-3 oder -4-Toxizität nach WHO auf. Die häufigste Nebenwirkung war die Diarrhö, die mit Grad 3 bzw. 4 bei 12% bzw. 1% im postoperativen Arm und mit 10% bzw. 1% im präoperativen Arm auftrat. Hauterythem, Übelkeit und Leukopenie waren weitere häufige Nebenwirkungen, Grad-3-Leukopenie und Übelkeit wurden bei weniger als 3% beobachtet. Die postoperative Komplikationsrate war in beiden Armen ähnlich; nach sofortiger Operation (postoperative Radiochemotherapie) entwickelten 12% der Patienten, nach präoperativer Radiochemotherapie 13% eine Anastomoseninsuffizienz, bei 4% (postoperative Radiochemotherapie) und 5% (präoperative Radiochemotherapie) Wundheilungsstörungen auf. Schlussfolgerung: Die Patientenrekrutierung verläuft sehr zufriedenstellend. Die neoadjuvante Radiochemotherapie wird gut toleriert und erhöht die postoperative Komplikationsrate nicht.

Phase II Trial of Carcinoembryonic Antigen Radioimmunotherapy With 131I-Labetuzumab After Salvage Resection of Colorectal Metastases in the Liver: Five-Year Safety and Efficacy Results

PURPOSE Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM. PATIENTS AND METHODS Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined. RESULTS With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade < or = 3 neutropenia and/or thrombocytopenia. CONCLUSION Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.

Pylorus Preservation Has No Impact on Delayed Gastric Emptying After Pancreatic Head Resection

Objectives Delayed gastric emptying (DGE) has been specifically attributed to pylorus-preserving pancreaticoduodenectomy (PPPD). As PPPD has been shown to be comparable with the classic Kausch-Whipple pancreaticoduodenectomy (KWPD) in terms of oncological radicality, DGE has advanced to be the leading argument for hemigastrectomy in PD. Methods A prospective, nonrandomized comparison of patients undergoing PPPD (n = 113), KWPD (n = 19), and duodenum-preserving, pancreatic head resection (DPPHR, n = 18) for various diseases was performed. First, groups were analyzed with regard to structural similarity; then, they were compared with special emphasis on DGE and other postoperative complications. Finally, further prognostic factors were sought that had an impact on DGE. Results The PPPD group was comparable with the KWPD group, but not to the DPPHR population. The in-clinic course after DPPHR compared favorably with PPPD as well as KWPD, and, here, no DGE occurred. The overall morbidity rates of PPPD and KWPD were comparable; 1 patient died in hospital (mortality rate, 0.7%). The gastric tube after PPPD and KWPD could be withdrawn at a median of 2 and 3 days, respectively, a liquid diet was started after 4 and 5 days, respectively, and a full diet was tolerated after 10 days each (n.s.). DGE was distributed evenly among PPPD (12%) and KWPD patients (21%, n.s.), and it was noted almost exclusively when other postoperative complications were present (P < 0.0001). No further prognostic factors influencing DGE could be identified. Conclusion Pylorus preservation does not increase the frequency of DGE. DGE almost exclusively occurs as a consequence of other postoperative complications. Therefore, DGE should not be used as an argument to advocate hemigastrectomy in PPPD.

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small‐volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine‐131 (131I)–labeled humanized anti–carcinoembryonic antigen (anti‐CEA) antibody (MAb) hMN‐14 in small‐volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this 131I‐labeled humanized anti‐CEA antibody in colorectal cancer patients with small‐volume disease or in an adjuvant setting.