Clemens F. Hess

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).

Adjuvant vs. neoadjuvant radiochemotherapy for locally advanced rectal cancer: the German trial CAO/ARO/AIO-94.

Aim  The standard treatment for patients with clinically resectable rectal cancer is surgery. Postoperative radiochemotherapy (RCT) is recommended for advanced disease (pT3/4 or pN+). In recent years, encouraging results of pre‐operative radiotherapy have been reported. This prospective randomized phase‐III‐trial (CAO/ARO/AIO‐94) compares the efficacy of neoadjuvant RCT to standard postoperative RCT. We report on the design of the study and first results with regard to toxicity of RCT and postoperative morbidity.

Organ Preservation by Transoral Laser Microsurgery in Piriform Sinus Carcinoma

OBJECTIVE: To determine the effectiveness of organ-preserving CO2 laser microsurgery for the treatment of piriform sinus carcinoma. METHODS: A retrospective review of 129 previously untreated patients undergoing CO2 laser microsurgery for the treatment of squamous cell carcinomas of the piriform sinus from 1981 to December 1996 was undertaken. The intention was complete tumor removal by preserving functionally important structures of the larynx. Distribution of tumors (Union Internationale Contre le Cancer/American Joint Committee on Cancer, 1992) was 24 cases with pT1, 74 with pT2, 17 with pT3, and 14 with pT4 disease. Node status was positive in 68% of patients. Seventy-five percent of patients had stage III or IV disease. Forty-two percent of the patients were treated solely with surgery, and 58% had surgery and postoperative radiotherapy. The median follow-up interval was 44 months. RESULTS: Eighty-seven percent of patients were controlled locally. Neck recurrences occurred in 14.0% of patients, metachronous distant metastases with locoregional control in 6.2%, and second primary tumors in 18.6%. Twenty percent of patients died of TNM-related deaths. The 5-year overall Kaplan-Meier survival rate was 71% for stages I and II and 47% for stages III and IV disease; the 5-year recurrence-free survival rates were 95% and 69%, respectively. CONCLUSION: A comparatively low local recurrence rate, a high recurrence-free survival rate, and the avoidance of laryngectomy favor function-preserving surgery of piriform sinus carcinomas. (Otolaryngol Head Neck Surg 2001; 124:58-67.)

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.

The impact of gross tumor volume (GTV) and clinical target volume (CTV) definition on the total accuracy in radiotherapy theoretical aspects and practical experiences.

Aim: To evaluate the impact of interobserver variability in the contouring of gross tumor volumes (GTVs) and clinical target volumes (CTVs) on the global geometric accuracy in radiation therapy. Material and Methods: In a review of the currently available literature, the magnitude of interobserver variability is analyzed, causes and consequences are discussed. Uncertainties due to inconsistencies in contouring are related to other sources of geometric errors, particularly patient positioning and organ motion. Results: Interobserver variability is a major – for some tumor locations probably the largest – factor contributing to geometric inaccuracy. Causes are multifactorial and include image- and observer-related factors, such as the subjective interpretation of image information. Conclusion: Consequences to reduce interobserver variability are proposed, among others the selection of adequate imaging modalities, intensified radiologic training, and the use of telecommunication tools.Ziel: Analyse er Bedeutung der Untersucher-Variabilität bei der Zielvolumendefinition für die Präzision der Strahlenbehandlung. Material und Methoden: Anhand einer Literaturübersicht wird die Größenordnung der Untersucher-Variabilität dargestellt, Ursachen und Konsequenzen werden diskutiert. Die Untersucher-Variabilität wird mit anderen Ursachen geometrischer Ungenauigkeiten verglichen, insbesondere der Lagerungsungenauigkeit und der Organbewegung. Ergebnisse: Die Untersucher-Variabilität ist ein bedeutender, für einige Tumorlokalisationen vielleicht der größte Faktor, der die geometrische Präzision beeinflusst. Die Ursachen sind multifaktoriell und beinhalten sowohl bild- als auch untersucherbezogene Faktoren, z. B. die subjektive Interpretation von Bildinformationen. Schlussfolgerung: Möglichkeiten zur Reduktion der Interobserver-Variabilität werden dargestellt, u. a. die Auswahl geeigneter Bildgebung, gezieltes radiologisches Training und der Einsatz moderner Telekommunikationsmethoden.

The Impact of Gross Tumor Volume (GTV) and Clinical Target Volume (CTV) Definition on the Total Accuracy in Radiotherapy

Aim: To evaluate the impact of interobserver variability in the contouring of gross tumor volumes (GTVs) and clinical target volumes (CTVs) on the global geometric accuracy in radiation therapy. Material and Methods: In a review of the currently available literature, the magnitude of interobserver variability is analyzed, causes and consequences are discussed. Uncertainties due to inconsistencies in contouring are related to other sources of geometric errors, particularly patient positioning and organ motion. Results: Interobserver variability is a major – for some tumor locations probably the largest – factor contributing to geometric inaccuracy. Causes are multifactorial and include image- and observer-related factors, such as the subjective interpretation of image information. Conclusion: Consequences to reduce interobserver variability are proposed, among others the selection of adequate imaging modalities, intensified radiologic training, and the use of telecommunication tools.Ziel: Analyse er Bedeutung der Untersucher-Variabilität bei der Zielvolumendefinition für die Präzision der Strahlenbehandlung. Material und Methoden: Anhand einer Literaturübersicht wird die Größenordnung der Untersucher-Variabilität dargestellt, Ursachen und Konsequenzen werden diskutiert. Die Untersucher-Variabilität wird mit anderen Ursachen geometrischer Ungenauigkeiten verglichen, insbesondere der Lagerungsungenauigkeit und der Organbewegung. Ergebnisse: Die Untersucher-Variabilität ist ein bedeutender, für einige Tumorlokalisationen vielleicht der größte Faktor, der die geometrische Präzision beeinflusst. Die Ursachen sind multifaktoriell und beinhalten sowohl bild- als auch untersucherbezogene Faktoren, z. B. die subjektive Interpretation von Bildinformationen. Schlussfolgerung: Möglichkeiten zur Reduktion der Interobserver-Variabilität werden dargestellt, u. a. die Auswahl geeigneter Bildgebung, gezieltes radiologisches Training und der Einsatz moderner Telekommunikationsmethoden.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN‐β) in children and adolescents with nasopharyngeal carcinoma, especially in high‐risk patients, have been promising.

Conformal radiotherapy planning of cervix carcinoma: differences in the delineation of the clinical target volume. A comparison between gynaecologic and radiation oncologists.

PURPOSE To assess uncertainties in the definition of the clinical target volume (CTV) for patients scheduled for primary radiotherapy of cervix carcinoma. METHODS AND MATERIALS Seven physicians (five radiation oncologists and two gynaecologists) independently contoured the CTVs for three patients. All observers were provided with the same clinical information. CTVs were entered directly in the treatment planning system. Differences were analysed qualitatively and quantitatively. RESULTS The qualitative analysis revealed a good agreement by all observers on anatomical structures identified to be at risk for tumour spread. Quantitatively, however, a large interobserver variability was found. The ratio between largest and smallest volumes ranged between 3.6 and 4.9 for all observers (3.6-4.9 for the radiation oncologists, 1.3-2.8 for the gynaecologists). The median three-dimensional difference in gravity centres ranged between 10.9 and 26.3mm for the respective patients. The ratio of common volumes to encompassing volumes ranged between 0.11 and 0.13 for the radiation oncologists, and between 0.30 and 0.57 for the gynaecologists. CONCLUSIONS Although there was a good consistency in outlined anatomical structures, for the radiation therapy of carcinomas of the uterine cervix a large interobserver variability in CTV delineation concerning the magnitude and relative location of volumes was observed. Compared to other factors, e.g. set-up and organ motion, interobserver variability in CTV definition seems to have the highest impact on the geometrical accuracy in the radiotherapy of this tumour entity.