Avoidance of Overtreatment of Rectal Cancer by Selective Chemoradiotherapy: Results of the Optimized Surgery and MRI-Based Multimodal Therapy Trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer carries a high risk of adverse effects. The aim of this study was to examine the selective application of nCRT based on patient risk profile, as determined by MRI, to find the optimal range between undertreatment and overtreatment. STUDY DESIGN: In this prospective multicenter observational study, nCRT before total mesorectal excision (TME) was indicated in high-risk patients with involved or threatened mesorectal fascia (≤1 mm), or cT4 or cT3 carcinomas of the lower rectal third. All other patients received primary surgery. RESULTS: Of the 1,093 patients, 878 (80.3%) were treated according to the protocol, 526 patients (59.9%) underwent primary surgery, and 352 patients (40.1%) underwent nCRT followed by surgery. The 3-year locoregional recurrence (LR) rate was 3.1%. Of 604 patients with clinical stages II and III, 267 (44.2%) had primary surgery; 337 (55.8%) received nCRT followed by TME. The 3-year LR rate was 3.9%, without significant differences between groups. In patients with clinical stages II and III who underwent primary surgery, 27.3% were diagnosed with pathological stage I. CONCLUSIONS: The results justify the restriction of nCRT to high-risk patients with rectal cancer classified by pretreatment MRI. Provided that a high-quality MRI diagnosis, TME surgery, and standardized examination of the resected specimen are performed, nCRT, with its adverse effects, costs, and treatment time can be avoided in more than 40% of patients with stage II or III rectal cancer with minimal risk of undertreatment. (clinicaltrials.gov NCT325649).

MRI-Based Use of Neoadjuvant Chemoradiotherapy in Rectal Carcinoma: Surgical Quality and Histopathological Outcome of the OCUM Trial.

BACKGROUND: Preoperative magnetic resonance imaging (MRI) allows highly reliable imaging of the mesorectal fascia (mrMRF) and its relationship to the tumor. The prospective multicenter observational study OCUM uses these findings to indicate neoadjuvant chemoradiotherapy (nCRT) in rectal carcinoma. METHODS: nCRT was indicated in patients with positive mrMRF (≤ 1 mm) in cT4 and cT3 carcinomas of the lower rectal third. RESULTS: A total of 527 patients (60.2%) underwent primary total mesorectal excision, and 348 patients (39.8%) underwent long-term nCRT followed by surgery. The mrMRF was involved in 4.6% of the primary surgery group and 80.7% of the nCRT group. Rates of resections within the mesorectal plane (90.8%), sparing of pelvic nerves on both sides (97.8%), and number of regional lymph nodes (95.3% with ≥ 12 lymph nodes examined) are indicative of high-quality surgery. Resection was classified as R0 in 98.3%, the pathological circumferential resection margin (pCRM) was negative in 95.1%. Patients in the nCRT group had more advanced carcinomas with a significantly higher rate of abdominoperineal excision. Independent risk factors for pCRM positivity were advanced stage (T4), metastatic lymph nodes, resection in the muscularis propria plane, and location in the lower third. CONCLUSIONS: The risk classification of rectal cancer patients by MRI seems to be highly reliable and allows the restriction of nCRT to approximately half of the patients with clinical stage II and III rectal carcinoma, provided there is a high-quality MRI diagnostic protocol, high-quality surgery, and standardized examination of the resected specimen.

Survival analysis in rectal carcinoma after neoadjuvant chemoradiation: various methods with different results.

PURPOSE: Survival is an important indicator of outcome quality in rectal carcinoma. The 5-year survival rate is the typical outcome measurement. In patients with neoadjuvant chemoradiation followed by curative surgery, 7 years of follow-up is recommended. Different methods of survival analysis lead to different results. Here, we compared four different methods. METHODS: The data of 439 patients with rectal carcinoma treated with neoadjuvant chemoradiation followed by curative total mesorectal excision (TME) surgery between 1995 and 2010 were analysed. After stratifying by stage, relative survival (RS), cancer-related survival (CRS), overall survival (OS) and disease-free survival (DFS) were compared. In particular, the 3-year disease-free survival rate was compared to the 5- and 7-year overall survival rates. RESULTS: In the total cohort, the 5-year survival rates ranged from 90% (RS), over 84% (CRS) and 83% (OS) to 72% (DFS). Depending on the stage of disease, the differences between the 5-year survival rates varied between 10 and 32 percentage points. The differences were lowest in UICC stage y0 and highest in UICC stage yIV. The 3-year DFS-rate was always lower (worse) than the 5-year OS rate and higher (better) than the 7-year OS rate, with the exception of stage yIV. CONCLUSIONS: Comparisons of survival are only meaningful if the same methods are applied. The 3-year rate of DFS was always worse than the rate of 5-year OS. Therefore, the 3-year rate of DFS appears to be a useful surrogate indicator in rectal carcinoma treatment studies.

Pretherapeutic MRI for decision-making regarding selective neoadjuvant radiochemotherapy for rectal carcinoma: interim analysis of a multicentric prospective observational study.

PURPOSE: To study the accuracy of different cutoffs for an involved circumferential resection margin (CRM) compared with T and N categories measured by MRI as basis for selective application of neoadjuvant radiochemotherapy (nRCT) in rectal carcinoma. MATERIALS AND METHODS: In a prospective multicenter observational study involving 153 primarily operated patients, the preoperative results of MRI with pathohistological findings of resected specimens were compared. RESULTS: For a cutoff of ≤1 mm for involvement of the CRM, the accuracy of preoperative MRI was 90.9% (139/153). The negative predictive value was 98.5% (134/136). The four participating departments did not differ significantly. For a cutoff of >2 mm and >5 mm, the rates of false-positive findings increased significantly from 5% to 12% and 35% with a decrease in accuracy to 82% and 62%, respectively. In contrast, the accuracy in predicting T (69.3%) and N categories (61.4%) was much lower. CONCLUSION: The indication for nRCT should be based on the determination of the minimal distance of the tumor from mesorectal fascia with a cutoff point of >1 mm as measured by MRI.

Prognosis of rectal carcinoma after multimodal treatment: ypTNM classification and tumor regression grading are essential.

AIM: The value of grading tumor regression after neoadjuvant therapy of rectal carcinoma was evaluated. PATIENTS AND METHODS: Analysis was carried out using prospective data of 225 patients with rectal carcinoma treated by neoadjuvant radiochemotherapy followed by radical resection with curative intent. For the histological regression grading, the method of Dworak et al. (1997) was used with a slight modification. RESULTS: After neoadjuvant radiochemotherapy, the most important prognostic factors are pathologically assessed circumferential resection margin, quality of surgery (plane of surgery), and the ypT and ypN classification. In addition, the histological regression grade of primary tumor and regional lymph nodes influence outcome, especially the local recurrence rate. CONCLUSION: After neoadjuvant therapy, the histological tumor regression grading should be assessed. A regression grading system based on the proposals of Dworak et al. (1997) is recommended.

Volume and outcome in rectal cancer surgery: the importance of quality management.

PURPOSE: For many years, the impact of the surgeon volume on short- and long-term outcome after rectal carcinoma surgery is controversially discussed. Literature and own department data were reviewed in order to clarify the impact of surgeon volume in the current era of total mesorectal excision surgery, multimodal therapy, quality management, and centralization of cancer care. METHODS: Uni- and multivariate analysis of data from 1,028 patients with solitary rectal carcinoma, treated between 1995 and 2010 at the Department of Surgery, University Hospital, Erlangen, Germany, was performed. Surgeons were subdivided according to the number of operations/year into high- (at least seven/year), medium- (three to six), and low- (less than three) volume surgeons. RESULTS: Of 1,028 patients, 800 (77.8 %) were operated by five high-volume surgeons, 193 (18.8 %) by seven medium-volume surgeons, and 35 (3.4 %) by 12 low-volume surgeons. Surgeon volume was significantly associated with postoperative mortality and the rate of positive pathological circumferential resection margin. In risk-adjusted analysis, after primary surgery, surgeon volume had a significant impact on observed overall survival and disease-free survival, but not on locoregional recurrence. After neoadjuvant radiochemotherapy, only observed overall survival was significantly influenced by surgeon volume. CONCLUSIONS: In surgical departments with special interest in rectal carcinoma, surgeon volume has some influence on short- and long-term outcome. Irrespective of this fact, specialization, experience, individual skill, hospital organization, and regular quality assurance are essential prognostic factors ensuring good results in rectal carcinoma surgery.

MRI-based indications for neoadjuvant radiochemotherapy in rectal carcinoma: interim results of a prospective multicenter observational study.

BACKGROUND: This study evaluated use of circumferential resection margin status in preoperative MRI (mrCRM) as an indication for neoadjuvant radiochemotherapy (nRCT) in rectal carcinoma patients. MATERIALS AND METHODS: In a multicenter prospective study, nRCT was given to patients with carcinoma of the middle rectum with positive mrCRM (≤1 mm), with cT3 low rectal carcinoma, and all patients with cT4 tumors. The short-term endpoints were pathologic pCRM (≤1 mm) as a strong predictor of local recurrence rate and the quality of total mesorectal excision according to the plane of surgery. These endpoints were compared in patients with and without nRCT. RESULTS: Of 230 patients that met the inclusion criteria, 96 (41.7%) received a long course of nRCT and 134 (58.3%) were primarily operated on. The pCRM was positive in 13 of 230 (5.7%) (primarily operated on, 2 of 134 [1.5%]; after nRCT, 11 of 96 [11%]). In 1 of 134 (0.7%) case, the mrCRM was falsely negative. Patients at participating centers varied in terms of preoperative stage but not in pCRM positivity (0%-13%, P = .340). The plane of surgery was mesorectal (good) in 209 of 230 (90.9%), intramesorectal (moderate) in 16 of 230 (7%), and the muscularis propria plane (poor) in 2.2% (5 of 230). CONCLUSIONS: Low pCRM positivity and the high quality of mesorectal excision support use of MRI-based nRCT in rectal carcinoma. nRCT was avoidable in 45% of patients with stage II and III disease without significant risk of undertreatment. Preoperative MRI thus allows identification of patients with high risk of local recurrence and use of selective nRCT.

Regional lymph node metastasis and locoregional recurrence of rectal carcinoma in the era of TME [corrected] surgery. Implications for treatment decisions.

BACKGROUND AND AIMS: For rectal carcinoma treated according to the concept of total mesorectal excision (TME surgery), the independent influence of regional lymph node metastasis on the locoregional recurrence risk is still in discussion. A reliable assessment of this risk is important for an individualised selective indication for neoadjuvant radio-/radiochemotherapy. METHODS: Analysis of literature, especially of the last 20 years, and consideration of pathological and oncological basic research. Multivariate analysis of data of the Erlangen Registry of Colorectal Carcinoma. RESULTS: The clinical assessment of the pretherapeutic regional lymph node status by the present available imaging methods is still unreliable. The analysis of the association between pretherapeutic regional lymph node status and locoregional recurrence risk has to be based on follow-up data of patients treated by primary surgery and has to be distinguished between patients treated by conventional and optimised quality-assured TME surgery, respectively. Data from Erlangen show an increase of the local recurrence risk for patients with at least four involved regional lymph nodes. CONCLUSIONS: For patients with at least four involved regional lymph nodes, a neoadjuvant radiochemotherapy may be indicated. However, today, the pretherapeutic diagnosis is uncertain and results in overtherapy in 40%. Thus, in case of positive lymph node findings by imaging methods, the benefits and risk of neoadjuvant therapy in such situations should always be discussed with the patient in the sense of informed consent and shared decision.

Quality management in rectal carcinoma: what is feasible?

PURPOSE: A cohort study was carried out to analyse quality indicators in the diagnosis and treatment of rectal carcinoma. METHODS: A total of 2,470 patients with rectal carcinoma treated between 1985 and 2007 at the Department of Surgery, University of Erlangen, were analysed and compared within four time intervals. RESULTS: Most of the indicators analysed from 2004 to 2007 fulfilled the defined target values. The indicators for process quality of surgical treatment and the surrogate indicators of outcome quality in surgery showed excellent results. Comparing this to previous data, it displays the new developments such as introduction of multimodal treatment for high-risk patients. While the rate of locoregional recurrences decreased, no significant improvement in survival was found. CONCLUSIONS: Careful analysis of quality indicators is important for both quality management and comparison of treatment results. The progress in diagnosis and treatment requires a continuous update of definitions and target values.

A uniform residual tumor (R) classification: integration of the R classification and the circumferential margin status.

BACKGROUND: Since the introduction of the TNM residual tumor (R) classification, the involvement of resection margins has been defined either as a microscopic (R1) or a macroscopic (R2) demonstration of tumor directly at the resection margin ("tumor transected"). METHODS: The recognition of the importance of the circumferential resection margin (CRM) in patients with rectal cancer patients raises the need for an alternative definition of resection margin involvement, namely, the importance of delineating tumor with a minimal distance from the CRM of

Magnetic resonance imaging (MRI)-based indication for neoadjuvant treatment of rectal carcinoma and the surrogate endpoint CRM status.

AIM: Is it possible to reduce the frequency of neoadjuvant therapy for rectal carcinoma and nevertheless achieve a rate of more than 90% circumferential resection margin (CRM)-negative resection specimens by a novel concept of magnetic resonance imaging (MRI)-based therapy planning? MATERIALS AND METHODS: One hundred eighty-one patients from Berlin and Mainz, Germany, with primary rectal carcinoma, without distant metastasis, underwent radical surgery with curative intention. Surgical procedures applied were anterior resection with total mesorectal excision (TME) or partial mesorectal excision (PME; PME for tumours of the upper rectum) or abdominoperineal excision with TME. RESULTS: With MRI selection of the highest-risk cases, neoadjuvant therapy was given to only 62 of 181 (34.3%). The rate of CRM-negative resection specimens on histology was 170 of 181 (93.9%) for all patients, and in Berlin, only 1 of 93 (1%) specimens was CRM-positive. Patients selected for primary surgery had CRM-negative specimens on histology in 114 of 119 (95.8%). Those selected for neoadjuvant therapy had a lower rate of clear margin: 56 of 62 (90%). CONCLUSION: By applying a MRI-based indication, the frequency of neoadjuvant treatment with its acute and late adverse effects can be reduced to 30-35% without reduction of pathologically CRM-negative resection specimens and, thus, without the danger of worsening the oncological long-term results. This concept should be confirmed in prospective multicentre observation studies with quality assurance of MRI, surgery and pathology.

[Uniform calculation of local recurrence rates--requirement for quality management in rectal carcinoma]. / Einheitliche Berechnung von Lokalrezidivraten--Voraussetzung für das Qualitätsmanagement beim Rektumkarzinom.

The local recurrence rate is an important indicator in the quality management of rectal carcinoma. The data of the German Study Group for Colorectal Carcinoma (SGCRC) and the Erlangen Registry for Colorectal Carcinoma (ERCRC) were used to demonstrate the influence of different calculation methods on the level of local recurrence rates. The application of uniform definitions, rules and presentations is necessary to enable national and international comparisons. Only 5-year local recurrence rates allow treatment quality to be definitely judged, especially when multimodal treatment was applied.

Confusion by frequent changes in staging of exocrine pancreatic carcinoma.

OBJECTIVES: The TNM/pTNM classification of anatomic extent before treatment is the strongest predictor of outcome in exocrine pancreatic carcinoma. Frequent changes in staging, published by the UICC in 1987, 1997, and 2002, lead to considerable problems. METHODS: The data on 272 patients with resection of a pancreatic ductal adenocarcinoma between 1978 and 1997 were analyzed. RESULTS: Two hundred sixty-five tumors were assigned to a higher pT category in 1997. Of them, 70 were reassigned to a lower pT category in 2002. No patient fulfilled the criteria of pT4 in 2002. Eighty-seven tumors were assigned to a higher pathologic stage in 1997. In 2002, 151 tumors were assigned to a lower pathologic stage. No patient was assigned to pathologic stage III. The staging systems of 1987 and 1997 are able to identify subgroups of patients with superior prognosis. The staging system of 2002 includes the same 12 patients in stage I as the classification of 1997. However, stage II contains an inhomogeneous group of 193 patients with poor prognosis. CONCLUSIONS: Changes in the TNM classification require a conversion of the data. Analysis and comparison of published results are very difficult and sometimes impossible if classification systems change too often. The present classification is well qualified for treatment choice and gives good information on prognosis after resection. It should be unchanged for at least 10 years.