Risk-Adapted Neoadjuvant Chemoradiotherapy in Rectal Cancer: Final Report of the OCUM Study.

PURPOSE: We investigated whether neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer can be restricted to those at high risk of locoregional recurrence (LR) without compromising oncological outcomes. PATIENTS AND METHODS: In a prospective multicenter interventional study, patients with rectal cancer (cT2-4, any cN, cM0) were classified according to the minimal distance between the tumor, suspicious lymph nodes or tumor deposits, and mesorectal fascia (mrMRF). Patients with a distance >1 mm underwent up-front total mesorectal excision (TME; low-risk group), whereas those with a distance ≤1 mm and/or cT4 and cT3 tumors in the lower rectal third received nCRT followed by TME surgery (high-risk group). The primary end point was 5-year LR rate. RESULTS: Of the 1,099 patients included, 884 (80.4%) were treated according to the protocol. A total of 530 patients (60%) underwent up-front surgery, and 354 (40%) had nCRT followed by surgery. Kaplan-Meier analyses revealed 5-year LR rates of 4.1% (95% CI, 2.7 to 5.5) for patients treated per protocol, 2.9% (95% CI, 1.3 to 4.5) after up-front surgery, and 5.7% (95% CI, 3.2 to 8.2) after nCRT followed by surgery. The 5-year rate of distant metastases was 15.9% (95% CI, 12.6 to 19.2) and 30.5% (95% CI, 25.4 to 35.6), respectively. In a subgroup analysis of 570 patients with lower and middle rectal third cII and cIII tumors, 257 (45.1%) were at low-risk. The 5-year LR rate in this group was 3.8% (95% CI, 1.4 to 6.2) after up-front surgery. In 271 high-risk patients (involved mrMRF and/or cT4), the 5-year rate of LR was 5.9% (95% CI, 3.0 to 8.8) and of metastases 34.5% (95% CI, 28.6 to 40.4); disease-free survival and overall survival were the worst. CONCLUSION: The findings support the avoidance of nCRT in low-risk patients and suggest that in high-risk patients, neoadjuvant therapy should be intensified to improve prognosis.

Selection of patients with rectal cancer for neoadjuvant therapy using pre-therapeutic MRI - Results from OCUM trial.

PURPOSE: No consensus is available on the appropriate criteria for neoadjuvant chemoradiotherapy selection of patients with rectal cancer. The purpose was to evaluate the accuracy of MRI staging and determine the risk of over- and undertreatment by comparing MRI findings and histopathology. METHOD: In 609 patients of a multicenter study clinical T- and N categories, clinical stage and minimal distance between the tumor and mesorectal fascia (mrMRF) were determined using MRI and compared with the histopathological categories in resected specimen. Accuracy, sensitivity, specificity, positive predictive, and negative predictive value (NPV) were calculated. Overstaging was defined as the MRI category being higher than the histopathological category. mrMRF and circumferential resection margin (CRM) were judged as tumor free at a minimal distance > 1 mm. The chi-squared test or Fisher's exact test were used. P < 0.05 was considered significant. RESULTS: The T category was correct in 63.5% (386/608) of patients; cT was overstaged in 22.9% (139/608) and understaged in 13.5% (82/608). MRI accuracy for lymph node involvement was 56.5% (344/609); 22.2% (28/126) of patients with clinical stage II and 28.1% (89/317) with clinical stage III disease were diagnosed by histopathology as stage I. The accuracy for tumor free CRM was 86.5% (527/609) and the NPV was 98.1% (514/524). In 1.7% (9/524) mrMRF was false negative. CONCLUSION: MRI prediction of the tumor-free margin is more reliable than the prediction of tumor stage. MRF status as determined MRI should therefore be prioritized for decision making.

[Reality of care of colorectal cancer in the State of Brandenburg : With special consideration of the number of hospital cases and certification as a colorectal cancer center]. / Die Versorgungsrealität des kolorektalen Karzinoms im Bundesland Brandenburg : Unter besonderer Berücksichtigung der Krankenhausfallzahlen und Zertifizierung als Darmkrebszentrum.

Analysis of the quality of care for colorectal cancer is an essential foundation for further development and is based on the comparison of the goals set and the actual quality of care. This publication presents the reality of care in the State of Brandenburg covering the complete spectrum of treating clinics based on the data of the clinical cancer register. This study analyzed the number of resected and examined lymph nodes, the quality of total mesorectal excision (TME), the residual tumor (R0) resection rate and the proportion of adjuvant therapy of colon cancer in Union internationale contre le cancer (UICC) stage III depending on the operation quota of hospitals and the certification as bowel cancer center according to Onkozert. Apart from the R status, the analyses showed no differences in the qualitative operation data from the clinical cancer register depending on the hospital volume.

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.

Genomics, microRNA, epigenetics, and proteomics for future diagnosis, treatment and monitoring response in upper GI cancers.

One major objective for our evolving understanding in the treatment of cancers will be to address how a combination of diagnosis and treatment strategies can be used to integrate patient and tumor variables with an outcome-oriented approach. Such an approach, in a multimodal therapy setting, could identify those patients (1) who should undergo a defined treatment (personalized therapy) (2) in whom modifications of the multimodal therapy due to observed responses might lead to an improvement of the response and/or prognosis (individualized therapy), (3) who might not benefit from a particular toxic treatment regimen, and (4) who could be identified early on and thereby be spared the morbidity associated with such treatments. These strategies could lead in the direction of precision medicine and there is hope of integrating translational molecular data to improve cancer classifications. In order to achieve these goals, it is necessary to understand the key issues in different aspects of biotechnology to anticipate future directions of personalized and individualized diagnosis and multimodal treatment strategies. Providing an overview of translational data in cancers proved to be a challenge as different methods and techniques used to obtain molecular data are used and studies are based on different tumor entities with different tumor biology and prognoses as well as vastly different therapeutic approaches. The pros and cons of the available methodologies and the potential response data in genomics, microRNA, epigenetics and proteomics with a focus on upper gastrointestinal cancers are considered herein to allow for an understanding of where these technologies stand with respect to cancer diagnosis, prognosis and treatment.

Ex Vivo Intra-arterial Methylene Blue Injection in Rectal Cancer Specimens Increases the Lymph-Node Harvest, Especially After Preoperative Radiation.

BACKGROUND: The examination of as large a number of lymph nodes as possible in rectal carcinoma resectates is important for exact staging. However, after neoadjuvant radiochemotherapy (RCT), it can be difficult to obtain a sufficient number of lymph nodes. We therefore investigated whether staining with methylene blue via the inferior mesenteric artery can lead to an increase in the yield of lymph nodes in rectal carcinoma tissue after neoadjuvant RCT. METHODS: In a prospective, unicentric study rectal carcinoma resectates from three consecutive groups of patients were examined (Group I, no staining; Group II, staining with methylene blue; Group III, again no staining). The numbers of lymph nodes examined were compared (a) between the groups and (b) between patients who had not, or who had, received neoadjuvant RCT. RESULTS: In all, 75 rectal carcinoma preparations were assessed. The yield of lymph nodes investigated before the use of staining (Group I) increased when staining was introduced (Group II), both for the patients without neoadjuvant RCT (20.9 vs. 31.3, p = 0.018) and for those who did receive this (15.0 vs. 35.1; p = 0.003). After withdrawal of the staining procedure (Group III), the lymph-node yield remained high for the patients without neoadjuvant RCT (31.3 vs. 30.4; p = 0.882), but it reverted to a lower value for those who did receive neoadjuvant RCT (35.1 vs. 24.2; p = 0.029). Before the introduction of staining (Group I), significantly fewer lymph nodes were examined for patients who received neoadjuvant RCT (15.0 vs. 20.9; p = 0.039). However, with staining (Group II), no difference was found associated with the use or non-use of neoadjuvant RCT (31.3 vs. 35.1; p = 0.520). CONCLUSION: The use of methylene blue staining of rectal carcinoma preparations leads to a significant increase in the number of lymph nodes examined after neoadjuvant RCT. This can be expected to improve the accuracy of lymph-node staging of neoadjuvant-treated rectal carcinoma.

Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma.

There is a growing amount of data supporting the concept that cancers originating from the proximal and distal colon are distinct clinicopathological entities. The incidence of MSI and BRAF mutation is strongly associated with right sided tumor location, whereas there are conflicting results for KRAS mutation rates. However, to date, no data exist whether and to what extent defined colonic subsites influence MSI status, KRAS and BRAF mutation rates. We selected primary colon cancer from 171 patients operated on at our institution between 2007 and 2010. BRAF, KRAS mutation rates and microsatellite instability were determined and correlated with clinicopathological features and tumor location. MSI-h cancers were significantly associated with poor histological grade but a lower rate of distant metastases. KRAS-mutated tumors were linked to lower T-stage and better differentiation. Colon carcinomas with BRAF mutation were significantly associated with distant metastatic spread and poor histological grade. Furthermore, we found that MSI-h status, KRAS and BRAF mutation rates varied remarkably among the colonic subsites irrespective of right- and left-sided origin, respectively. The results of the current study provide further evidence that a simple classification into right- and left-sided colon carcinoma does not represent the complexity of this tumor entity.

Prognostic factors assessed for 15,096 patients with colon cancer in stages I and II.

BACKGROUND: We focused on the risk factors for poor outcome after curative resection of a colon cancer in UICC stages I and II based on the data of the Germany-wide quality assurance study "colon/rectum cancer (primary tumor)." In some countries, all stage II colon cancer patients are encouraged to participate in a clinical trial. We feel that this approach is too broad. METHODS: Using the data of 15,096 patients operated on from January 1, 2000 to December 31, 2004, the following factors were analyzed with the Cox regression model: age, comorbidities, ASA score, gender, localization of the tumor (left colon vs. right colon), perioperative complications (yes/no), pT stage, grading (G1/G2 vs. G3/G4), L-status (lymph vessels invasion yes/no), and V-status (venous invasion yes/no). RESULTS: The probability of a local relapse in stages I and II was 1.5 and 4.6%, respectively, or distant metastases 4.7 and 10.2%, respectively. Only pT stage [hazard ratio (HR) for pT1 = 1, pT2 = 1.821, pT3 = 2.735, and pT4 = 5.881], L-status (HR for L1 = 1.393), age (HR per year = 1.021), as well as ASA score IV (HR = 4.536) had significant influence on tumor-free survival. CONCLUSIONS: Despite favorable prognosis and R0 resection, a small percentage of patients will still relapse. The most important risk factor comprising the tumor-free survival is the pT stage followed by L-status and age. These results should be taken into consideration when determining the course for adjuvant chemotherapy, especially if the course includes the recommendation of clinical trial participation for stage II colon cancer patients after an R0 resection.

Preliminary results of the first quality assurance project in rectal cancer in Poland.

UNLABELLED: When compared with other EU countries, Poland is in the last place in terms of efficacy of rectal cancer treatment. In order to remedy this situation, in 2008 Polish centres were given the opportunity to participate in an international programme for evaluating the treatment efficacy.The aim of the study was to present the results obtained during the first two years of research. MATERIAL AND METHODS: The study protocol covered 71 questions concerning demographic data, diagnostics, risk factors, peri- and post-operative complications, histopathology, and treatment plan at discharge. The patient and unit data were kept confidential. RESULTS: From 1 January 2008 to 30 December 2009, there were 709 patients recorded, of which 55.9% were males. At least one risk factor was found in approx. 3/4 of patients, while approx. 1/3 of patients were classified to group 3 and 4 according to ASA. The mean distance of the tumour from the anal margin was 8.5 cm; approx. 70% of patients were in the clinical stages cT3 and cT4; metastases were observed in 18.8%. Transrectal endoscopic ultrasonography (TREUS) was performed in 23.7% of patients, magnetic resonance imaging (MRI) in 2.5% and computed tomography (CT) scan - in 48.1%. In close to half of the patients, anterior or low anterior resection of the rectum was performed, and abdominoperineal resection in 1/4 of the patients. Anastomotic leakage was seen in 3.8% of patients, while 1.8% died during hospitalisation. CONCLUSIONS: It should be strived after that all the centres undertaking the treatment of rectal cancer should participate in the quality assurance programme. This should enable the achievement of good therapeutic results in patients with rectal cancer treated in Polish centres.

The care of patients with colon cancer: current treatment, and evaluation of new surgical approaches.

BACKGROUND: Multi-center observational studies in surgery can yield important findings, as long as they are appropriately designed and monitored and employ modern methods of statistical analysis. METHODS: In a multi-center quality assurance study carried out in 346 German hospitals from 2000 to 2004, data were collected from a total of 31 055 patients who underwent surgery for colon carcinoma. The current, overall state of medical care for this disease was analyzed, with particular attention to aspects of quality assurance. RESULTS: 46.7% of the patients were in the advanced, prognostically unfavorable stages UICC III and IV and had an overall 5-year survival of 53.8% in stage III and 9.8% in stage IV. Laparoscopic intention-to-treat procedures were performed on 1401 patients (4.7%), of whom 20.6% required conversion to laparotomy. The patients who required conversion to laparotomy had a worse overall outcome. 28 271 patients were treated with tumor resection and primary anastomosis; in this group, 3% (n = 844) developed an anastomotic leak. Logistic regression analysis identified the following risk factors for anastomotic leakage: duration of surgery, ileus, tumor localization in the left colon, and single-layer suturing. CONCLUSION: This multi-center observational study yields valid findings about the epidemiology and overall quality of medical care for colon carcinoma in Germany.

Current analysis of endoloops in appendiceal stump closure.

BACKGROUND: An inadequate closure of the appendix stump leads to intra-abdominal surgical site infection. The effectiveness of various appendiceal stump closure methods, for instance, staplers or endoloops, was evaluated. Many analyses show that the use of a stapler for transection and closure of the appendiceal stump lowers the risk of this infection but a statistically significant risk of postoperative intra-abdominal abscess or wound infection was not considered in any randomized study. The aim of this study was to evaluate the complications after using endoloops in a high-volume center. METHODS: The data of 1,790 patients who underwent laparoscopic appendectomy between January 1998 and December 2006 and a single center was prospectively acquired. The standard procedure used was an appendiceal stump closure using endoloops and a selective use of staplers. The outcome criteria for inclusion in the study were intra-abdominal abscess formations, other specific intraoperative and postoperative complications, and the different costs of the operation. RESULTS: Laparoscopic appendectomy was performed in 1,790 (80.8%) patients and open appendectomy in 425 (19.2%) patients. Conversion to open surgery occurred in 74 (4.13%) patients. Laparoscopic appendectomy with stump closure using endoloops was performed in 1,670 (97.3%) patients and stump closure using a stapler in 46 (2.7%) patients. Among 851 patients with acute appendicitis, 284 patients with perforated appendicitis, and 535 patients with other or no pathology, the rate of intra-abdominal abscess after using an endoloop or a stapler was not significantly different (1.5 vs. 0%, p = 0.587; 3.5 vs. 4.2%, p = 0.870; 0.7% vs. 0, p = 0.881, respectively). There were no significant differences between the endoloop group and the stapler group with respect to the other specific intraoperative and postoperative complications. CONCLUSION: This study shows the safety of the endoloop for clinical daily routine. A selective procedure for stump closure has been established. Appendiceal stump closure using an endoloop is an easy, safe, and cost-effective procedure.

Modified neoadjuvant short-course radiation therapy in uT3 rectal carcinoma: low local recurrence rate with unchanged overall survival and frequent morbidity.

PURPOSE: The purpose of this study is to investigate the value of a modified neoadjuvant short-course radiation therapy (SCRT) in uT3 rectal carcinoma, which, despite local R0 resectability, carries a greater risk of local recurrence than less invasive carcinomas. METHODS: Sixty-three patients with uT3 rectal carcinoma < or =10 cm above the anal verge received a modified 8 x 3 Gy pre-operative SCRT. Radiation-associated and peri-operative complications were recorded, and the patients were followed up for long-term oncological outcome and morbidity. RESULTS: In the study group, there were no severe adverse radiation-associated effects; the rate of peri-operative morbidity was 54.0% and that of in-hospital mortality is 4.8%. The probability (Kaplan-Meier estimate) of local recurrence was 3.9% with a probability of metachronic distant metastases of 26.8% (5-year rates). We found the probability of 5-year disease-free survival to be 70.5% and that of 5-year overall survival, 59.5%. Long-term complications were reported for 31.7% of patients. CONCLUSIONS: Compared to the literature-modified 8 x 3 Gy neoadjuvant SCRT and surgery in uT3, rectal carcinoma was associated with low local recurrence but frequent peri-operative complications. The decisive prognostic factor, distant metastasis, was unaffected. Difficulties included overestimation of tumour invasion depth by endosonography. Possible clinical consequences of the results are discussed.

Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival.

PURPOSE: There is a growing amount of data suggesting that carcinomas of the right and left colon should be considered as different tumor entities. Using the data and analysis compiled in the German multicentered study "Colon/Rectum Cancer," we aimed to clarify whether the existing differences influence clinical and histological parameters, the perioperative course, and the survival of patients with right- vs left-sided colon cancer. METHODS: During a 3-year period data on all patients with colon cancer were evaluated. Right- and left-sided cancers were compared regarding the following parameters: demographic factors, comorbidities, and histology. For patients who underwent elective surgery with curative intent, the perioperative course and survival were also analyzed. RESULTS: A total of 17,641 patients with colon carcinomas were included; 12,719 underwent curative surgery. Patients with right-sided colon cancer were significantly older, and predominantly women with a higher rate of comorbidities. Mortality was significantly higher for this group. Final pathology revealed a higher percentage of poorly differentiated and locally advanced tumors. Rate of synchronous distant metastases was comparable. However, hepatic and pulmonary metastases were more frequently found in left-sided, peritoneal carcinomatosis in right-sided carcinomas. Survival was significantly worse in patients with right-sided carcinomas on an adjusted multivariate model (odds ratio, 1.12). CONCLUSIONS: We found that right- and left-sided colon cancers are significantly different regarding epidemiological, clinical, and histological parameters. Patients with right-sided colon cancers have a worse prognosis. These discrepancies may be caused by genetic differences that account for distinct carcinogenesis and biological behavior. The impact of these findings on screening and therapy remains to be defined.

Quality of medical care in colorectal cancer in Germany.

BACKGROUND: To investigate recent developments in therapeutic approaches, we examine the quality of and discuss current trends in the routine treatment of colorectal cancer in Germany. MATERIAL AND METHODS: We conducted a prospective, multicentre, country-wide observational study in Germany at a representative number of hospitals providing care at all levels. RESULTS: The perioperative morbidity and mortality rates were found not to have changed for a given risk profile of patient and tumour characteristics. The resection rates and long-term oncological results achieved in clinical routine are comparable with those reported in the current literature for colorectal cancer. The quality of care of rectal carcinoma patients has improved significantly, as measured by perioperative oncosurgical criteria (abdominoperineal resection rate, total mesorectal excision rate and quality, and proportion of neoadjuvant procedures). CONCLUSION: At present, it remains to be seen whether these factors will lead to a further improvement in long-term results (e.g. rates of local recurrence), and this will require further critical analysis.

The significance of Meckel's diverticulum in appendicitis--a retrospective analysis of 233 cases.

Conflicting reports are found in the literature concerning whether to remove an incidentally discovered Meckel's diverticulum (MD). Between 1.1.1974 and 31.12.2000, at a single center, the perioperative data associated with appendectomy (AE) were recorded consecutively and analyzed retrospectively. All patients in whom an MD was discovered during an AE were included in the study. The clinical presentation, postoperative course, and follow-up in all MDs left in place were analyzed. During the course of 7927 AE, 233 MD (2.9%) were detected. Of these 80.7% (n = 188) were removed and 19.3% (n = 45) were left untouched. In 9% (n = 21) of all detected diverticula pathological changes were found. Ectopic tissue was seen in 12.2% (n = 23) of the MDs removed. The postoperative complication rates did not differ significantly between patients in whom the MD was removed (9.5%; n = 18) and those in whom it was not (17.7%; n = 8); in the latter group the appendicitis was of the more acute type (gangrenous or perforated) (24.4% vs. 4.3%). In 18 patients (40.0%) with non-removed MDs, a follow-up period of 14.1 5.8 years was achieved. Complications associated with a non-removed MD were not observed. If during the course of an AE a MD is detected, the present data, as well as those in the literature, suggest that an individualized approach should be taken. Meckel's diverticulum with obvious pathology should always be removed. In cases of gangrenous or perforated appendicitis, an incidentally discovered MD should be left in place, whereas in an only mildly inflamed appendix it should be removed.