Geerard L. Beets

Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data

BACKGROUND Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15-27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR. METHODS In PubMed, Medline, and Embase we identified 27 articles, based on 17 different datasets, for long-term outcome of patients with and without pCR. 14 investigators agreed to provide individual patient data. All patients underwent chemoradiation and total mesorectal excision. Primary outcome was 5-year disease-free survival. Kaplan-Meier survival functions were computed and hazard ratios (HRs) calculated, with the Cox proportional hazards model. Subgroup analyses were done to test for effect modification by other predicting factors. Interstudy heterogeneity was assessed for disease-free survival and overall survival with forest plots and the Q test. FINDINGS 484 of 3105 included patients had a pCR. Median follow-up for all patients was 48 months (range 0-277). 5-year crude disease-free survival was 83.3% (95% CI 78.8-87.0) for patients with pCR (61/419 patients had disease recurrence) and 65.6% (63.6-68.0) for those without pCR (747/2263; HR 0.44, 95% CI 0.34-0.57; p<0.0001). The Q test and forest plots did not suggest significant interstudy variation. The adjusted HR for pCR for failure was 0.54 (95% CI 0.40-0.73), indicating that patients with pCR had a significantly increased probability of disease-free survival. The adjusted HR for disease-free survival for administration of adjuvant chemotherapy was 0.91 (95% CI 0.73-1.12). The effect of pCR on disease-free survival was not modified by other prognostic factors. INTERPRETATION Patients with pCR after chemoradiation have better long-term outcome than do those without pCR. pCR might be indicative of a prognostically favourable biological tumour profile with less propensity for local or distant recurrence and improved survival. FUNDING None.

Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery

BACKGROUND Incomplete surgical removal of the circumferential tumour spread is believed to be the main cause of local recurrence after resection of rectal cancer. This study assessed the accuracy of magnetic resonance imaging (MRI) with a phased-array coil for preoperative staging and prediction of the distance of the tumour from the circumferential resection margin in a total mesorectal excision. METHODS 76 patients with primary rectal cancer were preoperatively assessed by MRI at 1.5 T, with a phased-array coil. Two observers independently scored, on two occasions, the tumour stage and measured the distance to the mesorectal fascia. Their findings were compared with the final histological findings. FINDINGS The MRI tumour stage agreed with the histological stage in 63 (83%) of 76 patients (weighted kappa=0.77 [95% CI 0.66-0.89]) for observer 1, and in 51 (67%) patients (weighted kappa=0.52 [0.37-0.67]) for observer 2. The intraobserver agreement on the tumour stage was good (kappa=0.80 [0.69-0.91]) for observer 1 but moderate (kappa=0.49 [0.34-0.65]) for observer 2. The interobserver agreement was moderate (kappa=0.53 [0.38-0.69]). In 12 patients with an obvious T4 tumour, a margin of 0 mm was correctly predicted. Of 29 patients for whom the pathologist reported a distance of at least 10 mm without specifying the actual distance, a distance of at least 10 mm was predicted in 28 by observer 1 and 27 by observer 2. For the remaining 35 patients, a regression curve was constructed; from this, a histological distance of at least 1.0 mm can be predicted with high confidence when the measured distance on MRI is at least 5.0 mm. INTERPRETATION MRI with a phased-array coil showed moderate accuracy and reproducibility for predicting the tumour stage of rectal cancers. The clinically more important circumferential resection margin can, however, be predicted with high accuracy and consistency, allowing preoperative identification of patients at risk of recurrence who will benefit from preoperative radiotherapy, more extensive surgery, or both.

Wait-and-See Policy for Clinical Complete Responders After Chemoradiation for Rectal Cancer

PURPOSE Neoadjuvant chemoradiotherapy for rectal cancer can result in complete disappearance of tumor and involved nodes. In patients without residual tumor on imaging and endoscopy (clinical complete response [cCR]) a wait-and-see-policy (omission of surgery with follow-up) might be considered instead of surgery. The purpose of this prospective cohort study was to evaluate feasibility and safety of a wait-and-see policy with strict selection criteria and follow-up. PATIENTS AND METHODS Patients with a cCR after chemoradiotherapy were prospectively selected for the wait-and-see policy with magnetic resonance imaging (MRI) and endoscopy plus biopsies. Follow-up was performed 3 to 6 monthly and consisted of MRI, endoscopy, and computed tomography scans. A control group of patients with a pathologic complete response (pCR) after surgery was identified from a prospective cohort study. Functional outcome was measured with the Memorial Sloan-Kettering Cancer Center (MSKCC) bowel function questionnaire and Wexner incontinence score. Long-term outcome was estimated by using Kaplan-Meier curves. RESULTS Twenty-one patients with cCR were included in the wait-and-see policy group. Mean follow-up was 25 ± 19 months. One patient developed a local recurrence and had surgery as salvage treatment. The other 20 patients are alive without disease. The control group consisted of 20 patients with a pCR after surgery who had a mean follow-up of 35 ± 23 months. For these patients with a pCR, cumulative probabilities of 2-year disease-free survival and overall survival were 93% and 91%, respectively. CONCLUSION A wait-and-see policy with strict selection criteria, up-to-date imaging techniques, and follow-up is feasible and results in promising outcome at least as good as that of patients with a pCR after surgery. The proposed selection criteria and follow-up could form the basis for future randomized studies.

Rectal Cancer: Assessment of Complete Response to Preoperative Combined Radiation Therapy with Chemotherapy--Conventional MR Volumetry versus Diffusion-weighted MR Imaging.

PURPOSE To determine diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging for assessment of complete tumor response (CR) after combined radiation therapy with chemotherapy (CRT) in patients with locally advanced rectal cancer (LARC) by means of volumetric signal intensity measurements and apparent diffusion coefficient (ADC) measurements and to compare the performance of DW imaging with that of T2-weighted MR volumetry. MATERIALS AND METHODS A retrospective analysis of 50 patients with LARC, for whom clinical and imaging data were retrieved from a previous imaging study approved by the local institutional ethical committee and for which all patients provided informed consent, was conducted. Patients underwent pre- and post-CRT standard T2-weighted MR and DW MR. Two independent readers placed free-hand regions of interest (ROIs) in each tumor-containing section on both data sets to determine pre- and post-CRT tumor volumes and tumor volume reduction rates (volume). ROIs were copied to an ADC map to calculate tumor ADCs. Histopathologic findings were the standard of reference. Receiver operating characteristic (ROC) curves were generated to compare performance of T2-weighted and DW MR volumetry and ADC. The intraclass correlation coefficient (ICC) was used to evaluate interobserver variability and the correlation between T2-weighted and DW MR volumetry. RESULTS Areas under the ROC curve (AUCs) for identification of a CR that was based on pre-CRT volume, post-CRT volume, and volume, respectively, were 0.57, 0.70, and 0.84 for T2-weighted MR versus 0.63, 0.93, and 0.92 for DW MR volumetry (P = .15, .02, .42). Pre- and post-CRT ADC and ADC AUCs were 0.55, 0.54, and 0.51, respectively. Interobserver agreement was excellent for all pre-CRT measurements (ICC, 0.91-0.96) versus good (ICC, 0.61-0.79) for post-CRT measurements. ICC between T2-weighted and DW MR volumetry was excellent (0.97) for pre-CRT measurements versus fair (0.25) for post-CRT measurements. CONCLUSION Post-CRT DW MR volumetry provided high diagnostic performance in assessing CR and was significantly more accurate than T2-weighted MR volumetry. Post-CRT DW MR was equally as accurate as volume measurements of both T2-weighted and DW MR. Pre-CRT volumetry and ADC were not reliable.

Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery

OBJECTIVE To determine the association of sarcopenia with postoperative morbidity and mortality after colorectal surgery. BACKGROUND Functional compromise in elderly colorectal surgical patients is considered as a significant factor of impaired postoperative recovery. Therefore, the predictive value of preoperative functional compromise assessment was investigated. Sarcopenia is a hallmark of functional compromise. METHODS A total of 310 consecutive patients who underwent oncologic colorectal surgery were included in a prospective digital database. Sarcopenia was assessed using the L3 muscle index utilizing Osirix on preoperative computed tomography. Groningen Frailty Indicator and Short Nutritional Assessment Questionnaire scores were used to assess frailty and nutritional compromise. Predictors for anastomotic leakage, sepsis, and mortality were analyzed by logistic regression analysis. RESULTS Age was an independent predictor of mortality [P = 0.04; odds ratio, 1.17; 95% confidence interval (CI), 1.01-1.37]. Thirty-day/in-hospital mortality rate in sarcopenic patients was 8.8% versus 0.7% in nonsarcopenic patients (P = 0.001; odds ratio, 15.5; 95% CI, 2.00-120). Sarcopenia was not predictive for anastomotic leakage or sepsis. Combination of high Short Nutritional Assessment Questionnaire score, high Groningen Frailty Indicator score, and sarcopenia strongly predicted sepsis (P = 0.001; odds ratio, 25.1; 95% CI, 5.11-123), sensitivity, 46%; specificity, 97%; positive likelihood ratio, 13 (95% CI, 4.4-38); negative likelihood ratio, 0.57 (95% CI, 0.33-0.97). CONCLUSIONS Functional compromise in colorectal cancer surgery is associated with adverse postoperative outcome. Assessment of functional compromise by means of a nutritional questionnaire (Short Nutritional Assessment Questionnaire), a frailty questionnaire (Groningen Frailty Indicator), and sarcopenia measurement (L3 muscle index) can accurately predict postoperative sepsis.

Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial.

AIM OF THE STUDY In patients from the Dutch TME trial patterns of local recurrence (LR) in rectal cancer were studied. The purpose was to reconstruct the most likely mechanisms of LR and the effect of preoperative radiotherapy. METHODS 1417 patients were analyzed; 713 were randomized into preoperative radiotherapy and total mesorectal excision (RT + TME), 704 into TME alone. Of the 114 patients with LR, the subsites of LR were determined and related to tumor and treatment factors. RESULTS Overall 5-year LR-rate was 4.6% in the RT + TME group and 11.0% in the TME group. Presacral local recurrences occurred most in both groups. Radiotherapy reduced anastomotic LR significantly, except when after low anterior resection (LAR) distal margins were less than 5 mm. Abdominoperineal resection (APR) mainly resulted in presacral LR. Even after resection with a negative circumferential resection margin, LR-rates were high. Thirty percent of the patients had advanced tumors, which resulted in 58% of all LRs. Lateral LR comprised 20% of all LR. Presacral and lateral LR resulted in a poor prognosis, in contrast to anterior or anastomotic LRs with a relatively good prognosis. CONCLUSIONS RT reduces LR in all subsites and is especially effective in preventing anastomotic LR after LAR. APR-surgery mainly results in presacral LR, which may be prevented by a wider resection. In the TME trial many advanced tumors were included, rather requiring chemoradiotherapy instead of RT. Currently, with good imaging techniques, better selection can take place. Especially lateral LR might be a problem in the future.

USPIO-enhanced MR Imaging for Nodal Staging in Patients with Primary Rectal Cancer: Predictive Criteria

PURPOSE To prospectively determine diagnostic performance of predictive criteria for nodal staging with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging in primary rectal cancer patients, with histopathologic findings as reference standard. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Twenty-eight rectal cancer patients (18 men, 10 women; mean age, 68 years) underwent USPIO-enhanced MR. Two observers with different experience evaluated each node on three-dimensional T2*-weighted images for border irregularity, short- and long-axis diameter, and estimated percentage (<30%, 30%-50%, or >50%) of white region within the node. Ratio of measured surface area of white region within the node to measured surface area of total node (ratio(A)) was calculated. Signal intensity (SI) of gluteus muscle (SI(GM)), total node (SI(TN)), and white (SI(WR)) and dark (SI(DR)) regions within the node were used to calculate SI(TN)/SI(GM) and SI(WR)/SI(DR) ratios. Lesion-by-lesion, receiver operating characteristic curve, and interobserver agreement analyses were performed. The most accurate and practical criterion was evaluated by observer 3. RESULTS In 28 patients, 236 lymph nodes were examined. Area under the receiver operating characteristic curve (AUC) of estimated percentage of white region and ratio(A) were 0.96 and 0.99 (observer 1) and 0.95 and 0.97 (observer 2), respectively. AUC of estimated percentage criterion for observer 3 was 0.96. AUC of border, short- and long-axis diameter, and SI(TN)/SI(GM) and SI(WR)/SI(DR) ratios were 0.65, 0.75, 0.79, 0.85, and 0.75 (observer 1) and 0.58, 0.75, 0.79, 0.89, and 0.79 (observer 2), respectively. Interobserver agreement (kappa value) for estimated white region between observers 1 and 2, 1 and 3, and 2 and 3 were 0.77, 0.79, and 0.84, respectively. For observers 1 and 2, kappa value for border was 0.28. For observers 1 and 2, intraclass correlation coefficient for short- and long-axis diameters, ratio(A), and SI(TN)/SI(GM) and SI(WR)/SI(DR) ratios were 0.91, 0.96, 0.91, 0.72, and 0.92, respectively. CONCLUSION Estimated percentage of white region and measured ratio(A) are the most accurate criteria for predicting malignant nodes with USPIO-enhanced MR imaging; the first criterion is the most practical.

Risk factors for adverse outcome in patients with rectal cancer treated with an abdominoperineal resection in the total mesorectal excision trial.

Objective:This study was performed to identify tumor- and patient-related risk factors for distal rectal cancer in patients treated with an abdominoperineal resection (APR) associated with positive circumferential resection margin (CRM), local recurrence (LR), and overall survival (OS). Background:The introduction of total mesorectal excision (TME) has improved the outcome of patients with rectal cancer. However, survival of patients treated with an APR improved less than of those treated with low anterior resections (LAR). Besides, an APR is associated with a higher LR rate. Methods:Patients were selected from the TME trial, which is a randomized, multicenter trial, studying the effects of preoperative radiotherapy (RT) in 1861 patients. Of the Dutch patients, 455 underwent an APR. Location of the bulk of the tumor was scored with surgery, pathology, or other reports. CRM was available from pathology reports. Result:A positive CRM was found in 29.6% of all patients, 44% for anterior, 21% for lateral, 23% for posterior, and 17% for (semi)circular tumor location (P < 0.0001). In a multivariate analysis, T-stage, N-stage, and tumor location were independent risk factors for CRM. If a (partial) resection of the vaginal wall was performed in women, 47.8% of patients still had a positive CRM. T-stage, N-stage, and CRM were risk factors for LR and age, T-stage, N-stage, CRM, and distance of the inferior tumor margin to the anal verge for OS. Conclusion:Age, T-stage, N-stage, CRM, distance of the tumor to the anal verge, and tumor location were independent risk factors for adverse outcome in patients treated with an APR for low rectal cancer. Anterior location, specifically in women, more often requires downstaging and/or more extended resection to obtain free margins.

Degradation of mesh coatings and intraperitoneal adhesion formation in an experimental model

In laparoscopic ventral hernia repair a mesh is placed in direct contact with the viscera, often leading to substantial adhesions. In this experimental study the ability of different coated and uncoated meshes to attenuate adhesion formation was examined.

Open or laparoscopic preperitoneal mesh repair for recurrent inguinal hernia? A randomized controlled trial.

AbstractBackground: Giant prosthetic reinforcement of the visceral sac (GPRVS), an open preperitoneal mesh repair, is a very effective groin hernia repair. Laparoscopic transabdominal preperitoneal repair (TAPP), based on the same principle, is expected to combine low recurrence rates with minimal postoperation morbidity. Methods: Seventy-nine patients with 93 recurrent and 15 concomitant primary inguinal hernias were randomized between GPRVS (37 patients) and TAPP (42 patients). Operating time, complications, pain, analgesia use, disability period, and recurrences were recorded. Results: Mean operating time was 56 min with GPRVS versus 79 min with TAPP (p < 0.001). Most complications were minor, except for a pulmonary embolus and an ileus, both after GPRVS. Patients experienced less pain after a laparoscopic repair. Average disability period was 23 days with GPRVS versus 13 days with TAPP (p= 0.03) for work, and 29 versus 21 days, respectively (p= 0.07) for physical activities. Recurrence rates at a mean follow-up of 34 months were 1 in 52 (1.9%) for GPRVS versus 7 in 56 (12.5%) for TAPP (p= 0.04). Hospital costs in U.S. dollars were comparable, with GPRVS at