Milou H. Martens

Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer

BACKGROUND The aim of this study was to establish the oncological and functional results of organ preservation with a watch-and-wait approach (W&W) and selective transanal endoscopic microsurgery (TEM) in patients with a clinical complete or near-complete response (cCR) after neoadjuvant chemoradiation for rectal cancer. METHODS Between 2004 and 2014, organ preservation was offered if response assessment with digital rectal examination, endoscopy, and MRI showed (near) cCR. Watch-and-wait was offered for cCR, and two options were offered for near cCR: TEM or reassessment after three months. Follow-up included endoscopy and MRIs every three months during the first year, and every six months thereafter. Long-term outcome was assessed with Kaplan-Meier curves. Functional outcome was assessed with colostomy-free survival and Vaizey incontinence score (0 = perfect continence, 24 = totally incontinent). RESULTS One hundred patients were included, with median follow-up of 41.1 months. Sixty-one had cCR at initial response assessment. Thirty-nine had near cCR, of whom 24 developed cCR at the second assessment and 15 patients underwent TEM (9 ypT0, 1 ypT1, 5 ypT2). Fifteen patients developed a local regrowth (12 luminal, 3 nodal), all salvageable and within 25 months. Five patients developed metastases, and five patients died. Three-year overall survival was 96.6% (95% confidence interval [CI] = 89.9% to 98.9%), distant metastasis-free survival was 96.8% (95% CI = 90.4% to 99.0%), local regrowth-free survival was 84.6% (95% CI = 75.8% to 90.5%), and disease-free survival was 80.6% (95% CI = 70.9% to 87.4%). Colostomy-free survival was 94.8% (95% CI = 88.0% to 97.8%), with a good continence after watch-and-wait (Vaizey = 3.4, SD = 3.9) and moderate after TEM (Vaizey = 9.7, SD = 5.1). CONCLUSIONS Organ preservation appears oncologically safe for selected rectal cancer patients with a cCR or near cCR after neoadjuvant chemoradiation when applying strict selection criteria and frequent follow-up, including endoscopy and MRI. The low colostomy rate and the good long-term functional outcome warrant discussing this option with the patient as an alternative to major surgery.

MRI and Diffusion-weighted MRI Volumetry for Identification of Complete Tumor Responders After Preoperative Chemoradiotherapy in Patients With Rectal Cancer: A Bi-institutional Validation Study.

Background: Retrospective single-center studies have shown that diffusion-weighted magnetic resonance imaging (DWI) is promising for identification of patients with rectal cancer with a complete tumor response after neoadjuvant chemoradiotherapy (CRT), using certain volumetric thresholds. Objective: This study aims to validate the diagnostic value of these volume thresholds in a larger, independent, and bi-institutional patient cohort. Methods: A total of 112 patients with locally advanced rectal cancer (2 centers) treated with a long course of CRT were enrolled. Patients underwent standard T2W-magnetic resonance imaging and DWI, both pre- and post-CRT. Two experienced readers independently determined pre-CRT and post-CRT tumor volumes (cm3) on T2W-magnetic resonance image and diffusion-weighted magnetic resonance image by means of freehand tumor delineation. Tumor volume reduction rates (&Dgr;volume) were calculated. Previously determined T2W and DWI threshold values for prevolume, postvolume, and &Dgr;volume were tested to “prospectively” assess their respective diagnostic value in discriminating patients with a complete tumor response from patients with residual tumor. Results: Twenty patients had a complete response. Using the average measurements between the 2 readers, areas under the curve for the pre-/post-/&Dgr;volumes was 0.73/0.82/0.78 for T2W-magnetic resonance imaging and 0.77/0.92/0.86 for DWI, respectively. For T2W-volumetry, sensitivity and specificity using the predefined volume thresholds were 55% and 74% for pre-, 60% and 89% for post-, and 60% and 86% for &Dgr;volume. For DWI volumetry, sensitivity and specificity were 65% and 76% for pre-, 70% and 98% for post-, and 70% and 93% for &Dgr;volume. Conclusions: Previously established DWI volume thresholds can be reproduced with good results. Post-CRT DWI volumetry offers the best results for the detection of patients with a complete response after CRT with an area under the curve of 0.92, sensitivity of 70%, and specificity of 98%.

Whole-liver CT texture analysis in colorectal cancer: Does the presence of liver metastases affect the texture of the remaining liver?

Background Liver metastases limit survival in colorectal cancer. Earlier detection of (occult) metastatic disease may benefit treatment and survival. Objective The objective of this article is to evaluate the potential of whole-liver CT texture analysis of apparently disease-free liver parenchyma for discriminating between colorectal cancer (CRC) patients with and without hepatic metastases. Methods The primary staging CT examinations of 29 CRC patients were retrospectively analysed. Patients were divided into three groups: patients without liver metastases (n = 15), with synchronous liver metastases (n = 10) and metachronous liver metastases within 18 months following primary staging (n = 4). Whole-liver texture analysis was performed by delineation of the apparently non-diseased liver parenchyma (excluding metastases or other focal liver lesions) on portal phase images. Mean grey-level intensity (M), entropy (E) and uniformity (U) were derived with no filtration and different filter widths (0.5 = fine, 1.5 = medium, 2.5 = coarse). Results Mean E1.5 and E2.5 for the whole liver in patients with synchronous metastases were significantly higher compared with the non-metastatic patients (p = 0.02 and p = 0.01). Mean U1.5 and U2.5 were significantly lower in the synchronous metastases group compared with the non-metastatic group (p = 0.04 and p = 0.02). Texture parameters for the metachronous metastases group were not significantly different from the non-metastatic group or synchronous metastases group (p > 0.05), although – similar to the synchronous metastases group – there was a subtle trend towards increased E1.5, E2.5 and decreased U1.5, U2.5 values. Areas under the ROC curve for the diagnosis of synchronous metastatic disease based on the texture parameters E1.5,2.5 and U1.5,2.5 ranged between 0.73 and 0.78. Conclusion Texture analysis of the apparently non-diseased liver holds promise to differentiate between CRC patients with and without metastatic liver disease. Further research is required to determine whether these findings may be used to benefit the prediction of metachronous liver disease.

T2 weighted signal intensity evolution may predict pathological complete response after treatment for rectal cancer

AbstractObjectivesTo determine the diagnostic value of T2-weighted signal intensity evolution in the tumour for detection of complete response to neoadjuvant chemoradiotherapy in patients with rectal cancer.MethodsThirty-nine patients diagnosed with locally advanced adenocarcinoma and treated with chemoradiotherapy (CRT), followed by surgery, underwent magnetic resonance imaging (MRI) before and after CRT on 1.5-T MRI using T2-weighted fast spin-echo (FSE) imaging. The relative T2-weighted signal intensity (rT2wSI) distribution in the tumour and post-CRT residual tissue was characterised by means of the descriptive statistical parameters, such as the mean, 95th percentile and standard deviation (SD). Receiver operating characteristic curves were used to determine the diagnostic potential of the CRT-induced alterations (Δ) in rT2wSI descriptives. The tumour regression grade (TRG) served as a histopathological reference standard.ResultsCRT induced a significant decrease of approximately 50% in all rT2wSI descriptives in complete responders (TRG1). This drop was significantly larger than for incomplete response groups (TRG2–TRG4). The ΔrT2wSI descriptives produced a high diagnostic performance for identification of complete responders, e.g. Δ95th percentile, ΔSD and Δmean resulted in accuracy of 92%, 90% and 82%, respectively.ConclusionsQuantitative assessment of the CRT-induced changes in the tumour T2-weighted signal intensity provides high diagnostic performance for selection of complete responders.Key Points• T2 weighted MRI helps predict response after chemoradiotherapy for rectal cancer. • Residual tumour and chemoradiotherapy-induced fibrosis have different T2 relaxation properties. • T2-weighted signal intensity evolution is a promising non-invasive marker of therapeutic response. • A pathologically complete response is associated with the largest signal intensity drop.

CT texture analysis in colorectal liver metastases: A better way than size and volume measurements to assess response to chemotherapy?

Background Response Evaluation Criteria In Solid Tumors (RECIST) are known to have limitations in assessing the response of colorectal liver metastases (CRLMs) to chemotherapy. Objective The objective of this article is to compare CT texture analysis to RECIST-based size measurements and tumor volumetry for response assessment of CRLMs to chemotherapy. Methods Twenty-one patients with CRLMs underwent CT pre- and post-chemotherapy. Texture parameters mean intensity (M), entropy (E) and uniformity (U) were assessed for the largest metastatic lesion using different filter values (0.0 = no/0.5 = fine/1.5 = medium/2.5 = coarse filtration). Total volume (cm3) of all metastatic lesions and the largest size of one to two lesions (according to RECIST 1.1) were determined. Potential predictive parameters to differentiate good responders (n = 9; histological TRG 1–2) from poor responders (n = 12; TRG 3–5) were identified by univariable logistic regression analysis and subsequently tested in multivariable logistic regression analysis. Diagnostic odds ratios were recorded. Results The best predictive texture parameters were Δuniformity and Δentropy (without filtration). Odds ratios for Δuniformity and Δentropy in the multivariable analyses were 0.95 and 1.34, respectively. Pre- and post-treatment texture parameters, as well as the various size and volume measures, were not significant predictors. Odds ratios for Δsize and Δvolume in the univariable logistic regression were 1.08 and 1.05, respectively. Conclusions Relative differences in CT texture occurring after treatment hold promise to assess the pathologic response to chemotherapy in patients with CRLMs and may be better predictors of response than changes in lesion size or volume.

Magnetization transfer ratio: a potential biomarker for the assessment of postradiation fibrosis in patients with rectal cancer.

ObjectivesMagnetization transfer-magnetic resonance imaging (MT-MRI) uses differences in the magnetization interaction of the free “unbound” water protons and the macromolecular-bound protons. The aim of this study was to evaluate whether the magnetization transfer ratio (MTR) may be used to identify fibrosis in patients with rectal cancer treated with chemoradiotherapy. Materials and MethodsThis study was part of a rectal cancer imaging study, which was approved by the local institutional review board. Twenty-six patients, treated with neoadjuvant chemoradiotherapy, underwent a standard MRI including T2-weighted sequences and a diffusion-weighted sequence. An axially oriented MT sequence was performed at the center of the (former) tumor location. Regions of interest were manually drawn on the MT-MRI (with reference to the T2-weighted and diffusion-weighted images), covering areas of residual tumor, fibrosis, or the normal or edematous rectal wall. The results were compared with that of the histopathological examination. Differences in MTR between the 4 tissue types were analyzed, and a receiver operating characteristic (ROC) curve was generated to assess the diagnostic potential. ResultsThirty-eight regions of interest were analyzed on the MT-MRI. The mean (SD) MTR of the fibrosis was 37.7% (2.7%), which was significantly higher than that of the residual tumor (29.6% [4.2%]; P < 0.001), the normal rectal wall (30.3% [4.7%]; P = 0.003), and the edematous rectal wall (18.2% [4.0%]; P < 0.001). The use of MTR resulted in an area under the ROC-curve of 0.96, a sensitivity of 88%, and a specificity of 90% for the diagnosis of fibrosis. ConclusionsMagnetization transfer ratio can be used to discriminate postradiation fibrosis from residual tumor and the normal rectal wall after chemoradiotherapy. Magnetization transfer imaging can thus be a promising tool for the unsolved dilemma of interpreting postradiation fibrosis in rectal cancer.

Prospective, Multicenter Validation Study of Magnetic Resonance Volumetry for Response Assessment After Preoperative Chemoradiation in Rectal Cancer: Can the Results in the Literature be Reproduced?

PURPOSE To review the available literature on tumor size/volume measurements on magnetic resonance imaging for response assessment after chemoradiotherapy, and validate these cut-offs in an independent multicenter patient cohort. METHODS AND MATERIALS The study included 2 parts. (1) Review of the literature: articles were included that assessed the accuracy of tumor size/volume measurements on magnetic resonance imaging for tumor response assessment. Size/volume cut-offs were extracted; (2) Multicenter validation: extracted cut-offs from the literature were tested in a multicenter cohort (n=146). Accuracies were calculated and compared with reported results from the literature. RESULTS The review included 14 articles, in which 3 different measurement methods were assessed: (1) tumor length; (2) 3-dimensonial tumor size; and (3) whole volume. Study outcomes consisted of (1) complete response (ypT0) versus residual tumor; (2) tumor regression grade 1 to 2 versus 3 to 5; and (3) T-downstaging (ypT<cT). In the multicenter cohort, best results were obtained for the validation of the whole-volume measurements, in particular for the outcome ypT0 (accuracy 44%-80%), with the optimal cut-offs being 1.6 cm(3) (after chemoradiation therapy) and a volume reduction of Δ80% to 86.6%. Accuracies for whole-volume measurements to assess tumor regression grade 1 to 2 were 52% to 61%, and for T-downstaging 51% to 57%. Overall accuracies for tumor length ranged between 48% and 53% and for 3D size measurement between 52% and 56%. CONCLUSIONS Magnetic resonance volumetry using whole-tumor volume measurements can be helpful in rectal cancer response assessment with selected cut-off values. Measurements of tumor length or 3-dimensional tumor size are not helpful. Magnetic resonance volumetry is mainly accurate to assess a complete tumor response (ypT0) after chemoradiation therapy (accuracies up to 80%).

Quality of Life in Rectal Cancer Patients After Chemoradiation: Watch-and-wait Policy Versus Standard Resection – A Matched-controlled Study

BACKGROUND: Fifteen to twenty percent of patients with locally advanced rectal cancer have a clinical complete response after chemoradiation therapy. These patients can be offered nonoperative organ-preserving treatment, the so-called watch-and-wait policy. The main goal of this watch-and-wait policy is an anticipated improved quality of life and functional outcome in comparison with a total mesorectal excision, while maintaining a good oncological outcome. OBJECTIVE: The aim of this study was to compare the quality of life of watch-and-wait patients with a matched-controlled group of patients who underwent chemoradiation and surgery (total mesorectal excision group). DESIGN: This was a matched controlled study. SETTINGS: This study was conducted at multiple centers. PATIENTS: The study population consisted of 2 groups: 41 patients after a watch-and-wait policy and 41 matched patients after chemoradiation and surgery. Patients were matched on sex, age, tumor stage, and tumor height. All patients were disease free at the moment of recruitment after a minimal follow-up of 2 years. MAIN OUTCOME MEASURES: Quality of life was measured by validated questionnaires covering general quality of life (Short Form 36, European Organization for Research and Treatment of Cancer QLQ-C30), disease-specific total mesorectal excision (European Organization for Research and Treatment of Cancer QLQ-CR38), defecation problems (Vaizey and low anterior resection syndrome scores), sexual problems (International Index of Erectile Function and Female Sexual Function Index), and urinary dysfunction (International Prostate Symptom Score). RESULTS: The watch-and-wait group showed better physical and cognitive function, better physical and emotional roles, and better global health status compared with the total mesorectal excision group. The watch-and-wait patients showed fewer problems with defecation and sexual and urinary tract function. LIMITATIONS: This study only focused on watch-and-wait patients who achieved a sustained complete response for 2 years. In addition, this is a study with a limited number of patients and with quality-of-life measurements on nonpredefined and variable intervals after surgery. CONCLUSIONS: After a successful watch-and-wait approach, the quality of life was better than after chemoradiation and surgery on several domains. However, chemoradiation therapy on its own is not without long-term side effects, because one-third of the watch-and-wait patients experienced major low anterior resection syndrome symptoms, compared with 66.7% of the patients in the total mesorectal excision group. See Video Abstract at http://links.lww.com/DCR/A395.

Whole-liver diffusion-weighted MRI histogram analysis: effect of the presence of colorectal hepatic metastases on the remaining liver parenchyma

Objectives To explore whether whole-liver diffusion-weighted MRI analysis (of the apparently normal liver parenchyma) can help differentiate between patients with colorectal liver metastasis and controls without liver disease. Materials and methods Ten patients with colorectal liver metastasis and 10 controls with no focal/diffuse liver disease underwent liver MRI at 1.5 T including diffusion-weighted imaging (DWI; b-values 0, 50, 100, 500, 750, 1000). Apparent diffusion coefficient (ADC) maps were calculated from the DWI images to carry out quantitative diffusion analyses. An experienced reader performed segmentation of the apparently nondiseased liver (excluding metastases/focal liver lesions) on the ADC maps. Histogram ADC parameters were calculated and compared between the patients and the controls. Results The mean liver ADC was 0.95×10−3 mm2/s for the patients versus 1.03×10−3 mm2/s for the controls (P=0.42). The fifth percentile of the ADC was significantly lower for the patients compared with the controls (0.45 vs. 0.69 10−3 mm2/s, P=0.01). The SD was significantly higher in the patient group (0.30 vs. 0.22, P<0.001). Median, skewness, kurtosis, and 30th–95th percentile were not significantly different between the two groups. Areas under the receiver operator characteristics curves to differentiate patients with metastatic liver involvement from healthy controls without liver disease were 0.79 for the fifth percentile and 0.95 for the SD. Conclusion Whole-liver diffusion-weighted MRI histogram analysis showed a significant shift towards lower fifth percentile ADC values and higher SD in patients with colorectal liver metastasis compared with controls without liver disease.

MRI surveillance for the detection of local recurrence in rectal cancer after transanal endoscopic microsurgery

ObjectivesTo evaluate diagnostic performance of follow-up MRI for detection of local recurrence of rectal cancer after transanal endoscopic microsurgery (TEM).MethodsBetween January 2006 and February 2014, 81 patients who underwent TEM were included. Two expert readers (R1 and R2), independently evaluated T2-weighted (T2W) MRI and diffusion-weighted (DWI) MRI for the detection of local recurrence, retrospectively, and recorded confidence on a five-point scale. Diagnostic performance of follow-up MRI was assessed using ROC-curve analysis and kappa statistics for the reproducibility between readers.Results293 MRIs were performed, 203 included DWI. 18 (22%) patients developed a local recurrence: luminal 11, nodal two and both five. Areas under the curve (AUCs) for local recurrence detection were 0.72 (R1) and 0.80 (R2) for T2W-MRI. For DWI, AUCs were 0.70 (R1) and 0.89 (R2). For nodal recurrence AUCs were 0.72 (R1) and 0.80 (R2) for T2W-MRI. Reproducibility was good for T2W-MRI (κ0.68 for luminal and κ0.71 for nodal recurrence) and moderate for DWI (κ0.57). AUCs and reproducibility for recurrence detection increased during follow-up.ConclusionsFollow-up with MRI after TEM for rectal cancer is feasible. Postoperative changes can be confusing at the first postoperative MRI, but during follow-up diagnostic performance and reproducibility increase.Key Points• Follow-up with MRI is feasible for follow-up after TEM for rectal cancer.• DWI-MRI is a useful addition to detect recurrences after TEM.• Postoperative changes can be confusing and can lead to underestimation of recurrence.• Appearance of intermediate signal at T2W-MRI is suspicious for recurrence.• Nodal staging remains challenging.