Sanne M. E. Engelen

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.

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.

Locally advanced rectal cancer: MR imaging for restaging after neoadjuvant radiation therapy with concomitant chemotherapy. Part I. Are we able to predict tumor confined to the rectal wall?

PURPOSE To retrospectively assess accuracy of magnetic resonance (MR) imaging after radiation therapy with concomitant chemotherapy for downsizing of the primary lesion to ypT0-2 tumor confined to rectal wall in locally advanced rectal cancer, with histopathologic findings as reference standard, and to evaluate additional value of volumetric analysis. MATERIALS AND METHODS The institutional review board approved the study and waived informed consent. Sixty-seven patients met criteria of the study. T2-weighted MR images obtained before and after radiation therapy with concomitant chemotherapy were assessed for tumor stage by expert abdominal radiologist, colorectal surgeon, and general radiologist. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated; tumor volume was measured (compared with Mann-Whitney U test). Findings were correlated with histopathologic findings. RESULTS Sixty-seven patients (38 men, 29 women; mean age, 63 years) who underwent radiation therapy with concomitant chemotherapy and surgery (all but one) were evaluated. The PPV for prediction of tumor confined to rectal wall (ypT0-2) was 91% (10 of 11), 86% (six of seven), and 88% (seven of eight) for expert abdominal radiologist, surgeon, and general radiologist, respectively. In 24 patients, sensitivity was 42% (10), 25% (six), and 29% (seven). ypT0-2 tumors had significantly smaller volumes than did ypT3-4 tumors before radiation therapy with concomitant chemotherapy (55 vs 92 cm(3), P = .038). Volume reduction rates were significantly higher in ypT0-2 than in ypT3-4 tumors (89% vs 61%, P < .001). If volume before radiation therapy with concomitant chemotherapy was 50 cm(3) or smaller and volume reduction rate was 75% or higher, excised tumor was always confined to rectal wall (ypT0-2). By using these criteria, 43% (six of 14) of cases with overstaging could have been predicted to be ypT0-2 tumors correctly. CONCLUSION Downsizing to ypT0-2 tumors can be accurately predicted by combining morphologic tumor staging predictions with results from volumetric analyses. MR images obtained after radiation therapy with concomitant chemotherapy might be helpful in more individualized treatment planning.

Accuracy of Gadofosveset-enhanced MRI for Nodal Staging and Restaging in Rectal Cancer

Objective:To prospectively assess the accuracy of gadofosveset-enhanced magnetic resonance imaging (MRI) for nodal staging and restaging in rectal cancer. Background:Accurate preoperative assessment of nodal disease in rectal cancer impacts treatment management. Staging with modern imaging techniques (computed tomography, MRI and endorectal ultrasound) is insufficiently accurate for clinical decision making. This study aims to assess the accuracy of MRI using a novel lymph node magnetic resonance contrast, gadofosveset, for nodal staging and restaging in rectal cancer using a per node comparison with histology as the reference standard. Methods:Sixty-eight patients underwent gadofosveset-enhanced MRI at 1.5T. Twenty-six patients (primary staging group I) were treated with total mesorectal excision (with or without preoperative 5 × 5 Gy) and 42 (restaging group II) underwent a long course of chemoradiation followed by a restaging MRI and resection. Nodes were scored as benign or malignant by 2 radiologists (experienced and junior reader) first on standard MRI, then on gadofosveset-enhanced MRI. For group I the primary staging MRI was compared with histology. In group II the second, restaging MRI was compared with histology. Results:For the experienced reader, sensitivity, specificity, and area under the ROC-curve (AUC) improved from 76%, 82% and 0.84 on standard MRI to 80%, 97% and 0.96 on gadofosveset-MRI (P < 0.001). For the junior reader results improved from 69%, 85%, and 0.85 on standard MRI to 70%, 95%, and 0.93 on gadofosveset-MRI (P = 0.03). Interobserver agreement was good on both standard MRI (&kgr; 0.73) and gadofosveset-MRI (&kgr; 0.71). Conclusions:This study shows high reproducibility and significantly improved accuracy compared to standard MRI for gadofosveset-enhanced MRI for nodal staging and restaging in rectal cancer.

Locally advanced rectal cancer: MR imaging for restaging after neoadjuvant radiation therapy with concomitant chemotherapy. Part II. What are the criteria to predict involved lymph nodes?

PURPOSE To prospectively determine diagnostic performance of predictive criteria for nodal restaging after radiation therapy with concomitant chemotherapy by using ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging in patients with rectal cancer. MATERIALS AND METHODS After institutional review board approval and informed consent were obtained, 39 patients (24 men, 15 women; mean age, 64 years) with rectal cancer underwent USPIO-enhanced two-dimensional (2D) T2-weighted fast spin-echo, three-dimensional (3D) T1-weighted gradient-echo, and 3D T2*-weighted MR for restaging. Two observers evaluated nodes for border irregularity, short- and long-axis diameters, and estimated percentage of white region (<30%, 30%-50%, or >50%) within the node (3D T2*-weighted images). Ratio of the measured surface area of the white region within the black node to the measured surface area of the total node (Ratio(A)) was calculated. Signal intensity (SI) in gluteus muscle (SI(GM)) and in total node (SI(TN)) were used to calculate SI(TN)/SI(GM) ratio. Histopathologic findings were reference standard. Receiver operating characteristic (ROC) curves were compared and interobserver agreement was determined. RESULTS Lesion-by-lesion analysis was feasible in 201 lymph nodes. Area under the ROC curve (AUC) of border and short- and long-axis diameters for observer 1 were 0.85, 0.87, and 0.88 and for observer 2 were 0.70, 0.89, and 0.87, respectively. AUC for estimated percentage of white region within the node, Ratio(A), and SI(TN)/SI(GM) ratio for observer 1 were 0.98, 0.99, and 0.62 and for observer 2 were 0.97, 0.98, and 0.65, respectively. AUC for USPIO-enhanced MR criteria was significantly better than AUC for conventional MR criteria (P < .01). All criteria except border irregularity and SI(TN)/SI(GM) ratio showed high interobserver agreement (kappa > 0.79). CONCLUSION The most reliable predictors for identifying benign nodes after radiation therapy with concomitant chemotherapy by using USPIO-enhanced MR imaging for restaging in patients with rectal cancer were estimated percentage of white region within the node and Ratio(A). Measurements on standard 2D T2-weighted fast spin-echo images versus primary staging results offer reasonably good accuracy to identify benign lymph nodes after therapy.

Modern multidisciplinary treatment of rectal cancer based on staging with magnetic resonance imaging leads to excellent local control, but distant control remains a challenge.

AIM The purpose of this multicenter cohort study was to evaluate whether a differentiated treatment of primary rectal cancer based on magnetic resonance imaging (MRI) can reduce the number of incomplete resections and local recurrences and improve recurrence-free and overall survival. METHODS From February 2003 until January 2008, 296 patients with rectal cancer underwent preoperative MRI using a lymph node specific contrast agent to predict circumferential resection margin (CRM), T- and N-stage. Based on expert reading of the MRI, patients were stratified in: (a) low risk for local recurrence (CRM>2mm and N0 status), (b) intermediate risk and (c) high risk (close/involved CRM, N2 status or distal tumours). Mainly based on this MRI risk assessment patients were treated with (a) surgery only (TME or local excision), (b) preoperative 5 × 5 Gy+TME and (c) a long course of chemoradiation therapy followed by surgery after a 6-8 week interval. RESULTS Overall 228 patients underwent treatment with curative intent: 49 with surgery only, 86 with 5 × 5 Gy and surgery and 93 with chemoradiation and surgery. The number of complete resections (margin>1mm) was 218 (95.6%). At a median follow-up of 41 months the three-year local recurrence rate, disease-free survival rate and overall survival rate is 2.2%, 80% and 84.5%, respectively. CONCLUSION With a differentiated multimodality treatment based on dedicated preoperative MR imaging, local recurrence is no longer the main problem in rectal cancer treatment. The new challenges are early diagnosis and treatment, reducing morbidity of treatment and preferably prevention of metastatic disease.

Mri After Chemoradiotherapy of Rectal Cancer: A Useful Tool to Select Patients for Local Excision

PURPOSE: If identification of good responders to neoadjuvant chemoradiotherapy in rectal cancer is possible, there might be opportunities for local excision in selected patients. The aim of this study was to determine whether postchemoradiation MRI in rectal cancer can accurately identify ypT0 to 2/ypN0, because both features are essential for identification of good responders. METHODS: Seventy-nine patients (4 hospitals) underwent postchemoradiation MRI, 62 received a lymph node-specific contrast agent (ultrasmall superparamagnetic iron oxide). An expert and general radiologist prospectively predicted whether the tumor penetrated the mesorectal fat and whether nodes were sterilized after chemoradiation. Histology was the reference standard. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: For prediction of whether a tumor penetrated the bowel wall, there was an negative predictive value of 0.90 and 0.76 for the expert and general radiologist, respectively. The negative predictive value for prediction of nodal status was 0.95 and 0.85 for expert and general radiologist, respectively. CONCLUSION: This prospective multicenter study demonstrates that MRI with a lymph node-specific contrast agent interpreted by an expert radiologist can select ypT0 to 2/ypN0 rectal cancer with low risk of undetected nodal metastases or invasion through the bowel wall. These patients could thus have been selected for local excision. However, future studies will have to prove equal outcome of such a modified surgical approach compared with current practice.

Role of Preoperative Local and Distant Staging in Rectal Cancer

Preoperative imaging in rectal cancer is very important, as accurate staging determines optimal treatment strategy. In this review, imaging modalities for locoregional and distant staging in rectal cancer are discussed. For local staging, superficial tumors are best staged using endorectal US (EUS), as EUS is the most accurate modality for assessment of tumor ingrowth into the rectal wall layers. The more advanced tumors are best imaged using MRI, because MRI accurately predicts the distance from tumor to mesorectal fascia, and thus the circumferential resection margin (CRM), as well as possible invasion into surrounding organs. For the prediction of the nodal status none of the three imaging modalities - EUS, MRI and CT - can be reliably used for clinical decisionmaking. Only MRI using lymph node specific contrast (such as ultrasmall paramagnetic iron oxide-enhanced MRI) seems promising for the detection of nodal disease. For the detection of distant metastases transabdominal ultrasound and chest X-ray are used as a primary screening tool. However, for the high prevalence group (stage III) both methods are insufficiently sensitive, and CT of the chest plus abdomen is preferred.

Magnetic Resonance Imaging of Anorectal Diseases

The selective use of magnetic resonance imaging (MRI) has provided high resolution images of soft tissue for the management of cancer and complicated fistula-in-ano. It also has provided a better understanding of normal anorectal anatomy and the functional interaction of the pelvic floor and perineal structures during provocative maneuvers such as defecation, squeezing, and straining. Its use in rectal cancer has better defined the role of neoadjuvant therapies during follow-up. In complex cryptogenic fistula and perianal Crohn’s disease, MRI has assisted in the use of new reoperative techniques such as the LIFT procedure (ligation of intersphincteric fistula tract), fistula plugs, and fibrin glues, as well as in identifying patients best suited to advancement anoplasty and bowel diversion. This chapter outlines the normal (magnetic resonance) anatomy of the anorectum and the role of MRI in staging rectal cancer and anorectal fistulas, the interpretation of which has proven essential in the reconstructive/reoperative case.

Vasovist ® in Lymph Node Imaging: Present Status and Future Development

Nodal tumor spread in cancer patients is associated with a poor prognosis [1–;3]. Multimodality treatment in cancer — combining surgery with pre- and/or postoperative systemic +/− radiation therapy — aims at eradicating microscopic tumor deposits in the surgical bed and locoregional nodes, as well as at sterilizing occult metastases in distant organs and distant lymph nodes. The effectiveness of multimodality treatment for the high-risk groups has been shown in multiple cancer treatment trials [4]. Combined preoperative modality treatment, however, carries a considerable perioperative morbidity and mortality [5, 6, 7] and it is questioned whether, with multimodality treatment of all cancer patients, the overall increased morbidity will outweigh the clinical effectiveness. The Dutch TME trial has shown in rectal cancer surgery that when rectal tumor nodes were involved, the local recurrence rate at 5 years was significantly lower for patients who received standard preoperative radiation therapy compared with patients who underwent immediate surgery. However, this was at the expense of radiotherapy toxicity and a significant increase in perioperative morbidity in terms of perineal wound leakage [8].