Local Staging of Rectal Cancer: A Review of Imaging

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1 CME JOURNAL OF MAGNETIC RESONANCE IMAGING 33: (2011) Review Local Staging of Rectal Cancer: A Review of Imaging Regina G.H. Beets-Tan, MD, PhD, 1 * and Geerard L. Beets, MD, PhD 2 During the past decades the management of patients with rectal cancer has substantially changed, with a significant reduction in local recurrence rates following the introduction of better imaging, better surgery, and more efficient neoadjuvant therapy. This review discusses the clinically relevant information radiologists should know on staging of rectal cancer patients. The crucial role of the radiologist in patient management is explained. Furthermore, the evidence for the use of magnetic resonance imaging (MRI) in staging and restaging of rectal cancer patients as well as the main features that need to be evaluated when interpreting rectal cancer MRI are given. New diagnostic challenges as a result of new treatment options are also discussed. Key Words: review; rectal cancer; staging; magnetic resonance imaging J. Magn. Reson. Imaging 2011;33: VC 2011 Wiley-Liss, Inc. CLINICAL BACKGROUND IN DEVELOPED COUNTRIES colorectal cancer is the third most common cancer in men after prostate and lung, and the second most common in women after breast cancer. Worldwide, colorectal cancer accounts for 8% of all cancer mortality (1). One-third of colorectal cancers occur in the rectum and in addition to the risk for distant metastases an important concern in rectal cancer is a high local recurrence rate, as opposed to colonic cancer. Until years ago local recurrence rates of 30% were not uncommon, with a wide variability ranging from 10% 50%. Surgery The increasing knowledge that the high local recurrence rate was related to the quality of the surgery led 1 GROW School for Oncology & Developmental Biology. Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands. 2 GROW School for Oncology & Developmental Biology. Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands. *Address reprint requests to: R.G.H.B.-T., Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. r.beets.tan@mumc.nl Received January 4, 2010; Accepted December 7, DOI /jmri View this article online at wileyonlinelibrary.com. to the improvement and standardization of the surgical technique into a procedure that has become known as the total mesorectal excision (TME) (2). In this procedure the rectum is removed together with the mesorectum and the surrounding envelope, the mesorectal fascia. It is in this mesorectum that most of the involved lymph nodes and tumor deposits can be found. With the old technique of blunt dissection there was a risk of leaving behind parts of the mesorectum, with the potential for recurrence. This concept was reinforced by the important findings on the circumferential surgical resection margin (CRM) (3,4). Until that time surgeons and pathologist were mainly concerned with proximal and distal resection margins, and much less with the anterior, posterior, and lateral margins. It became clear that the closer the tumor comes to the circumferential resection margin, and the more irregular that resection margin is, the higher the risk for recurrence (4). Presumably this is due to the higher risk of leaving behind parts of the primary tumor, involved lymph nodes, and isolated tumor deposits. Adjuvant Therapy Another approach to improve local control is the use of adjuvant therapy. Many trials have addressed the benefit of various preoperative and postoperative (chemo)radiation regimes. Overall, one can conclude that the more effective regimes provide around a 50% reduction in local recurrence rate when compared to surgery alone. After a consensus statement of the National Institutes of Health (NIH) in 1990, postoperative chemoradiation became the standard for stage II III rectal cancer in the US and many other countries (5). In 2004 a trial convincingly showed that chemoradiation is better administered preoperatively than postoperatively, and this gradually led to a change in practice (6). In Europe several large trials have evaluated a short 1-week preoperative course of 5 5Gyfollowed by immediate surgery, and all trials showed an important benefit of this regimen over surgery alone (7 9). This short course of preoperative radiotherapy has now become standard in many European institutions for the majority of rectal cancer patients. The short course is insufficient for some of the more advanced tumors where downsizing is required, and these patients are generally treated with a long course of chemoradiation. VC 2011 Wiley-Liss, Inc. 1012

2 Rectal Cancer Imaging 1013 A preoperative course of chemoradiation typically consists of a 6-week delivery of a dose around 50 Gy with a concomitant chemotherapy often of the 5-fluorouracil (5-FU)-type. The resection is performed after an interval of 4 8 weeks after completion of the chemoradiation. During the chemoradiation and the interval, the tumors often shrink, called downsizing, and sometimes even completely disappear. Although the exact benefit is not yet established, this offers the possibility to perform a smaller resection in case of a previously involved surrounding organ in very advanced tumors, or the possibility to perform more sphincter-saving surgery in distal tumors. Still considered experimental, it even offers the option in very good responders to perform a local excision of the small tumor remnant, or to consider a nonoperative approach in a clinical complete responder (10 12). MULTIDISCIPLINARY DECISION-MAKING AND THE ROLE OF THE RADIOLOGIST In the decision process whether or not to give neoadjuvant treatment and, if so, which type of neoadjuvant treatment, there is an increasing need to assess the risk for local recurrence with preoperative imaging. Stratification in risk for local recurrence allows a costeffective use of neoadjuvant therapy, with the aim to avoid undertreatment and minimize overtreatment. The most important risk factors for local recurrence that imaging should address are: the T stage of the primary tumor, the distance of the tumor to the mesorectal fascia, and the nodal status. Restaging after chemoradiation was traditionally not performed but may become important in the near future, as discussed below. What is important in the decision for an individual patient depends not only on the patient and the tumor, but also on the clinician and institution treating the patient. When a team only uses two basic treatment options, surgery for stage I disease and neoadjuvant long course chemoradiation for all other patients, there is little added value of assessing the distance from the mesorectal fascia, whereas this is very important information when clinicians are also considering the third treatment option of a short preoperative course of radiotherapy. The nodal status is less relevant for decision-making in institutions where most patients are treated with some form of neoadjuvant treatment, but may be very relevant in institutions were stage I disease and even some stage II patients are treated with surgery only. Restaging after chemoradiation only makes sense when clinicians are willing to adapt the treatment according to the response. It is important for radiologists to be aware of the national and local treatment policies to estimate the relevance of the imaging information they provide. The best way to achieve optimal management is in multidisciplinary meetings on the management of individual patients (13). The interaction between the surgical, medical, and radiation oncologist, and the pathologist and radiologist and others involved, are not only beneficial for the treatment of the patient, but this is also an ideal forum to gain mutual knowledge. The role of the radiologist is to help the decision process by giving information on the preoperative imaging, to help quantifying risks for recurrence, and to advise on alternative staging methods, taking into account information that could come from other specialties, like endorectal ultrasound and positron emission tomography (PET) scans. This requires a full understanding of the disease as well as a full understanding of what impact false- positive or false-negative findings can have on treatment choice and outcome. The more accurate the preoperative risk assessment is done in pretreatment setting, the better the multidisciplinary team (MDT) can opt for the treatment scheme with the highest chance for cure outweighing the chance of increased morbidity or mortality of an aggressive treatment against the chance for local control. PRIMARY IMAGING OF RISK FACTORS FOR LOCAL RECURRENCE Tumor Stage Endorectal ultrasound (EUS) has long been the only imaging method for staging rectal cancer and is very accurate for assessing the tumor ingrowth into the bowel wall. Initial studies reported overall accuracies for EUS and T-staging varying between 69% and 97%. EUS is very accurate for the discrimination between T1, limited to the submucosa, and T2 tumors with ingrowth in the muscular bowel wall, because it is the only method that images all the layers of the bowel wall (14,15). Although the sensitivity for predicting a tumor that penetrates the bowel wall (T3) is high (90%), the specificity is lower (75%), indicating overstaging errors, caused by T2 tumors that show spontaneous desmoplastic stranding in the perirectal fat. EUS has the same difficulties as all other imaging techniques in differentiating between fibrotic stranding with or without tumor cells. Furthermore, a selection bias occurred in many initial single-center studies where the majority of patients included had nonstenosing tumors. Although EUS is accurate in identifying large T3 and T4 tumors, it is limited like endorectal magnetic resonance imaging (MRI) in that accurate positioning of the probe remains difficult or impossible in high and/or stenosing tumors. Two articles by German groups provide level 2 evidence of the performance of EUS (16,17). In two multicenter studies, one including 499 and one including 3501 patients, EUS in a general setting showed accuracy and sensitivity of EUS of 30% 40% less than in the initial expert single-center reports. The main reason for the lower performance in general centers is the operator dependency of EUS. A further downside of EUS is the inherent low contrast resolution and the limited field of view, making it a less suitable method for the evaluation of the mesorectal fascia in areas other than prostate, vagina, and seminal vesicles. Planar imaging techniques such as computed tomography (CT) and MRI do not share some of the disadvantages of EUS. The performance of MRI and CT is less subject to the performer s/reader s skill and the availability of these images for surgeons and

3 1014 Beets-Tan and Beets Figure 1. Axial MR image of a patient with T4 rectal cancer. The tumor penetrates the mesorectal fascia anteriorly (black arrow) and invades the cervix (white arrow). radiotherapists for planning the treatment has made MRI the preferred imaging technique for local staging of rectal cancer. Phased array MRI showed overall accuracies for T staging between 65% and 86%. MRI is very accurate for identifying large T3 and T4 tumors (Fig. 1), with sensitivities for prediction of T3 varying between 80% 86% and specificity varying between 71% 76% (15). Most staging failures with phased array MRI occur in the differentiation between T1 and T2 lesions and between T2 and borderline T3 lesions. A T1 tumor, limited to the submucosa, cannot be reliably distinguished from T2 because the submucosal layer is generally not visualized on phased array MRI. Like EUS, MRI has some difficulty in determining lesions on the border of T2 and T3 with a desmoplastic reaction (18) (Figs. 2, 3). There are very few studies investigating the assessment of T stage with conventional or multislice spiral CT and the results are difficult to interpret. Due to the inherent low contrast resolution, CT lacks sufficient accuracy for distinction between the individual bowel wall layers, although CT can be useful to exclude large and locally advanced tumors (19). Studies comparing CT and MRI in patients with locally advanced disease have generally shown a tendency for CT to overstage disease. The results are somewhat conflicting, but it is generally felt that MR performs better than CT (19 21). Sacral bone invasion was better depicted on MRI as well as demonstration of involvement of urinary bladder and uterus (20). Circumferential Resection Margin (CRM) Many single-center studies have shown that MRI is highly accurate for the prediction of an involved CRM (18,22 24). The results of a systematic review of all published data so far clearly confirms the high performance of MRI for CRM prediction in rectal cancer surgery (25). The pooled data analysis of 7 studies shows a sensitivity varying between 60% 88% and Figure 2. Axial MR images of two patients with rectal tumors that show desmoplastic strands growing into the perirectal fat. (a) A pt2 tumor, while (b) is a pt3 tumor. Note that it is not possible to distinguish between a T2 and T3 tumor on these images. When a tumor shows desmoplasia, MRI cannot differentiate between desmoplasia without (white arrows in a) and with (black arrows in b) tumor. Reprinted from The Lancet 2001 Feb 17;357(9255): , Beets-Tan RG, Beets GL, Vliegen RF, Kessels AG, Van Boven H, De Bruine A, von Meyenfeldt MF, Baeten CG, van Engelshoven JM. Accuracy of magnetic resonance imaging in prediction of tumour-free resection margin in rectal cancer surgery. With permission from Elsevier.

4 Rectal Cancer Imaging 1015 Figure 3. Axial MR images of two patients with rectal tumors that show desmoplastic strands growing into the perirectal fat. (a) A pt2 tumor, while (b) is a pt3 tumor. Note again that is not possible to distinguish between a T2 and T3 tumor when the tumor shows desmoplastic reactions. MRI cannot differentiate between desmoplasia without and with tumor. specificity between 73% 100% (25). From the individual studies, however, it is still unclear how often the information of MRI influenced the treatment, and how this was dealt with in the analysis. An audit on outcome of rectal resections in our department has shown that with standard use of MRI in the preoperative workup the proportion of incomplete resections has been reduced by half, through better selection for neoadjuvant treatment and extensive surgery (26). A large European study in 11 centers with 408 patients showed that MRI agreed in 82% with histology for the prediction of tumor extent in the mesorectal fat and showed a sensitivity of 59%, specificity of 92%, positive predictive value (PPV) of 54%, and NPV of 94% for the prediction of an involved CRM (Figs. 4, 5) (27). The results suggest that after a short learning curve MRI is also reliable outside expert centers. Modern multislice CT (MSCT) is faster in acquisition and less expensive than MRI and, when accurate, would allow local and distant staging in a single Figure 4. Axial T2W FSE MR image of a male patient with a high-risk rectal tumor stratified for long course chemoradiation. There is a bulky T3 tumor in the low rectum with involved resection margin anteriorly (white arrow). Figure 5. Coronal MR image of a patient with low rectal tumor. MRI is highly predictive for tumors limited to the bowel wall. The hypointense right wall (black arrow) and left wall (white arrow) indicates that the tumor is a T2 and does not threaten the mesorectal fascia.

5 1016 Beets-Tan and Beets examination. A Dutch multicenter study has investigated CT for the prediction of an involved CRM with the first generations 4 16 slice CT techniques in 250 patients (28). The results show that MSCT was accurate in the high tumors that have a wide and free CRM, with a sensitivity, specificity, PPV, and NPV of 70%, 96%, 85%, and 92%, respectively, for prediction of an involved CRM. For low rectal tumors the accuracy was only moderate. Another study also found a high NPV for the prediction of an involved CRM and considerable overstaging (29). The inherent lowcontrast resolution of CT together with the complex tapered anatomy of the mesorectum with little or no fat low down at the pelvic floor may all contribute to the inaccuracy of CT in this area. The poor accuracy of CT in low anteriorly located tumors was confirmed by another study that also demonstrated a high variability among observers for prediction of involved CRM (30). The role of new generation MSCT for CRM has so far not been established and strong evidence and comparison with MRI is lacking. Nodal Stage With the change from postoperative to preoperative chemoradiation there was an increasing need to identify involved lymph nodes in order to minimize both over- and undertreatment. In addition, there is a small group of patients with a superficial tumor where the surgeon is considering a local excision, a procedure with minimal morbidity and mortality but with a small risk of leaving behind involved lymph nodes in the mesorectum. An accurate selection of node negative disease would be of help in the selection of this procedure. Identifying nodal disease with imaging remains difficult. Size criteria result in only a moderate accuracy. Lymph nodes with a diameter of 10 mm or more are invariable malignant, but as many as 94% of the involved nodes are smaller than 5 mm (31). A recent meta-analysis showed that the receiver operator characteristic (ROC) curves of CT, EUS, and MRI were only moderate (25). Although in this meta-analysis EUS performed slightly better than CT or MRI, a recent study showed nodal understaging in at least 22% of patients staged with EUS or MRI (32). Although modern high-resolution MR images allow visualization of lymph nodes as small as 2 mm, reliable differentiation of the malignant from benign nodes is not possible in the very small nodes. Lymph node characterization is more accurate with the larger (5 mm) nodes that can be evaluated for their size, shape, border, and signal intensity. A round node that is larger than 8 mm in size, has an indistinct border, and is heterogeneous in signal is very much likely to be involved (Fig. 6) (33,34). In a rectal cancer with only small lymph nodes in the mesorectum a standard MRI will not provide sufficient accuracy. Lymph node-specific contrast agents such as ultrasmall superparamagnetic particles of iron oxide (USPIO) have been reported to provide a higher accuracy for lymph node characterization in a variety of cancers (35). This has also been confirmed for rectal cancer in Figure 6. Axial T2W FSE MR image of a patient with T3N2 rectal tumor. Note the node (black arrow) behind and at tumor level that is round, larger than 8 mm in size, and isointense to the tumor (white arrow). Based on its MR characteristics the node is likely to be involved. a multicenter study, showing a high sensitivity and specificity (91% and 93%, respectively) for the prediction of nodal status per patient. The problem at present, however, is that USPIO contrast has not been FDA- or EMEA-approved, and it will not be available for clinical use in the coming years. 18F-Fluorodeoxyglucose (FDG)-PET has shown disappointing results for N-staging in rectal cancer. Heriot et al (36) demonstrated a sensitivity of only 29% for predicting mesorectal lymph node involvement, probably due to the limitation of the presently available low-resolution PET machines to detect small volume disease. RESTAGING AFTER CHEMORADIATION THERAPY Modern neoadjuvant treatment schedules with their significant downsizing and downstaging have raised the question of whether or not it is safe to change the original treatment plan after a good response. For patients with a tumor in very close proximity or invading the anal sphincter or a surrounding organ, this could result in sparing of the sphincter or organ. Reliable imaging can help in this decision. More controversial is a local excision of the tumor remnant in the bowel wall after a very good response, or even a completely nonoperative wait-and-see approach in very selected patients with a complete response. For the selection of patients for these two treatment options a good restaging procedure of both the primary tumor and the lymph nodes is essential. Although FDG-PET can predict the degree of response 2 weeks after the start of the chemoradiation (37,38), the assessment of the response is best performed at the end of the interval between

6 Rectal Cancer Imaging 1017 Figure 7. Axial T2-weighted FSE MR images of a patient with rectal tumor (white arrow) before chemoradiation (a) and 8 weeks after chemoradiation (b). The tumor responded well to the chemoradiation with remaining thickened, hypointense wall corresponding to fibrosis at the site of the previous tumor (black arrow). It is very difficult on MRI to differentiate between fibrosis with and without tumor remnants. At histology residual tumor was still found, staged as yt3. chemoradiation and surgery, typically 6 8 weeks. The main difficulty in assessing the response to chemoradiation is the distinction between fibrosis with and without residual tumor. Studies evaluating the ability of MRI after chemoradiation to predict tumor clearance from the mesorectal fascia have shown a high NPV of 100%, at the expense of many false-positives leading to a low PPV of 50% 60% (39,40). The areas of hypointense fibrotic tissues are difficult to interpret, and radiologists tend to err on the safe side, leading to overstaging and relatively high FP rates. The same problem in interpreting fibrosis leads to difficulties in MR assessment of complete tumor regression after chemoradiation. Although MRI cannot accurately differentiate between fibrosis without (yt0, y is a prefix indicating the stage after chemoradiotherapy) and with tumor remnants in the bowel wall (yt2) (Fig. 7), it can accurately predict tumors that after preoperative chemoradiation have been downstaged to tumors limited to the bowel wall. Two studies reported a PPV of 83% and 91% and the PPV increased to 94% when >70% volume downsizing was combined with MR morphological changes (41,42). Thus, despite recent advances in clinical MR equipment and improvement in MR image resolution, the detection of very small volumes of disease remains a problem with techniques that only give information on morphological data. Although FDG-PET provides additional functional information, it cannot solve the problem of detection of residual tumor in fibrosis, as shown by a study on the assessment of clearance from the mesorectal fascia (40). A second area of importance for restaging after rectal cancer is the assessment of lymph nodes after chemoradiotherapy (CRT). Secondary staging after chemoradiation should be considered separately, as the behavior of a treated previously involved node may differ from a primary benign lymph node. There have been only a few reports on the accuracy of MRI methods to detect lymph node disease on a patient basis after chemoradiation, showing accuracy rates of 65% 88% with sensitivities and specificities varying from 33% 82% and 68% 95%, respectively (39,43 45). A study on the role of restaging with USPIOenhanced MRI showed that the addition of USPIO improved accuracy for detection of nodal metastases but that the results of restaging MRI without USPIO were satisfactory for selecting the yn0, with NPV of 94%, at the expense of 53% PPV (46). FUTURE PERSPECTIVES As MR techniques continue to advance, quantification of acquired MR data enables us to combine the morphological information on the tumor with functional information. The ability of perfusion MR techniques in monitoring treatment response have been reported (47). Diffusion-weighted imaging (DWI) is another upcoming MR technique, introduced in the 1990s in neurological MRI, but recent reports suggest also a potential use in oncology (48 50). The challenge is whether these new MR techniques will be able to solve the problem of the detection of small-volume disease in irradiated rectal cancer, in rectal cancer nodes, and in distant metastases. CONCLUSION In the multidisciplinary treatment of rectal cancer there is an increased demand for accurate selection of patients with different risk for local recurrence, because treatment is tailored according to the individual risk.

7 1018 Beets-Tan and Beets Imaging, and specifically MRI, can have a prominent role in this decision-making strategy. It requires a change in the attitude of radiologists involved in rectal cancer management. They need to be aware of what information is relevant for the clinicians in their centers, and assume a more active role in the multidisciplinary discussions. EUS is the method of choice for selection of small superficial tumors. MRI is the preferred technique to assess the large tumors and the distance to the mesorectal fascia. MRI is superior to CT for assessing invasion of the surrounding organs and structures, especially in low tumors that are at high risk for local recurrence. Nodal status assessment at present is not very reliable unless large (8 mm) nodes are visualized. The detection of small metastatic nodes could be improved with new MR techniques such as perfusion, diffusion, and molecular MRI, as well as new MR contrast agents that combine functional and morphological data. Restaging of rectal cancer after chemoradiation is useful only when alteration of the treatment plan is considered for good responders. FDG-PET during chemoradiation can predict patients who will respond well, and MRI can sometimes be helpful to identify tumors that have regressed from the mesorectal fascia or that have been downstaged. The main limitation of present imaging techniques, however, is the detection of small tumor volume within fibrosis. APPENDIX Standard Rectal MR Protocol MRI using an endorectal coil, although initially promising for assessment of tumor ingrowth in the bowel wall (51), has not been adopted as standard imaging and EUS remains the method of choice for staging superficial rectal tumors. Endorectal MRI has not gained worldwide acceptance for the larger tumors. Phased array MRI is already accurate. An endorectal MRI remains cumbersome in application both for the patients and the MR team and positioning of the coil is difficult in high and/or stenosing tumors. Furthermore, this technique does not allow an accurate evaluation of the CRM and the mesorectal nodes at a distance from the coil because of its small field of view. Phased array MRI has thus become the standard MR technique for state of the art staging of rectal cancer. The patient is scanned in supine position. No bowel preparation is required nor are spasmolytica routinely given. Only occasionally spasmolytica may be helpful in patients presenting with high anteriorly located tumors to reduce the motion artifacts that are caused by adjacent small bowel loops. Although distension of the rectal wall by luminal filling could help the less experienced radiologist for better identification of the tumor, it is not necessary and even not recommended once the radiologist is more experienced in reading rectal MRI. Distention of the lumen causes overstretching of the rectal wall. Specifically, in lowlying tumors it can hamper the accurate assessment of surrounding nodes and of the distance of the tumor to the mesorectal fascia. It has been reported that Table 1 MR Rectal Protocol at 1.5 T MRI Sagittal, axial, and coronal 2D T2W FSE Repetition time / echo time (msec) 8456 /130 Number of slices 30 Slice thickness 3 Slice gap 2 Flip angle (degrees) 90 Matrix FOV (mm) Echotrain length 25 Number of signal averages (NSA) 6 Acquisition time (min) 603 Parameters of standard T2W FSE sequences. overstretching of the wall results in overestimation of an involved CRM in 50% of the cases (52). The standard rectal MR protocol comprises T2- weighted fast spin echo (T2W FSE) sequences in three planes, the sagittal, axial, and coronal planes (53). T2W FSE images allow for a good contrast between tumor, surrounding high signal of mesorectal fat, and the very thin mesorectal fascia. In this respect fat suppression sequences are not recommended, as on fat suppression images the anatomy of the mesorectal fascia is not as well imaged. A sagittal T2W FSE sequence should first be obtained in order to locate the tumor. Based on the sagittal sequence axial and coronal T2W FSE sequences are planned and it is especially important to angle the plane exactly perpendicular and parallel to the tumor axis. 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