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Gastroenterology & Hepatology
Rectal cancer presents significant diagnostic and therapeutic challenges, with neoadjuvant therapy playing a pivotal role in improving resectability and patient outcomes. Magnetic resonance imaging (MRI) serves as a critical tool in assessing treatment response.
- rectal cancer
- neoadjuvant therapy
- magnetic resonance imaging
- treatment response
1. Introduction
Colorectal cancer remains a significant health challenge; it is the second most common cause of cancer mortality in the United States in 2023. Furthermore, despite a decline in the overall incidence rates of colorectal cancer, the proportions of younger patients and patients with rectal cancer among newly diagnosed cases of colorectal cancer have notably increased over recent years. This underscores the urgency for effective treatment strategies and assessment methodologies for the evolving demographic of patients with colorectal cancer [1].
Recent years have seen a shift from traditional surgery towards organ-preserving treatments, including non-operative management (NOM) [2,3,4,5] for patients with rectal cancer who achieve pathological complete response after neoadjuvant therapy [5,6,7]. However, while such novel organ-preserving strategies offer numerous advantages over traditional surgery, there is a crucial knowledge gap in the treatment response assessment pertaining to these strategies. Of several modern imaging techniques, rectal magnetic resonance imaging (MRI) is promising for the purpose of treatment response assessment, but to date, the literature remains lacking concerning its use in the post-neoadjuvant therapy setting in patients with rectal cancer [4,8,9,10,11,12,13].
2. Overview of Neoadjuvant Therapy
2.1. Neoadjuvant Therapy
Neoadjuvant therapy refers to any treatment administered before the standard definitive surgical resection (i.e., total mesorectal excision) and is usually indicated in patients with locally advanced rectal cancer [14,15]. While the National Comprehensive Cancer Care guidelines recommend neoadjuvant therapy to any patient with T3-, T4-, T1-2 with N+, or locally unresectable or inoperable cancer due to coexisting medical conditions [15], the European Society for Medical Oncology emphasizes the use of MRI to stratify patients into different treatment subgroups [14]. Remarkably, neoadjuvant therapy allows patients who achieve a complete response to enter a “watch-and-wait” protocol, also known as NOM, to avoid surgical complications [16]. Extensive research has been conducted to propose different neoadjuvant therapy strategies to improve patient outcomes. In the following paragraphs, we provide insight into these strategies.
The traditional neoadjuvant therapy approach is the administration of capecitabine or infusion fluorouracil chemotherapy with long- or short-course radiotherapy (RT) [15]. While long-course RT delivers 45–50 Gy over 25–30 fractions, short-course RT provides 25 Gy over five fractions (commonly described as “5 × 5”) in just a week [15]. Short-course RT has been shown to lead to a reduced recurrence rate but is associated with increased local side effects [17,18,19].
Total neoadjuvant therapy (TNT) is an approach that delivers both systemic chemotherapy and chemoradiotherapy (CRT) before surgery, consisting of induction chemotherapy followed by CRT or consolidation chemotherapy administered after CRT [15,20]. The goals are to decrease the rate of distant metastasis and to increase the rate of clinical complete response (up to 40% in a recent meta-analysis) [21]. Some of the relevant clinical trials on TNT include the following:
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The Organ Preservation of Rectal Adenocarcinoma (OPRA) trial compared patients on INCT-CRT (Induction Chemotherapy with Chemoradiotherapy) and patients on CRT-CNCT (Chemoradiotherapy with Consolidation Chemotherapy). Remarkably, approximately 75% of both patient groups underwent the NOM protocol and both patient groups had similar outcomes in terms of 3-year disease-free survival (76% and 76%, log-rank p = 0.98), local recurrence-free survival (94% and 94%, log-rank p = 0.78), distant metastasis-free survival (84% and 82%, log-rank p = 0.67), and local tumor regrowth (40% and 27%, log-rank p = 0.03). In terms of rectum preservation, however, more patients from the CRT-CNCT group achieved rectum preservation compared to patients from the INCRT-CRT group (60% [95% confidence interval [CI]: 52–68] vs. 47% [95% CI: 39–56]), which justifies initially providing INCT-CRT in cases where NOM is preferred [20].
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The Rectal cancer And Pre-operative Induction Therapy Followed by Dedicated Operation (RAPIDO) trial showed a decreased rate of distant metastasis at 3 years of follow-up, reflected by the rate of disease-related treatment failure, in patients treated with experimental short-course RT, TNT, and total mesorectal excision (rate of ~24%) compared to patients treated with standard long-course CRT, total mesorectal excision, and optional adjuvant chemotherapy (rate of ~30%), albeit both patient groups had comparable rates of locoregional failure [22]. The recently published 5-year follow-up results showed a similar pattern in terms of distant metastasis; however, the rate of locoregional failure, reflected by the rate of locoregional recurrence, was higher in patients treated with the experimental approach (rate of ~12%) compared to patients treated with standard approach (rate of ~8%). These results highlight the necessity of further refining the neoadjuvant therapy approach [23].
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The Unicancer Gastrointestinal Group and Pertenariat de Recherche en Oncologie Digestive (PRODIGE 23) trial compared one group of patients who received standard CRT, total mesorectal excision, and adjuvant FOLFOX (“standard-of-care”) and another group of patients who received neoadjuvant FOLFIRINOX therapy (“TNT”), CRT (radiotherapy and fluorouracil), TME, and adjuvant FOLFOX or capecitabine. The TNT group showed increased 3-year disease-free survival (76% vs. 69%; hazard ratio (HR) 0.69 [95% CI: 0.49−0.97]; p = 0.034), increased 3-year rate of metastasis-free survival (79% vs. 72%; HR 0.64, [95% CI: 0.44–0.93] (p = 0.017), and increased pathologic complete response rate (12% vs. 28%) (p < .001) [24]. The 7-year follow-up presented in the last American Society of Clinical Oncology meeting showed that the TNT group had an absolute increase of 7.6% for disease-free survival, 6.9% for overall survival, 9.9% for metastasis-free survival, and 5.7% for cancer-specific survival, as well as decreased locoregional relapse (5.3% vs. 8.1%, p = 0.38) [25].
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Recently published results from the Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery (PROSPECT) trial aimed to evaluate the outcomes of patients who received neoadjuvant chemotherapy but without RT among patients with T2 node-positive, T3 node-negative, or T3 node-positive and candidates for sphincter-sparing surgery. They found that neoadjuvant chemotherapy (FOLFOX) was non-inferior to the standard CRT approach in regard to disease-free survival (HR 0.92 [90.2% CI: 0.74 to 1.14]) (p = 0.005) [26].
Finally, a novel approach with immunotherapy has been proposed for a subgroup of patients with locally advanced rectal cancer and mismatch repair deficiency: Cercek et al. conducted a prospective phase 2 study involving 12 patients who completed treatment with dostarlimab (anti-PD-1 monoclonal antibody), and all of them had a complete clinical response and underwent NOM at the time of publication of the phase 2 results [27]. Other more recent results from other investigators have supported the results from Cercek et al.’s phase 2 study [28,29].
2.2. Response Assessment
Recently, an international consensus was formulated to standardize the treatment response categorization of patients with rectal cancer who are undergoing organ preservation strategies after CRT [30]. The core objective of this consensus is to offer researchers and clinicians a well-defined, standardized framework for assessing and conveying the efficacy of organ preservation strategies. According to this consensus, following treatment with an organ preservation strategy, patients are categorized into three specific groups based on findings from digital rectal examination, endoscopy, and MRI, as follows:
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Clinical complete response: This response is reflected by normal findings on digital rectal examination, an unremarkable rectal wall with or without fibrosis, and no adenopathy on MRI. Endoscopy findings are not required for clinical complete response categorization.
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Near-complete response: This response is reflected by smooth indurations and/or minimal mucosal abnormalities on digital rectal examination; irregular or smooth mucosa irregularities, superficial ulcer, and persistent erythema on endoscopy; and apparent decrease in size with predominant fibrosis and without or with borderline lymph nodes on MRI.
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Incomplete response: This response is reflected by a palpable tumor on digital rectal examination as well as a visible tumor with or without nodal regression on endoscopy and MRI.
3. Restaging MRI Protocol
3.1. Preparation
Spasmolytic agents are usually part of the motion-mitigation strategy within the restaging MRI protocol, but their use is not mandatory. The survey led by Gollub et al. found that 47% of academic institutions use spasmolytics (glucagon, 1 mg, administered intravenously/intramuscularly/subcutaneously; or hyoscyamine butyl bromide, 20 mg, administered intravenously) for rectal cancer MRI in the baseline or neoadjuvant setting [31]. Spasmolytic agents reduce peristalsis-causing artifacts, especially on the diffusion-weighted imaging (DWI) sequence of the upper rectum. Fasting for 2 h before scanning decreases small bowel peristalsis [32].
Of note, while the baseline MRI protocol does not require a microenema, it is crucial to use a microenema in the restaging MRI protocol to minimize gas-related artifacts, consequently enhancing the quality of DWI. It is recommended to administer a microenema 15 min before the scan [33,34].
Numerous guidelines suggest a minimum field strength of 1.5 Tesla (T) for MRI in rectal cancer cases. The choice between 1.5 T and 3.0 T for rectal cancer imaging lacks consensus. While MRI at 3 T offers several advantages, including faster image acquisition and improved spatial resolution with a higher signal-to-noise ratio, these advantages come at the expense of higher susceptibility artifacts, which might impact DWI particularly [32,35].
3.2. Coils
The patient should be positioned in a supine posture. Instead of endorectal coils, which can lead to discomfort and rectal distention while potentially affecting the measured distance between the tumor and circumferential resection margin [36], pelvic phased-array surface coils are recommended. These surface coils should be positioned with their lower edge just below the pubic bone or, for cases involving low rectal tumors, placed at least 10 cm below the symphysis pubis. The upper edge of the coil should align with the sacral promontory [32].
3.3. Sequences
Large field-of-view (FOV) T2-weighted imaging is essential for evaluating tumor extension beyond the mesorectal compartment, especially when assessing nodes outside the total mesorectal excision zone. These images should encompass the region from the origin of the superior mesenteric artery to the inguinal regions [32,37].
High-resolution T2-weighted imaging should have a field of view (FOV) of 16–20 cm, slice thickness of 2–3 mm, in-plane resolution less than 1 × 1 mm, with no gap between slices, and an echo time (TE) of 80–110 ms, depending on the field strength. High-resolution, small FOV T2-weighted imaging, in particular, is crucial for assessing delicate structures that demand maximum contrast resolution, such as the rectal wall, mesorectal fat, mesorectal lymph nodes, and peritoneal reflection. This sequence is vital not only for T and N staging but also for detailed scrutiny of extramural vascular invasion (EMVI), differentiation between mesorectal tumor deposits and lymph nodes, and the evaluation of peritoneal reflection involvement [38]. The sequence should involve imaging in the oblique axial, oblique coronal, and true sagittal planes relative to the tumor’s location; this approach is critical to prevent volume averaging and to avoid misinterpretation of tumor extension [39]. In cases of extensive tumors, acquiring oblique axial and oblique coronal T2-weighted images at different angles is sometimes necessary to assess orientation and extension at various levels. Oblique small FOV T2-weighted imaging aligned with the anal canal assists in the local staging of low rectal tumors and their relationship to the sphincter complex.
DWI is a functional imaging sequence that relies on rate differences in the random motion of the water molecules within the tissue of interest. A higher signal indicates the restricted ability of water molecules to diffuse within the microenvironment. Restricted diffusion is associated with abscesses, hypercellular tumors, and benign and malignant lymphatics (lymph nodes, spleen). DWI adds to the accuracy of conventional morphological MRI sequences, especially in the post-treatment setting. Even though DWI cannot distinguish benign and malignant lymph nodes, it is a helpful tool in detecting and differentiating such lymph nodes from common benign mimickers like varicose veins and phleboliths, among others [40]. The use of multiple b values (50 s/mm2, 400 s/mm2, and 800 s/mm2) in a single DWI acquisition not only saves time but also enhances diagnostic capabilities [32].
Small FOV DWI is essential in evaluating residual tumors to determine a clinical complete response and thereby determine further selection for NOM [41]. It is important to emphasize that DWI can detect recurrent tumors before they become apparent on endoscopy [42]. Small FOV DWI has been shown to provide better subjective image quality and higher accuracy for post-treatment reevaluation compared to full FOV DWI [43,44]. Most protocols use b values ≥ 1000 s/mm2 to minimize false T2 shine-through from submucosal and luminal edema. One study compared the use of two high b values (b = 1000 s/mm2 and b = 2000 s/mm2), showing that b = 2000 s/mm2 resulted in higher tumor conspicuity compared to b = 1000 s/mm2 [45]. With small FOV DWI, luminal gas has been shown to be the main cause of susceptibility artifacts, potentially obscuring actual lesions or creating pseudo lesions [32].
3.4. Intravenous Contrast
Even though the reliability of the postcontrast sequences in the posttreatment setting is not as accurate, for example, because of the enhancement in the posttreatment and inflammatory changes, both the Society of Abdominal Radiology and the European Society of Gastrointestinal and Abdominal Radiology suggest that intravenous contrast may be considered as an optional tool in specific scenarios, for example in situations where image quality is compromised by artifacts [31,46].
4. Rectal MRI Response Assessment
4.1. Why Assessment Matters
Conducting an MRI after neoadjuvant CRT is crucial for assessing the cancer’s response to treatment, detecting new disease sites, re-evaluating the extent of the disease, and planning further treatment (e.g., surgery or NOM).
4.2. When to Evaluate
The optimal timing for the initial assessment of tumor response remains a point of contention within the field. Research suggests that the rate of achieving pathological complete response increases significantly after 12 weeks following radiotherapy [47]. Nonetheless, some surgical groups express reservations about performing operations beyond 8 weeks following RT. Their concerns are rooted in fears of radiation-induced pelvic fibrosis and associated surgical complications [48]. These apprehensions underscore the importance of early identification of poor or incomplete responders.
Efforts to shift the decision point from the conventional 6- to 8-week post-radiotherapy period to a later window of 10 to 12 weeks may not necessarily adversely impact surgery-related morbidity or mortality [49]. Moreover, extending the surveillance window might prove advantageous since prolonged intervals may be useful to enhance response rates [50]. It also offers the opportunity to initiate consolidation CRT for metastatic high-risk patients, a decision that could potentially benefit from TNT [49]. This strategic approach emphasizes the need for a more comprehensive understanding of when to assess tumor response and its potential implications for patient management.
4.3. Pre-Assessment Preparations
Before presenting findings from restaging MRI of the rectum, it is crucial to delve into the patient’s clinical history, including the results of digital rectal examinations and any conducted endoscopic procedures. It is equally important to consider the type of treatment administered, whether it is CRT or TNT, along with the time elapsed since the completion of the last treatment session [51]. When the availability of prior clinical records is limited or absent, drawing substantiated conclusions becomes an intricate challenge.
Moreover, conducting an assessment of the baseline MRI scan, when available, assumes great significance as a preparatory step before embarking on the interpretation of the restaging rectal MRI. This initial examination serves to illuminate critical facets, encompassing tumor localization, tumor characteristics, and the potential presence of mucinous components. Notably, following neoadjuvant therapy, it is essential to recognize that the normal rectal wall near or opposite the treated tumor may experience edematous thickening, which could be mistakenly identified as a residual tumor, often termed “pseudotumor,” by some observers [52]. Thus, establishing a correlation with the baseline rectal MRI stands as a highly beneficial practice, aiding in the precise determination of the tumor bed’s location [53]. Scar tissue should follow the same distribution and shape as the primary tumor [54]. This integrated approach enhances the accuracy of interpretation and minimizes the potential for misinterpretations.
4.4. How to Evaluate the Tumor Response
In managing locally advanced rectal cancer, radiologists are pivotal in assessing treatment response, specifically during the “tumor assessment” phase. Successful response to treatment in rectal tumors typically results in morphologic changes on imaging, including size reduction and fibrotic transformation.
4.5. How to Evaluate Mesorectal Fascia Status
The most crucial element of all in the treatment assessment of rectal cancer is the reassessment of the mesorectal fascia (MRF). Achieving clearance of the MRF on restaging high-resolution T2-weighted MRI holds a positive predictive value of up to 90% for a clear margin upon pathological examination, which may support a shift toward less invasive surgical approaches [77,78]. Conversely, when the MRF is approached by dense hypointense fibrosis or by an intermediate tumor signal intensity, the MRF should be considered involved for both, even though the likelihood of tumor presence upon pathological assessment is lower for the former as compared to the latter, since distinguishing purely fibrotic tissue from fibrosis with residual tumor cells is challenging [77,78].
The updated lexicon by the SAR DFP employs the term “MRF,” which is an anatomical term, as opposed to circumferential resection margin (CRM), which relates to the operative surgical margin, dependent on the surgical approach [63].
The status of the MRF hinges on the shortest distance between the MRF and the outermost part of the rectal tumor, including extramural vascular invasion, tumor deposits, or disrupted capsule-positive lymph nodes [79]. Lymph nodes with intact capsules are not considered involved, as they do not correlate with increased local recurrence rates [79,80]. The SAR DFP template utilizes a three-tiered system for MRF status: “involved” for a distance less than 0.1 cm, “threatened” for a distance of 0.1–0.2 cm, and “clear” for a distance of more than 0.2 cm [81].
DWI may also play a role in predicting MRF status [82]. However, it often overestimates the disease extent, particularly in anterior locations and in tumors close to the anal verge, as confirmed by a whole-mount study [83].
4.6. How to Evaluate Rxtrarectal Disease
CR, nCR, and iCR responses are also contingent on the assessment of extrarectal disease. When there are no lymph nodes, EMVI, or tumor deposits, we categorize the response as CR. In cases where any of these factors fall into borderline territory, the response is categorized as nCR. However, if any of these factors raise suspicion, the response is deemed iCR.
5. Structured Reporting
There are a number of studies that have shown the value of structured reporting in rectal cancer [97,98,99]. Furthermore, American and European societies have proposed lexicons and standardized reports for this purpose [63,81,100].
A recently updated consensus statement from the SAR proposes the following terminology for treatment response assessment in rectal cancer [63]:
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CR and nCR response categories are grouped together because they can be closely monitored safely, and most cases of nCR will reach CR at 6–12 weeks after neoadjuvant therapy [101]. Both CR and nCR imply that both T2-intermediate signal and restricted diffusion have resolved entirely or almost completely.
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iCR should be applied when, even though the tumor volume has decreased, there is residual T2-intermediate signal and/or restricted diffusion.
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The term recurrence should be used only after local excision or total mesorectal excision, while the term regrowth should be used after chemotherapy or RT. The latter applies when, after having documented CR, there is a new tumor in the bowel wall (local), adjacent structures (loco-regional), or lymph nodes. Dowel wall regrowth can be suspected when a prior low-signal intensity scar is a new area of T2-intermediate signal or restricted diffusion, thickening, or heterogeneity [63].
Also, on the SAR webpage, a structured reporting template to evaluate the response to treatment is available [102]. This structured reporting template lists the MRI features to evaluate in different scenarios. These features include the following:
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Restricted diffusion and low ADC in the tumor or tumor bed: present, absent, or artifact/equivocal/not available.
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T2 signal intensity in the tumor or tumor bed: intermediate, mixed, entirely dark, nearly normalized appearance of rectal wall, or bright mucin.
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Distance of the inferior margin of the treated tumor to the anal verge and to the top of the sphincter complex/anorectal junction.
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Relationship of the treated tumor to the anterior peritoneal reflection: above, straddles, or below.
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Craniocaudal length and maximal wall thickness (current and pre-treatment measurements for both features).
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EMVI: no (no EMVI evident at pre-treatment imaging), no (complete regression), yes (partial regression), or yes (unchanged from baseline).
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Shortest distance of tumor/fibrosis to the MRF.
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Tumor deposit, lymph node, or EMVI threatening the MRF: yes or no.
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In the case of a low-rectal tumor, is there an invasion of the anal sphincter complex? no, extends into the internal sphincter, extends into intersphincteric space, or extends into or through the external sphincter.
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Lymph nodes and/or tumor deposits: mesorectal/superior rectal or extra-mesorectal.
This entry is adapted from the peer-reviewed paper 10.3390/jcm13010172
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