Response evaluation after neoadjuvant treatment for rectal cancer using modern MR imaging: a pictorial review
In recent years, neoadjuvant chemoradiotherapy (CRT) has become the standard of care for patients with locally advanced rectal cancer. Until recently, patients routinely proceeded to surgical resection after CRT, regardless of the response. Nowadays, treatment is tailored depending on the response to chemoradiotherapy. In patients that respond very well to CRT, organ-preserving treatments such as watch-and-wait are increasingly considered as an alternative to surgery. To facilitate such personalized treatment planning, there is now an increased demand for more detailed radiological response evaluation after chemoradiation. MRI is one of the main tools used to assess response, but has difficulties in assessing response within areas of post-radiation fibrosis. Hence, MR sequences such as diffusion-weighted imaging are increasingly adopted in clinical MR protocols to improve the differentiation between tumor and fibrosis. In this pictorial review, we discuss the strengths and weaknesses of modern MR imaging, including functional imaging sequences such as diffusion-weighted MRI, for response evaluation after chemoradiation treatment and provide the main pearls and pitfalls for image interpretation.
KeywordsRectal neoplasms Magnetic resonance imaging Diffusion magnetic resonance imaging Chemoradiotherapy
Response evaluation with MR imaging can serve as a surgical roadmap and help identify (near-)complete responders for organ-preserving treatments
Diffusion-weighted MRI improves the performance of MRI to discriminate between tumor and fibrosis, but certain pitfalls need to be taken into account
Knowledge on specific patterns of morphology and diffusion signal can be helpful to improve response evaluation with MRI
Introduction and clinical background
Neoadjuvant therapy has become the standard of care for patients with locally advanced rectal cancer. Neoadjuvant treatment can consist of a short course of radiotherapy (5 × 5 Gy) +/− a prolonged waiting interval or a long course of combined chemoradiotherapy (CRT) . The main aim of CRT is to downsize and downstage the tumor to increase the chance of a complete resection and consequently reduce the local recurrence risk. Moreover, organ-preserving treatment strategies (local excision or ‘watch-and-wait’) have recently been introduced as a potential option for patients that show a (near-)complete response to CRT.
Magnetic resonance imaging (MRI) is since many years considered pivotal for the staging and treatment planning of primary rectal tumors. Nowadays, MRI is also increasingly incorporated in clinical routine to assess response and restage tumors after CRT. While in the past the surgical strategy was mainly determined based on the findings of primary staging, the findings of restaging MRI are now increasingly used to guide further treatment. Current guidelines therefore recommend to routinely perform MRI for restaging of rectal cancer after CRT .
Restaging after CRT can impact treatment planning in two ways:
First, the findings on post-CRT MRI can serve as a ‘roadmap’ to optimize the surgical strategy. In distal tumors that primarily invaded the anal sphincter, downsizing may cause the tumor to retract from the sphincter, thereby allowing sphincter-preserving surgery after CRT. Similarly, retraction from initially invaded organs in T4 tumors may allow conversion from extended resection into standard total mesorectal excision (TME).
Second, with the current paradigm shift toward organ-preserving treatment strategies, MRI—together with digital rectal examination and endoscopy—can have a role in selecting the right candidates. About 15–25% of patients undergo a complete response after CRT . When these complete responding patients are accurately selected, surgery with its associated morbidity and even mortality can be omitted with good results in terms of overall and disease-free survival as well as with improved quality of life in recently published studies [4, 5, 6]. When patients are included in a watch-and-wait program, imaging can also play a role in patient monitoring. Although the intensity of follow-up and modalities used differ between published studies, patients are typically regularly monitored with the aim to detect tumor recurrences as early as possible so that salvage surgery can still be performed. These patients have shown comparable outcomes compared to patients operated immediately after CRT . MRI is routinely included in the follow-up program in several reports and can be particularly beneficial for the detection of mesorectal (e.g., nodal) sites of recurrence [5, 6].
These developments increase the demand for an accurate radiologic evaluation of response. With this pictorial review, we discuss the strengths and weaknesses of modern MRI imaging, including functional imaging sequences such as diffusion-weighted MRI, for response evaluation after chemoradiation treatment and provide the main pearls and pitfalls for image interpretation.
Protocol and patient preparation
Morphologic evaluation of tumor response
As a result of successful response to treatment, rectal tumors typically decrease in size while undergoing a fibrotic transformation. Untreated (non-mucinous) tumors show intermediate signal intensity on T2-weighted MRI that is lower than that of fat tissue, but higher than that of the normal muscular layer of the bowel wall. When tumor tissue becomes fibrotic, the signal drops considerably and the tumor bed becomes markedly hypointense. A small minority of tumors develop a mucinous response as a result of CRT, leading to an increase in signal after CRT . At histopathology, these ‘mucin’ lakes typically contain no or rare isolated tumor cells . A mucinous transformation in primarily non-mucinous tumors should therefore be considered a good prognostic sign. This should not be confused with primarily mucinous tumors that have an overall poorer prognosis and tend to show a poor response to CRT (see separate section on ‘Mucinous and signet-ring subtype’ below). Reductions in tumor volume in the range of 60–80% have been reported in literature to correlate with a good response to treatment . Although in oncology Response Evaluation Criteria in Solid Tumors (RECIST) is often used as a unidimensional size measurement system to assess response, RECIST is not commonly used in rectal cancer, because it can be difficult to reproducibly measure irregularly shaped rectal tumors in one plane. 3D whole volume tumor measurements have been reported to be better reproducible and more accurate to assess response , but these measurements can be very time consuming. As a practical alternative, the recent ESGAR guidelines therefore suggest to measure the tumor length before and after CRT, as reported measurement reproducibility for this metric is good and it at least offers some estimation of the change in tumor size/volume as a result of treatment .
MR tumor regression grade
TRG1 = thin low signal fibrosis with no evidence of intermediate signal intensity
TRG2 = dense low signal fibrosis with no evidence of intermediate signal intensity
TRG3 = predominant low signal fibrosis with scattered or focal intermediate signal intensity
TRG4 = predominant intermediate signal intensity with minimal fibrosis
TRG5 = intermediate signal intensity with no evidence of fibrosis
Interobserver agreement for assessment of mrTRG has been reported to be good , but agreement between the mrTRG and pathologic TRG rather low and the performance of mrTRG to identify complete responders has been shown to be limited with reported sensitivity of 74% and specificity of 63% . The mrTRG has however been shown (mainly by reports from the UK) to be beneficial as a biomarker to distinguish between good and poor response groups and to predict survival outcomes [17, 18, 19, 20]. We are currently awaiting the results of the first randomized trial from the UK to stratify treatment management based on the mrTRG as a biomarker to select good and poor responders . One group introduced a modified mrTRG system for mucinous tumors which also showed a correlation with pathologic treatment response . Another group recently introduced a modified mrTRG system incorporating DWI findings and suggested a benefit to predict prognosis . Results of these single reports remain to be validated.
Morphologic patterns of response
Morphologic MRI as a surgical roadmap post-CRT
Mucinous and signet-ring subtype
Diffusion-weighted imaging (DWI) is a technique that analyses how water molecules can move (‘diffuse’) in a certain tissue. Diffusion-weighting is achieved by applying diffusion-sensitizing gradients to a T2-weighted sequence. The degree of diffusion-weighting applied is referred to as the ‘b value,’ commonly in the range of b800–1000 s/mm2 for visual assessment. In normo- or low cellular tissue, water can move freely causing a decay of the signal on high b value images. In highly cellular tissues, the diffusion capacity of water is restricted and the signal is retained. This makes DWI a very suitable technique to detect malignant tumors, as has been demonstrated by numerous reports in various cancer types, including rectal cancer [40, 41]. Diffusion-weighted images are typically assessed in conjunction with the corresponding apparent diffusion coefficient (ADC) map. An ADC map is a parametric map that reflects the degree of water diffusivity for each voxel within the image, with a high signal representing free diffusion and a low signal representing restricted diffusion. It can also be used to derive quantitative diffusion-measurements (see section on ‘Quantitative functional imaging’ below).
DWI for response evaluation: pearls and pitfalls
The basic principal of DWI interpretation on restaging MRI is fairly simple: high signal on DWI within the bowel wall or fibrosis at the location of the tumor bed indicates residual tumor, while the absence of signal is suggestive of a complete response. With this approach, several authors have shown that addition of DWI to standard T2-weighted sequences can significantly improve the performance of MRI to differentiate between patients with a complete tumor response and those with residual tumor [26, 27, 28, 29, 30]. In a meta-analysis, pooled sensitivity to predict response was significantly higher for studies including a DWI sequence (84%), compared to studies using only standard MRI (50%) .
There are, however, several pitfalls that may hamper correct interpretation of diffusion images. Misinterpretation of T2 shine-through effects, misinterpretation of low intensity on ADC maps, and misinterpretation of high signal caused by susceptibility artifacts are among the most common pitfalls encountered .
Low ADC signal in fibrosis (‘T2 dark-through’)
Patterns of response on DWI
Lymph node assessment after CRT
It is well-known that nodal staging poses one of the main challenges for radiologists in rectal cancer imaging. Traditionally, radiologists mainly relied on nodal size as the main criterion for malignancy, even though size is known to be an unreliable predictor. Many of the nodal metastases in rectal cancer occur in small-sized nodes while on the other hand false positives frequently occur in reactively enlarged benign nodes. Morphological criteria such as the round shape, irregular border, and heterogeneous signal intensity can help characterize malignant nodes , although these criteria can be difficult to assess in small nodes. It is generally acknowledged that performance of MRI for nodal restaging after CRT is better than in the primary staging setting, with negative predictive values of up to 95% to identify ypN0 patients . As a result of CRT, the majority of lymph nodes decrease in size or even completely disappear on MRI. These nodes have a low risk of harboring metastases. Nodes that remain clearly visible after CRT are still at risk . Although the optimal size cut-off after CRT remains a topic of debate, the recent ESGAR guidelines propose a cut-off of 5 mm (short axis) to diagnose yN+ nodes after CRT .
Quantitative functional imaging
In recent years, increasing numbers of reports have focused on quantitative imaging approaches to assess response to CRT in rectal cancer. Although part of this research focusses on use of routine T2-weighted imaging (e.g., T2W tumor volumetry and quantification of T2W signal intensities), most research has focused on use of functional imaging sequences. The most frequently investigated technique is diffusion-weighted MRI.
Quantitative DWI assessment
Other functional imaging and image quantification techniques
Second to DWI, the most commonly researched functional MRI technique is dynamic contrast enhanced (DCE) or ‘perfusion’ MRI. By measuring the inflow of intravenously injected contrast agents into vessels and the leakage of contrast into the extracellular space, DCE-MRI can extract quantitative and semi-quantitative parameters related to tissue perfusion and microvascularity, which have shown significant correlations with response [65, 66, 67]. Although already routinely applied in prostate and breast imaging, in rectal cancer, DCE-MRI has so far mainly been applied in research settings and its use is not (yet) advised for clinical routine . Less commonly investigated techniques include MR spectroscopy, magnetization transfer (MT) imaging, and blood oxygenation level-dependent (BOLD) MR. More advanced methods of DWI acquisition such as intravoxel incoherent motion (IVIM) imaging and diffusion kurtosis imaging have also recently been introduced. In addition, there is a growing interest for the use of advanced image post-processing techniques such as Radiomics to extract multiple quantifiable measures (‘features’) from routinely acquired MRI sequences to acquire a radiological tumor phenotype. These methods are to date still in premature stages of research and not yet ready to be adopted in clinics. Since the focus of this pictorial review is on clinical MR methods to assess response, to provide a complete overview of these quantitative approaches would be beyond the scope of the current paper.
Recent developments in rectal treatment urge the need for an accurate radiological response evaluation. Reduction in volume and fibrotic transformation are the two main signs of response that can be appreciated on morphological (T2-weighted) MRI and used to help guide the treatment strategy after CRT. Morphological MRI is mainly hampered by its inability to discriminate between sterilized fibrosis and fibrosis still containing viable tumor. This limits the performance of MRI to identify complete responders, which is an increasingly important clinical issue given the recent paradigm shift in rectal cancer treatment toward organ-preserving treatments. Addition of diffusion-weighted imaging to the MR protocol improves the performance to discriminate between tumor and fibrosis, but certain pitfalls need to be taken into account. Knowledge on specific patterns of morphology and diffusion signal can help to further optimize diagnostic performance. Image quantification methods are promising and may provide valuable imaging biomarkers to assess response, but to date these methods are still in the research phase and not yet ready to be adopted into clinics.
All authors (DL, TB, RB-T) contributed to the literature search, manuscript writing and editing. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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- 4.Martens MH, Maas M, Heijnen LA et al (2016) Long-term outcome of an organ preservation program after neoadjuvant treatment for rectal Cancer. J Natl Cancer Inst 108(12). https://doi.org/10.1093/jnci/djw171
- 6.van der Valk MJM, Hilling DE, Bastiaannet E et al (2018) Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. Lancet 391:2537–2545Google Scholar
- 13.Martens MH, van Heeswijk MM, van den Broek JJ et al (2015) 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? Int J Radiat Oncol Biol Phys 93:1005–1014PubMedCrossRefGoogle Scholar
- 21.Battersby NJ, Dattani M, Rao S et al (2017) A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial. Trials 18:394PubMedPubMedCentralCrossRefGoogle Scholar
- 22.Park SH, Lim JS, Lee J et al (2017) Rectal mucinous adenocarcinoma: MR imaging assessment of response to concurrent chemotherapy and radiation therapy—a hypothesis generating study. Radiology 285:124–133Google Scholar
- 29.Song I, Kim SH, Lee SJ, Choi JY, Kim MJ, Rhim H (2012) Value of diffusion-weighted imaging in the detection of viable tumour after neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer: comparison with T2 weighted and PET/CT imaging. Br J Radiol 85:577–586PubMedPubMedCentralCrossRefGoogle Scholar
- 32.Krdzalic J, Maas M, Engelen S et al (2017) MRI can accurately predict sphincter preservation after chemoradiation. Insights Imaging 8(Suppl 1):S187 (conference proceeding)Google Scholar
- 45.Santiago I, Barata MJ, Figueiredo N, Pares O, Matos C (2018) The tram track sign: a new, highly specific and reliable sign for the detection of complete response after neoadjuvant therapy in rectal cancer. Insights Imaging 9(Suppl 2):661 (conference proceeding)Google Scholar
- 57.Nougaret S, Vargas HA, Lakhman Y et al (2016) Intravoxel incoherent motion-derived histogram metrics for assessment of response after combined chemotherapy and radiation therapy in rectal cancer: initial experience and comparison between single-section and volumetric analyses. Radiology 280:446–454PubMedPubMedCentralCrossRefGoogle Scholar
- 66.Petrillo M, Fusco R, Catalano O et al (2015) MRI for assessing response to neoadjuvant therapy in locally advanced rectal cancer using DCE-MR and DW-MR data sets: a preliminary report. Biomed Res Int. 2015;2015:514740.Google Scholar
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