In the USA 39,220 new cases of rectal cancer occurred in 2016.1 Despite the introduction of the screening programs, several patients are diagnosed in a locally advanced stage. Mortality has decreased thanks to prevention and early diagnosis and to effective management of the disease2-12, such as the standardization of operative procedures and the introduction of adjuvant and neoadjuvant therapy13-23, which determines a reduction of recurrence risk and a decrease of tumour size.
Preoperative chemo-radiotherapy (pCRT) combined with following total mesorectal excision is the standard procedure of care for locally advanced rectal cancer (LARC).13-24 However, there is an increase of conservative treatment strategies application for patients with substantial tumour regression after pCRT and “wait and see” policy for patients with complete pathological response. The advantage of this strategy is the reduction of morbidity and the possibility to provide a “true” organ-sparing approach. In this scenario, it is necessary to individualize the selection criteria for these strategies that accurately can assess neoadjuvant treatment response. Functional approaches have been exploited by several authors because of their capability to assess the residual tissue ″vitality”.25-35 FDG positron emission tomography coupled with computed tomography (PET/CT) is widely used and it is considered the best technique for early response monitoring after pCRT in LARC.13-14 However, other functional approaches including dynamic contrast enhanced-MRI (DCE-MRI) and diffusion weighted imaging (DWI) have been adopted to discriminate responder by non-responder patients and complete
The objective of this manuscript is to present an update about the imaging modalities used in LARC staging with a specific focus on morphological MRI. Furthermore, a systematic review about the performance of imaging in the tumour response assessment after neoadjuvant therapy has been performed. We report diagnostic accuracy findings in terms of false and true positives, false and true negatives number for morphological MRI, DCE-MRI, DWI and PET/CT.
The role of imaging is to provide a loco-regional staging as accurate as possible with the aim to assess the degree of tumour infiltration and extension. Moreover, the features detected by radiological imaging allow to evaluate pCRT response for guiding surgeon towards patient tailored strategies.36-74
In LARC, CT scan roughly show tumour size and its possible infiltration to internal organs: in fact, it can provide excellent contrast between tissues with large difference in X-ray absorption (bone
PET/CT provides functional tissue information concerning metabolic activity fused with the morphological details of CT. The integration of tissue metabolic activity with anatomic information can improve its accuracy more that PET or CT when considered alone.48-49
Morphological MRI (T2 weighted images) has shown superior potential because it can provide an accurate evaluation not only of the tumour extent, but also of the adjacent soft tissues. Morphological MRI allows for comprehensive evaluation of disease stage including tumour infiltration degree, a precise assessment of the neoplasia distance by mesorectal fascia (circumferential margin) and an effective assessment of lymph nodes involvement and mesorectal infiltration.26
Traditionally, tumour response assessments have been achieved measuring the percentage reduction of the tumour size according to the response evaluation criteria in solid tumours (RECIST), as the change in tumour size is generally thought to be correlated with treatment efficacy.17,50-53 However, this assessment approach is insensitive to early treatment changes, and it makes difficult to distinguish between active tumour and post-treatment fibrosis.
In fact, morphological MRI has been considered not to be conclusive in pCRT tumour response assessment since pathological down-staging is not always accompanied with tumour size effective reduction.17,23-26,50-53 However, the high temporal resolution obtainable using more powerful sequences has allowed to perform perfusion and dynamic studies after paramagnetic contrast agent administration. The latter MRI techniques permit to obtain functional tissue information concerning the vitality of the tissue essential to differentiate fibrosis from residual tumour after anti-angiogenetic treatments.
In scientific literature the potential of DCE-MRI has been reported as a promising evaluation tool to monitor and predict therapy response thanks to the relationship between tumour growth and angiogenesis.5-7,19,24-25 It is well known that angiogenesis is a key factor in the growth and dissemination of cancer. The characterization of the tumour angiogenic status on an individual patient basis could allow patient tailored treatments.24
Many clinical trials in rectal cancer have demonstrated that angiogenesis inhibition can increase treatment effectiveness. Consequently, imaging modalities able to assess tumour vascularization might improve the treatment management in patients affected by LARC.6-7,24-25
To assess tissue perfusion by means of DCE-MRI several approaches to analyse time intensity curve (TIC) have been proposed. The most commonly used in the clinical radiological practice is the TIC visual inspection approach.54 The main drawback of this qualitative approach is its dependence upon the experience of the operator and the absence of reproducibility. Petrillo
To overcome the limitations related to visual inspection alone, the quantitative or semi-quantitative approach for DCE-MRI data analysis have been proposed and investigated.
Quantitative model-based analysis involves compartmental tracer kinetic modelling20-21 and pixel-by-pixel or region of interest based estimation of kinetic features, by means of a non-linear regression. The latter has been introduced to better correlate quantitative model-based features with physiological tissue properties. Kim
To overcome previous problems several authors58-61 performed semi-quantitative analysis. Lavini
Because many of the conducted studies are relatively small and study design is very heterogeneous, the evidence on DCE-MRI is rather inconsistent. Therefore, future research should aim at increasing sample sizes and standardization of imaging techniques and analyses.61
The use of DWI into a standard MR protocol is progressively increasing thanks to its capability in the tumour detection, characterization as well as its potentiality in the monitoring and in the prediction of treatment response.8-12,62-65 By means of DWI data analysis is possible to estimate water molecules mobility that is related to cell density, vascularity, viscosity of extracellular fluid and cell membrane integrity.12 By measuring these properties with apparent diffusion coefficient (ADC) and other diffusion coefficients characteristics of intravoxel incoherent motion, the DWI could be used as an imaging biomarker to better select patients with reduced prognosis who will benefit from a more aggressive neoadjuvant treatment.8-12 It was demonstrated that ADC values in LARC correlate with prognostic factors including the mesorectal fascia status, the nodal stage and the histological differentiation grade.8,40,62 There are several ways to analyse DWI data including visual evaluation, volumetric assessment, and ADC measurements. Visual DWI evaluation has been shown to improve the MRI performance to differentiate between patients with and without residual tumour after pCRT. Another approach is to measure the volume before and after therapy. Ha
ADC measure (before, during, and after therapy) is the most widely studied approach to assess therapy response. Increases in ADC values after treatment are linked to decreases in tissue cellularity and thus it provides indirect evaluation of chemotherapy induced cell death. Kim
However, the evidence regarding the use of pre, during and post treatment ADC measurements to assess tumour response has so far been inconsistent, which is also related to the fact that ADC measurement are influenced by variations in MR scanner hardware, field strength, acquisition protocols and measurement methods. Lack of standardization hampers the implementation of ADC in clinical practice and should be the focus of future studies.61
PET/CT is constantly increasing in rectal cancer management for its ability to predict treatment response.50 Avallone
The review is the result of autonomous studies without protocol and registration number.
Several electronic database were searched: PubMed (US National Library of Medicine,
All titles and abstracts were analysed and exclusively the studies reporting morphological MRI, DCE-MRI, DWI or PET/CT results in the preoperative therapy response assessment for LARC were retained.
If not otherwise stated, all the studies reviewed herein fulfil the following criteria: English language; thorough clinical characterization of the patients with rectal cancer studied by means morphological MRI, DCE-MRI, DWI and PET/CT to discriminate responders versus non responders to pCRT and exclusion of studies using other diagnostic techniques; articles, reviews and studies that did not present data about specificity, sensibility, positive and negative predictive value of tests treated were excluded; articles, reviews and studies that did not present data about specificity, sensibility, positive and negative predictive value of tests treated were excluded; reviews, general overview articles and congress abstracts were excluded. There was not defining a minimum number of patients as inclusion criteria due to the small number of studies for each imaging modality. Information extracted from each study included title, authors, year of publication, sample size, diagnostic modality and approach, reference standard, true and false positives number, true and false negatives number.
Review Manager (version 5.2) was used to perform data analysis for systematic review. The PRISMA statement for reporting systematic review was used.75
True and false positives number, true and false negatives number for each paper were collected and used to obtain the forest plots reporting the sensitivity, specificity values and relative 95% confidence intervals. ROC curves were also constructed. Moreover, to assess the quality and bias risk of diagnostic accuracy studies included in the review was used QUADAS-2 tool.76
By using the search terms described earlier, we identified 309 studies from 2005 through 2016. One hundred eight studies used other diagnostic techniques than morphological MRI, DCE-MRI, DWI and PET/CT; 98 had different topic respect to presurgery therapy assessment; 78 were excluded for insufficient data (absence of sensibility and specificity value). Twenty-five studies remained for inclusion in our systematic review (Figure 2).
Table 1 shows the number of included studies and the overall number of participants grouped by diagnostic modality.
Number of studies and participants for each diagnostic modality DCE-MRI = dynamic contrast enhanced MRI; DWI = diffusion weighted imaging
Diagnostic modality
Studies
Participants MRI
6
329 DCE-MRI
6
340 DWI
4
133 PET/CT
7
366 MULTIMODAL IMAGING
2
70
Details regarding the number of patients, imaging modality, the accuracy values and examined parameters were recorded. Table 2 summarizes the main characteristics of the examined methodologies in LARC studies.
Main characteristics summary of included studies in the systematic review: for each study the table reports imaging modality used; number of patients examined; parameters examined ADC = apparent diffusion coefficient; DWI = diffusion weighted imaging; SUV = standardized uptake value; TIC = time intensity curve; TRG = tumour regression grade
Imaging modality
Authors
Approach
N. patients
Gold standard
Barbaro
Score system
53
TNM
Denecke
Morphologic criteria
23
TNM MRI
Dresen
Morphologic + volumetric criteria
67
TNM
Intven
Relative volume
51
TRG
Petrillo
Score system
106
TRG
Petrillo
Relative volume
29
TRG
Intven
Relative Ktrans
51
TRG
Kim
Relative Ktrans
50
TNM DCE-MRI
Martens
TIC slope
30
TRG
Petrillo
TIC visual inspection
106
TRG
Petrillo
Relative volume
29
TRG
Petrillo
Standardized index of shape
74
TRG
Birlik
ADC
43
TRG DWI
Ippolito
ADC
30
TRG
Monguzzi
ADC
31
TRG
Petrillo
Relative volume
29
TRG MULTIMODAL IMAGING
Intven
Relative volume + relative Ktrans
51
TRG
Marouf
MRI + DWI Score system
19
TNM
Altini
SUV
68
TRG
Capirci
SUV
81
TRG
Ippolito
SUV
30
TRG PET/CT
Murcia
SUV
41
TRG
Sun
Total lesion glycolysis
35
TRG
Yoon
Dual-point index
61
TRG
Palma
SUV
50
TRG
Figure 3 reports the values of true positive (TP), false positive (FP), false negative (FN), true negative (TN), sensitivity and specificity estimates and their confidence intervals (95%) for each study, subdivided according to the diagnostic modality used for therapy response assessment in LARC. Figure 4 shows ROC for each diagnostic modality.
Table 3 reports the diagnostic performance for each imaging modality in terms of sensitivity, specificity, positive predictive value and negative predictive value.
Performance pooled analysis for MRI, diffusion weighted imaging (DWI), dynamic contrast enhanced MRI (DCE-MRI), PET/CT and multimodal imaging DCE-MRI = dynamic contrast enhanced MRI; DWI = diffusion weighted imaging
Performance
Sensitivity
Specificity
Positive
Negative
Accuracy MRI
75,84
78,21
74,34
79,55
77,13 DCE-MRI
87,18
84,15
82,42
88,51
85,55 DWI
75,95
79,25
84,51
68,85
77,27 PET/CT
80,25
83,08
79,27
83,92
81,82 MULTIMODAL IMAGING
85,00
96,08
89,47
94,23
92,96
Figure 5 shows the bias risk and applicability analysis results. A very low risk of bias was present for the studies included in this systematic review.
The objective of this systematic review was to evaluate the different imaging modalities (morphological MRI, DWI, DCE-MRI, PET/CT and multimodal imaging) in LARC management after pCRT. We collected the current evidence of the role of functional MRI and PET/CT in the assessment of pathological response after pCRT in LARC. The objective was linked to the potentiality of imaging to guide surgeon choice. In fact, patients with substantial (partial response) tumour regression after pCRT could be candidate to conservative strategy while patients reporting a complete response could be subjected to a “wait and see” policy. The advantage is the reduction of morbidity and the possibility to provide a “true” organ-sparing approach.
Our results, using a systematic review of literature and the ROC curves analysis, showed that multimodal imaging combining morphological and functional might achieve better results having the best accuracy in term of sensitivity and specificity (85% and 96%, respectively). However, it should be noted that only two studies have been retrieved from the literature for a total number of only 70 participants subjected to multimodal MRI examination.56,63 Intven
Moreover, DCE-MRI following to PET/CT showed a high diagnostic accuracy (sensitivity 87% and 80% respectively, specificity 84% and 83% respectively) and their results are also more reliable than conventional MRI and DWI alone (Figure 3 and 4). Instead, for morphological MRI alone, the sensitivity was of 76% and specificity of 78%. For DWI, the sensitivity was of 76% and specificity was of 79%. Our findings are comparable with recent meta-analysis that indicated that addition of DWI to standard MRI in a multimodal approach improves the sensitivity for T-staging after pCRT from 50% to 84%.12
Instead, Ippolito
However, PET/CT showed an inferior diagnostic accuracy in comparison of DCE-MRI in pre-surgical assessment of therapy response in LARC but it had a high predict value in the early evaluation of therapy response. The early response assessment by PET/CT was a predictor of non-complete pathological therapy response allowing practical modification of treatment.
Kim
As well as PET/CT, DWI technology can be efficient for predicting pathological complete response in LARC77-80 but inefficient to assess late response in pre-surgical phase. Chen
Therefore, multimodal assessment combining different imaging modalities might be the best option for local restaging of locally advanced rectal cancer after CRT in pre-surgical phase.81 According to this theory, recently Ippolito
A number of limitations of this analysis must be recognized. Most papers report on a limited number of patients and heterogeneity within the included studies with respect to patient selection, neoadjuvant treatment and imaging protocols and analyses. This pooled analysis should be regarded as an indicator of the general performance of functional MRI and PET/CT in the therapy response assessment. Validation and implementation in a multicenter setting are still awaited. Standardization of MRI acquisition protocols and data post processing approaches is mandatory to guarantee results reproducibility. Multicenter studies using large patient populations are needed to validate the role of functional imaging in order to identify those patients who may benefit from a less aggressive therapeutic approach after CRT.
We can conclude that in local staging, morphological MRI is superior respect to CT and PET/CT permitting a correct assessment of the disease extent, of the lymph node involvement, of the mesorectal fascia and of the sphincter complex for surgical planning. On the other side, in restaging for therapy response assessment, Multimodal MRI followed by DCE-MRI seem to give more promising results respect to PET/CT, DWI and conventional MRI. Multimodal Imaging including morphological and functional MRI and DCE-MRI alone could allow to better discriminate responder by non responders patients after neoadjuvant therapy with a high diagnostic accuracy.
In the future, the scientific research should be focused on the integration and combination of functional imaging modalities including also clinical data and molecular biomarkers. A greater number of studies should be performed in the future for each modality to improve the reliability of any conclusion.