Guiding Post-Treatment Decisions in Rectal Cancer: mrTRG Is a Practical Place to Start

August 15, 2014

The authors propose that current policies regarding the use of chemoradiotherapy or short-course preoperative radiotherapy have resulted in an approach to rectal cancer management that often represents overtreatment, with significant loss of quality of life for patients.

Glynne-Jones and colleagues offer a clear evidence-based review of rectal cancer management. This review addresses four topical areas: patient selection, prognostic factors, the perceived limitations of MRI, and whether there is a role for functional imaging.[1] The authors propose that current policies regarding the use of chemoradiotherapy (CRT) or short-course preoperative radiotherapy (SCPRT) have resulted in an approach to rectal cancer management that often represents overtreatment, with significant loss of quality of life for patients. In the post–total mesorectal excision (TME) era, a number of practice-changing trials, such as the German-led randomized controlled trial (Sauer et al) and the Medical Research Council (MRC) CR07 and National Cancer Institute of Canada Clinical Trials Group C016 trial, supported the use of preoperative therapy.[2,3] These trials shaped current guidelines, but their selection criteria for preoperative therapy were relatively indiscriminant. Consequently, there has been a low threshold for CRT and SCPRT in clinical practice.

Of note, the MRC CR07 trial was designed prior to the reporting of the results of the MERCURY study.[4] The authors acknowledge this trial limitation and suggest that future trials should incorporate MRI staging to select the population offered preoperative treatment.[2] The implication is that preoperative therapy can be offered when oncologic gains are likely, while low-risk patients can avoid unnecessary morbidity.

The authors emphasize that better use should be made of preoperative knowledge of prognostic factors for local and distant recurrence in rectal cancer. Could the selective use of preoperative chemotherapy alone for resectable tumor (“safe” MRI-identified circumferential resection margin [mrCRM]) with other adverse radiologic features, such as extramural venous invasion identified on MRI (mrEMVI) and MRI-identified T3c disease (mrT3c), reduce the rate of systemic failure? In the TME era, local recurrence has become much rarer, with rates of < 10% observed, whereas metastatic disease is reported in up to 40% of patients.[2,3,5] Using CRT to downstage an already resectable tumor provides a suboptimal dose of chemotherapy and may unnecessarily subject patients to the morbidity of radiotherapy. Systemic chemotherapy alone may be preferable; in the colon and rectum, evidence is emerging to support the use of preoperative systemic chemotherapy.[6,7] The BACCHUS trial (National Clinical Trials Identifier NCT01650428), which is currently recruiting, is also testing this principle in MRI-identified high-risk patients. The approach is gaining momentum and will be a valuable addition to guidelines.

With preoperative MRI and optimal TME surgery, audited by histopathologic evaluation, it is also possible to avoid CRT in patients with resectable early-stage disease-and this would include mrT3b disease (tumor invasion ≤ 5 mm beyond the muscularis propria, predicted mrCRM-clear and mrEMVI-negative) in this good-prognosis group.[8] Another area of controversy has involved definitions of what constitutes a safe MRI resection margin. The only prospective evidence to date has shown that increasing the distance from tumor to the mesorectal fascia from 1 mm to a 2-mm cut-off does not reduce the risk of local recurrence and may lead to unnecessary morbidity from overtreatment.[9]

In the past, MRI was thought to have a limited ability to assess the relationship between the tumor and the levator muscle; more recently, the MERCURY II low rectal cancer study prospectively validated a low rectal cancer staging system.[11,12] This system is effective because it uses high-resolution MRI, which enables optimal definition of the relationship between the tumor and the intersphincteric plane. Furthermore, post-treatment MRI is also able to accurately stage the distal TME/intersphincteric plane.[11] Although there has been much interest in newer techniques, such as diffusion-weighted imaging and functional imaging, these have failed to show any advantage over high-resolution MRI. Staging is heavily dependent on a clear depiction of surgical anatomy. Given that the tumor is comparatively poorly depicted on diffusion-weighted MRI (Figure), perhaps it should come as no surprise that at present this modality adds no value to a high-resolution staging assessment.

It is obvious from pathologic assessment of nodes that a technique that relies on measurement of the diameter of the nodes to predict whether or not tumor is present is likely to result in poor accuracy and to be clinically unhelpful.[12] For this reason, measuring the size of lymph nodes is not recommended for preoperative staging of rectal cancer. Although not perfect, the best method for identifying malignant nodes is to assess whether mixed intranodal signal and/or irregularity of the border is present.[13] Historically, any histopathologic nodal involvement predicted for pelvic recurrence, with observed rates of 30% to 40%. However, when optimal TME surgery is performed and the disease burden is confined to the mesorectum (N1 disease), the risk of pelvic recurrence does not significantly escalate.[14] The argument is increasingly made that these cases do not routinely require CRT.[15] However, this argument does not hold true for pelvic sidewall nodes, seen in 11% of all patients staged by MRI but not evident as a cause of recurrence in patients with MRI-defined good-prognosis tumors who are undergoing primary surgery.[16]

There is a critical need for techniques and modalities that accurately measure response. These will make it possible to select suitable patients for organ-saving treatment, and will determine the optimal extent of treatment response. The authors express a good deal of hope regarding the capabilities of functional imaging (such as diffusion-weighted imaging, dynamic contrast enhancement, or spectroscopy) for tissue characterization and for prediction and assessment of tumor response. However, these modalities have yet to be prospectively validated with predefined criteria, compared against existing high-resolution MRI methods, or correlated with survival outcomes-all essential prerequisites if such techniques are to gain acceptance as clinically relevant biomarkers. Meanwhile, T2-weighted MRI reliably evaluates prognostic tumor features, and long-term oncologic outcomes have been reported. The Table compares the evidence base for morphologic and functional imaging, highlighting the current gap in long-term follow-up between the two techniques. Just as good-quality cancer surgery cannot be assumed, neither can accurate MRI reporting, which is highly dependent on the MRI technique and interpretation. Both good-quality surgery and accurate MRI interpretation require training and specialization, but these are readily achieved through implementation of training programs and auditing of performance.[17,18]

It is tempting to shorten the examination time by reducing the resolution of T2-weighted images. At first glance, similar-looking high-contrast soft-tissue images are obtained, but the MRI interpretation will be much poorer if the lower-resolution images are evaluated. Differences in image resolution and interpretation criteria are the chief cause of the variations in accuracy reported in the literature, but when the technique is standardized consistently, accurate results are achieved.[4] High-resolution MRI requires a small field of view (160 mm × 160 mm), a small voxel size (1 mm3), and a high signal-to-noise ratio (SNR > 1); these parameters can be achieved by ensuring a sufficient acquisition time. The Figure clearly demonstrates that by using this technique it is possible to produce T2-weighted images with excellent resolution; in contrast, the resolution of diffusion- and perfusion-based imaging is poor, and the images are thus difficult to interpret reliably.

The authors discuss the use of high-quality T2-weighted images for the assessment of tumor regression grade (mrTRG). The mrTRG was derived from the pathologic tumor regression grade (pTRG) systems; it most closely resembles the Mandard pTRG grade.[19] In the MERCURY study, response was evaluated using mrTRG.[19] There was a significant difference in disease-free survival (DFS) and overall survival (OS) between mrTRG 1–3 (good response) and mrTRG 4/5 (poor response) (P < .001); the 5-year DFS was 72% and 27%, respectively.[19] In an independent dataset, we found a similar significant difference in DFS and OS: mrTRG 1/2 (good response), mrTRG 3 (intermediate response), and mrTRG 4/5 (poor response) had a 3-year DFS of 82%, 72%, and 61%, respectively.[20] The interobserver reliability between radiologists was moderate to substantial, with kappa values of 0.55 to 0.65.[19] mrTRG has also been shown to be the most reliable of current methods for assessing response prior to surgery. It has been evaluated in several prospective trials and is emerging as the most promising “biomarker” for the evaluation of response, one which might be used to stratify rectal cancer patients with regard to future management. Good responders appear to behave similarly to those who achieve a pathologic complete response; thus, in these patients it is feasible to consider deferral of surgery with intensive follow-up. On the other hand, the possibility of offering poor responders further therapy may shift their mrTRG results into a more favorable prognostic group prior to surgery. We plan to test this approach in a prospective randomized trial.

This review by Glynne-Jones et al makes important suggestions for improving current rectal cancer guidelines and recognizes the advancing evidence base for radiologic evaluation of prognostic factors such as predicted CRM, extramural vascular invasion, depth of extramural spread, and an mrTRG-based response. There has been much investment in functional and metabolic imaging techniques, but thus far prospective validation has proven to be elusive. Given the inherently poor spatial information these modalities provide, it is unlikely that functional or metabolic techniques could guide operative management, and their potential to alter routine clinical practice remains a consistent but nonetheless distant hope.

Financial Disclosure:Drs. Battersby, Balyasnikova, and Brown receive funding support from the National Institute for Health Research Biomedical Research Centre and the Pelican Cancer Foundation.

References:

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