INTRODUCTION
In the current climate of total neoadjuvant therapy (TNT) for locally advanced rectal cancers (LARCs), the preoperative use of chemotherapy has gained acceptance for a wide spectrum of reasons. Two recent trials, RAPIDO (Rectal Cancer and Preoperative Induction Therapy Followed by Dedicated Operation) [
1] and UNICANCER-PRODIGE 23 [
2], have been instrumental in paving the way for a TNT approach in LARC treatment. Both trials showed improvements in distant metastasis-free survival and pathological complete response rates. Despite this, no improvement was observed in the local control rate or in overall survival. Similarly, the OPRA (Organ Preservation of Rectal Adenocarcinoma) trial [
3] provided a head-to-head comparison between the 2 TNT approaches—induction chemotherapy and consolidation chemotherapy—and showed superior organ preservation with a consolidation chemotherapy approach. However, the overall survival rate was similar to historical control rates. Indirect evidence indicates that consolidation chemotherapy works best in patients with good responses to neoadjuvant radiation therapy (NART; “good responders”). The role of consolidation chemotherapy in patients with poor response to radiation therapy (“poor responders”) is uncertain [
4]. The popular use of consolidation chemotherapy in poor responders, especially those with persistent involvement of mesorectal fascia (MRF) after NART, is not evidence-based. The real-time benefit of additional chemotherapy in reducing MRF involvement, and thereby decreasing the extent of surgery, has not been assessed. The current study, focusing on clinical-radiological correlation, was conducted to assess the impact of consolidation chemotherapy in downstaging the MRF involvement in LARCs with persistent involvement of MRF after NART.
The primary objective was to assess the impact of consolidation chemotherapy on MRF involvement in patients who had received NART. The secondary objective was to correlate the radiological response after consolidation chemotherapy, as shown on magnetic resonance imaging (MRI)-based local disease imaging, with the actual procedure performed.
RESULTS
Overall, 46 patients with LARCs with involvement of MRF on MRI-1 were screened. After NART, 4 patients exhibited free MRF on MRI-2, while the remaining 42 patients had persistent MRF involvement. The latter patients were then offered consolidation chemotherapy to reduce the involvement of the MRF. On MRI-3, 12 patients had downstaging of MRF involvement, while the remaining 30 had persistent involvement of the MRF. A cohort diagram is presented in
Fig. 2, and the disease and treatment characteristics are shown in
Table 1.
Comparison of MRI-2 and MRI-3
MRI parameters studied and compared between MRI-2 and MRI-3 included T2 signal intensity, tumor length, MRF involvement, EMVI, restriction on DWI, T category, N category, extramesorectal lateral pelvic nodes, and involvement of the sphincter-levator muscle complex
The authors observed significant downstaging of T2 signal intensity, tumor length, involvement of MRF, diffusion restriction, and N category between MRI-2 and MRI-3 (P<0.05 on tests of symmetry). No significant change was observed for T category, extramesorectal nodes, EMVI, and involvement of the sphincter-levator complex upon serial comparison between MRI-2 and MRI-3 (
Table 2).
The serial values of the MRI parameters were examined for any clinically relevant changes, and radiologists reported the MRI-predicted extent of surgery based on the 2 sequential MRIs. Among the morphological parameters, clinically relevant downstaging was observed for only T2 signal intensity and diffusion restriction on DWI (standardized mean difference, >0.3). No clinically relevant change was noted in the remaining parameters, and thus no change was found in MRI-predicted surgery.
Concordance between MRI prediction of surgery and actual surgery performed
Upon analysis of 41 patients who underwent surgery, surgery was performed in the TME plane, e-TME plane, and b-TME plane in 21, 12, and 8 patients, respectively. Five patients underwent no surgery: 3 patients had disease progression, and 2 patients with planned exenteration opted out and defaulted.
The radiologist-predicted extent of surgery based on MRI alone was compared to the actual procedure performed. Agreement testing showed a Cohen κ coefficient of 0.375 (standard error, 0.125; P=0.001), suggesting a weak agreement between the 2 variables. Similarly, correlation testing revealed a Spearman rank coefficient of 0.231 (standard error, 0.164; P=0.146), suggesting a weak correlation (
Table 3).
Concordance between MR-TRG and P-TRG
The 5-point MR-TRG system was compared and correlated with the similar P-TRG system to identify any potential association between the 2 methods of assessing tumor response to neoadjuvant treatment. Agreement testing revealed a Cohen kappa coefficient of −0.017 (standard error, −0.082; P=0.822), suggesting disagreement between the methods. Correlation testing revealed a Spearman rank correlation coefficient of 0.205 (standard error, 0.161; P=0.122), suggesting a weak correlation (
Table 4).
Regression analysis for factors impacting radiological response
Binomial regression analysis was used to analyze the impact of various baseline disease factors (T category, N category, presence of extramesorectal nodes, quadrant of MRF involvement, histopathological variety, type of radiation therapy, and number of cycles of consolidation chemotherapy) on the radiological response (change in MRI-based parameters after completion of all neoadjuvant treatment) (
Table 5). Disease histology significantly impacted the degree of radiological response to neoadjuvant treatment. Twenty patients with poorly differentiated or signet ring cell tumors had an inferior response relative to 26 patients with well or moderately differentiated tumors (hazard ratio, 0.134; 95% confidence interval, 0.026–0.687; P=0.016).
DISCUSSION
In the rapidly evolving treatment paradigm for rectal cancer, survival outcomes are an attribute of the stage at presentation, treatment received, and overall disease biology. The recently published RAPIDO trial [
1] and UNICANCER-PRODIGE 23 trial [
2] provide evidence for inculcation of a complete chemotherapy schedule in the neoadjuvant setting, reducing the risk of distant metastatic relapse. While the RAPIDO trial [
1] involved short-course radiation therapy with 6 cycles of capecitabine and oxaliplatin (CAPOX) or fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for high-risk LARCs, the UNICANCER-PRODIGE 23 trial [
2] involved 6 cycles of induction chemotherapy with long-course chemoradiation therapy for all LARCs. The high-risk LARC subgroup included patients with T3 and T4 node-positive cancers as well as MRF involvement, presence of lateral lymph nodes, or EMVI. The results indicated a 7.5% increment in distant metastasis-free survival and a near doubling in the pathological complete response rate. However, no improvement was observed in either overall survival or local disease control. Similarly, the OPRA trial [
3] showed improvement in organ preservation with a consolidation chemotherapy-based TNT approach relative to induction chemotherapy-based TNT. Overall survival outcomes of both TNT approaches remained similar to the historical control, likely because consolidation chemotherapy selectively benefits good responders.
Experts are debating the role of adjuvant chemotherapy after preoperative radiation therapy [
8]. It possibly seems superfluous to subject patients to additional chemotherapy for a 7.5% increment in distant metastasis-free survival without any overall survival advantage. No trials have reported on the actuarial rates of local downstaging observed with the use of consolidation chemotherapy. Analyzing the results of the STELLAR trial, Negri and Aschele [
4] suggested a careful risk profile-based use of consolidation chemotherapy over and above radiation therapy. The role of additional chemotherapy (consolidation chemotherapy) is uncertain and remains to be studied.
In the current study, the authors analyzed the treatment course of high-risk LARCs that were treated with consolidation chemotherapy in view of persistent involvement of MRF following chemoradiation. An MRI-based repeat assessment was done after at least 4 cycles of consolidation chemotherapy. The mean age of the cohort was 38.5 years, and 43.5% of patients had poorly differentiated histology with or without signet ring cells. This patient population is reflective of the population with aggressive cancer increasingly seen in Asia [
9].
MRI has progressively made its way into the diagnostic and treatment algorithm of LARCs. In 2006, the MERCURY Study Group described MRI as the most appropriate tool to predict the surgical planes for rectal cancer, with superior local control rates [
10]. Kulkarni et al. [
11] showed that reassessment MRI scans have good specificity and high negative predictive value for predicting CRM and tumor response; however, they have low sensitivity. Adding to the initial experience of the MERCURY Study Group, Patel et al. [
6] demonstrated the utility of restaging MRI to differentiate good and poor responders to standard chemoradiation and tailor further neoadjuvant treatment accordingly prior to surgical treatment. The MR-TRG system has been shown to help differentiate the response to chemoradiation [
7,
12]. With the MERCURY II Study, Battersby et al. [
13] showed the predictive capability of MRI in guiding the plane of surgery for high-risk rectal cancers. DWI sequences have gained acceptance in clinical application for response assessment after neoadjuvant radiation over the last decade [
14].
The current report describes changes in various morphometric MRI parameters during the neoadjuvant treatment course of LARCs. Use of consolidation chemotherapy after NART led to downstaging in several parameters, including T2 signal intensity, tumor length, MRF involvement, diffusion restriction, and N category between sequential response assessment MRI scans. However, clinically relevant downstaging was seen for only T2 signal intensity and diffusion restriction on DWI. Thus, after combining the clinical relevance of various parameters to predict the actual plane of surgery, no change was seen in the MRI-predicted extent of the procedure.
Signet ring cell adenocarcinomas (SRCAs) are known to respond relatively poorly to standard chemoradiation treatment [
15,
16]. In this study, poorly differentiated tumors with or without signet ring cell histology showed a poor radiological response to neoadjuvant treatment in comparison to well or moderately differentiated tumors. A previously published report from the present authors’ team emphasized the same [
15]. Patients with signet ring cell tumors had inferior response rates to traditional neoadjuvant treatment strategies, with inferior survival relative to patients with non–signet tumors (P<0.001). The superiority of the TNT strategy in SRCA cancers remains to be confirmed. Signet ring cells are currently being tested in organoids for treatment with different systemic agents [
17].
The current study revealed a poor correlation between the MRI-predicted extent of surgery and the actual procedure performed. The MRI-predicted tumor response did not correspond with the actual histopathological tumor response. The authors postulate that the utility of MRI for response assessment in this high-risk SRCA cohort requires further testing with a larger sample size. The high-risk SRCA patients could underlie the poor capability of MRI parameters to appropriately predict the tumor response in the current study.
The addition of consolidation chemotherapy has been shown to increase the pathological downstaging of LARCs, resulting in increased pathological complete response rates without any clinically relevant increase in toxicity profile [
18–
20]. However, the use of consolidation chemotherapy to downstage the MRF involvement and thereby decrease the extent of surgery remains to be proven. In the RAPIDO trial [
1], the positive CRM rate was 9% in both the standard and experimental arms. Inadequate MRI-based sequential response assessment in high-risk LARCs has been highlighted as a contributor to the lower-than-expected benefit of the TNT approach used in the RAPIDO trial [
21]. The results of MRI-based response assessment for high-risk LARCs in the RAPIDO trial [
1] and UNICANCER-PRODIGE 23 trial [
2] will further elucidate the real-time effect of consolidation chemotherapy on local downstaging. The TRIGGER study [
22] is a feasibility study currently being conducted to stratify the management of LARCs according to MRI-based assessment. In that study, researchers are testing the utility of MR-TRG in evaluating the response to NART and differentiating between good and poor responders.
A strength of the current report is that it is the first study to elucidate the relationship between consolidation chemotherapy and objective changes in MRI parameters, in the subgroup of mucinous tumors. The study involved analysis of a high-risk subgroup for which consolidation chemotherapy is often used for local downstaging without any objective evidence. The study emphasizes the need for a dedicated radiology team to guide the treatment protocol based on timely sequential MRI assessments.
The limitations of this study relate to its retrospective design and limited sample size. LARCs with poor differentiation are known to display inferior response to neoadjuvant treatment, and this could affect the predictive capacity of MRI-based response assessment.
The authors emphasize the need for evidence supporting the use of consolidation chemotherapy for local downstaging to increase the resectability of high-risk rectal cancers. The unwarranted use of consolidation chemotherapy in nonresponders potentially increases the time to surgery without any decrease in the planned extent of surgical resection. This could underlie poor outcomes in the high-risk subgroup of LARCs with MRF involvement at baseline. We suggest that it may be reasonable to increase the extent of surgery after radiation therapy for these poorly responsive tumors as opposed to subjecting patients to further chemotherapy with little real-time benefit.
This was a hypothesis-generating study. Various aspects of the treatment of mucinous rectal cancers, including the responsiveness to chemotherapy, the utility of MRI in response assessment, and appropriate time points for response assessment, require prospective research with a large sample size.
In conclusion, evidence is lacking regarding the use of consolidation chemotherapy in reducing MRF involvement in LARCs. The potential benefit of additional chemotherapy after NART in decreasing the extent of planned surgery by reducing margin involvement requires prospective research with a large sample size to draw practice-changing conclusions. The use of MRI for predicting the extent of surgery (TME, e-TME, or b-TME) after NART in patients with mucinous histology at baseline requires prospective validation.