The current multidisciplinary management of rectal cancer

Abstract Multidisciplinary management of rectal cancer has rapidly evolved over the last several years. This review describes recent data surrounding total neoadjuvant therapy, organ preservation, and management of lateral pelvic lymph nodes. It then presents our treatment algorithm for management of rectal cancer at The University of Texas MD Anderson Cancer Center in the context of this and other existing literature. As part of this discussion, the review describes how we tailor management based upon both patient and tumor‐related factors in an effort to optimize patient outcomes.


| INTRODUC TI ON
Over the last 10 years, management of rectal cancer has evolved across multiple fronts.As a result, at The University of Texas MD Anderson Cancer Center, we have experienced a change in our practice across oncologic specialties along these fronts.
Applications of multimodal therapy have moved more heavily to the up-front (preoperative) setting with the advent of total neoadjuvant therapy (TNT).Utilization of the robotic platform for rectal cancer surgery has expanded to include multivisceral resections and locoregional nodal dissection (including lateral pelvic lymph node dissection).Herein, we review each of these developments and how they have influenced our current, multidisciplinary approach to rectal cancer management at MD Anderson Cancer Center.

| TOTAL NEOADJ U VANT THER APY
Regarding the appropriate use of TNT, guidelines from the United States, Europe, and Japan differ.Unlike American guidelines published by the National Comprehensive Cancer Network, which offer TNT as a possible treatment strategy for all T3 or greater or node-positive rectal cancers, European and Japanese guidelines suggest TNT be used more selectively. 1European recommendations suggest TNT for high-risk, low rectal tumors or those with lateral pelvic lymph node involvement. 2Japanese recommendations are based on the principle of upfront surgery with prophylactic lateral pelvic lymph node dissection for tumors below the peritoneal reflection, and reserve chemoradiotherapy only for high-risk tumors and those that would benefit from pretreatment to improve resectability, without officially mentioning TNT. 3 The use of TNT at MD Anderson Cancer Center derives from an evaluation of trials that address the risks and benefits associated with TNT, optimal preoperative treatment sequencing, and whether TNT can allow some patients to safely avoid surgery.Among patients with locally advanced rectal cancer, we aim to stratify patients into low-, intermediate-, and high-risk groups based on available data summarized below and patient and tumor-related factors, employing TNT primarily in intermediate-and high-risk patients.Indeed, we tailor our approach to each patient and their disease to craft a personalized treatment strategy.

| PRODIG E-23
TNT protocols have most prominently been addressed by two large randomized controlled trials: PRODIGE 23 and RAPIDO. 4,5In the PRODIGE 23 trial, which addressed the benefit of treatment intensification, patients with locally advanced rectal cancer receiving TNT (FOLFOXIRI followed by long-course chemoradiation) demonstrated high treatment compliance and a moderate rate of grade 3-4 adverse events (45%).Compared with patients receiving standard chemoradiotherapy, patients receiving TNT had similar complication rates but less postoperative sexual dysfunction and a higher rate of pathologic complete response (pCR; 27.8% vs. 12.1%).TNT conferred improved 3-year disease-free survival (75.7% vs. 68.5%)and a lower rate of distant metastases (17% vs. 25%).The updated longterm outcomes reported at the 2023 American Society of Clinical Oncology (ASCO) annual meeting showed significant improvement of all outcomes in the TNT arm, with an absolute increase in 5-year survival 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. 6The local recurrence rates were not different between the arms.
The results of this study have led us to incorporate this treatmentintensified TNT regimen into our practice for patients with locally advanced rectal cancer who have bulky tumors (in an effort to induce maximum regression) and those at high risk of systemic failure (e.g.patients with extramural vascular invasion (EMVI) and those with lateral pelvic lymph node disease).Indeed, we attempt to balance the toxicity of this regimen and lack of data regarding non-operative management with this approach with the improved disease-free survival it may confer for these patients, a finding that has been supported by recent work assessing the impact of TNT with induction chemotherapy on disease-free survival. 7

| R APIDO
In the RAPIDO trial, which evaluated whether standard chemotherapy and short course radiation could be used as an effective TNT strategy, patients with locally advanced rectal cancer treated with TNT (short course radiation followed by FOLFOX/CAPOX) exhibited higher rates of pCR (28.4% vs. 14.3%),lower rates of disease-related treatment failure rate (23.7% vs. 30.4%),and a lower rate of distant metastases (20.0% vs. 26.8%).Again, TNT did not confer a better overall survival benefit compared with standard therapy.However, recently published 5-year follow-up of the RAPIDO trial demonstrated that, at a median follow-up of 5.6 years, patients treated with TNT exhibited a higher rate of locoregional recurrence (10% vs. 6% standard therapy) that more often breached the mesorectum (21% vs. 4%). 8There remained no difference in overall survival between the groups.However, patients treated with TNT continued to demonstrate a similar reduction in disease-related treatment failure and distant metastases at 5 years.At MD Anderson, while we acknowledge the appeal of short-course radiation therapy to patients and healthcare systems, the higher rate of locoregional recurrence with the RAPIDO regimen and lack of data regarding its use in non-operative management has caused us to limit utilization of this short-course radiation-based TNT regimen to specific situations (e.g.patients with metastatic disease in whom we aim to provide expeditious local disease control in the pelvis before promptly initiating systemic therapy, patients in whom long-course chemoradiation is not feasible for logistic reasons).

| S TELL AR
The STELLAR trial, a recently-published trial evaluating a shortcourse radiation-based TNT regimen similar to that used in the RAPIDO trial, compared outcomes among patients with T3-4 and/ or N+ low to mid rectal cancer treated with short-course radiation followed by four cycles of CAPOX to those treated with conventional long-course chemoradiation. 9Patients treated with TNT exhibited increased rates of pCR (22.5 vs. vs.12.6% standard therapy).
However, local recurrence-free survival and distant metastasis-free survival did not differ between the groups.Interestingly, patients treated with TNT experienced improved OS (86.5% vs. 71.5% standard therapy), through rates of acute severe (grade 3-4) toxicity were double in patients treated with TNT (26.5% vs. 12.6% standard therapy).Moreover, the median follow-up for patients on the trial was less than 3 years (35 months).
The results of this trial, particularly with respect to improved OS despite similar recurrence-and distant metastasis-free survival, are difficult to reconcile with the results from PRODIGE-23 and RAPIDO detailed above.Moreover, the relatively short follow-up for patients in the trial limits interpretation of the data.For these reasons, the results of the STELLAR trial have not strongly influenced our treatment algorithms at MD Anderson Cancer Center.

| OPR A
The OPRA trial addressed the question of whether surgery could be safely avoided (i.e.organ preservation, non-operative management, Watch and Wait) in patients with an excellent clinical response to TNT in light of the pCR rates noted in TNT trials above.Patients with stage II or III rectal cancer were randomized to either FOLFOX chemotherapy followed by long-course chemoradiation or long-course chemoradiation followed by FOLFOX.They subsequently underwent either non-operative management or TME based on tumor response.Preliminary 3-year disease-free survival did not significantly differ between the induction (FOLFOX followed by long-course chemoradiation) and consolidation (long-course chemoradiation followed by FOLFOX) groups (78% vs. 77%), nor did distant metastasisfree survival (81% vs. 83%).Consolidation chemotherapy, however, was associated with increased rates of organ preservation at 3 years (58% vs. 43%) with decreased rates of local regrowth once a cCR was achieved (27% vs. 40%).
At MD Anderson Cancer Center, we favor using long-course chemoradiation followed by consolidation chemotherapy for the majority of our patients with locally advanced rectal cancer, particularly in patients with low rectal cancers who would maximally benefit from non-operative management.This regimen offers a TNT regimen option that maximizes local tumor treatment response with a standard systemic regimen for patients without high risk for systemic failure.Moreover, we have data specifically addressing the role of this regimen in non-operative management in patients with rectal cancer as well as its association with a potentially high rate of organ preservation (up to 50%).
A summary of the advantages and disadvantages of the regimens described in the three trials presented above (PRODIGE-23, RAPIDO, OPRA) can be found in Table 1.

| MANAG EMENT OF L ATER AL PELVI C LYMPH NODE S
The management of suspicious lateral pelvic lymph nodes, which we classify as regional disease, in the setting of locally advanced rectal cancer remains an area of active investigation. 10,11However, work by our group and others has provided insight that informs our current approach to lateral pelvic lymph nodes.
Work by several groups has helped identify parameters associated with local recurrence in lateral lymph node compartments.
Studies from South Korea and the United Kingdom initially identified a higher rate of lateral local recurrence after chemoradiotherapy and total mesorectal excision (TME) among patients with rectal cancer with lateral pelvic lymph nodes ≥10 mm. 12,13This was refined by the Lateral Node Study Consortium, which demonstrated that lateral lymph nodes ≥7 mm on initial MRI was associated with a lateral local recurrence rate of nearly 20% after preoperative chemoradiation and TME. 14The group also showed that in patients with lateral pelvic lymph nodes ≥7 mm on initial MRI who underwent neoadjuvant chemoradiation, TME, and lateral pelvic lymph node dissection, local recurrence rates in the lateral lymph node basin were 5.7% at 5 years compared to a rate of 19.5% in patients who underwent neoadjuvant chemotherapy and TME alone, findings supported by a subsequent multinational study of patients from the Netherlands, United States, and Australia. 14,15This suggests that adding lateral pelvic lymph node dissection to TME after neoadjuvant therapy improves local control in patients with suspicious or enlarged nodes on initial staging.
Identifying selection criteria for patients to undergo lateral pelvic lymph node dissection is further informed by work by our group that assessed radiologic findings of lateral pelvic lymph nodes and pathologic and oncologic outcomes among patients with clinically suspicious lateral pelvic lymph node metastasis who received TNT and underwent lateral pelvic lymph node dissection in addition to TME. 16 In this cohort of patients with clinical stage II-III rectal cancer with baseline enlarged lateral pelvic lymph node (n = 158), lateral pelvic lymph node dissection was performed in 88 patients (56%), TA B L E 1 Advantages and disadvantages to total neoadjuvant therapy regimens and current pattern of utilization.0][21][22] Recent work from our group detailed our experience with 40 patients undergoing robotic lateral pelvic lymph node dissection after preoperative chemoradiation, 90% of whom underwent this dissection with concomitant TME for their primary tumor. 22Rate of major morbidity was 10%, a median of six lymph nodes were obtained, and local recurrence rate was 2.5%.

| E VIDEN CE-BA S ED INDIVIDUALIZED TRE ATMENT AT MD ANDER SON C AN CER CENTER
As previously mentioned, at MD Anderson Cancer Center, we employ TNT selectively, tailoring treatment to tumor-and patientassociated risk factors and treatment goals.Considerations that influence therapy decisions include tumor distance from the anal verge, nodal involvement (including lateral pelvic lymph nodes), circumferential resection margin status, and the presence of EMVI (Figure 1).The MD Anderson approach highlights the importance of high-quality surgery with TME (and in some cases beyond-TME approaches as required for margin-negative resection) and a negative circumferential resection margin (CRM) as well as thoughtful use of chemotherapy and radiation.For all patients, we begin with intensive initial evaluation and staging with high-quality imaging to allow for appropriate risk stratification (Table 2).This includes serologic evaluation, detailed history and physical examination, and endoscopic evaluation performed by the treating surgeon, along with high-quality rectal MRI.MRI enables appropriate assessment of the CRM, extramural vascular invasion, distance from the anal verge, and lateral pelvic lymph nodes.Using this information, we stratify patients into low-risk, intermediate-risk, and highrisk groups.In general, in patients who are surgical candidates, we consider margin-negative resection with adequate lymphadenectomy including a TME and negative CRM as a critical component of rectal cancer treatment.Indeed, the MRC CR07 trial demonstrated a 3-year local recurrence rate of 4% among rectal cancer patients undergoing TME with negative CRM. 23 Even among patients with stage III disease who underwent TME with negative CRM, local recurrence rate was only 6%.5][26][27] As an example, the recently published final results from the OCUM trial demonstrated a very low local recurrence rate (4.4% at 5 years) for low-risk patients (upper rectal tumors, middle and lower rectal tumors without mesorectal fascia involvement, suspicious lymph nodes, or tumor deposits). 27is compares favorably with data regarding up-front surgery in previously published studies (3.3%-5.8%)as well as to similar patients treated with chemoradiation in prospective, randomized trials. 9,28-30Moreover, based on data from the PROSPECT trial, among patients with low-risk stage II-III cancer, response to induction FOLFOX informs whether radiation may be safely omitted. 31Taken together, we generally omit radiation in patients with clear CRM (≥2 mm), high rectal tumors (those above the peritoneal reflection), and patients with low-risk mid rectal tumors who demonstrate excellent response to induction chemotherapy and without threatened CRM (Table 3).[34][35] F I G U R E 1 Tumor factors considered in risk-stratification and decisions regarding total neoadjuvant therapy (TNT).Tumor location, risk of local failure, and risk of distant failure are all considered when deciding about the optimal therapy regimen for a given patient.In general, we strongly consider administering TNT to patients at high risk for local and distant failure, those with low tumors at high risk for distant failure, and those with low tumors at high risk for both local and distant failure.
Regarding TNT regimens, among patients with adequate performance status who have aggressive tumors at high risk for systemic failure (i.e.EMVI, multiple lateral pelvic lymph nodes), we favor treatment intensification with triplet induction chemotherapy followed by long-course chemoradiation as described in the PRODIGE-23 study due to the survival benefit demonstrated in the trial.For patients with mid-or low-lying tumors or patients with some high-risk features in whom triplet chemotherapy is deemed unnecessary who would like to attempt organ preservation, we utilize chemoradiation followed by consolidation chemotherapy as described in the OPRA trial.We currently utilize the RAPIDO regimen comprising shortcourse radiation therapy followed by CAPOX or FOLFOX only in select patients with synchronous metastatic disease who require pelvic radiation or those unable to receive long-course chemoradiation (Table 1).
Finally, regarding lateral pelvic lymph nodes, our approach involves assessment of T category and lateral pelvic lymph node appearance on MRI to stratify patients with respect to risk of lateral pelvic lymph node disease. 10This stratification then helps determine our approach to lateral pelvic lymph node dissection in the context of tailored therapy.Patients with radiographically abnormal lateral pelvic nodes at the time of diagnosis are restaged after neoadjuvant therapy, and those with nodes ≥5 mm and/or with suspicious malignant features (i.e.irregular borders, internal heterogeneity) undergo lateral pelvic lymph node dissection (Table 3).Patients with lateral pelvic nodes <5 mm without suspicious features after neoadjuvant therapy are, meanwhile, possibly offered observation of their lateral nodes and dissection is deferred. 10 summary, treatment of locally advanced rectal cancer at MD Anderson Cancer Center involves a tailored approach that carefully assesses patient and tumor factors.Our approach considers existing data regarding the benefits of systemic chemotherapy, external beam radiation, and TNT with respect to local recurrence, survival, and tumor downstaging and weighs this agains the risks of chemotherapy and radiation.Additionally, we employ TNT in select rectal cancer patients deemed appropriate candidates in which to attempt organ preservation and who are agreeable to attempting this approach.In doing so, our multidisciplinary team aims to optimize patient outcomes from both an oncologic and quality of life perspective.

FU N D I N G I N FO R M ATI O N
No funding was received for this article.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Dr. George J. Chang serves as a member of the editorial board for Annals of Gastroenterological Surgery.

E TH I C S S TATEM ENTS
Approval of the research protocol: N/A.
disease-free and overall survival • Decreased rates of developing distant metastases • High rate of grade 3-4 adverse events • No specific data on use as part of non-operative management strategy • Radiation after chemotherapy allows less time for tumor shrinkage • Aggressive tumors at high risk for systemic failure (i.e.EMVI, multiple lateral pelvic lymph nodes) RAPIDO Short-course radiation followed by FOLFOX • Well-tolerated • Convenience of short-course radiation • Higher rates of locoregional recurrence compared to standard therapy • No specific data on use as part of non-operative management strategy • Synchronous metastatic disease who require pelvic radiation • Unable to receive longto chemotherapy allows maximal time for tumor shrinkage • Excellent rates of organ preservation • No treatment intensification for patients at high risk of distant metastases • Mid-or low-lying tumors who would like to attempt organ preservation or tumors with positive/threatened CRM, without significant risk for systemic failure in whom triplet chemotherapy is unnecessary.and pathological positive lateral pelvic lymph nodes were present in 30 patients (34% of those undergoing lateral pelvic lymph node dissection).The decision to perform lateral pelvic lymph node dissection was made by considering multiple factors, with particular emphasis on baseline malignant characteristics and post-treatment size ≥5 mm of lateral pelvic lymph nodes, findings that supported previous work from our group assessing patients undergoing LPLND treated only with preoperative chemoradiation. 17 Finally, retrospective analysis of patients undergoing LPLND at our institution demonstrated that radiographically evident LPLNs on pretreatment MRI rarely occur in patients with primary tumors above the peritoneal reflection and that patients with primary tumors above the peritoneal reflection rarely undergo LPLND.18Although we acknowledge the impact of pre-treatment size, malignant characteristics, and post-treatment size, the decision making in clinical practice is often complex and requires incorporation of the primary tumor factors (sidedness, distance from the anal verge, baseline malignant features, response to TNT), time factors (interval from radiotherapy to radiologic assessment), and patient factors (surgical risk).