Neoadjuvant therapy for rectal adenocarcinoma

INTRODUCTION — 

Surgery is often used to treat rectal adenocarcinomas. However, only patients with early-stage (stage I) rectal adenocarcinoma (table 1) have a high cure rate with surgery alone. (See "Surgical treatment of rectal cancer".)

For nonmetastatic rectal adenocarcinomas that are larger or more invasive, initial management with neoadjuvant (ie, preoperative) therapy is used to reduce tumor burden prior to pursuing surgery or other management strategies. In some cases, neoadjuvant therapy may permit nonoperative management for those patients who achieve a clinical complete response (cCR). (See 'Nonoperative management' below.)

This topic will present the various approaches to neoadjuvant therapy for rectal adenocarcinoma. Other topics related to the clinical presentation, diagnosis, and management of rectal adenocarcinoma are discussed separately.

●(See "Clinical presentation, diagnosis, and staging of colorectal cancer".)

●(See "Pretreatment locoregional staging evaluation for rectal cancer".)

●(See "Adjuvant therapy after neoadjuvant therapy for rectal cancer" and "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy".)

●(See "Adjuvant therapy after neoadjuvant therapy for rectal cancer" and "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy".)

PRETREATMENT STAGING EVALUATION — 

It is important that patients with newly diagnosed rectal cancer are accurately staged prior to treatment, which is briefly summarized here. Full details on staging evaluation for locoregional and metastatic disease are discussed in detail separately. (See "Clinical presentation, diagnosis, and staging of colorectal cancer" and "Pretreatment locoregional staging evaluation for rectal cancer", section on 'Clinical evaluation' and "Endoscopic ultrasound for evaluating patients with rectal cancer".)

●Evaluation for metastatic disease – All patients should be evaluated for metastatic disease with a contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis. Serum levels of the tumor marker carcinoembryonic antigen (CEA) should be assayed prior to treatment. Elevated pretreatment CEA levels that do not normalize post-treatment imply the presence of persistent disease and the need for further evaluation. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Computed tomography scan' and "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Tumor markers'.)

●Staging evaluation of the primary tumor and locoregional lymph nodes – The selection of appropriate patients with nonmetastatic rectal adenocarcinoma for initial neoadjuvant therapy depends on accurate preoperative locoregional staging. This is mainly accomplished through physical examination, endoscopy, and imaging evaluation with rectal magnetic resonance imaging (MRI) and/or transrectal endoscopic ultrasound (EUS). (See "Pretreatment locoregional staging evaluation for rectal cancer", section on 'Clinical evaluation'.)

High-resolution rectal MRI and transrectal EUS are both acceptable imaging methods to determine preoperative local tumor stage. Both are more accurate than axial CT scans for assessing the depth of tumor invasion, nodal involvement, and the status of the circumferential resection margin (CRM). However, optimal thin-section (high-resolution) rectal MRI using a surface pelvic phased-array coil MRI is generally preferred, if available, because of its greater utility in assessing the CRM. EUS is only able to assess the status of the CRM for anteriorly located tumors. (See "Endoscopic ultrasound for evaluating patients with rectal cancer", section on 'Circumferential resection margin'.)

The pretreatment imaging evaluation of rectal cancer is discussed in detail separately. (See "Pretreatment locoregional staging evaluation for rectal cancer", section on 'Imaging evaluation'.)

INDICATIONS FOR NEOADJUVANT THERAPY — 

For certain patients with nonmetastatic rectal adenocarcinomas, initial management with neoadjuvant (ie, preoperative) therapy (with chemotherapy and/or radiation therapy [RT]) is used to reduce tumor burden prior to pursuing surgery or other management strategies. In some cases, neoadjuvant therapy may permit nonoperative management for those patients who achieve a clinical complete response (cCR). (See 'Nonoperative management' below.)

We suggest initial treatment with neoadjuvant therapy rather than upfront surgery for patients with any of the following:

●Clinical (c)T3-T4 primary tumor – (see 'cT3-4 primary tumor' below)

●Clinically lymph node-positive disease, regardless of the primary tumor stage – (see 'Clinically node-positive disease' below)

●Mesorectal fascia involvement – (see 'Mesorectal fascia involvement' below)

●cT3-T4 or node-positive distal tumor located ≤5 cm from the anal verge – (see 'Distal tumors and sphincter preservation' below)

Neoadjuvant therapy is also an alternative to upfront surgery for select patients with distal clinical T1N0 or T2N0 rectal cancer who are poor candidates for abdominal surgery or in whom upfront surgery would result in a permanent colostomy. As further randomized trials are necessary, patients interested in this management strategy should be treated ideally in the context of a clinical trial. (See 'cT1-T2 N0 disease' below.)

cT3-4 primary tumor — Clinical T3 or T4 rectal adenocarcinoma (table 1) is a definitive indication for neoadjuvant therapy that is supported by data from randomized trials. These are patients who, if resected initially, would likely require postoperative RT. Data from randomized trials and a meta-analysis [1] suggest that neoadjuvant therapy is associated with a more favorable long-term toxicity profile and fewer local recurrences than postoperative (adjuvant) therapy; overall survival (OS) appears similar. (See 'Preoperative versus postoperative therapy' below and 'Efficacy' below.)

cT3 N0 primary tumor — For all patients with cT3N0 rectal adenocarcinoma by endoscopic ultrasound (EUS) or MRI, even proximal tumors, we offer neoadjuvant therapy given the limitations of staging imaging studies.

Although some data suggest that cT3N0 tumors that do not threaten the mesorectal fascia have low rates of local recurrence after total mesorectal excision (TME) alone [2-8], as many as one-fifth of these patients may be understaged by preoperative imaging. As an example, in an observational study of 188 patients with EUS/MRI-staged cT3N0 tumors who received preoperative chemoradiation (CRT), 41 (22 percent) were found to have pathologically positive mesorectal lymph nodes at the time of surgery [9]. Given the downstaging effect of CRT, it is likely that an even larger number of these patients would have been found to have node-positive disease (and would have been offered postoperative adjuvant therapy) had surgery been undertaken initially. Issues related to the accuracy of locoregional staging in patients with newly diagnosed rectal cancer are discussed in detail separately. (See "Pretreatment locoregional staging evaluation for rectal cancer".)

What is the role of extramural tumor invasion depth? — For patients with cT3N0 rectal tumors, selecting neoadjuvant therapy based on depth of extramural tumor invasion is not part of standard clinical practice in the United States. However, this approach is supported by clinical guidelines in Europe [10].

Data suggest that T3 tumors with >5 mm of extramural invasion have a higher rate of nodal involvement [11] and distant metastases as well as a lower cancer-specific survival compared with tumors that have a depth of penetration of 5 mm or less [12-15]. Preoperative high-resolution MRI can identify those patients with cT3 tumors and <5 mm of extramural tumor invasion, who may have a good outcome with surgery alone [16]. However, T3 stage subclassification using depth of extramural penetration is not incorporated into American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging (table 1). In addition, extramural invasion is not a validated prognostic factor in rectal cancer. (See "Pretreatment locoregional staging evaluation for rectal cancer", section on 'T3 disease and the depth of extramural invasion'.)

By contrast, some guidelines suggest that extramural tumor invasion can be used to identify high-risk T3 tumors [15,17]. Guidelines for treatment of rectal cancer from the European Society for Medical Oncology (ESMO) suggest that patients with a depth of invasion beyond the muscularis propria that is 5 mm or less are appropriate candidates for upfront surgery rather than neoadjuvant therapy, even if they are node positive, as long as the levators are not threatened, the mesorectal fascia is clear, and there is no extranodal extension [10]. This approach is appropriate for those with mid and upper rectal cancers where adjuvant therapy can be administered for those with lymph node involvement, but not for those with distal rectal cancer.

Clinically node-positive disease — For patients who have a suspicion of node-positive disease by MRI or EUS, regardless of T stage, the determination of "node positivity" can be particularly difficult. Most lymph nodes involved by rectal adenocarcinoma are less than 1 cm, but not all lymph nodes seen with MRI or EUS represent metastatic disease. MRI can assist in the determination of whether small, visualized nodes are likely to be malignant by detecting mixed intranodal signal and/or irregularity of the border. (See "Pretreatment locoregional staging evaluation for rectal cancer", section on 'Principles of rectal cancer staging by imaging'.)

Neoadjuvant therapy is also an appropriate option for patients with cT1 or T2 tumors if they have involved lymph nodes. Thus, evaluation for ultrasound-guided fine needle aspiration biopsy of the lymph nodes should be given to any patient who has a cT1 or cT2 tumor and questionable perirectal lymph nodes.

Mesorectal fascia involvement — Neoadjuvant therapy is an option if the preoperative staging evaluation suggests that the tumor invades or "threatens" (ie, is within 2 mm of) the mesorectal fascia, which is the circumferential resection margin (CRM) when TME is performed. Data from several trials indicate that this finding is highly predictive of residual tumor at the CRM, which places the patient at high risk of local recurrence and inferior survival. For anterior tumors, the status of the CRM can be predicted with either EUS or MRI, while for posterior or posterolateral tumors, MRI is the preferred strategy. (See "Pretreatment locoregional staging evaluation for rectal cancer".)

Although there are fewer data to validate this approach, these patients are appropriate candidates for neoadjuvant therapy in an attempt to downstage the tumor and permit a CRM-negative resection. One of the main benefits for preoperative, as compared with postoperative, CRT in the German Rectal Cancer Study Group trial (which did not focus on patients with evidence of mesorectal fascia involvement) was a reduction in the rate of local recurrence. (See 'Preoperative versus postoperative therapy' below.)

Distal tumors and sphincter preservation

cT3-T4 or node-positive disease — For patients with distal cT3-T4 or node-positive rectal adenocarcinomas, a major goal of neoadjuvant therapy is to convert the surgical procedure from an abdominoperineal resection (APR) to a sphincter-preserving operation, such as a lower anterior resection (LAR) with coloanal anastomosis [18-22]. Whether or not an APR is required is somewhat subjective, and this makes determining this particular benefit of neoadjuvant therapy difficult to quantify, at least in terms of sphincter preservation. Sphincter preservation rates are highly dependent on the skill and experience of the surgeon, factors that are difficult to document.

The most common method to determine if neoadjuvant therapy has increased the rate of sphincter preservation is through clinical assessment, in which the operating surgeon examines the patient prior to the start of therapy and declares the type of operation required [23]. In the population under study, this rate is then compared with the actual operation that was carried out.

Unfortunately, few reported series provide results from patients who underwent such a prospective assessment by their surgeon and were declared to need an APR before the start of preoperative therapy. The incidence of sphincter preservation in such reports ranges from 39 to 94 percent, averaging 67 percent (table 2) [24-32]. Analyses of local control, survival, and bowel function are encouraging but not definitive.

High-quality definitive evidence is lacking that neoadjuvant therapy can consistently convert patients who need an APR to where an LAR is feasible. The German trial of preoperative versus postoperative CRT demonstrated that patients undergoing preoperative CRT were twice as likely to undergo a sphincter-sparing operation (39 versus 19 percent) [33]. However, the absolute rates of APR in the two cohorts were not significantly different. (See 'Preoperative versus postoperative therapy' below.)

cT1-T2 N0 disease — Most patients with a distal cT1N0 or cT2N0 rectal cancer are treated with upfront surgery. However, neoadjuvant therapy followed by a less extensive resection may be an alternative to upfront surgery for select patients with distal clinical T1N0 or T2N0 rectal cancer who are unfit for extensive abdominal surgery or in whom upfront surgery would lead to a permanent colostomy. As further randomized trials are necessary, patients interested in this management strategy should ideally be treated in the context of a clinical trial.

●Neoadjuvant therapy followed by local transanal excision – In select patients with a cT1-T2 N0 small distal rectal cancer, neoadjuvant CRT followed by a local transanal excision may be an alternative approach to upfront TME [32,34-44]. As an example, in a single-arm phase II trial (ACOSOG Z6041) of 79 patients with cT2N0 distal rectal cancer treated with neoadjuvant CRT with CAPOX followed by local excision, the three-year disease-free survival (DFS) was 88 percent and the three-year local recurrence rate was 4 percent [37]. Furthermore, in a randomized trial of patients with T2 rectal cancer comparing neoadjuvant CRT followed by local excision with a laparoscopic TME, recurrence rates were similar between the two treatment arms [44]. A single-arm phase II trial (NEO) of early-stage (cT1-T3 N0) rectal tumors treated with three months of neoadjuvant chemotherapy (either FOLFOX or CAPOX) followed by local excision and observation suggested high two-year locoregional relapse-free survival (90 percent) [41]. Further details on neoadjuvant therapy followed by transanal excision are discussed separately. (See "Transanal endoscopic surgery (TES)", section on 'Early rectal cancer'.)

●Neoadjuvant therapy followed by radical excision – Although more controversial, patients with a distal clinical T1N0 or T2N0 rectal cancer who require an APR may be evaluated for neoadjuvant therapy in an effort to convert the operation to a sphincter-sparing surgery such as LAR or proctectomy with coloanal anastomosis. The major difficulty in this situation is that many of these patients, if operated on initially, would be found to have node-negative pathologic T1 to T2 tumors for which neither RT nor chemotherapy would be administered. At many institutions, the decision to use neoadjuvant therapy may commit the patient to more treatment than necessary. This is because of the significant downstaging that often occurs with neoadjuvant therapy. Patients who are found to have negative nodes following neoadjuvant therapy may have been positive at presentation, and the presence of positive nodes is a marker for an increased risk of systemic recurrence. (See "Adjuvant therapy after neoadjuvant therapy for rectal cancer", section on 'Benefit of postoperative chemotherapy'.)

However, if the patient is a poor surgical candidate or declines APR, initial neoadjuvant therapy (typically CRT or total neoadjuvant therapy [TNT]) may be chosen, followed by a restaging evaluation with MRI or EUS. A sphincter-sparing resection should only be undertaken at that time if a negative distal margin can be achieved and if presurgical anorectal sphincter function is adequate. (See "Surgical treatment of rectal cancer", section on 'Local excision' and "Overview of the management of rectal adenocarcinoma", section on 'Stage I disease'.)

NEOADJUVANT THERAPY FOR NONMETASTATIC DISEASE

General approach — The treatment for locally advanced rectal cancer is evolving. The following represents our suggested approach to neoadjuvant therapy (algorithm 1).

●Testing for dMMR/MSI-H – All patients should be tested for mismatch repair deficiency (dMMR; both germline and somatic tumor testing) and high microsatellite instability (MSI-H), which influences selection of therapy.

●Total neoadjuvant therapy – For most patients with mismatch repair proficient (pMMR) locally advanced rectal cancer and clinical T4 disease, clinical N2 disease, a low-lying rectal tumor (≤5 cm from the anal verge) (figure 1), involved or threatened mesorectal fascia, or extramural venous invasion, we suggest total neoadjuvant therapy (TNT; ie, a course of neoadjuvant oxaliplatin-based chemotherapy and a course of neoadjuvant radiation therapy [RT]) rather than neoadjuvant chemoradiation (CRT) alone. For patients who will receive TNT, sequencing of RT and chemotherapy as well as selection of RT schedule and chemotherapy regimen is presented separately. (See 'Total neoadjuvant therapy for locally advanced tumors' below.)

●Neoadjuvant chemotherapy and selective use of CRT – For most patients with pMMR, clinical T2N1M0, T3N0M0, or T3N1M0 rectal adenocarcinoma who are eligible for sphincter-sparing surgery, we suggest neoadjuvant chemotherapy with modified FOLFOX-6 followed by selective, response-guided use of CRT rather than neoadjuvant CRT alone prior to surgery. In a randomized trial, this approach demonstrated similar disease-free survival (DFS) and overall survival (OS). Most patients (approximately 90 percent) also avoided CRT and were presumably spared from any late radiation-associated toxicities. (See 'Neoadjuvant chemotherapy and selective use of CRT' below.)

●Selecting an RT regimen – For patients with nonmetastatic rectal cancer who will be receiving a neoadjuvant therapy regimen that integrates RT, options include long-course RT or short-course RT. Selecting between these RT regimens is discussed separately. (See 'Selecting an RT regimen' below.)

●Nonoperative management for complete clinical responders – Nonoperative management is an acceptable alternative to surgery for those patients who experience a clinical complete response (cCR) to neoadjuvant therapy, especially TNT. It is important to have mature data to ensure that survival outcomes are equivalent, given rectal cancer can recur as late as 5 and 10 years after treatment completion. Some long-term data are available in the OPRA trial, which is discussed separately [45]. (See 'Sequencing of RT and chemotherapy' below.)

For patients who achieve a cCR with no evidence of residual tumor on digital rectal examination, rectal MRI, and direct endoscopic evaluation, an initial nonoperative approach is an option in the hands of an experienced multidisciplinary team. Given the degree to which the risk of local and distant relapse has not been adequately characterized, any decision for nonoperative management should involve a careful discussion with the patient on their risk tolerance and ability to follow an intensive surveillance schedule. (See 'Nonoperative management' below.)

●dMMR/MSI-H tumors – For patients with a locally advanced dMMR/MSI-H rectal tumor who are candidates for neoadjuvant therapy, we suggest initial treatment with immunotherapy rather than chemotherapy or RT. Patients with a cCR to immunotherapy may be offered surveillance (ie, nonoperative management) as an alternative to surgery. (See 'Mismatch repair deficient/MSI-H tumors (neoadjuvant immunotherapy)' below.)

Total neoadjuvant therapy for locally advanced tumors

Definition — TNT consists of a course of neoadjuvant (ie, preoperative) oxaliplatin-based chemotherapy and a separate course of neoadjuvant RT (either long-course neoadjuvant CRT or short-course RT), both of which are administered prior to planned surgical resection of the primary rectal tumor.

Patient selection — For most patients with locally advanced rectal cancer without distant metastases and any of the following clinical features, we suggest TNT rather than neoadjuvant CRT alone. Such clinical features include:

●Clinical T4 disease

●Clinical N2 disease

●A low-lying rectal tumor (≤5 cm from the anal verge)

●Involved or threatened mesorectal fascia

●Extramural venous invasion

In a randomized trial, TNT with oxaliplatin-based chemotherapy and CRT improved pathologic complete response (pCR) rates as well as DFS and was better tolerated than neoadjuvant CRT alone. (See 'Rationale and benefits' below.)

Patients with a cCR after completion of TNT also have the option of omitting surgery (with close surveillance for disease recurrence), which offers a chance at rectal preservation. (See 'Nonoperative management' below.)

For cT3N0 disease that is low lying and would require either an abdominoperineal resection (APR) or a very low coloanal anastomosis, the decision to pursue TNT for the primary goal of organ preservation is a complex decision that requires careful explanations of the pros and cons with the patient.

Rationale and benefits — For patients with locally advanced rectal cancer, the rationale for TNT is to intensify neoadjuvant therapy by adding neoadjuvant chemotherapy and CRT prior to planned surgery to improve resectability, pCR rates, enhance organ preservation, and improve DFS and OS. TNT also increases chemotherapy compliance since systemic therapy is administered in the preoperative setting rather than the postoperative setting. Postoperative chemotherapy initiation may be delayed due to postoperative complications; chemotherapy is also more difficult to tolerate in the postoperative setting, and some patients are unable to complete the full course of chemotherapy. Other benefits of TNT include the treatment of potential systemic disease early and more effectively compared with adjuvant administration of chemotherapy. (See 'Sequencing of RT and chemotherapy' below.)

Initial data from observational studies [46] and early clinical trials [47-55] comparing TNT with neoadjuvant CRT suggested clinical benefit for this approach, including improved rates of resectability, pCR, and rectal preservation. Studies also initially suggested that OS was either improved with TNT [56] or similar between these management strategies [57-59]. These data also suggest that TNT reduces the risk of distant metastatic disease, presumably due to the neoadjuvant administration of chemotherapy [56,59].

In a subsequent open-label phase III trial (PRODIGE 23), TNT using neoadjuvant chemotherapy with FOLFIRINOX and conventionally fractionated (ie, long-course) neoadjuvant CRT (followed by surgery and adjuvant chemotherapy) improved pCR rates, DFS, and OS relative to neoadjuvant CRT (followed by surgery and adjuvant chemotherapy) [60,61]. In this trial, 461 patients with clinical T3 or T4 rectal cancer <15 cm from the anal verge were randomly assigned to either [60,61]:

●TNT using three months of modified FOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² day 1, and fluorouracil [FU] 2400 mg/m² over 46 hours every 14 days) followed by long-course CRT (50 Gy administered over in 25 fractions plus concurrent capecitabine), total mesorectal excision (TME), and three months of adjuvant chemotherapy (clinician's choice of FOLFOX or capecitabine).

or

●Long-course CRT followed by surgery and six months of adjuvant chemotherapy (FOLFOX or capecitabine).

At interim analysis (median follow-up of 47 months), relative to neoadjuvant CRT, TNT improved DFS (three-year DFS 76 versus 69 percent, hazard ratio [HR] 0.69, 95% CI 0.49-0.97) and pCR rates (28 versus 12 percent) in the entire study population [60]. DFS benefit was also seen across clinically relevant subgroups, including patients with clinical T4 disease, node-positive disease, low-lying rectal tumors, extramural tumor invasion, and an involved or threatened mesorectal fascia (predicted lateral surgical margin ≤1 cm). For the entire study population, OS was similar between the two treatment arms (three-year OS 91 versus 88 percent, stratified HR 0.65, 95% CI 0.40-1.05). In extended follow-up (median of 82 months), TNT and neoadjuvant CRT resulted in seven-year DFS of 68 versus 62 percent, respectively (restricted mean survival time [RMST] difference of 5.7 months, p = 0.05), and seven-year OS of 82 versus 76 percent, respectively (RMST difference 4.4 months, p = 0.03) [61]. Preliminary data from an abstract reported a numerical advantage favoring TNT over neoadjuvant CRT for DFS (HR 0.80, 95% CI 0.58-1.11) and OS (HR 0.73, 95% CI 0.48-1.09) [62,63]. Although the study was underpowered to detect a difference in OS between the treatment arms, we believe that the absolute benefits in DFS and OS with TNT are both clinically meaningful.

Neoadjuvant FOLFIRINOX was well tolerated, with most patients (92 percent) completing all courses of chemotherapy [60]. By contrast, among the patients assigned to preoperative CRT, only 79 percent received any adjuvant chemotherapy, and only 81 percent of these completed all six months of therapy. Neoadjuvant chemotherapy also did not increase surgical morbidity or reduce compliance with CRT or adjuvant chemotherapy.

Patients who received most oxaliplatin preoperatively also had less neurotoxicity [60]. During adjuvant therapy, both treatment groups had similar rates of grade 1 or 2 peripheral sensory neuropathy (64 percent), but grade 3 peripheral sensory neuropathy rates were lower in those treated with TNT/neoadjuvant FOLFIRINOX (12 versus 21 percent), despite similar cumulative exposure to oxaliplatin.

Selection of RT schedule — For most patients selecting between neoadjuvant radiation therapy (RT) schedules for TNT, we suggest the use of conventionally fractionated (ie, long-course) CRT (50.4 to 54 Gy total administered over 28 to 31 daily fractions) rather than short-course RT (25 Gy total administered over 5 daily fractions). Short-course RT is an alternative for those who are anticipated to not tolerate the potential toxicities of long-course CRT.

This approach is extrapolated from a randomized phase III trial (RAPIDO) that demonstrated lower locoregional recurrence rates with neoadjuvant long-course CRT relative to TNT with short-course RT and neoadjuvant chemotherapy [64,65]. Randomized trials have not directly compared TNT regimens that integrate these different RT schedules (ie, short-course RT versus long-course CRT, both followed by neoadjuvant chemotherapy and surgery).

In patients with locoregionally advanced rectal cancer, randomized trials have compared TNT using short-course RT and neoadjuvant chemotherapy (followed by surgery) versus neoadjuvant long-course CRT (followed by surgery and adjuvant chemotherapy). In one randomized phase III trial (RAPIDO) with long-term follow-up, neoadjuvant long-course CRT decreased the rate of locoregional recurrence (LRR) versus TNT using short-course RT [65]. Most data also suggest similar DFS and OS between these strategies [64-67], except for one randomized trial (STELLAR) which suggested an OS advantage for TNT using short-course RT [68]. Data are as follows:

●In an international open-label phase III trial (RAPIDO), 920 patients with locally advanced rectal cancer with either cT4a/b or cN2 disease, extramural vascular invasion, involved mesorectal fascia, or enlarged lateral lymph nodes were randomly assigned to either [64,65]:

•TNT using short-course RT (25 Gy total administered over five daily fractions) followed by 18 weeks of neoadjuvant chemotherapy (six cycles of capecitabine plus oxaliplatin [CAPOX] or nine cycles of FOLFOX), followed by surgery.

or

•Neoadjuvant long-course CRT (50.4 Gy total administered over 28 fractions, or 50 Gy total administered over 25 fractions [approximately five weeks]) with concurrent capecitabine, followed by surgery and optional adjuvant chemotherapy (eight cycles of CAPOX or 12 cycles of FOLFOX). Of note, fewer than 50 percent of patients initiated postoperative chemotherapy, which was not mandatory.

In extended follow-up (median of 5.6 years), relative to neoadjuvant long-course CRT, TNT with short-course RT had worse five-year LRR rates after R0 or R1 resection (10 versus 6 percent) and rates of breached mesorectum (21 versus 4 percent) [65]. TNT with short-course RT improved the pCR rate (28 versus 14 percent) [64] and reduced the incidence of distant metastases at five years (23 versus 30 percent). However, both treatments had similar rates of disease-related treatment failure (28 versus 34 percent at five years, HR 0.79, 95% CI 0.63-1) and OS (five-year OS 82 versus 81 percent, HR 0.91, 95% CI 0.70-1.19).

For most patients in this study, TNT using short-course RT was generally well tolerated with good compliance and limited late toxicities. Preoperative grade ≥3 toxicity rates were higher with TNT using short-course CRT compared with neoadjuvant long-course CRT (48 versus 25 percent) [69], which is expected given these included toxicities from neoadjuvant chemotherapy as part of TNT. However, serious treatment-related adverse events were similar between the treatment arms (38 versus 34 percent) [64]. Treatment compliance was also high with TNT using short-course CRT (over 80 percent) [69]. In long-term follow-up, TNT with short-course RT also did not compromise health-related quality of life, bowel function, and late grade ≥3 toxicity rates [70].

●In a noninferiority phase III trial (STELLAR), 599 patients with cT3-4 or node-positive locally advanced rectal cancer were randomly assigned to either [68]:

•TNT using short-course RT (25 Gy in five fractions over one week), followed by four cycles of capecitabine plus oxaliplatin (CAPOX), followed by surgery and adjuvant chemotherapy (two cycles of CAPOX).

or

•Neoadjuvant long-course CRT (50 Gy in 25 fractions over five weeks) with concurrent capecitabine, followed by surgery and adjuvant chemotherapy (six cycles of CAPOX).

At a median follow-up of 35 months, relative to neoadjuvant long-course CRT, TNT with short-course RT was noninferior for three-year DFS (65 versus 62 percent), but it improved three-year OS (87 versus 75 percent). Three-year metastasis-free survival (77 versus 75 percent) and locoregional recurrence rates (8 versus 11 percent) were similar between the two treatment arms. Grade ≥3 toxicities during preoperative treatment were higher with TNT and short-course RT compared with neoadjuvant CRT (27 versus 13 percent).

●In a phase III trial (Polish II), 541 patients with cT4 or fixed cT3 rectal cancer were randomly assigned to short-course RT followed by chemotherapy (three cycles of FOLFOX) prior to surgery versus long-course CRT with concurrent oxaliplatin plus bolus FU and leucovorin (LV) [66,71]. At a median follow-up of seven years, both treatment arms demonstrated similar eight-year OS (49 percent each), cumulative incidence of local or distant failure [66], complete resection rates (77 versus 71 percent), and pCR rates (16 versus 12 percent) [66]. Preoperative toxicity rates were lower with the short-course RT [66]. However, interpretation and generalizability of these study results is limited by the inclusion of oxaliplatin-containing CRT; oxaliplatin is not used concurrently with RT for rectal cancer because it does not improve outcomes and is more toxic compared with fluoropyrimidine-based CRT. (See 'Oxaliplatin' below.)

Selection of chemotherapy regimen — For patients selecting between chemotherapy for TNT, options include neoadjuvant FOLFIRINOX (table 3) [64,65], FOLFOX (table 4) [45,72], or CAPOX (table 5) [45,68,72]. The optimal neoadjuvant systemic regimen is not established since they have not been directly compared in randomized trials.

For patients with good Eastern Cooperative Oncology Group performance status (less than 2) (table 6) who are medically fit to tolerate aggressive systemic therapy, we suggest FOLFIRINOX rather than FOLFOX or CAPOX, as this regimen as part of TNT improved DFS outcomes when compared with neoadjuvant CRT alone in a phase III trial (PRODIGE 23) [60]. Further details of this study are discussed separately. (See 'Rationale and benefits' above.)

CAPOX or FOLFOX are appropriate alternatives for less medically fit patients at higher risk of treatment-related toxicity. For patients who may not be able to complete the full course of neoadjuvant chemotherapy, CAPOX is preferred since it is administered every three weeks and contains more oxaliplatin per cycle compared with FOLFOX and FOLFIRINOX. Studies evaluating CAPOX and FOLFOX as part of TNT are discussed separately. (See 'Sequencing of RT and chemotherapy' below.)

We administer between 12 to 16 weeks (three to four months) of neoadjuvant chemotherapy, regardless of the chosen regimen.

In patients with pMMR locally advanced rectal cancer, studies are evaluating the addition of immunotherapy to the chemotherapy portion of TNT, but this approach remains investigational [73,74].

Sequencing of RT and chemotherapy — For patients with locally advanced rectal cancer who will receive TNT, the optimal order of neoadjuvant radiation therapy (RT) and neoadjuvant chemotherapy is not established. Our approach is as follows:

●For patients without clinical suspicion for distant metastatic disease on initial staging studies, either sequencing approach (either chemotherapy followed by RT; or RT followed by chemotherapy) is reasonable. FOLFIRINOX is typically administered prior to neoadjuvant RT, per the clinical protocol used in PRODIGE 23; further studies are needed to establish the tolerability of FOLFIRINOX after neoadjuvant RT. CAPOX or FOLFOX may be administered either before or after RT as DFS and OS outcomes are similar regardless of how the treatments are sequenced during TNT.

●For patients in whom metastatic disease is highly suspected, but cannot be clinically confirmed on initial staging studies, we start with neoadjuvant chemotherapy followed by neoadjuvant RT. By administering chemotherapy first, the clinician can assess if the tumor biology is responsive to initial systemic chemotherapy and whether other treatment approaches are necessary.

●For all patients who start TNT with neoadjuvant chemotherapy, close monitoring for locoregional and metastatic disease progression is warranted. During neoadjuvant chemotherapy, we reevaluate with a contrast-enhanced CT scan of the chest, abdomen, and pelvis every two months to assess for metastatic disease. We also monitor the primary tumor for locoregional disease progression after two months of chemotherapy with either an endoscopy or a contrast-enhanced rectal MRI.

•Patients whose primary tumor demonstrates an objective response after two months of chemotherapy and who have no distant metastases after completing neoadjuvant chemotherapy may proceed to neoadjuvant RT followed by evaluation for surgical resection. (See 'Selection of RT schedule' above.)

•For patients with stable or progressive locoregional disease in the primary tumor and no distant metastases after two months of neoadjuvant chemotherapy, we discontinue chemotherapy and move directly to neoadjuvant RT for locoregional disease control. This approach is particularly important in the setting of a tumor with dMMR/MSI-H, a substantial proportion of which may be resistant to neoadjuvant chemotherapy [75]. Neoadjuvant immunotherapy is an alternative option for patients with dMMR/MSI-H tumors. (See 'Mismatch repair deficient/MSI-H tumors (neoadjuvant immunotherapy)' below.)

•Patients who develop metastatic disease during or shortly after neoadjuvant chemotherapy should be evaluated for later-line systemic therapy for metastatic rectal cancer, which is discussed separately. (See "Second- and later-line systemic therapy for metastatic colorectal cancer".)

There are limited data comparing the optimal sequencing of chemotherapy and RT during TNT. Randomized phase II trials of patients with locally advanced rectal cancer treated with TNT suggest similar DFS and OS outcomes regardless of how these treatments are sequenced. Data are as follows:

●In a separate open-label phase II trial (Organ Preservation of Rectal Adenocarcinoma [OPRA] trial, 324 patients with stage II or III rectal cancer (based on MRI staging) were randomly assigned to four months of oxaliplatin-based chemotherapy (FOLFOX or CAPOX) administered either before or after fluoropyrimidine-based CRT [45,72]. Patients were restaged 8 to 12 weeks after TNT, and those with a complete or near-complete response were offered watchful waiting; those with an incomplete response had TME. At a median follow-up of five years, chemotherapy followed by CRT had inferior rates of organ preservation versus CRT followed by chemotherapy (TME-free survival, 39 versus 54 percent) [45]. However, five-year DFS (71 versus 69 percent) and three-year OS (15 versus 12 deaths) were similar between the treatment arms [45,72].

In this study, patients on surveillance who were treated with TME after tumor regrowth also had similar DFS as those treated with immediate TME after restaging (five-year DFS 64 percent each) [45]. Surveillance (ie, nonoperative management) after completion of neoadjuvant therapy is discussed separately.

●In an open-label phase II trial (CAO/ARO/AIO-12), 311 patients with clinical T3 to T4 and/or node-positive rectal cancer were randomly assigned to initial neoadjuvant CRT (using concurrent FU and oxaliplatin) followed by neoadjuvant chemotherapy with FOLFOX and then surgery; or initial neoadjuvant chemotherapy followed by neoadjuvant CRT [76,77]. At median follow-up of 43 months, both treatments had similar three-year DFS (73 percent each), incidence of locoregional recurrence (6 versus 5 percent), and rates of distant metastases (18 versus 6 percent) [77]. Pathologic complete response rates were lower for patients treated with chemotherapy followed by RT rather than the opposite sequence (17 versus 25 percent) [76]. However, interpretation of these results is limited by the inclusion of oxaliplatin-containing CRT; oxaliplatin is not used concurrently with RT for rectal cancer because it does not improve outcomes and is more toxic compared with fluoropyrimidine-based CRT. (See 'Oxaliplatin' below.)

Neoadjuvant chemotherapy and selective use of CRT

Treatment approach — For most patients with clinical T2N1M0, T3N0M0, or T3N1M0 rectal adenocarcinoma who are eligible for sphincter-sparing surgery, we suggest neoadjuvant chemotherapy with modified FOLFOX-6 followed by the selective, response-guided use of chemoradiation (CRT) rather than neoadjuvant CRT alone prior to surgery. In a randomized phase III trial (PROSPECT), this approach demonstrated similar DFS and OS relative to neoadjuvant CRT alone. Most patients (approximately 90 percent) also avoided CRT and were presumably spared from any late radiation-associated toxicities [78]. However, clinicians who choose neoadjuvant chemotherapy plus selective use of CRT should discuss the risks with their patients, including the need for long-term data on local recurrences and OS [79] and how the toxicity profile differs compared with neoadjuvant CRT alone. (See 'Efficacy and toxicity' below.)

For patients who are treated with neoadjuvant chemotherapy and selective use of CRT, our approach is as follows:

●We administer six cycles (three months) of neoadjuvant modified FOLFOX-6 followed by restaging imaging with a contrast-enhanced MRI of the pelvis.

●For patients treated with neoadjuvant FOLFOX whose primary tumor demonstrates a clinical response of 20 percent or more on restaging imaging, we omit CRT and proceed directly to surgical resection of the primary tumor. In the PROSPECT trial, approximately 90 percent of patients were able to omit CRT due to an appropriate response to chemotherapy [78].

●By contrast, patients treated with neoadjuvant FOLFOX whose primary tumor demonstrates a clinical response less than 20 percent (or those who are unable to tolerate FOLFOX) should be additionally treated with neoadjuvant CRT prior to surgery.

●There is clinical variability in the use of adjuvant chemotherapy after surgical resection of the primary tumor. Although adjuvant chemotherapy was optional in the PROSPECT trial, six cycles of adjuvant FOLFOX were administered in most patients.

The use of initial chemotherapy prior to CRT in patients with higher-risk disease (T4 or more extensive nodal disease) is discussed separately. (See 'Total neoadjuvant therapy for locally advanced tumors' above.)

Efficacy and toxicity — Patients with T2N1, T3N0, and T3N1 rectal adenocarcinoma can be effectively treated with neoadjuvant chemotherapy followed by a selective, response-guided use of CRT prior to surgery, based on data from randomized trials [78,80]. Rectal cancer is responsive to neoadjuvant chemotherapy, and high-quality surgical resection is associated with low rates of local recurrence (12 percent or less) in patients with T2N1, T3N0, and T3N1 tumors [81]. Nevertheless, long-term follow-up of this approach is needed since rectal cancer can have late recurrences (between 5 to 10 years or longer).

Neoadjuvant chemotherapy plus selective use of CRT also allows most patients (90 percent) to omit RT and avoid its late toxicities. Such late RT toxicities include infertility; premature menopause; bowel, bladder, and sexual dysfunction; pelvic fractures; subsequent malignancies; and impaired bone marrow reserve. Such deintensified therapy is preferred by most patients, including younger patients with early-onset rectal cancer; those of childbearing age who wish to avoid infertility; those who received prior pelvic RT for a different malignancy; and those who prioritize preserving long-term sexual function, which is an important concern among cancer survivors. (See "Epidemiology and risk factors for colorectal cancer", section on 'Early onset colorectal cancer' and "Overview of sexual dysfunction in female cancer survivors" and "Overview of sexual dysfunction in male cancer survivors".)

Based on data from initial studies [82,83], a multicenter, noninferiority, open-label phase III trial (PROSPECT) was conducted in 1128 patients with previously untreated clinical stage T2 node-positive, T3 node-negative, and T3 node-positive rectal cancer who were candidates for neoadjuvant CRT and sphincter-sparing surgery [78]. Most primary tumors were in the middle to upper rectum, with a median distance of 8 cm from the anal verge. Clinical staging was confirmed using MRI of the pelvis, although contrast-enhanced CT of the chest, abdomen, and pelvis plus endorectal ultrasound was an acceptable alternative. Patients could not have the following high-risk features: T4 primary tumor, N2 disease (ie, four or more pelvic lymph nodes with a short-axis diameter >10 mm), a low-lying tumor, or tumor visible within 3 mm of the radial margin (potential compromise of the mesorectal fascia). Patients were randomly assigned to either:

●Neoadjuvant chemotherapy with six cycles (three months) of modified FOLFOX-6 followed by surgical resection if the primary tumor demonstrated a clinical response rate to chemotherapy of 20 percent or more. Patients with a clinical response rate of less than 20 percent received CRT followed by surgery.

or

●Long-course CRT followed by surgery.

Among those treated with neoadjuvant FOLFOX, approximately 10 percent also received CRT (9 percent preoperatively and 1 percent postoperatively). Most patients treated with neoadjuvant FOLFOX (approximately 80 percent) also received adjuvant FOLFOX for a median of six cycles, which was suggested but not mandated.

At median follow-up of 58 months, neoadjuvant chemotherapy with selective use of CRT was similar to neoadjuvant CRT alone for DFS (five-year DFS 81 versus 79 percent, HR 0.92, 95% CI 0.74-1.14), OS (five-year OS 89.5 versus 90.2 percent, HR 1.04, 95% CI 0.74-1.44) and local recurrence rates (five-year incidence 1.8 versus 1.6 percent; HR 1.18, 95% CI 0.44-3.46). Both treatment arms also demonstrated similar rates of surgical resection (99 versus 97 percent), pathologically complete (R0) resection (90.4 versus 91.2 percent), and complete response (22 versus 24 percent).

As expected, toxicity profiles differed based on the timing and treatment. During neoadjuvant therapy, grade ≥3 toxicity rates were higher for FOLFOX than CRT (41 versus 23 percent) [78]. Patients treated with neoadjuvant FOLFOX also reported less diarrhea and better overall bowel function, whereas those treated with neoadjuvant CRT reported less anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting [84].

Postoperatively, grade ≥3 toxicity rates were lower for FOLFOX than CRT (26 versus 33 percent) [78]. One year after completing surgery, patients treated with neoadjuvant FOLFOX reported less fatigue and neuropathy and better sexual function compared with those who received neoadjuvant CRT [84]. Bladder function and health-related quality of life were similar in both treatment arms. Further follow-up is necessary to confirm the long-term toxicity benefits of omitting CRT in this population.

Other studies have also suggested that neoadjuvant chemotherapy may permit more selective use of CRT without compromising long-term outcomes in nonbulky, resectable rectal tumors. In a separate phase III trial (FOWARC) conducted in China, 495 patients with clinical stage II or III resectable rectal cancer within 12 cm of the anal verge were randomly assigned to neoadjuvant therapy with either modified FOLFOX6 alone, CRT with concurrent modified FOLFOX-6, or neoadjuvant RT with concurrent FU [80,85].

At median follow-up of 45 months, three-year DFS was similar between all treatment arms (77 versus 74 versus 73 percent with FOLFOX, FOLFOX plus RT, and FU plus RT, respectively), as were OS (91 versus 89 versus 91 percent) and local recurrence rates (8 versus 7 versus 8 percent) [80]. However, neoadjuvant FOLFOX had the lowest pCR rate (7 percent) relative to FOLFOX plus RT (28 percent) and FU plus RT (14 percent). In extended follow-up of this study, 10-year DFS (61 versus 63 versus 53 percent), OS (73 versus 72 versus 67 percent), and local recurrence rates (9.6 versus 8 versus 10.8 percent) remained similar between the three treatment arms [85].

Selecting an RT regimen — For patients with nonmetastatic rectal cancer who are receiving a neoadjuvant therapy regimen that integrates radiation therapy (RT), the approach to selecting an appropriate RT regimen is as follows:

●For most patients with bulky N2 or T4 tumors, we suggest conventional-fractionation RT with concurrent fluoropyrimidine chemotherapy (ie, long-course CRT) rather than the short-course Swedish approach to RT alone. (See 'Long-course chemoradiation' below.)

Short-course RT represents an acceptable alternative to long-course CRT for many patients who do not have a cT4 or N2 tumor. (See 'Short-course radiation therapy' below.)

●For most patients undergoing long-course CRT, we suggest infusional FU (225 mg/m² daily) administered five days per week during RT rather than bolus FU. Oral capecitabine (825 mg/m² twice daily, five days per week) is an appropriate alternative. (See 'Choice of chemotherapy during RT' below.)

Long-course chemoradiation — Largely based on the German Rectal Cancer Study Group trial, neoadjuvant CRT with conventional fractionation RT followed by adjuvant chemotherapy was previously the standard approach to treatment of rectal adenocarcinoma in the United States. (See 'Indications for neoadjuvant therapy' above and "Pretreatment locoregional staging evaluation for rectal cancer".)

Several randomized trials and at least two meta-analyses have demonstrated that concurrent administration of chemotherapy with conventional fractionation RT is critical to the success of this approach, at least in terms of local failure rates [86-90]. As a result, the addition of chemotherapy to conventional fractionation RT has become a standard approach to neoadjuvant CRT.

Clinical trials of neoadjuvant CRT have focused on two main questions: the comparative benefit of preoperative versus postoperative CRT and the optimal chemotherapy component.

Preoperative versus postoperative therapy — Adjuvant CRT had been the standard of care for resectable rectal cancer until a seminal trial from Germany firmly established the role of neoadjuvant CRT. (See "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy".)

The seminal German Rectal Cancer Study Group trial randomly assigned 823 patients with clinically staged T3/4 or node-positive rectal cancer to the same CRT regimen administered either preoperatively or postoperatively: 50.4 Gy in 28 daily fractions to the tumor and pelvic lymph nodes concurrent with infusional FU (1000 mg/m² daily for five days during the first and fifth weeks of RT) [33]. All patients underwent TME and four additional cycles of adjuvant single-agent FU (500 mg/m² bolus daily for five days every four weeks). The patients randomly assigned to postoperative treatment all received an RT boost of 5.4 Gy. Of note, only 5 percent of the patients in either group had T1/2 node-positive tumors.

At a median follow-up of 46 months, preoperative CRT was associated with a significantly lower pelvic relapse rate (6 versus 13 percent with postoperative therapy); the difference persisted with longer follow-up, although it was of a lower magnitude at 10 years (7 versus 10 percent) [91]. The five-year DFS (68 versus 65 percent) and OS rates (76 versus 74 percent) were similar for preoperative and postoperative therapy, respectively; 10-year rates were also comparable (DFS approximately 68 percent in both groups, OS approximately 60 percent in both groups).

Stage distribution at surgery was suggestive of significant downstaging effects. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage distribution (I to IV) was 25, 29, 25, and 6 percent for the preoperative group, compared with 18, 29, 40, and 7 percent in the postoperative group. Among the 194 patients with low-lying tumors who were thought preoperatively to require an APR, those undergoing preoperative CRT were twice as likely to undergo a sphincter-sparing operation (39 versus 19 percent).

Other studies have also evaluated preoperative CRT. As examples:

●Preoperative CRT was directly compared with postoperative CRT in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-03, which randomly assigned patients with operable rectal cancer (regardless of stage) to one of two groups [92]:

•Preoperative therapy, consisting of one cycle of weekly bolus FU and LV for six weeks, two courses of FU and LV (daily for five days during the first and fifth course of RT) concomitant with pelvic irradiation (50.4 Gy), surgery, and then four cycles of postoperative weekly bolus FU and LV.

•Postoperative therapy, which consisted of surgery, one cycle of weekly bolus FU plus LV, two cycles of FU and LV concomitant with pelvic RT, and then four cycles of weekly bolus FU and LV.

Accrual did not reach planned levels, and the protocol was closed early. In the final analysis of 267 enrolled patients, preoperative therapy was associated with a significantly higher rate of five-year DFS (65 versus 53 percent), but only a trend toward better OS (75 versus 66 percent), and no difference in locoregional control (five-year cumulative incidence of locoregional recurrence 11 percent in both arms).

●A trial conducted in Korea compared preoperative and postoperative CRT using capecitabine alone (1650 mg/m² daily during RT) in 240 patients with cT3 or node-positive rectal cancer [93]. Only four patients total had T2N+ tumors. All patients received four cycles of postoperative capecitabine (2500 mg/m² daily). The pCR rate was 17 percent after preoperative CRT. At a median follow-up of 52 months, the three- and five-year DFS rates were similar in both groups, as were the cumulative rates of local recurrence (3 versus 2 percent). The sphincter-sparing rates were similar in the two groups, although among patients with low-lying tumors, the preoperative CRT arm had a higher rate of sphincter-sparing surgery (68 versus 42 percent).

Prognosis and extent of tumor regression

●Impact of postoperative stage on prognosis – Data from the German Rectal Cancer Study Group trial and others indicate that survival in patients with rectal cancer undergoing neoadjuvant therapy is driven by the post-therapy pathologic (yp) stage and not the pretherapy clinical (c) stage.

Two reports from the German Rectal Cancer Study Group focused on prognostic stratification in patients undergoing neoadjuvant CRT [94,95]. Prognosis was related to the final tumor (T) stage in the surgical specimen as well as the presence of involved lymph nodes in the surgical specimen (table 7). According to the tumor, node, metastasis (TNM) staging system of the combined AJCC/UICC, the "y" prefix added to the pathologic (p) stage designates a TNM stage that is assigned after multimodality therapy (table 1). (See "Pathology and prognostic determinants of colorectal cancer", section on 'Tumor regression after neoadjuvant therapy'.)

The poor outcomes seen in patients with ypN2 disease in this and other reports [96-99] suggest that these patients are good candidates for novel treatment approaches, such as expanded postoperative chemotherapy, although this is not yet a standard approach.

●Tumor regression grade – Prognosis has also correlated with tumor regression grade (TRG), which incorporates the degree of fibrosis [100,101] as well as the percentage of viable tumor cells (table 8) [94,95,102]. The better prognosis with higher TRG was maintained with long-term follow-up (table 7) [95].

Of note, this is only one of several available and commonly used systems to assess TRG (table 9). Of the various TRG systems in use, some score only the presence of residual tumor, while others assess residual tumor plus any residual tissue taking the place of tumor (eg, fibrosis, inflammation, pools of acellular mucin, necrosis, and/or calcification). In addition, the tier systems range from three to five. The TRG system used by the combined AJCC/UICC (table 10) [103] for surgical specimens after preoperative RT or CRT for rectal cancer (per the College of American Pathologists [CAP] guidelines [104]) differs from that used by the German Rectal Cancer Study Group. However, one analysis concluded that the AJCC staging manual system is the most accurate and should be adopted as the standard [105]. The AJCC/CAP TRG system has been validated independently in a series of patients undergoing long-course CRT followed by surgery for mid to low rectal adenocarcinoma [106].

Regardless of which system is used, whether and how TRG could be used to modify the postoperative treatment strategy (eg, whether adjuvant chemotherapy could be avoided in those with a favorable TRG) are not clear. (See "Adjuvant therapy after neoadjuvant therapy for rectal cancer", section on 'Benefit of postoperative chemotherapy'.)

Importantly, TRG scores have not accounted for the possible involvement of lymph nodes. Accumulating data support the view that patients with initially clinically positive perirectal lymph nodes who have pathologically negative lymph nodes after preoperative RT or CRT have an excellent outcome [107,108]. The correlation between the different values of TRG and the incidence of positive nodes is an area of active investigation [109].

The use of imaging-based preoperative TRG stratification systems to select patients for nonoperative management after neoadjuvant therapy is discussed in detail separately. (See 'Assessing for complete clinical response following neoadjuvant therapy' below.)

Assessing treatment response and timing of surgery — Most patients undergoing long-course CRT undergo reimaging of the primary site approximately four to six weeks after the end of treatment to assess treatment response.

●Responders – The optimal interval between completion of neoadjuvant long-course conventional fractionation CRT and surgery in rectal adenocarcinoma is not established. However, for most patients who have a radiographic response to CRT as determined by repeat post-treatment imaging, we suggest surgical resection within 7 to 10 weeks following the completion of CRT. Waiting a longer period of time may not improve the pCR rate, and the delay may increase the difficulty of surgical resection and the postoperative morbidity.

Traditionally, the interval between completion of neoadjuvant conventional fractionation CRT and surgery in rectal adenocarcinoma has been six weeks (approximately 11 to 12 weeks after the start of RT) as this was the duration used in the seminal German Rectal Cancer Study Group trial [33]. (See 'Preoperative versus postoperative therapy' above.)

However, the process of tumor regression takes time [110]. In one study examining this issue, a tumor of size 54 cm³ would require an interval of 20 weeks from after the start of treatment to surgery to regress to <0.1 cm³ (10 volume-halving times = 140 days) [111]. These results suggest that there might be a benefit to delaying surgery beyond six weeks.

To date, at least five randomized trials have examined the time interval between CRT and surgery [112-116], only two of which have shown a higher pCR rate with longer as compared with shorter wait times [113,116]. In neither trial did higher pCR rates with delayed surgery translate into better oncologic outcomes (survival, recurrence).

A meta-analysis of data from four of these trials and 22 other nonrandomized series (totaling 25,445 patients) came to the following conclusions [113-117]:

•Compared with a standard six- to eight-week interval from completion of neoadjuvant RT to surgery, an interval of eight weeks or more was associated with greater odds of a pCR (odds ratio [OR] 1.41, 95% CI 1.30-1.52) and tumor downstaging (mainly the T stage, OR 1.33, 95% CI 1.04-1.72), but no differences in rates of complete (R0) resection, sphincter preservation, or complication.

•The higher rate of a pCR translated into reduced distant metastases (OR 0.71, 95% CI 0.54-0.93) and overall recurrences (OR 0.76, 95% CI 0.58-0.98), but not reduced local recurrences (OR 0.83, 95% CI 0.49-1.42) or OS (OR 1.02, 95% CI 0.71-1.45).

Not surprisingly, consensus-based guidelines on this issue are discordant:

•Guidelines from the European Society for Medical Oncology (ESMO) state that in practice there is wide variation in the timing of surgery (4 to 12 weeks) and that longer intervals may enhance pCR rates, but this risks repopulation, delays the use of postoperative chemotherapy, and risks subsequent metastases [10].

•National Comprehensive Cancer Network (NCCN) [118] guidelines suggest that surgery be performed 5 to 12 weeks following full-dose neoadjuvant CRT.

●Nonresponders – Some patients will not achieve meaningful regression in tumor size or stage with neoadjuvant CRT; in this group, outcomes may be poorer if surgery is delayed [119]. Patients who do not respond well to neoadjuvant CRT should be identified early after the end of CRT and undergo surgery without delay.

Complications — As long as waiting times are fewer than 11 weeks, the available data suggest that preoperative CRT does not increase the perioperative complication rate from surgical resection [33,92,120,121]. In the German study (a six-week waiting time between the end of CRT and surgery), the incidence of grade 3 or 4 gastrointestinal toxicity was similar in both the preoperative and postoperative CRT groups (28.8 versus 31.7 percent, respectively), and postoperative morbidity rates were not higher with neoadjuvant therapy [33]. Compared with postoperative RT, significantly fewer patients undergoing neoadjuvant therapy had chronic anastomotic strictures (2.7 versus 8.5 percent).

On the other hand, data from another randomized trial (GRECCAR-6) suggest that the perioperative complication rate may be higher among those who undergo delayed surgery at 11 as compared with 7 weeks after completing CRT. (See 'Assessing treatment response and timing of surgery' above.)

However, RT is associated with late adverse effects:

●Multimodality therapy negatively affects anorectal function after TME. In a meta-analysis of 25 studies examining long-term functional outcomes after rectal cancer resection with preoperative (chemo)radiotherapy, the majority of studies (14 of 18) reported higher rates of anorectal dysfunction after preoperative (chemo)radiotherapy [122]. In particular, fecal incontinence occurred more often in irradiated patients (risk ratio [RR] 1.67, 95% CI 1.36-2.05), and manometric results (mean resting pressures, maximum squeeze pressures) were significantly worse relative to patients undergoing TME alone. The contribution of RT to bowel and anorectal problems after treatment for colorectal cancer is discussed in detail separately. (See "Approach to the care of colorectal cancer survivors", section on 'Bowel and anorectal problems'.)

●Patients undergoing treatment for rectal cancer are also at risk for sexual dysfunction. The risk is higher in those undergoing APR compared with low anterior resection (LAR), in those undergoing non-TME versus TME surgery, and in patients who undergo combined modality treatment that includes RT. The independent contribution of surgical technique (and of nerve preservation in particular) versus that of RT and whether preoperative as compared with postoperative CRT alters rates of sexual dysfunction after treatment for rectal cancer are unknown. (See "Approach to the care of colorectal cancer survivors", section on 'Sexual dysfunction' and "Management of intra-abdominal, pelvic, and genitourinary complications of colorectal surgery", section on 'Sexual dysfunction'.)

●Sacral insufficiency fractures are a relatively uncommon late complication of pelvic RT [123-125]:

•In one report, the incidence of sacral insufficiency fractures at three years after preoperative CRT was 3 percent overall; however, females appeared to be at higher risk (5.8 versus 1.6 percent in males) [123].

•A higher rate of sacral insufficiency fractures (7.1 percent) was reported in a retrospective review of 492 patients treated with CRT for rectal cancer over a nine-year period [125]. Independent risk factors associated with fracture were osteoporosis, female sex, and age greater than 60 years.

Choice of chemotherapy during RT

Fluoropyrimidines — For most patients, we suggest infusional FU (on the days when radiation therapy [RT] is delivered, five days per week) rather than bolus FU during neoadjuvant RT. Daily capecitabine is an appropriate alternative.

●Infusional versus bolus FU – Although the techniques and dose of irradiation are similar in published CRT studies, there is marked variability in the administration of chemotherapy. Some studies (eg, the German trial [33]) use bolus FU alone, while others use bolus LV-modulated FU [86,87] for five consecutive days during the first and last weeks of RT.

Retrospective data suggest that infusional, rather than bolus, FU during RT increases the likelihood of a pCR in patients with locally advanced rectal cancer [126]. However, the preference at many institutions, including ours, for concomitant infusional FU during RT is based mainly on an intergroup study that demonstrated superiority of adjuvant concurrent infusional FU compared with bolus FU during RT in patients with resected rectal cancer. (See "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy".)

●Capecitabine – Capecitabine has been shown to be therapeutically equivalent to infusional FU when used during concomitant CRT, albeit with a different toxicity profile [127-130]. As an example, a phase III German trial directly compared CRT (50.4 Gy) with concomitant capecitabine (825 mg/m² twice daily on days 1 to 38) versus infusional FU (1000 mg/m² b^y continuous infusion on days 1 to 5 and 29 to 33) in 401 patients with locally advanced rectal cancer who were treated in the neoadjuvant setting [127]. At a median follow-up of 52 months, the local recurrence rate was similar (6 versus 7 percent with infusional FU), but the distant metastasis rate was lower with capecitabine (19 versus 28 percent). Capecitabine was not inferior to FU for five-year OS (the primary endpoint). Patients in the capecitabine group had more hand-foot skin reactions, fatigue, and proctitis than did those in the FU group, whereas leucopenia was more frequent with FU.

One concern is that capecitabine metabolism is variable, and systemic exposure to capecitabine correlates poorly with efficacy and toxicity [131]. The variable bioavailability of oral fluoropyrimidines in individual patients raises concerns as to adequate dosing of these agents. However, if capecitabine is chosen, it is reasonable to use 825 mg/m² twice daily, five days per week, during RT. Similarly, based on the administration schedule adopted in the NSABP R-04 trial [128], if infusional FU is chosen, we limit the chemotherapy treatment to the days that RT is administered (ie, Monday through Friday), rather than continuous infusion, because of better tolerability.

Oxaliplatin — Outside of the context of a clinical trial, we suggest not adding oxaliplatin to fluoropyrimidine-based CRT. Toxicity is clearly worse compared with CRT using a fluoropyrimidine alone and efficacy is not yet proven.

Oxaliplatin has become an important component of treatment for advanced colorectal cancer; in addition, oxaliplatin plus FU and LV outperforms FU/LV alone in adjuvant treatment of stage III colon cancer and has been adopted as a standard regimen. (See "Initial systemic therapy for metastatic colorectal cancer" and "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

Data from at least 10 randomized trials of the addition of a platinum drug (nine oxaliplatin, one cisplatin) to fluoropyrimidine-based CRT in a total of 5599 patients with stage II or III rectal cancer [80,128,129,132-142] were the subject of a systematic review and meta-analysis [143], which came to the following conclusions:

●The addition of a platinum derivative significantly increased the likelihood of a pCR at the time of surgery (OR 1.31, 95% CI 1.10-1.55) and reduced the likelihood of a distant recurrence (OR 0.78, 95% CI 0.66-0.92).

●These benefits did not translate into improvements in OS (HR for death 0.93, 95% CI 0.82-1.05), DFS (HR 0.91, 95% CI 0.83-1.01), or local recurrence (OR 0.83, 95% CI 0.66-1.05).

●The addition of a platinum agent increased rates of grade 3 or 4 toxicities, including diarrhea, nausea, neurosensory toxicity, and fatigue.

Agents that are not used — Outside of the context of a clinical trial, we do not add irinotecan, or inhibitors of angiogenesis, or the epidermal growth factor receptor (EGFR) to fluoropyrimidine-based CRT.

●Nonrandomized trials suggested benefit from adding irinotecan to the CRT regimen [144-146], but benefit could not be shown in an Radiation Therapy Oncology Group (RTOG) trial in which 106 patients with T3/4 distal rectal cancer were randomly assigned to continuous infusional FU (225 mg/m² daily) concurrent with hyperfractionated RT (55.2 to 60 Gy at 1.2 Gy twice daily) or to infusional FU (225 mg/m² daily, five days per week) plus irinotecan (50 mg/m² once weekly for four weeks) and concurrent conventional fractionation RT (50.4 to 54 Gy in daily 1.8 Gy fractions) [147]. For surgically treated patients, the pCR rate was similar in both arms (30 versus 26 percent with irinotecan), as were rates of acute and late toxicity.

●Most (but not all) early reports suggest that the addition of bevacizumab (a humanized monoclonal antibody targeting the vascular endothelial growth factor [VEGF]) or aflibercept (a recombinant fusion protein that functions as a decoy receptor, preventing VEGFA, VEGFB, and placenta growth factor [PlGF] from binding to their receptors) to conventional FU-based CRT provides encouraging pCR rates, although the data on postoperative complications have been mixed [148-152]. However, the impact of this strategy on long-term outcomes, especially post-treatment complications, awaits the development and completion of phase III trials.

●Early reports are also mixed regarding the benefit of adding cetuximab or panitumumab, two humanized monoclonal antibodies targeting the EGFR, to conventional FU-based CRT [47,153-157]. The impact of this strategy on long-term outcomes, especially post-treatment complications, awaits the completion of phase III studies.

Radiation therapy techniques

●RT techniques – Radiation therapy techniques for rectal cancer initially used simple two-dimensional (2D) treatment planning based on radiographs of bony pelvic structures. Treatment field designs included parallel opposed fields (anterior-posterior [AP] and posterior-anterior [PA]), posterior and lateral opposed fields (PA and right/left lateral), and "box field" techniques. However, with these techniques, large volumes of normal tissue were often irradiated, leading to treatment-related acute and late toxicity.

The introduction of CT-based treatment planning allowed for accurate identification and delineation of relevant target volumes in three dimensions. Combining CT-based treatment planning with multileaf collimators facilitated three-dimensional (3D) conformal radiation therapy (3D-CRT) with increased treatment accuracy and reduction in normal tissue irradiation. However, many of the lymph node targets in the pelvis are concavely shaped, and 3D-CRT techniques do not easily allow for the sparing of normal tissue between those targets. For this reason, inverse planned treatment techniques, such as intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT), are increasingly being used for pelvic RT. These technologies are based on the delivery of highly modulated dose fluence from multiple directions to limit high-dose volumes outside the treatment target; thus, IMRT and VMAT support the delivery of concavely shaped dose distributions. The main rationale behind these techniques is the reduction of dose to organs at risk with the expectation of lower radiation-induced early- and late-toxicity.

Multiple-dose planning studies have examined whether IMRT and VMAT also result in improved treatment plans for patients with rectal cancer. Overall, these data demonstrate that IMRT and VMAT treatment plans deliver significantly reduced RT doses to bowel, bladder, and bony structures in the pelvis and even take into account common uncertainties in treatment delivery, such as day-to-day variations in organs-at-risk (OAR) positioning [158,159]. There is increasing use of IMRT in the preoperative management of rectal cancer Surveys confirm an increasing trend in the use of IMRT across the National Health System (NHS) with almost 60 percent of radiology centers using it as their preferred RT treatment modality for rectal cancer [160,161].

There is limited clinical experience with the use of proton therapy in rectal cancer, and this modality will require further investigation [162].

●Patient positioning – Prone positioning of the patient may also help reduce the volume of the small bowel within the pelvis. Other maneuvers to reduce the volume of the small bowel include treatment with a full bladder and the use of bowel displacement techniques such as a bellyboard (a device with a false tabletop to allow the upper abdominal contents to fall anteriorly) [20]. In 3D conformal plans, shaped lateral fields reduce the dose to the small bowel located in the anterior and superior aspects of the pelvis. For IMRT and VMAT planning, the small bowel should be included as an avoidance structure, but even for these plans, simulation maneuvers can greatly assist with minimizing small bowel exposure. A marker is generally placed at the anal verge. Intravenous, rectal, and small-bowel contrast can be administered during simulation for accurate target and normal tissue delineation if MRI fusions or other mechanisms for tumor delineation are anticipated to be difficult.

●Treatment fields – External beam radiation treatment fields for rectal carcinoma should encompass the potential sites at greatest risk for harboring disease, including the presacral space, primary tumor site, and (for patients who are status-post APR) the perineum. Other areas at risk include the internal iliac and distal common iliac nodes. Generally, the para-aortic region is excluded from radiation fields as the risk of disease involving this region is sufficiently low, whereas the morbidity from treatment is sufficiently high. The external iliac nodes may be covered for lesions involving the anterior structures, including the bladder, prostate, and vagina. Notably, T4a lesions involving the anterior peritoneum only do not require coverage of external iliac nodes. Inguinal node coverage is an option for tumors invading the anal canal distal to the dentate line.

Traditional four- or three-field techniques can be used to treat most cases of rectal cancer. However, it may be difficult to achieve optimal OAR doses depending on the patient anatomy. For the 3D-CRT AP and PA fields, traditional borders are as follows: the superior field edge is placed at the L5/S1 interspace, the inferior field edge should be at least 4 to 5 cm below gross disease while covering the entire mesorectum, and the lateral border should be shaped with multileaf collimators to cover a 1.5 cm margin around the pelvic brim. For postoperative cases, the distal field edge is approximately 5 cm below the best estimate of the preoperative tumor bed and (if an APR has been performed) below the perineum. Lateral fields have the same superior and inferior borders. The posterior border should encompass the entire sacrum with a 1 cm margin to ensure presacral cover, and the anterior border should extend approximately 4 cm anterior to the rectum (ensuring adequate coverage of the mesorectum) while blocking as much of the anterior abdominal contents and bladder as possible without compromising nodal coverage. If the tumor has considerable extrarectal extension, these guidelines should be modified to ensure that all disease is encompassed with an appropriate margin.

Since CT-based planning dominates contemporary treatment, contour delineation of elective and high-risk clinical target volumes (CTVs) helps to ensure that the above blocks cover the entire treatment volume for a given patient. The elective CTV includes the entire mesorectum and the perirectal, presacral, and internal iliac lymph nodes, with a superior border at the bifurcation of the common iliac arteries and an inferior border at the pelvic floor or 2 cm beyond gross disease. External iliac lymph nodal regions should be included if there is anterior pelvic organ involvement. The high-risk CTV extends for 1.5 to 2.5 cm superior/inferior beyond the primary gross tumor volume (GTV) and/or 1 cm beyond involved lymph nodes and should include the elective CTV volume (including mesorectum and nodal regions) within that extent.

Contemporary IMRT or VMAT planning may assist in facilitating target coverage while minimizing OAR exposure, particularly for patients with difficult anatomy or large amounts of small bowel falling into the pelvis.

●Dosing – For rectal cancer, the usual RT dose given to initial pelvic fields is 45 Gy in 25 fractions of 1.8 Gy each. An additional tumor boost may be administered, usually through opposed lateral fields, to an additional 5.4 to 9 Gy. Historically, the small bowel was excluded from the boost volume after approximately 50 Gy to minimize acute and late toxicity, but this can largely be achieved with IMRT or subfielding of the 3D conformal plan. In retrospective studies, compared with 3D conformal planning, IMRT planning is associated with lower rates of grade ≥2 diarrhea and genitourinary toxicity [158,159,163-170].

In patients with resectable early-stage rectal cancer (cT2-T3 with tumors <5 cm, cN0-N1 with lymph nodes <8 mm), a phase II trial (OPERA) demonstrated that a boost of brachytherapy (90 Gy over 3 fractions) improved the organ preservation rate at three years (81 versus 59 percent) relative to boost RT (9 Gy over 5 fractions) but had a higher local regrowth rate (39 versus 17 percent) [171]. In patients with tumors less than 3 cm in size treated with boost brachytherapy, the organ preservation rate was 93 percent. However, the clinical relevance of boost brachytherapy is limited as this study was performed prior to the era of more contemporary treatments such as TNT and neoadjuvant chemotherapy followed by selective use of CRT.

Short-course radiation therapy — In many countries, short-course RT has been adopted as the standard preoperative approach for operable rectal adenocarcinomas based on two randomized trials demonstrating that this approach is associated with long-term outcomes comparable to those with long-course CRT. However, in many institutions, particularly in the United States, long-course CRT is still the preferred approach for most patients, particularly those with T4 and/or bulky tumors or if the circumferential resection margin (CRM) or complete resection status are predicted to be at risk. Neoadjuvant short-course RT (or short-course RT followed by chemotherapy) represents an option (although not preferred over long-course CRT with or without chemotherapy) for T3 any N disease with a clear CRM, or T1-2, N1-2 disease.

Many institutions in the United States are using short-course RT prior to rectal surgery in selected patients, such as those thought not to be able to tolerate long-course CRT, and in the setting of metastatic disease to minimize delays in initiation of systemic therapy. (See 'Synchronous unresectable metastases' below.)

Efficacy — Short-course RT has been compared with surgery alone and with conventional long-course CRT.

●Short-course RT versus surgery alone – At least three phase III trials have demonstrated improved local control in patients with rectal cancer receiving short-course preoperative RT followed by surgery versus surgery alone but more long-term side effects [2,3,22,172]. As examples:

•In a clinical trial conducted in Sweden, 1168 patients with resectable rectal cancer were randomly assigned to receive 25 Gy delivered in five fractions in one week followed by surgery versus surgery alone [22,172]. After five years, RT was associated with significant improvements in both local control (89 versus 73 percent) and OS (58 versus 48 percent). With long-term follow-up, the number of hospital admissions for gastrointestinal disorders (bowel obstruction, abdominal pain) was two- to fourfold higher in irradiated patients [172].

•In a subsequent clinical trial conducted in the Netherlands, 1861 patients with resectable rectal cancer were randomly assigned to TME alone or high-dose-rate RT (5 x 5 Gy) followed by TME, preoperative RT was associated with an improvement in the five-year local recurrence rate compared with TME alone (5.6 versus 10.9 percent) but similar five-year survival (64 percent in both groups) [2,3]. Despite comparable rates of intraoperative and postoperative complications overall, the irradiated group had significantly more perineal wound problems following APR than those undergoing surgery alone (29 versus 18 percent) [173]. They also had more sexual dysfunction and slower recovery of bowel function [174], and with long-term follow-up, they had more fecal incontinence (62 versus 38 percent), anal blood loss (11 versus 3 percent), dissatisfaction with bowel function [175], and problems with erections [176].

●Short-course RT versus long-course CRT – Several randomized trials comparing short-course Swedish-style RT with conventional fractionation long-course CRT have concluded that the rates of local recurrence (at least for non-distal tumors), DFS, distal recurrence, OS, and toxicity are comparable [177-179]. As examples:

•A trial conducted in Poland involving 316 patients with T3/4 rectal cancer compared conventional fractionation RT (50.4 Gy) in conjunction with bolus FU and LV during weeks 1 and 5 versus short-course RT (5 x 5 Gy fractions with surgery within seven days of the last RT dose) [177]. The pCR rate was significantly higher in the conventional CRT group (16 versus 1 percent), and there were fewer cases of radial margin positivity (4 versus 13 percent), but the rate of sphincter preservation in both groups was comparable (58 and 61 percent, respectively). Early radiation toxicity was higher in the CRT group (18 versus 3 percent), but rates of local recurrence (9 versus 14 percent), DFS (58 versus 56 percent), and severe late toxicity (10 versus 7 percent) were not significantly different.

•In the Trans-Tasman Radiation Oncology Group (TROG) 01.04 trial, 326 patients with T3 rectal cancer were randomly assigned to short-course RT (5 x 5 Gy fractions) or conventional fractionation CRT (50.4 Gy with concomitant infusional FU) [178]. Patients in the short-course RT arm also received six courses of postsurgical adjuvant chemotherapy, while those in the conventional fractionation CRT group received four courses. As with the prior trial, the pCR rate was significantly higher with long-course CRT (15 versus 1 percent), but no difference in rates of margin positivity or sphincter preservation. At a median follow-up of nearly six years, patients receiving long-course CRT had a small but statistically insignificant lower cumulative local recurrence rate at both three years (4.4 versus 7.5 percent) and five years (5.7 versus 7.5 percent). There were also no significant differences in the rates of distant recurrence, relapse-free survival, OS, or late grade 3 or 4 toxicity.

●A subset analysis of the 79 patients with distal tumors treated on the TROG 01.04 trial revealed a cumulative incidence of local recurrence of 12.5 percent for short-course RT and 0 percent for long-course CRT. However, a later meta-analysis of this and three other trials [66,177,180] concluded that the difference in local failure rate for low-lying tumors (<5 cm from the anal verge) with short-course RT versus long-course CRT was not significantly different (pooled OR for local failure 0.87, 95% CI 0.53-1.44) [181].

For most patients treated with total neoadjuvant therapy, long-course RT is preferred to short-course RT. Further details are discussed separately. (See 'Selection of RT schedule' above.)

Timing of surgery — There is no widely accepted standard approach to timing of surgery after short-course RT and clinical practice is variable. In our view, if neoadjuvant chemotherapy is not used, either immediate surgery (<10 days after the first RT fraction) or delayed surgery (four to eight weeks after the end of RT) is acceptable.

The optimal timing of surgery after short-course RT is debated, and there is no consensus as to the best approach. Most randomized trials that compared short-course RT followed by surgery versus surgery alone, or short-course RT versus long-course CRT prior to surgery, used an interval to surgery of seven days after completion of short-course RT [22,177,178,182]. However, in the Dutch TME trial, the median interval between the end of short-course RT and surgery was 21 days [2]. An alternative approach is to delay surgery for four to eight weeks, with the possibility of enhanced tumor downstaging and at least some pCRs [183-186]. On the other hand, other studies have suggested that an even shorter interval between the end of short-course RT and surgery (ie, zero to three days) might be beneficial, hypothesizing that a poor leukocyte response or treatment-related leukopenia might be contributory to worse outcomes when surgery is delayed, even by one week [187-189].

The Stockholm III trial, a noninferiority trial that directly compared short-course RT with immediate surgery, short-course RT with delayed (four to eight weeks) surgery, and long-course RT with delayed (four to eight weeks) surgery in 843 patients with resectable primary rectal cancer [190]. It appeared to be oncologically safe to delay surgery for four to eight weeks after the end of short-course RT, with fewer postoperative complications than with short-course RT with surgery within a week. However, the trial took 15 years to accrue and was amended after one year to allow participating hospitals to accrue only to the two short-course RT arms, resulting in imbalances among the groups. Furthermore, there was no concurrent chemotherapy in the long-course RT arm, and very few patients in any of the arms received adjuvant chemotherapy (15, 13, and 19 percent of those in the short-course RT with immediate surgery, short-course RT with delayed surgery, and long-course RT arms, respectively). The use of neoadjuvant chemotherapy was not reported. These deficiencies render the results from the intention-to-treat analysis uninterpretable.

The optimal interval between the end of short-course RT and surgery was later addressed in a secondary analysis of 810 patients who were randomized in the Stockholm III trial and analyzed as treated (not intended); patients were stratified according to the overall treatment time (OTT; defined as the number of days between the start of RT and surgery) [191]. Among the patients receiving short-course RT, there were significantly more complications in those with an OTT of 8 to 13 days than in those with an OTT of 7 days, 5 to 7 weeks, or 8 to 13 weeks. When compared with patients with an OTT of 8 to 13 days, the risks of overall and any infectious complications were significantly lower in those with an OTT of 5 to 7 or 8 to 13 weeks. The risk of any surgical complications was reduced in those with an OTT of 8 to 12 weeks compared with those with an OTT of 8 to 13 days. There were no differences in 30- or 90-day mortality rates among the groups. Oncologic outcomes were not reported. Based on this analysis, the authors concluded that surgery should optimally be delayed for 4 to 12 weeks after the end of short-course RT.

Clinical T4 and/or large bulky tumors — Short-course RT has generally not been pursued for patients with cT4 or large bulky tumors. However, encouraging results have been noted in several trials for short-course RT in conjunction with systemic induction chemotherapy. (See 'Total neoadjuvant therapy for locally advanced tumors' above.)

NONOPERATIVE MANAGEMENT — 

For select patients with rectal adenocarcinoma who achieve a clinical complete response (cCR) to neoadjuvant therapy, nonoperative management (ie, the "watch and wait" strategy) using close surveillance is an alternative to immediate surgery. Nonoperative management may allow such patients to potentially avoid surgery, which can preserve rectal function and improve patient quality of life.

●Candidates for nonoperative management include:

•Patients with mismatch repair proficient (pMMR)/microsatellite stability (MSS) tumors who receive total neoadjuvant therapy (TNT) and achieve a cCR. (See 'Assessing for complete clinical response following neoadjuvant therapy' below.)

•Patients with mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) tumors who undergo neoadjuvant immunotherapy and achieve a cCR. (See 'Mismatch repair deficient/MSI-H tumors (neoadjuvant immunotherapy)' below.)

●We do not offer nonoperative management to those who receive neoadjuvant chemoradiation (CRT) alone or those who are treated with neoadjuvant chemotherapy followed by selective, response-guided CRT. (See 'Neoadjuvant chemotherapy and selective use of CRT' above.)

●Patients who are candidates for nonoperative management should be evaluated and monitored at a center of excellence in the multidisciplinary management of rectal cancer. Data on the long-term oncologic outcomes of nonoperative management are evolving. As such, patients should be provided with a careful and detailed discussion about the benefits and risks of nonoperative management versus immediate resection. (See 'Benefits and risks' below.)

●Nonoperative management requires careful surveillance with clinical visits, digital rectal examination, endoscopy, and imaging studies. (See 'Surveillance schedule for nonoperative management' below.)

Assessing for complete clinical response following neoadjuvant therapy — Some patients with rectal adenocarcinoma who undergo neoadjuvant therapy may achieve a cCR, which is defined as scar only with no clinical evidence of residual tumor on digital rectal examination, rectal MRI, and high-definition flexible endoscopy. Patients who achieve a cCR are eligible for nonoperative management with surveillance (algorithm 1). (See 'Surveillance schedule for nonoperative management' below.)

As the data for the oncologic outcomes of nonoperative management are evolving, the evaluation for clinical response following neoadjuvant should only be carried out at a center of excellence for the multidisciplinary management of rectal adenocarcinoma. (See 'Benefits and risks' below.)

●Who can be evaluated? – Patients with pMMR/MSS tumor who receive TNT and those with dMMR/MSI-H tumors who undergo neoadjuvant immunotherapy can be evaluated for cCR and nonoperative management. We do not offer nonoperative management to those who receive neoadjuvant CRT alone or those who are treated with neoadjuvant chemotherapy followed by response-guided radiation therapy (RT).

●When should patients be evaluated? – Patients who receive TNT with neoadjuvant chemotherapy followed by CRT should be assessed for clinical response no earlier than eight weeks after completion of CRT to allow time for the RT to exert its full antitumor effects [72]. Patients who receive TNT with neoadjuvant CRT followed by chemotherapy should be assessed for tumor response within four weeks of completing chemotherapy.

Patients with dMMR/MSI-H tumors who are treated with neoadjuvant immunotherapy may also be assessed for a clinical response every two to three months while on treatment [192]. (See 'Mismatch repair deficient/MSI-H tumors (neoadjuvant immunotherapy)' below.)

●Criteria for clinical complete response – Patients with a cCR following neoadjuvant therapy must meet all the following criteria [118,193-195]:

•Digital rectal examination – A digital rectal examination should demonstrate a smooth, flat scar and no nodularity.

•MRI rectum – A gadolinium-enhanced MRI of the rectum with diffusion-weighted imaging should demonstrate a fibrotic, linear scar with low signal intensity on T2-weighted images, no diffusion restriction, and no clinically suspicious lymph node involvement.

•High-definition flexible endoscopy – A high-definition flexible endoscopy should demonstrate a pale, smooth scar with or without telangiectasias; no ulceration, nodularity, or mucosal irregularities; and no stricture [195].

●Criteria for near complete response – Patients with a near complete response meet the following criteria. Those with a near complete response who still desire nonoperative management may be reevaluated in eight weeks to see if they eventually meet criteria for a cCR [196,197].

•Digital rectal examination – A digital rectal examination demonstrates smooth induration or superficial minor mucosal irregularity.

•MRI rectum – A gadolinium-enhanced MRI of the rectum demonstrates, on T2-weighted imaging, downstaging with or without residual fibrosis (table 11) [198], small areas of residual signal, and complete or partial regression of lymph nodes. Diffusion-weighted imaging demonstrates small areas of residual high signal intensity.

•High-definition flexible endoscopy – A high-definition flexible endoscopy demonstrates irregular small mucosal nodules, superficial ulceration, or mild persistent erythema.

●No clinical complete response or tumor regrowth – Patients who do not achieve a cCR or those who demonstrate tumor regrowth after a cCR or near complete response should be treated with surgery. (See "Surgical treatment of rectal cancer".)

●What are the roles of other diagnostic studies? – We do not typically use random sampling biopsies to determine clinical response. In patients who meet criteria for a cCR, additional biopsies of the affected area do not offer additional diagnostic value [199,200]. In patients with a high clinical suspicion of tumor regrowth, biopsies do not provide comprehensive pathologic evaluation of the entire tumor site and may result in a false-negative outcome (ie, report no pathologic evidence of cancer when it is truly present). Therefore, such patients should still proceed to surgery [201].

●The role of circulating tumor deoxyribonucleic acid (ctDNA) in evaluating for nonoperative management is also not established and further studies are necessary.

Surveillance schedule for nonoperative management — We offer the following posttreatment surveillance schedule to patients with rectal adenocarcinoma who achieve a cCR following neoadjuvant therapy and elect for nonoperative management. (See 'Assessing for complete clinical response following neoadjuvant therapy' above.)

Such patients should be monitored at a center of excellence with expertise in the nonoperative management of rectal cancer. This posttreatment surveillance schedule is generally consistent with clinical guidelines from the National Comprehensive Cancer Network (NCCN) [118].

●History, physical examination, and carcinoembryonic antigen (CEA) every three to six months for two years, and then every six months for a total of five years.

●Digital rectal examination and proctoscopy or flexible sigmoidoscopy every three to four months for two years, and then every six months for a total of five years.

●Gadolinium-enhanced MRI of the rectum every six months for up to two years, and then yearly thereafter for a total of five years.

●Contrast-enhanced CT of the chest and abdomen every 6 to 12 months for a total of five years.

●Colonoscopy at one year following completion of therapy. If an advanced adenoma is present, repeat the colonoscopy in one year. If no advanced adenoma is present, repeat the colonoscopy in three years, and then every five years.

Benefits and risks — For rectal adenocarcinoma that is treated with neoadjuvant CRT alone or TNT, the rate of pathologic complete response (pCR; ie, no tumor on the surgical specimen) ranges between 16 and 27 percent [52,64,65,71,94,202,203]. Among such patients who achieve a cCR after neoadjuvant therapy, most observational studies with long-term follow-up suggest that nonoperative management is associated with high rates of rectal preservation and similar disease-free survival (DFS) compared with immediate surgery [45,72,199,202-216]. However, local regrowth can occur in up to one-third of patients who receive nonoperative management [45,67,213,214,217]. In addition, some observational studies suggest that, relative to surgery, nonoperative management is associated with higher rates of distant metastases and worse overall survival (OS) [215,218,219].

Therefore, it is necessary to conduct randomized trials that compare nonoperative management with resection in patients who achieve a cCR after neoadjuvant therapy to accurately assess long-term outcomes. This is especially important given that rectal cancer can have late recurrences as far out as 5 to 10 years after treatment completion.

Data on the outcomes for nonoperative management after various neoadjuvant strategies are as follows:

●Nonoperative management after TNT – Nonoperative management after TNT has been evaluated in various clinical trials.

•In a randomized phase II trial (OPRA), 324 patients with stage II or III rectal adenocarcinoma (based on MRI staging) were randomly assigned to two different strategies for sequencing chemotherapy and CRT during TNT (chemotherapy either before [induction] or after [consolidation] long-course CRT) [45,72]. Full details of the OPRA trial are discussed separately. (See 'Sequencing of RT and chemotherapy' above.)

Patients were restaged 8 to 12 weeks after TNT with digital rectal examination, flexible sigmoidoscopy, and rectal MRI. Those with a complete or near-complete response were offered surveillance (ie, watchful waiting), whereas those with an incomplete response received total mesorectal excision (TME). At a median follow-up of five years, consolidation chemotherapy resulted in higher rates of organ preservation relative to induction chemotherapy (TME-free survival, 54 versus 39 percent) [45]. Among the 225 patients who entered surveillance, approximately 36 percent (81 patients) developed tumor regrowth. Among those 81 patients with tumor regrowth, almost all (99 percent) occurred within the first three years after treatment completion. Patients on surveillance who were treated with TME after tumor regrowth had similar DFS as those who had immediate TME after restaging (five-year DFS 64 percent each) [45].

•In a single-arm phase II trial (NO-CUT), 180 patients with cT3-4 or cN1-2, pMMR, lower/middle rectal adenocarcinoma were treated with TNT (four cycles of CAPOX followed by long-course CRT). After completing TNT, patients with a cCR (26 percent) underwent nonoperative management with surveillance, whereas those who did not were treated with rectal surgery (74 percent). In preliminary results, at a median follow-up of 26 months, patients treated with nonoperative management had a distant relapse-free survival of 97 percent and a local regrowth rate of 15 percent [217]. At a median follow-up of 10 months, those treated with surgery had a distant-relapse free survival of 74 percent and a local regrowth rate of 9 percent.

●Nonoperative management after neoadjuvant CRT – Surveillance after neoadjuvant CRT was evaluated in a systematic review and meta-analysis of 23 observational cohort studies that included 867 patients with rectal adenocarcinoma treated with neoadjuvant CRT [213]. Median follow-up ranged between 12 and 68 months.

•The pooled two-year local regrowth rate with nonoperative management was 16 percent. For those with local regrowth, the proportion who underwent salvage therapy was 95 percent; among those with salvage surgery, the rate of sphincter preservation was 50 percent. Longer intervals between neoadjuvant CRT and assessment of clinical response were associated with lower rates of local regrowth.

•In studies comparing patients with a cCR who had nonoperative management and those with surgery and a confirmed pCR on postoperative pathology, there were no differences in distant recurrences or cancer-specific mortality. Although nonoperative management was associated with worse DFS compared with surgery, which was mainly driven by intraluminal local tumor regrowth, there was no difference in OS. The two-year local regrowth rate ranged between 5 to 21 percent for surveillance after cCR and between 0 to 8 percent for surgery that confirmed a pCR.

•In studies comparing patients with a cCR who were managed with either a nonoperative approach or surgery, the two-year local regrowth rate ranged from 3 to 30 percent for surveillance and 0 to 2 percent for surgery.

Outcomes for nonoperative management after neoadjuvant CRT are also available from an international multicenter registry (International Watch and Wait Database [IWWD]) [214]. In this study, 1009 patients who received neoadjuvant therapy were managed with surveillance (a watch-and-wait approach) rather than surgery.

•For the entire cohort, the five-year DFS and OS were 94 and 85 percent, respectively.

•Among the subgroup of 880 patients who demonstrated a cCR, CRT alone was the most frequently used strategy for neoadjuvant therapy (84 percent). At a median follow-up of 3.3 years, the two-year cumulative incidence of local regrowth was 25 percent (213 patients). Most local regrowth was diagnosed in the first two years (88 percent), with 97 percent located in the bowel wall and 3 percent in regional nodes. For those with a cCR, the five-year DFS and OS were 97 and 89 percent.

•Among the subgroup of 148 patients with local regrowth and details of surgical treatment, TME resection was more frequently performed than local excision (78 versus 22 percent). The rate of distant metastases was higher among the 148 patients with local regrowth than the 880 patients who had cCR and surveillance (18 versus 8 percent). For those with local regrowth, the five-year DFS and OS were 84 and 75 percent, respectively.

●Is there a role for nonoperative management following chemotherapy? – We do not offer nonoperative management to patients who are achieve a cCR to initial treatment with neoadjuvant chemotherapy alone, as there is no high-quality evidence to support this approach. Neoadjuvant chemotherapy followed by the selective, response-guided use of CRT is discussed separately. (See 'Neoadjuvant chemotherapy and selective use of CRT' above.)

However, some studies suggest that nonoperative management is associated with higher rates of distant metastatic disease and worsened OS relative to surgery [215,218,219]. As an example, a retrospective case series compared the outcomes of 113 patients who achieved a cCR after neoadjuvant therapy and were managed nonoperatively versus 136 patients who had a pCR after neoadjuvant therapy and mesorectal excision [215]. Rectal preservation was achieved in 93 of the 113 patients who were managed nonoperatively. In addition, among those managed nonoperatively, all 22 tumor regrowths were detected on routine surveillance and treated with salvage surgery. However, patients who were managed nonoperatively and had a local regrowth had a higher rate of distant metastases than those whose tumors did not recur (36 versus 1 percent). In addition, OS was inferior for surveillance relative to surgery (DFS 90 versus 98 percent). In another observational study, nonoperative management was associated with a higher rate of distant metastatic disease relative to those who underwent total mesorectal excision and had a near-complete pCR (23 versus 10 percent) [219].

MISMATCH REPAIR DEFICIENT/MSI-H TUMORS (NEOADJUVANT IMMUNOTHERAPY) — 

For patients with mismatch repair deficient (dMMR) locally advanced rectal cancer who are candidates for neoadjuvant therapy, we suggest initial management with immunotherapy (dostarlimab, pembrolizumab, nivolumab) rather than chemotherapy or radiation therapy (RT). Patients with a clinical complete response (cCR) to immunotherapy may be offered nonoperative management with surveillance. Neoadjuvant immunotherapy results in sustained, high rates of cCR and offers the potential to avoid the long-term morbidity associated with surgery and RT. Patients who select this approach must be willing to accept the uncertainty of long-term outcomes, the small risk of fatal side effects from immunotherapy, and the need for very close follow-up. (See 'Nonoperative management' above.)

A subset of rectal tumors (approximately 3 percent [220]) are dMMR/high microsatellite instability (MSI-H). Patients with dMMR/MSI-H metastatic colorectal cancer are extremely responsive to immune checkpoint inhibitors. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'DNA mismatch repair deficient/microsatellite unstable tumors' and "Second- and later-line systemic therapy for metastatic colorectal cancer", section on 'dMMR/MSI-H tumors'.)

In patients with locally advanced dMMR/MSI-H colorectal cancer, neoadjuvant immunotherapy is associated with high cCR and pathologic complete response (pCR) rates, based on data from observational studies and early-phase clinical trials [221-236]. For those treated with neoadjuvant single-agent immunotherapy, longer treatment duration is associated with higher complete response rates [237]. Further randomized trials are necessary to confirm these results. By contrast, studies in dMMR/MSI-H rectal cancer have noted a diminished response to neoadjuvant chemoradiation (CRT) [75].

In an open-label, single-arm phase II trial, 12 patients with dMMR stage II or III (94 percent) rectal cancer received dostarlimab (500 mg every three weeks) for six months, which was to be followed by standard CRT and surgery. Patients with a cCR after dostarlimab (ie, no residual disease on digital and endoscopic rectal examination as well as no residual disease on rectal MRI) could proceed without CRT and surgery [192]. At a minimum of six months of follow-up (range 6 to 25 months), cCRs were seen in all 12 patients (100 percent) with no evidence of residual or recurrent tumor on MRI, fluorodeoxyglucose (FDG)-positron emission tomography (PET), endoscopic or digital rectal examination, or biopsy. No patient has required chemotherapy, radiation, or surgery. Treatment was well-tolerated with no grade ≥3 toxicities. In an updated analysis of this trial, among a cohort of 50 patients with dMMR locally advanced rectal cancer, all 49 patients who completed dostarlimab had a cCR and proceeded to nonoperative management; 37 patients had a sustained cCR at 12 months [238]. At a median follow-up of 30 months, the two-year recurrence-free survival was 96 percent.

ADJUVANT THERAPY

Adjuvant therapy following neoadjuvant CRT — Indications for and choice of adjuvant chemotherapy following resection in patients who have received neoadjuvant chemoradiation (CRT) or radiation therapy (RT) are addressed in detail separately. (See "Adjuvant therapy after neoadjuvant therapy for rectal cancer".)

Adjuvant therapy following TNT — For patients who received total neoadjuvant therapy (TNT), our approach to adjuvant therapy is as follows (see 'Total neoadjuvant therapy for locally advanced tumors' above):

●We omit adjuvant chemotherapy for those who were treated with at least four months of neoadjuvant chemotherapy.

●For patients who only receive two months of neoadjuvant chemotherapy during TNT (eg, due to stable or progressive disease in the primary tumor that results in premature discontinuation of chemotherapy and initiation of neoadjuvant RT for local disease control), we offer two months of adjuvant chemotherapy to complete a total of four months of chemotherapy.

Adjuvant therapy following neoadjuvant chemotherapy and selective use of CRT — For patients who have received neoadjuvant chemotherapy followed by selective, response-guided use of chemoradiation (CRT), the approach to adjuvant therapy is discussed separately. (See 'Neoadjuvant chemotherapy and selective use of CRT' above.)

LOCAL TREATMENT FOR PATIENTS WITH DISTANT METASTASES

Potentially resectable metastases — There are no established guidelines for pelvic irradiation in patients with synchronous, potentially resectable metastases (predominantly in liver), most of whom will begin treatment with systemic chemotherapy. A few studies have sought to elucidate the role of local treatments, such as radiation therapy (RT), in this setting; however, given the small patient cohorts and variable use of chemotherapy, results are not conclusive and treatment must be individualized. For potentially operable patients who still have operable disease after initial systemic chemotherapy, timing of resection of the primary and liver metastases (simultaneous versus staged) is discussed in detail separately. (See "Hepatic resection for colorectal cancer liver metastasis", section on 'Synchronous colorectal liver metastases'.)

The contribution of pelvic RT to outcomes (especially survival) in patients with synchronous, potentially resectable liver metastases is unclear. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [118] suggest that one of the following strategies is acceptable: initial chemotherapy followed by short-course RT or long-course chemoradiation (CRT) and then followed by resection (synchronous or staged), or initial CRT or short-course RT followed by chemotherapy and then resection. In this setting, we prefer short-course RT rather than long-course CRT; this approach is also supported by European Society for Medical Oncology (ESMO) guidelines [10].

There have been multiple approaches to patients with synchronous, potentially resectable metastases, some of which include RT and some of which do not [239-243]. Information regarding the natural history and patterns of recurrence in patients who undergo complete resection of both synchronous rectal cancer and liver metastases has not been well documented. The following data are available:

●In a retrospective evaluation of 89 patients presenting with synchronous liver metastases and rectal cancer, 30 percent of whom received perioperative RT, 25 patients (28 percent) developed a pelvic recurrence; the difference between those who did and those who did not receive pelvic RT was potentially clinically meaningful, although it was not statistically significant (15 versus 34 percent, p = 0.066) [240]. However, there was little influence of pelvic RT on overall survival (OS). In the subgroup of 56 patients who underwent local treatment for the liver metastases, the two-year OS rates were 80 and 74 percent in patients who did and who did not receive pelvic RT (p = 0.616).

●A second retrospective analysis included 185 patients who underwent complete resection of a rectal primary and synchronous liver metastases at a single institution over an 18-year period [241]. Chemotherapy was administered to 180 patients (97 percent), while pelvic RT was given to 91 patients (49 percent) either before (n = 65) or after (n = 26) rectal resection. At a median follow-up of 44 months, 130 patients (70 percent) had a disease recurrence, and these recurrences usually involved distant sites (liver, lung), rather than locoregional recurrences at the primary tumor site, even in patients treated without pelvic RT. Overall, pelvic recurrence was an uncommon event and was observed as an isolated episode in <5 percent of patients. Patients who did or did not receive RT had similar rates of recurrence (63 versus 67 percent), pelvic recurrence (11 versus 16 percent), and isolated pelvic recurrence (9 versus 8 percent). In addition, use of RT did not improve disease-specific survival.

In this setting, the influence of chemotherapy and RT on OS is likely small relative to the survival benefit of surgically resecting all gross disease, and in our view, efforts should focus on achieving margin-negative resections of both the primary site and metastases above all else. Neoadjuvant chemotherapy and RT may enhance the possibility of a complete resection. Even when a complete resection is clearly possible, prevention of recurrence through the addition of chemotherapy and/or RT, delivered either preoperatively or postoperatively, remains a worthy goal, as locoregional recurrence can be extremely morbid. Future studies are needed to sort out the relative benefits of both RT and chemotherapy in resectable stage IV disease.

Synchronous unresectable metastases — For patients who present with synchronous, unresectable stage IV disease and a symptomatic rectal primary tumor, we suggest short-course RT in conjunction with modern combination systemic chemotherapy. This approach may allow patients to avoid surgery, even those with a nearly obstructing lesion. By contrast, a benefit for short-course RT or long-course CRT for asymptomatic patients with unresectable metastatic disease is not established, and we would generally not pursue RT for most of these patients, focusing instead on palliative systemic chemotherapy. This approach is consistent with consensus-based guidelines from the NCCN [118].

For patients with a symptomatic rectal primary tumor and synchronous, unresectable metastatic disease, creation of a diverting stoma or palliative resection is often carried out before initiation of systemic chemotherapy to obtain fast relief from symptoms and to avoid complete bowel obstruction or perforation necessitating emergency surgery. Another nonsurgical option is placement of a stent (if feasible). (See "Locoregional methods for management of metastatic colorectal cancer", section on 'Unresectable metastatic disease' and "Locoregional methods for management of metastatic colorectal cancer", section on 'Nonsurgical palliative options'.)

If placement of a stent is not feasible, RT with modern combination systemic chemotherapy may allow selected patients to avoid surgery, even those with a nearly obstructing lesion [244-246]. This issue was addressed in a phase II study in which 40 patients with symptomatic primary rectal cancer and synchronous unresectable metastases received short-course RT (5 x 5 Gy) and oxaliplatin-based systemic chemotherapy; median survival was 11.5 months, and only eight patients (20 percent) required surgery during the course of their disease [245]. Pelvic symptoms were completely resolved in 30 percent, and another 35 percent had significant improvement.

POST-TREATMENT SURVEILLANCE AND SURVIVORSHIP — 

Post-treatment surveillance for patients who are treated with nonoperative management following neoadjuvant therapy is discussed separately. (See 'Surveillance schedule for nonoperative management' above.)

Recommendations for post-treatment surveillance following operative management and issues that arise in long-term survivors of rectal cancer (genitourinary problems, bowel and anorectal dysfunction) are discussed in detail separately. (See "Post-treatment surveillance for colorectal cancer" and "Approach to the care of colorectal cancer survivors".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Colorectal cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Colon and rectal cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Treatment of metastatic colorectal cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – For patients with locally advanced rectal adenocarcinomas, initial management with neoadjuvant (ie, preoperative) therapy is used to reduce tumor burden prior to pursuing surgery or other management strategies (algorithm 1). (See 'Introduction' above.)

●Pretreatment considerations – For patients with rectal cancer, the selection of appropriate candidates for initial neoadjuvant therapy, depends on accurate preoperative locoregional staging, which includes rectal MRI and/or transrectal endoscopic ultrasound (EUS). All patients should be tested for deficient mismatch repair (dMMR; germline and somatic tumor testing), which influences selection of neoadjuvant therapy. (See 'Pretreatment staging evaluation' above.)

●Patients with nonmetastatic disease, proficient mismatch repair

•Indications for neoadjuvant therapy – Indications for neoadjuvant therapy (chemotherapy and/or radiation therapy [RT]) include:

-Clinical (c)T3-T4 primary tumor – (see 'cT3-4 primary tumor' above)

-Clinically lymph node-positive disease, regardless of the primary tumor stage – (see 'Clinically node-positive disease' above)

-Mesorectal fascia involvement – (see 'Mesorectal fascia involvement' above)

-cT3-T4 or node-positive distal tumor located ≤5 cm from the anal verge – (see 'Distal tumors and sphincter preservation' above)

Neoadjuvant therapy is an alternative option for select patients with distal clinical T1N0 or T2N0 rectal cancer in whom upfront surgery would result in a permanent colostomy. Patients interested in this management strategy should be evaluated and treated in a multidisciplinary setting (ideally in the context of a clinical trial) and be informed about the risks and benefits of each approach. (See 'cT1-T2 N0 disease' above.)

•Total neoadjuvant therapy – Total neoadjuvant therapy (TNT) consists of a course of neoadjuvant (ie, preoperative) oxaliplatin-based chemotherapy and a separate course of neoadjuvant RT (either long-course neoadjuvant chemoradiation [CRT] or short-course RT), both of which are administered prior to planned surgical resection of the primary rectal tumor. (See 'Total neoadjuvant therapy for locally advanced tumors' above.)

-Patient selection – For most patients with locally advanced rectal cancer without distant metastases and either clinical T4 disease; clinical N2 disease; a low lying rectal tumor (≤5 cm from the anal verge); involved or threatened mesorectal fascia; and/or extramural venous invasion, we suggest TNT rather than neoadjuvant CRT alone (Grade 2C). In a randomized trial, this approach improved pathologic complete response (pCR) rates, disease-free survival (DFS), and overall survival (OS), and was well-tolerated. (See 'Patient selection' above and 'Rationale and benefits' above.)

-Selection of RT schedule – For most patients selecting between RT schedules for TNT, we suggest the use of conventionally fractionated (ie, long-course) CRT (50.4 to 54 Gy total administered over 28 to 31 daily fractions) rather than short-course RT (25 Gy total administered over five daily fractions) (Grade 2C) due to lower locoregional recurrence rates with this approach. Short-course RT is an alternative for those who are anticipated to not tolerate the potential toxicities of long-course CRT. (See 'Selection of RT schedule' above.)

-Selection of chemotherapy – For patients receiving the chemotherapy portion of TNT who have a good Eastern Cooperative Oncology Group performance status (less than 2) (table 6) and are medically fit to tolerate aggressive systemic therapy, we suggest FOLFIRINOX (table 3) rather than FOLFOX or CAPOX (Grade 2C). CAPOX (table 5) or FOLFOX (table 4) are appropriate alternatives for less medically fit patients at higher risk of treatment-related toxicity. We administer between 12 to 16 weeks (three to four months) of neoadjuvant chemotherapy, regardless of the chosen regimen. (See 'Selection of chemotherapy regimen' above.)

-Sequencing of RT and chemotherapy during TNT – For patients without clinical suspicion for metastatic disease on initial staging studies, either TNT sequencing approach is reasonable (chemotherapy followed by RT; or RT followed by chemotherapy), as the optimal order is not established. FOLFIRINOX is typically administered prior to neoadjuvant RT. CAPOX or FOLFOX may be administered either before or after RT, as DFS and OS outcomes are similar regardless of how these regimens are sequenced during TNT. (See 'Sequencing of RT and chemotherapy' above.)

For patients in whom metastatic disease is highly suspected, but cannot be clinically confirmed on initial staging studies, we start with neoadjuvant chemotherapy followed by neoadjuvant RT to assess if the tumor biology is responsive to systemic therapy. (See 'Sequencing of RT and chemotherapy' above.)

For all patients who start TNT with neoadjuvant chemotherapy, close monitoring for locoregional and metastatic disease progression is warranted. (See 'Sequencing of RT and chemotherapy' above.)

-Adjuvant therapy – For patients who received TNT, we omit adjuvant chemotherapy for those who were treated with least four months of neoadjuvant chemotherapy. (See 'Adjuvant therapy' above.)

•Neoadjuvant chemotherapy and selective use of CRT – For most patients with clinical T2N1M0, T3N0M0, or T3N1M0 rectal adenocarcinoma who are eligible for sphincter-sparing surgery, we suggest neoadjuvant chemotherapy with modified FOLFOX-6 followed by selective, response-guided use of CRT rather than neoadjuvant CRT alone prior to surgery (Grade 2B). In a randomized trial, this approach demonstrated similar DFS and OS. Most patients (approximately 90 percent) also avoided CRT and were presumably spared from any late radiation-associated toxicities. (See 'Neoadjuvant chemotherapy and selective use of CRT' above.)

•Selecting an RT regimen – For patients who are receiving neoadjuvant therapy that integrates RT, the approach to selecting between long-course CRT and short-course RT is as follows:

-For most patients with bulky N2 or T4 tumors, we suggest conventional fractionation RT with concurrent fluoropyrimidine chemotherapy (ie, long-course CRT) rather than the short-course Swedish approach to RT alone (Grade 2C). (See 'Long-course chemoradiation' above.)

Short-course RT represents an acceptable alternative to long-course CRT for many patients who do not have a cT4 or N2 tumor. (See 'Short-course radiation therapy' above.)

-For most patients undergoing long-course CRT, we suggest infusional fluorouracil (FU; 225 mg/m² daily) administered five days per week during RT rather than bolus FU (Grade 2C). Oral capecitabine (825 mg/m² twice daily, five days per week) is an appropriate alternative. (See 'Choice of chemotherapy during RT' above.)

•Management of complete clinical responders (nonoperative management) – For select patients with rectal adenocarcinoma who achieve a clinical complete response (cCR) to neoadjuvant therapy, nonoperative management (ie, the "watch and wait" strategy) using close surveillance is an alternative to immediate surgery. Nonoperative management may allow such patients to potentially avoid surgery, which can preserve rectal function and improve patient quality of life. (See 'Nonoperative management' above.)

-Patients with mismatch repair proficient (pMMR)/microsatellite stability (MSS) tumors who receive TNT and achieve a cCR are candidates for nonoperative management. We do not offer nonoperative management to those who receive neoadjuvant CRT alone or those who are treated with neoadjuvant chemotherapy followed by selective, response-guided CRT. (See 'Assessing for complete clinical response following neoadjuvant therapy' above.)

-Patients who are candidates for nonoperative management should be evaluated and monitored at a center of excellence in the multidisciplinary management of rectal cancer. Data on the long-term oncologic outcomes of nonoperative management are evolving. As such, patients should be provided with a careful and detailed discussion about the benefits and risks of nonoperative management versus immediate resection. (See 'Benefits and risks' above.)

-Nonoperative management requires careful surveillance with clinical visits, digital rectal examination, endoscopy, and imaging studies. (See 'Surveillance schedule for nonoperative management' above.)

●Patients with nonmetastatic, dMMR/MSI-H tumors – For patients with locally advanced dMMR/high microsatellite instability (MSI-H) rectal cancer who are candidates for neoadjuvant therapy, we suggest initial treatment with an immune checkpoint inhibitor (dostarlimab, nivolumab, or pembrolizumab) rather than chemotherapy or RT (Grade 2C), as this approach results in sustained, high rates of cCR and may allow patients to potentially avoid pelvic RT and surgery. (See 'Mismatch repair deficient/MSI-H tumors (neoadjuvant immunotherapy)' above.)

•Patients with a cCR to immunotherapy may be offered nonoperative management with surveillance. (See 'Nonoperative management' above.)

•Patients who select this approach must be willing to accept the uncertainty of long-term outcomes, the small risk of fatal side effects from immune checkpoint inhibitors, and the need for very close follow-up.

●Patients with synchronous metastatic disease

•For patients with synchronous, potentially resectable liver metastases, any of the following strategies is acceptable: initial chemotherapy followed by short-course RT or long-course CRT and then followed by resection (synchronous or staged), or initial CRT or short-course RT followed by chemotherapy and then resection. In this setting, we suggest short-course RT rather than long-course CRT (Grade 2C). (See 'Potentially resectable metastases' above.)

•For patients presenting with synchronous, categorically unresectable stage IV disease and a symptomatic primary tumor who are not amenable to stenting, we suggest short-course pelvic RT in conjunction with combination systemic chemotherapy rather than chemotherapy alone (Grade 2C). This approach may allow selected patients to avoid surgery, even those with a nearly obstructing lesion. We do not generally pursue RT for asymptomatic patients with unresectable metastatic disease. (See 'Synchronous unresectable metastases' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges David P Ryan, MD, who contributed to earlier versions of this topic review.