Neoadjuvant therapy for rectal adenocarcinoma

INTRODUCTION — Surgical resection is the cornerstone of curative treatment for rectal adenocarcinomas. Invasive small rectal adenocarcinomas may be effectively managed with limited surgical procedures, such as local excision. However, most patients have more deeply invasive tumors that require more extensive transabdominal surgery, such as low anterior resection (LAR) or abdominoperineal resection (APR). Others present with locally advanced tumors that are adherent or fixed to adjoining structures, such as the sacrum, pelvic sidewalls, prostate, or bladder. The surgical and oncologic management of these patients varies greatly depending on the stage and location within the rectum. (See "Pretreatment local staging evaluation for rectal cancer" and "Surgical treatment of rectal cancer".)

Tumors in the upper and middle rectum can usually be managed with LAR, coloanal anastomosis, and preservation of the anal sphincter. Although the resulting anorectal function may be imperfect, the risk of postoperative sexual and urinary dysfunction is lessened by preservation of the pelvic autonomic nerves, which is possible in most cases, particularly with total mesorectal excision (TME) (figure 1). (See "Radical resection of rectal cancer", section on 'Total mesorectal excision' and "Surgical treatment of rectal cancer", section on 'Techniques of low anterior resection'.)

Management of adenocarcinomas within 5 cm of the anal verge (figure 2)) poses major challenges. APR has long been considered the standard operation, but it entails a permanent colostomy and a high incidence of sexual and urinary dysfunction. (See "Surgical treatment of rectal cancer", section on 'Abdominoperineal resection'.)

Sphincter-sparing approaches for lower rectal adenocarcinomas have evolved along two pathways:

●For small superficial tumors that are confined to the rectal wall, local excision may offer local control and survival rates that are comparable with APR, while preserving sphincter function. (See "Surgical treatment of rectal cancer", section on 'Local excision'.)

●For larger or more invasive tumors, neoadjuvant therapies have been utilized to promote tumor regression; one potential benefit is increased likelihood of sphincter-sparing surgery, if cancer control is not compromised.

This topic review will discuss neoadjuvant approaches to therapy in patients with rectal adenocarcinoma. Clinical manifestations, diagnosis, and pretreatment staging, surgical management, postoperative adjuvant therapy, and post-treatment follow-up surveillance, as well as management of primary rectal squamous cell cancers, are discussed elsewhere. (See "Clinical presentation, diagnosis, and staging of colorectal cancer" and "Pretreatment local staging evaluation for rectal cancer" and "Radical resection of rectal cancer" and "Surgical treatment of rectal cancer" and "Adjuvant therapy after neoadjuvant therapy for rectal cancer", section on 'Benefit of postoperative chemotherapy' and "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy" and "Post-treatment surveillance after colorectal cancer treatment" and "Clinical features and staging of anal cancer".)

INDICATIONS FOR NEOADJUVANT TREATMENT — The only definitive indication for neoadjuvant therapy, supported by the results of randomized trials, is the presence of a clinical (c) T3 or cT4 tumor, as defined by the pretreatment staging evaluation. For these patients, we recommend preoperative (neoadjuvant) chemoradiation (CRT) or short-course radiotherapy (RT) rather than initial resection followed by adjuvant therapy. (See 'T3/4 tumors' below and "Pretreatment local staging evaluation for rectal cancer", section on 'Principles of rectal cancer staging by imaging'.)

High-quality evidence to support a clear benefit from neoadjuvant CRT, as compared with initial surgery, for other subgroups of patients with rectal cancer is lacking. However, we also suggest neoadjuvant therapy for other "relative" indications, including:

●The presence of clinically node-positive disease in a patient with magnetic resonance imaging (MRI)- or transrectal endoscopic ultrasound (EUS)-staged cT1/2 rectal cancer (see 'T1/2 and clinically node positive' below)

●Tumor that appears to invade or "threaten" the mesorectal fascia on preoperative imaging, given the decreased likelihood of achieving a tumor-free circumferential resection margin (CRM) with upfront surgery (see 'Mesorectal fascia involvement' below)

On the other hand, the use of preoperative therapy for a distal clinical T1N0 or T2N0 rectal cancer in an attempt to convert the operation from a needed abdominoperineal resection (APR) into a low anterior resection (LAR) or proctectomy with coloanal anastomosis is controversial and not yet an accepted standard of care. However, if the patient is a poor surgical candidate or declines APR, initial RT or CRT may be chosen, followed by a restaging evaluation with MRI or EUS. (See 'T1-2N0 tumors' below.)

Definitive indications

T3/4 tumors — The only definitive indication for neoadjuvant therapy, supported by the results of randomized trials, is the presence of cT3 or cT4 rectal adenocarcinoma (table 1). These are patients who, if resected initially, would likely require postoperative RT. Data from randomized trials and a meta-analysis [1] suggest that preoperative therapy is associated with a more favorable long-term toxicity profile and fewer local recurrences than postoperative (adjuvant) therapy; overall survival appears similar. (See 'German Rectal Cancer Study Group trial' below and 'Versus surgery alone' below.)

Clinical T3N0 tumors — Given the limitations of current imaging, we consider all patients with cT3N0 rectal adenocarcinoma by EUS or MRI to be appropriate candidates for neoadjuvant therapy, even proximal tumors. However, there is disagreement on this point, and guidelines from both NCCN and ESMO both support upfront surgery for selected patients, such as those with proximal tumors [2,3].

The optimal management of cT3N0 rectal adenocarcinoma (cT3N0 based on preoperative EUS and/or MRI) is debated. Some of these patients have a sufficiently favorable prognosis that questions have been raised as to the necessity of postoperative adjuvant therapy after upfront total mesorectal excision (TME). (See "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy", section on 'Can adjuvant therapy be omitted in any patient?'.)

Others have questioned the utility of upfront therapy for patients with cT3N0 tumors that do not threaten the mesorectal fascia, particularly those involving the upper rectum, given the favorable low rates of local recurrence after TME alone in the Dutch TME trial, retrospective analyses, and one prospective observational study (OCUM) [4-10].

On the other hand, as many as one-fifth of these patients may be understaged by preoperative imaging. In a review of 188 patients with EUS/MRI-staged cT3N0 tumors who received preoperative CRT, 41 (22 percent) were found to have pathologically positive mesorectal lymph nodes at the time of surgery [11]. 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 recommended for 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 elsewhere. (See "Pretreatment local staging evaluation for rectal cancer".)

Contribution of depth of extramural penetration — The approach of selecting patients with cT3N0 rectal tumors for preoperative therapy based on depth of extramural tumor invasion is not yet standard, at least in the United States, although this approach is supported in guidelines from ESMO [2].

A number of studies have shown that T3 tumors with >5 mm of extramural invasion have a higher rate of nodal involvement [12] 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 [13-16]. These findings have led some to suggest that it is not necessarily the distinction between T2 and T3 tumors that may potentially govern treatment decisions, but the identification of high-risk T3 tumors with a >5 mm depth of extramural tumor invasion [16,17]. In fact, updated 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 [2].

While 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 [18], T3 stage subclassification using depth of extramural penetration is not incorporated into tumor, node, metastasis (TNM) staging (table 1), and it is not yet validated as a prognostic factor in rectal cancer. (See "Pretreatment local staging evaluation for rectal cancer", section on 'T3 disease and the depth of extramural invasion'.)

Relative indications

T1/2 and clinically node positive — For patients who have T1 or T2 tumors (table 1) and a suspicion of node-positive disease by MRI or EUS, 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 local staging evaluation for rectal cancer", section on 'Principles of rectal cancer staging by imaging'.)

Neoadjuvant therapy might be considered an appropriate option for these patients if they had involved lymph nodes. Thus, careful consideration 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 may also be considered if the preoperative staging evaluation suggests that the tumor invades or "threatens" (ie, is within 1 to 2 mm of) the mesorectal fascia, which is the 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 local staging evaluation for rectal cancer".)

Although there are fewer data to validate this approach, these patients are appropriate candidates for preoperative 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 discussed below (which did not focus on patients with evidence of mesorectal fascia involvement) was a reduction in the rate of local recurrence. (See 'German Rectal Cancer Study Group trial' below.)

Distal tumors and sphincter preservation

T3 or node-positive — For patients with distal T3 or node-positive rectal adenocarcinomas, a major goal of preoperative therapy is to convert the surgical procedure from an APR to a sphincter-preserving operation, such as an LAR with coloanal anastomosis [19-23]. 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 preoperative 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 [24]. 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) [25-33]. Analyses of local control, survival, and bowel function are encouraging but not definitive.

High-quality definitive evidence is lacking that preoperative therapy can consistently convert patients who need an APR to where a 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) [34]. However, the absolute rates of APR in the two cohorts were not significantly different. (See 'German Rectal Cancer Study Group trial' below.)

T1-2N0 tumors — Preoperative CRT or chemotherapy alone followed by local transanal excision might be feasible as an alternative to total mesorectal excision in good responders with cT2N0 distal rectal cancer [33,35-43].

Local excision for high-risk T1-3 rectal cancer remains an area of intense controversy where opinions are based on small experiences in patient cohorts with variable risks of nodal and thus local and systemic recurrence. We continue to advise caution in adopting these approaches as well as the need to have lengthy and complex discussion with patients regarding the potential risks of local recurrence and death. We believe that these risks are often poorly understood by patients and their caregivers. This approach is consistent with guidelines from the National Comprehensive Cancer Network (NCCN), and ESMO, which both consider that transabdominal surgery is the preferred approach in this setting unless the patient is at high surgical risk because of age, frailty, extensive comorbidity, or refuses transabdominal surgery [2,3]. (See "Transanal endoscopic surgery (TES)", section on 'Early rectal cancer'.)

The use of preoperative therapy for a distal clinical T1N0 or T2N0 rectal cancer in an attempt to convert the operation from a needed APR into a LAR or proctectomy with coloanal anastomosis is also controversial and not yet an accepted standard of care. 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 recommended. At many institutions, the decision to use neoadjuvant therapy commits the treating team to both the RT and a four-month course of postoperative adjuvant chemotherapy. 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 RT or CRT 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'.)

PRETREATMENT STAGING EVALUATION — It is vitally important that patients with newly diagnosed rectal cancer are accurately staged prior to treatment. Staging of distant disease extent as well as locoregional staging modalities are discussed in detail elsewhere; the most important issues are summarized below. (See "Clinical presentation, diagnosis, and staging of colorectal cancer" and "Pretreatment local staging evaluation for rectal cancer", section on 'History, physical examination, and endoscopy' and "Endoscopic ultrasound for evaluating patients with rectal cancer".)

A computed tomography (CT) scan to evaluate the liver, retroperitoneal nodes, and chest is indicated in all patients. 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'.)

Positron emission tomography scans do not appear to add significant information to CT scans for routine preoperative staging of rectal cancer, but they may be useful in specific circumstances (eg, evaluation of patients who are thought to be present or future candidates for resection of isolated hepatic liver metastases). (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Positron emission tomography scans'.)

●Locoregional staging – The selection of appropriate patients with rectal adenocarcinoma for initial radiotherapy (RT) or chemoradiation (CRT), rather than surgery, is heavily dependent on accurate preoperative locoregional staging, which is mainly accomplished through physical examination, endoscopy, and imaging evaluation with MRI and/or transrectal endoscopic ultrasound (EUS). (See "Pretreatment local staging evaluation for rectal cancer", section on 'History, physical examination, and endoscopy'.)

Either EUS or high-resolution MRI is an acceptable radiographic method 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, if available, optimal thin-section (high-resolution) MRI using a surface pelvic phased-array coil MRI is generally preferred when patients are being evaluated for neoadjuvant therapy approaches 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'.)

This subject is discussed in detail elsewhere. (See "Pretreatment local staging evaluation for rectal cancer", section on 'Imaging evaluation'.)

OVERVIEW OF OUR APPROACH TO NEOADJUVANT THERAPY — Therapy for locally advanced rectal cancer is in evolution, particularly with regard to whether clinical complete responders to neoadjuvant therapy can be safely managed nonoperatively. The following represents our suggested approach to therapy with currently available information, which is outlined in the algorithm (algorithm 1):

●Long-course chemoradiation (CRT) versus short-course radiotherapy (RT) – For patients with nonmetastatic rectal cancer who are appropriate candidates for neoadjuvant therapy, the best regimen has not been established. For most patients, we suggest conventional fractionation RT with concurrent fluoropyrimidine chemotherapy (ie, long-course CRT) rather than the short-course Swedish approach of RT alone, especially for bulky or T4 tumors. Updated National Comprehensive Cancer Network (NCCN) guidelines consider that 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 circumferential resection margin, or T1-2, N1-2 disease [44].

However, outside of the United States, short-course RT has been adopted in many institutions as the standard preoperative approach for operable rectal cancer, and this is an acceptable alternative for many patients. We would not pursue this for a bulky or T4 tumor. Many institutions in the United States are using short-course RT in selected patients, such as those with a borderline performance status or substantial comorbidity who may not to tolerate full-course CRT, as well as prior to surgery in the setting of synchronous metastatic disease to minimize delays in initiating chemotherapy. (See 'Long-course chemoradiation' below and 'Short-course radiotherapy' below and 'Local treatment for patients with distant metastases' below.)

●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. In a randomized trial, this approach demonstrated similar disease-free and overall survival. 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.)

●Total neoadjuvant therapy – For most patients with locally advanced rectal cancer and clinical T4 disease, clinical N2 disease, a low-lying rectal tumor (≤5 cm from the anal verge), 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 RT) rather than neoadjuvant 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 below. (See 'Total neoadjuvant therapy for locally advanced tumors' below.)

●Nonoperative management for complete clinical responders – Nonoperative management for clinical complete responders to conventional neoadjuvant therapy is a controversial issue. Despite the lack of randomized trials, nonoperative management is becoming an acceptable alternative for those patients who experience a clinical complete response (cCR) to neoadjuvant therapy, especially TNT. It should be emphasized that mature data are not yet available to ensure that survival outcomes are equivalent, and this is particularly important given the natural history of rectal cancer and the rate of late recurrences between 5 and 10 years after resection.

Year 2020 consensus-based guidelines from the NCCN state that for patients who achieve a cCR with no evidence of residual tumor on digital rectal examination (DRE), rectal MRI, and direct endoscopic evaluation, an initial nonoperative approach may be considered with an experienced multidisciplinary team. However, there is not uniform agreement on whether nonoperative approaches should be considered standard at this time, even among the authors and editors associated with this topic review. 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 as to their risk tolerance. (See 'Avoidance of radical surgery' below.)

●Deficient mismatch repair and upfront immunotherapy – All patients should be tested for deficient mismatch repair (dMMR; both germline and somatic tumor testing). Upfront immunotherapy is not yet a standard approach for treatment of locally advanced dMMR rectal cancer, but it may be chosen as a non-standard approach by patients who place a high value on potentially avoiding pelvic RT and surgery. (See 'Neoadjuvant immunotherapy for dMMR tumors' below.)

TREATMENT OPTIONS FOR NONMETASTATIC DISEASE

Long-course chemoradiation — Largely based on the German Rectal Cancer Study Group trial, neoadjuvant chemoradiation (CRT) with conventional fractionation radiotherapy (RT) has become a standard approach to treatment of rectal adenocarcinoma in the United States. (See 'Indications for neoadjuvant treatment' above and "Pretreatment local 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 [45-49]. 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

German Rectal Cancer Study Group trial — 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 in patients not receiving 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 fluorouracil (FU; 1000 mg/m² daily for five days during the first and fifth weeks of RT) [34]. All patients underwent total mesorectal excision (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) [50]. The five-year disease-free survival (DFS; 68 versus 65 percent) and overall survival 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, overall survival 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 abdominoperineal resection (APR), those undergoing preoperative CRT were twice as likely to undergo a sphincter-sparing operation (39 versus 19 percent).

Other trials

●NSABP R-03 – 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 [51]:

•Preoperative therapy, consisting of one cycle of weekly bolus FU and leucovorin (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 (as described above), 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 overall survival (75 versus 66 percent, p = 0.065), and no difference in locoregional control (five-year cumulative incidence of locoregional recurrence 11 percent in both arms).

●Korean trial – A specific benefit for preoperative CRT could not be shown in a Korean trial that compared preoperative and postoperative CRT using capecitabine alone (1650 mg/m² daily during RT) in 240 patients with cT3 or node-positive rectal cancer [52]. 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 [53,54]. 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 3). 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 [55-58] 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 [59,60] as well as the percentage of viable tumor cells (table 4) [53,54,61]. The better prognosis with higher TRG was maintained with long-term follow-up (table 3) [54].

Of note, this is only one of several available and commonly used systems to assess TRG (table 5). 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 6) [62] for surgical specimens after preoperative RT or CRT for rectal cancer (which was recommended in College of American Pathologists [CAP] guidelines [63]) 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 [64]. 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 [65].

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 [66,67]. The correlation between the different values of TRG and the incidence of positive nodes is an area of active investigation [68].

The use of imaging-based preoperative TRG stratification systems to select patients for nonoperative management after neoadjuvant therapy is discussed in detail below. (See 'Tumor response assessment and follow-up' 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 [34]. (See 'German Rectal Cancer Study Group trial' above.)

However, the process of tumor regression takes time [69]. 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) [70]. 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 [71-75], only two of which have shown a higher pCR rate with longer as compared with shorter wait times [72,75]. 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 [72-76]:

•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 overall survival (OR 1.02, 95% CI 0.71-1.45).

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

•Updated guidelines from the European Society for Medical Oncology (ESMO) provide no specific recommendation other than to 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 [2].

•National Comprehensive Cancer Network (NCCN) [44] 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 [77]. 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 [34,51,78,79]. In the German study described above (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 [34]. 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 the randomized GRECCAR-6 trial (discussed above) 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 [80]. 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 elsewhere. (See "Approach to the long-term survivor of colorectal cancer", 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 long-term survivor of colorectal cancer", 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 [81-83]:

•In one report, the incidence of sacral insufficiency fractures at three years after preoperative CRT was 3 percent overall; however, women appeared to be at higher risk (5.8 versus 1.6 percent in men) [81].

•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 [83]. 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 recommend infusional FU (on the days when 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 described above [34]) use bolus fluorouracil (FU) alone, while others use bolus LV-modulated FU [45,46] 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 [84]. However, the current 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 in patients not receiving 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 [85-88]. As an example, a phase III German trial directly compared CRT (50.4 Gy) with concomitant capecitabine (825 mg/m² t^wice 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 [85]. 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 overall survival (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 [89]. 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 [86], 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" 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 [86,87,90-101] were the subject of a systematic review and meta-analysis [102], 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 overall survival (hazard ratio [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 recommend not adding 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 [103-105], but benefit could not be shown in a 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) [106]. 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 [107-111]. 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 epidermal growth factor receptor (EGFR), to conventional FU-based CRT [112-117]. The impact of this strategy on long-term outcomes, especially post-treatment complications, awaits the completion of phase III studies.

Radiation technique — In the treatment of abdominopelvic tumors, careful attention must be paid to RT technique. It is generally not appropriate to treat rectal tumors with anteroposterior-posteroanterior (AP-PA) fields alone. With this field arrangement, the anterior structures receive a high dose; since these structures are not substantially at risk for local failure, the two-field technique results in increased treatment-related toxicity without a significant improvement in local control. At our institutions, we generally treat patients with a four-field box technique using three-dimensional conformal RT (3D-CRT), although a three-field technique with right and left lateral fields and a posterior field is also reasonable. The use of lateral fields permits sparing of a portion of the bladder and some anteriorly placed small bowel.

●Dose and schedule – Patients are treated in the prone position. For those with disease limited to the submucosa and muscularis propria, pelvic irradiation to 45 Gy in 25 fractions is given using a four-field technique, followed by the first field reduction, with lateral fields to 50.4 Gy, and a second field reduction (if appropriate), with lateral fields to 54 Gy. Patients are treated at 1.8 Gy per day in five fractions per week. For the initial fields (45 Gy), the superior border should be 1.5 cm above the level of the sacral promontory, and the lower border of the field should be 4 to 5 cm below the defined tumor bed. Laterally, the AP-PA fields extend 1 to 1.5 cm beyond the true bony pelvis. To treat the entire presacral space with adequate margins and the full dose, the lateral fields are designed so that the posterior border encompasses the entire sacrum with a 1 cm margin posterior to the sacrum. Anteriorly, the fields are designed to encompass the previous tumor bed, including the posterior wall of the vagina for females and a large portion of the prostate for males.

After 45 Gy, lateral fields with an approximately 3 cm margin around the marked tumor bed are typically used for three fractions to bring the dose to 50.4 Gy. This is followed by a further field reduction to a 2 cm margin around the marked tumor bed to bring the dose to 54 Gy. A small bowel series must be performed to ensure that no small bowel is within these lateral boost fields.

Based on patterns of failure in contemporary series analyzing patients who have undergone TME and sphincter-conservation surgery, some authors have suggested a modification in the clinical target volume to reduce the amount of normal tissue in the treated field [118].

●Role of intensity-modulated RT – Intensity-modulated RT (IMRT) is an advanced form of 3D-CRT that changes the intensity of radiation in different parts of a single radiation beam while the treatment is delivered. IMRT relies on computer control capabilities to maximize the delivery of radiation to the planned treatment volume while minimizing radiation to normal tissue outside the target. Early data from retrospective series and phase II trials suggest good compliance, low rates of acute bowel toxicity, and high pCR rates after preoperative IMRT with concurrent fluoropyrimidine therapy [119-126].

However, there are no randomized trials comparing IMRT with conventional 3D-CRT, and its routine use cannot yet be recommended. Where available, we would consider use of IMRT in unique clinical situations that require extreme conformality of radiation to the target (rectal cancer, the mesorectum, and nodes) with avoidance of surrounding normal tissues (small bowel, bladder, pelvic bone) because of prior pelvic RT or underlying comorbidities (eg, inflammatory bowel disease).

Short-course radiotherapy — 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. Updated NCCN guidelines consider that 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 [44].

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.)

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

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 [4,5,23,127]. As examples:

●The early Swedish study randomly assigned 1168 patients to receive 25 Gy delivered in five fractions in one week followed by surgery versus surgery alone [23,127]. After five years, RT was associated with significant improvements in both local control (89 versus 73 percent) and overall survival (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 [127].

●In a later Dutch trial in which 1861 patients with resectable rectal cancer were randomized 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) [4,5]. 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) [128]. They also had more sexual dysfunction and slower recovery of bowel function [129], 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 [130], and problems with erections [131].

Versus conventional chemoradiation — At least three 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, overall survival, and toxicity are comparable [132-134]. The two largest trials are described below:

●A Polish trial 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) [132]. 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.

●The Trans-Tasman Radiation Oncology Group (TROG) 01.04 trial, randomly assigned 326 patients to short-course RT (5 x 5 Gy fractions) or conventional fractionation CRT (50.4 Gy with concomitant infusional FU) [133]. 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, overall survival, 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 [132,135,136] 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) [137].

Additional data on the benefits of short-course RT used as a component of total neoadjuvant therapy are discussed below. (See 'Total neoadjuvant therapy for locally advanced tumors' below.)

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. Specific recommendations for patients undergoing short-course RT as a component of total neoadjuvant therapy are discussed below. (See 'Sequencing of RT and chemotherapy' below.)

The optimal timing of surgery after short-course RT is debated, and there is no consensus as to the best approach. Most of the major trials described above, which 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 [23,132,133,138]. However, in the Dutch TME trial, the median interval between the end of short-course RT and surgery was 21 days [4]. An alternative approach is to delay surgery for four to eight weeks, with the possibility of enhanced tumor downstaging and at least some pCRs [139-142]. 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 [143-145].

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 [146]. 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) [147]. 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.

ESMO guidelines suggest that either approach (immediate surgery <10 days after the first RT fraction or delayed surgery four to eight weeks after the end of RT) is acceptable [2].

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' 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 disease-free survival (DFS) and overall survival (OS) relative to neoadjuvant CRT alone. Most patients (approximately 90 percent) also avoided CRT and were presumably spared from any late radiation-associated toxicities [148]. 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 [149] 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 [148].

●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. Adjuvant therapy after neoadjuvant therapy for rectal cancer is discussed separately. (See "Adjuvant therapy after neoadjuvant therapy for rectal cancer".)

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' below.)

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 [99,148]. 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 [150]. 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 [151,152], 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 [148]. 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) [148]. 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 [153].

Postoperatively, grade ≥3 toxicity rates were lower for FOLFOX than CRT (26 versus 33 percent) [148]. 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 [153]. 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 non-bulky, 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 [99,154].

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 overall survival (91 versus 89 versus 91 percent) and local recurrence rates (8 versus 7 versus 8 percent) [99]. However, neoadjuvant FOLFOX had the lowest pathologic complete response rate (7 percent) relative to FOLFOX plus RT (28 percent) and FU plus RT (14 percent). In preliminary results from 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 [154].

Total neoadjuvant therapy for locally advanced tumors

Definition — Total neoadjuvant therapy (TNT) consists of a course of neoadjuvant (ie, preoperative) oxaliplatin-based chemotherapy and a course of neoadjuvant RT (either long-course 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 rates as well as disease-free survival (DFS) and was better tolerated than neoadjuvant CRT alone. (See 'Rationale and benefits' below.)

Patients with a complete clinical response 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 'Avoidance of radical surgery' below.)

For cT3N0 disease that is low lying and would require either an 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, pathologic complete response (pCR) rates, enhance organ preservation, and improve survival. In a randomized trial (PRODIGE 23), TNT using neoadjuvant chemotherapy with FOLFIRINOX and conventionally fractionated (ie, long-course) CRT (followed by surgery and adjuvant chemotherapy) improved pCR rates and DFS relative to neoadjuvant CRT (followed by surgery and adjuvant chemotherapy) [155]. However, most data suggest similar overall survival (OS) between these management strategies.

TNT increases chemotherapy compliance since systemic therapy is administered in the preoperative rather than postoperative setting. Other benefits 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 [156] and early clinical trials [114,157-164] comparing TNT with neoadjuvant CRT suggested clinical benefit for this approach, including improved rates of resectability, pCR, and rectal preservation.

A randomized phase III trial (PRODIGE 23) was subsequently conducted in 461 patients with clinical T3 or T4 rectal cancer <15 cm from the anal verge [155]. Patients were randomly assigned to either:

●TNT using three months of modified FOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m² day 1, and 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), 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 a median follow-up of 46.5 months, relative to neoadjuvant CRT, TNT improved DFS (three-year DFS 76 versus 69 percent, HR 0.69, 95% CI 0.49-0.97) and pCR rates (28 versus 12 percent) in the entire study population [155]. 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). Long-term follow-up of OS and DFS in this trial are needed.

Neoadjuvant FOLFIRINOX was well tolerated, with most patients (92 percent) completing all courses of chemotherapy. 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. 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.

Similar outcomes for pCR rates, DFS, and OS have also been confirmed in meta-analyses of randomized trials (with or without observational studies) comparing TNT with neoadjuvant CRT alone [165-167], with the exception of one meta-analysis that suggested an OS benefit for TNT [168]. These data also suggest that TNT reduces the risk of distant metastatic disease, presumably due to the neoadjuvant administration of chemotherapy [167,168].

Selection of RT schedule — For most patients selecting between neoadjuvant 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 [169,170]. 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 [170]. Most data also suggest similar DFS and OS between these strategies [135,169,170], except for one randomized trial (STELLAR) which suggested an OS advantage for TNT using short-course RT [171]. 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 [169,170]:

•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) [170]. TNT with short-course RT improved the pCR rate (28 versus 14 percent) [169] 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 0.63-1.00) 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) [172], 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) [169]. Treatment compliance was also high with TNT using short-course CRT (over 80 percent) [172]. 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 [173].

●In a non-inferiority phase III trial (STELLAR), 599 patients with cT3-4 or node-positive locally advanced rectal cancer were randomly assigned to either [171]:

•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 non-inferior 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 months of FOLFOX) prior to surgery versus long-course CRT with concurrent oxaliplatin plus bolus FU and LV [135,174]. 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 [135], complete resection rates (77 versus 71 percent), and pCR rates (16 versus 12 percent) [135]. Preoperative toxicity rates were lower with the short-course RT [135]. 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' above.)

Selection of chemotherapy regimen — For patients selecting between chemotherapy for TNT, options include neoadjuvant FOLFIRINOX (table 7) [169,170], FOLFOX (table 8) [175], or CAPOX (table 9) [171,175]. The optimal neoadjuvant systemic regimen is not established since they have not been directly compared in randomized trials.

For patients with good ECOG performance status (less than 2) (table 10) 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) [155]. 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 recommended 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.

Sequencing of RT and chemotherapy — For patients with locally advanced rectal cancer who will receive TNT, the optimal order of neoadjuvant 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 deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H), a substantial proportion of which may be resistant to neoadjuvant chemotherapy [176]. Neoadjuvant immunotherapy is an alternative option for patients with dMMR/MSI-H tumors. (See 'Neoadjuvant immunotherapy for dMMR tumors' 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 "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy".)

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 [175]. 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 three years, chemotherapy followed by CRT had inferior rates of organ preservation versus CRT followed by chemotherapy (TME-free survival, 41 versus 53 percent). However, three-year DFS (76 versus 75 percent) and OS (15 versus 12 deaths) were similar between the treatment arms.

In this study, patients treated with TME after restaging also had similar three-year DFS as those who were observed and treated with TME after tumor regrowth. Nonoperative management after completion of TNT is discussed separately. (See 'Nonoperative management (watch and wait)' below.)

●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 [177,178]. 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) [178]. Pathologic complete response rates were lower for patients treated with chemotherapy followed by RT rather than the opposite sequence (17 versus 25 percent) [177]. 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' above.)

Alternative strategies

Avoidance of radical surgery

Nonoperative management (watch and wait) — Despite the lack of randomized trials, nonoperative management is becoming an acceptable alternative for those patients who experience a clinical complete response (cCR) to neoadjuvant therapy, especially to TNT. It should be emphasized that mature data are not yet available to ensure that survival outcomes are equivalent to conventional operative management, and this is particularly important given the natural history of rectal cancer and the rate of late recurrences between 5 and 10 years after resection. There is not uniform agreement on whether nonoperative approaches should be considered standard at this time, even among the authors and editors associated with this topic review [179].

As examples:

●Year 2020 consensus-based guidelines from the NCCN state that for patients who achieve a cCR with no evidence of residual tumor on digital rectal examination (DRE), rectal MRI, and direct endoscopic evaluation, an initial nonoperative approach may be considered with an experienced multidisciplinary team [44].

●Year 2020 guidelines from the American Society of Colon and Rectal Surgeons state that patients with an apparent clinical complete response to neoadjuvant therapy should typically be offered radical resection [180], although a "watch and wait" management approach could be considered for highly selected patients in the context of a protocolized setting.

Modern conventional fractionation concomitant CRT protocols with and without neoadjuvant chemotherapy, and short-course RT approaches combined with induction chemotherapy can achieve a pCR (ie, no tumor in the surgical specimen) in 16 to 27 percent of rectal cancers [53,161,174,181-183].

Most retrospective series registry reports and systematic reviews report excellent outcomes in patients who achieve a pCR after preoperative therapy [182,184]. These favorable results have led some to question whether selected patients with radiologic and clinical evidence of a complete response after neoadjuvant therapy might be able to avoid surgery altogether

No randomized trials are available in which patients with a cCR to neoadjuvant therapy were assigned to surgery or no surgery. However, data on the long-term outcomes of nonsurgically treated patients are available from accumulating reports [175,181,185-197], the most important of which are described in detail below:

●The strategy of using TNT for organ preservation was addressed in the OPRA trial, described above, in which 324 patients with MRI stage II or III rectal cancer were randomly assigned to four months of oxaliplatin-based chemotherapy before (induction) or after (consolidation) long-course fluoropyrimidine-based CRT [175]. (See 'Sequencing of RT and chemotherapy' above.)

Patients were restaged 8 to 12 weeks after TNT with DRE, flexible sigmoidoscopy and MRI, 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 three years, patients treated with consolidation rather than induction chemotherapy had significant higher rates of organ preservation (TME-free survival, 53 versus 41 percent).

●The safety of a watch and wait approach for locally advanced rectal cancer after a cCR following neoadjuvant CRT was addressed in a systematic review and meta-analysis of 23 studies (all retrospective or prospective cohorts, no randomized trials) totaling 867 patients [194]. Overall, 10 of the 23 studies provided sufficient data to calculate a pooled two-year local regrowth rate with the watch and wait approach (15.7 percent, 95% CI 11.8-20.1). Following local regrowth, the pooled proportion of patients who had salvage therapy was 95.4 percent; sphincter preservation was achieved in 49.8 percent of patients undergoing salvage surgery. Longer intervals between neoadjuvant CRT and assessment of clinical response were associated with lower rates of local regrowth.

In the eight studies comparing patients managed with a watch and wait strategy with patients who underwent radical surgery with a cCR or pCR, there were no significant differences in distant recurrences, cancer-specific mortality, or overall survival. However, the patients managed with a watch and wait approach did have poorer DFS than those who underwent radical surgery, driven by the intraluminal local regrowth. In the five studies comparing patients with a cCR managed with a watch and wait approach with those who had radical surgery and were found to have a pCR, the two-year local regrowth rates ranged from 4.8 to 21 percent with watch and wait (versus a 0 to 7.7 percent two-year rate of local recurrence after radical surgery). In the three studies comparing patients with a cCR managed with a watch and wait approach versus radical surgery, the two-year local regrowth rate ranged from 3.3 to 30.4 percent with watch and wait (versus a 0 to 2.2 percent local recurrence rate in patients with a cCR who had radical surgery).

●Data on nonoperative management in patients with a cCR following neoadjuvant therapy for rectal cancer are also available from the International Watch and Wait Database (IWWD), an international multicenter registry [195]. Of the 1009 patients submitted to the registry between 2015 and 2017 who received neoadjuvant treatment and were managed with a watch and wait approach rather than radical resection (which included 192 patients treated in Brazil and 149 who were enrolled in the OnCoRe database, described above), there were 880 with a cCR. CRT was the most commonly used neoadjuvant strategy. At a median follow-up of 3.3 years, the two-year cumulative incidence of local regrowth was 25.2 percent, 88 percent of all local regrowth was diagnosed in the first two years, and 97 percent was located in the bowel wall (3 percent in regional nodes only). Details of surgical treatment were only available for 148 of the 213 patients with local regrowth. In total, 115 (78 percent) of the 148 patients with a local recurrence needed a TME resection for local regrowth; the remainder had local excision. Distant metastases developed in 71 patients (8 percent) during follow-up. Among the patients with local regrowth, the proportion of distant metastases was higher (38 of 213, 18 percent). Five-year DFS for the whole group was 94 percent, and five-year overall survival was 85 percent.

●Not all reports are favorable, however [196,198]. A retrospective case series compared the outcomes of 113 patients who achieved a cCR after completing neoadjuvant therapy and agreed to a watch and wait strategy versus those of 136 patients who had a pCR after neoadjuvant therapy and mesorectal excision [196]. All 22 regrowths in the watch and wait group were detected on routine surveillance and treated with salvage surgery, and rectal preservation was achieved in 93 of the 113 patients. However, patients in the watch and wait group who had a local recurrence had a higher rate of distant metastases than those whose tumors did not recur (36 versus 1 percent), and survival was inferior in the watch and wait group compared with the surgically treated patients (DFS 90 versus 98 percent).

Taken together, most of the data suggest that a careful endoscopic, clinical, and radiographic evaluation might be able to identify patients who have a complete clinical response to upfront therapy and who have a good likelihood of local tumor control and may not need surgery. However, none of these data are from trials that randomly assigned patients with a cCR to surgery or no surgery, and they all suffer from significant limitations.

Globally, several additional prospective randomized trials of nonoperative therapy in complete responders to induction therapy are underway (including NCT02514278, NCT02794520, NCT01047969, and NCT03426397) that use accurate pelvic MRI staging at baseline and predefined criteria for a cCR, which should resolve lingering concerns about long-term outcomes by comparing the intervention of avoiding surgery in patients identified as having a cCR. Eligible patients should be encouraged to enroll.

Local excision in lieu of total mesorectal excision after chemoradiation — Local excision is an accepted surgical option for cT1 rectal adenocarcinomas. However, local excision as the sole surgical treatment for ≥cT2N0 rectal cancer after CRT is still considered investigational because of concerns for micrometastases in the mesorectum and residual disease in the excision bed, both of which could contribute to higher rates of recurrence and a poorer outcome compared with definitive surgery. (See "Surgical treatment of rectal cancer", section on 'Local excision'.)

There has been increasing interest in the use of transanal endoscopic surgery (TES) as a mechanism for evaluating pathologic response to neoadjuvant CRT in patients with cT1-3N0 rectal cancer, with further surgical treatment dictated by the pathologic findings on the local excision specimen [43]. There are conflicting data from systematic reviews as to whether or not outcomes (local recurrence, survival) are inferior in patients who undergo a subsequent TME after a local excision has been performed; the available data are probably insufficient to answer this question [199,200]. Furthermore, others have shown that as many as one-fifth of patients with ypT1 to ypT2 tumors after CRT are ypN+, and that local excision would result in untreated metastatic disease in these patients [201]. This subject is discussed in detail elsewhere. (See "Transanal endoscopic surgery (TES)", section on 'T1-3N0 rectal cancer following neoadjuvant therapy'.)

For all of these reasons, we do not support TES as the sole surgical treatment in patients with ≥cT2N0 disease who undergo local excision and have any residual tumor after CRT. Furthermore, in patients with ≥cT2N0 tumors who achieved a pCR with preoperative CRT, further prospective studies are needed to demonstrate that long-term outcomes with local excision are comparable with those attained with conventional surgery [43]. In our view, local excision should only be used after CRT in patients who are frail or otherwise unfit for abdominal surgery or in the setting of a clinical trial. This subject is discussed in detail elsewhere. (See "Transanal endoscopic surgery (TES)", section on 'T1-3N0 rectal cancer following neoadjuvant therapy'.)

Tumor response assessment and follow-up — Consistent with consensus-based guidelines from the NCCN [44], patients who achieve a cCR after neoadjuvant therapy with no evidence of residual tumor on DRE, rectal MRI, and direct endoscopic evaluation may be considered for an initial nonoperative approach with an experienced multidisciplinary team. There is no standard classification of response based upon DRE, endoscopy, and MRI; one approach, which is based on the schema used at MSKCC, is outlined in the table (table 11) [202]. We would consider that only patients who are classified as a cCR are eligible for nonoperative management. For most patients, we would repeat these studies every three months for two years, and then every six months to complete five years of surveillance.

A major obstacle to selecting patients who may avoid radical surgery is that pCR can most accurately be determined after a full pathologic examination of the resected specimen. There is no single test that is capable of identifying patients with complete tumor regression following neoadjuvant therapy. A combination of clinical and endoscopic findings does not provide sufficient information to allow identification of patients with a sustained cCR who are likely to have a pCR. The limitations of this approach can be illustrated by a study from the MSKCC in which all patients undergoing preoperative CRT were subjected to resection; 75 percent of the complete clinical responders had persistent foci of tumor that were not detectable on preoperative DRE or proctoscopy [203].

In our view, the decision to pursue or not to pursue surgery should not be based solely on the absence of clinically palpable or visible tumor after neoadjuvant treatment. A major problem is the risk of lymph node metastases despite complete primary tumor regression. Even in ypT0 rectal cancers treated with TME, the risk of lymph node metastases or mesorectal deposits is as high as 12 percent [204-206]. (See 'Prognosis and extent of tumor regression' above.)

The role of imaging for restaging for assessment of the primary tumor and regional nodes after neoadjuvant therapy has been the subject of several studies, and all suggest that neither MRI, computed tomography (CT), transrectal endoscopic ultrasound (EUS), or integrated positron emission tomography (PET)/CT alone is sufficiently accurate to identify the true complete responders [207-219]. A major problem with MRI is that it is difficult to differentiate small areas of residual tumor from fibrosis, and readers tend to overestimate the presence of tumor [214,220-222]. PET/CT findings that suggest a cCR are also associated with a low positive predictive value for a pCR (39 percent in one systematic review [223]).

Nevertheless, MRI has been increasingly used in addition to DRE and endoscopy for this assessment. When MRI is used, as part of the evaluation, the TRG is a critical aspect of the evaluation (table 12) [207,224,225]. According to this widely used 5-tiered schema, only patients with a TRG1 or 2 radiographic response on MRI would be eligible for a nonoperative approach. Alternative MRI TRG schema have been proposed [226].

Neoadjuvant immunotherapy for dMMR tumors — Upfront immunotherapy followed by nonoperative management for clinical complete responders cannot yet be considered a standard approach for rectal cancers with deficient mismatch repair (dMMR). However, individuals with dMMR tumors who place a high value on avoiding the long-term morbidity associated with surgery and pelvic RT might choose this non-standard approach if they are willing to accept the uncertainty of long-term outcomes, the small risk of fatal side effects from checkpoint inhibitors, and the need for very close follow-up (every four month pelvic MRI, digital rectal examination, sigmoidoscopy with biopsy).

A small subset of rectal tumors (approximately 3 percent [227]) are dMMR, the biologic footprint of which is high levels of microsatellite instability (MSI-H). The presence of dMMR/MSI-H indicates potential responsiveness to immunotherapy using immune checkpoint inhibitors in the setting of metastatic disease. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Patients with deficient DNA mismatch repair/microsatellite unstable tumors' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Microsatellite unstable/deficient mismatch repair tumors'.)

Colorectal cancer with dMMR/MSI-H has a favorable prognosis overall, but in the setting of locally advanced rectal cancer, some have noted a diminished response to conventional neoadjuvant CRT approaches [176], although this is not a universal finding [228]. On the other hand, high levels of pathologic complete or near complete response have been observed following neoadjuvant immunotherapy [229-235], and several trials are now exploring this option, including in the setting of locally advanced rectal cancer [236,237].

Early data are available from a small prospective trial, in which 12 patients with dMMR stage II or III (94 percent) rectal cancer first received single-agent therapy with the anti PD-1 monoclonal antibody dostarlimab (500 mg every three weeks) for six months, which was to be followed by standard CRT and surgery; patients who had a complete clinical response after dostarlimab (defined as the absence of residual disease on digital and endoscopic rectal examination as well as the absence of residual disease on rectal MRI with no restricted diffusion on T2-weighted imaging), could proceed without CRT and surgery [237]. In an early report, in which all 12 patients had at least six months of follow-up after completion of dostarlimab (median follow-up 12 months after study enrollment, range 6 to 25 months), all 12 had a complete clinical response with no evidence of residual or recurrent tumor on MRI, fluorodeoxyglucose-PET, endoscopic or DRE, or biopsy. No patient has required chemotherapy, radiation, or surgery. Treatment was well-tolerated with no ≥grade 3 adverse effects. Long-term oncologic outcomes were not reported.

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

For patients who received 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.

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 radiotherapy (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 elsewhere. (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) [44] 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 [2].

There have been multiple approaches to patients with synchronous, potentially resectable metastases, some of which include RT and some of which do not [238-242]. 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) [239]. However, there was little influence of pelvic RT on overall survival. In the subgroup of 56 patients who underwent local treatment for the liver metastases, the two-year overall survival 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 [240]. 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 overall survival 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 [44].

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 and palliation in patients who present with stage IV colorectal cancer", section on 'Incurable metastatic disease' and "Locoregional methods for management and palliation in patients who present with stage IV 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 [243-245]. 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 [244]. Pelvic symptoms were completely resolved in 30 percent, and another 35 percent had significant improvement.

Resource-stratified guidelines — The approach outlined above assumes that health care resources are not a limiting factor. Resource-stratified guidelines for treatment of patients with late-stage colorectal cancer are available from the American Society of Clinical Oncology [246]. They include specific recommendations for initial diagnostic evaluation, systemic therapy, surgical management of patients with potentially resectable metastatic disease, and issues specific to primary site RT in patients with metastatic disease.

POST-TREATMENT SURVEILLANCE AND SURVIVOR ISSUES — Recommendations for post-treatment cancer surveillance and issues that arise in long-term survivors of rectal cancer (genitourinary problems, bowel and anorectal dysfunction) are discussed in detail elsewhere. (See "Post-treatment surveillance after colorectal cancer treatment" and "Approach to the long-term survivor of colorectal cancer".)

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 topics (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: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pretreatment considerations – The selection of appropriate candidates for initial radiotherapy (RT) or chemoradiation (CRT), rather than surgery, depends on accurate preoperative locoregional staging, which includes pelvic MRI and/or transrectal endoscopic ultrasound (TEUS). All patients should be tested for deficient mismatch repair (dMMR; germline and somatic tumor testing), given the potential to consider upfront immunotherapy. (See 'Pretreatment staging evaluation' above.)

Our approach to treatment is outlined in the algorithm (algorithm 1) and described below.

●Patients with nonmetastatic disease, proficient mismatch repair

•Indications for neoadjuvant therapy

-For patients with clinical T3/4 rectal adenocarcinoma, we recommend preoperative (neoadjuvant) CRT or short-course RT rather than initial resection followed by adjuvant therapy (Grade 1B). (See 'T3/4 tumors' above.)

-For patients with clinically node-positive disease regardless of the primary tumor (T) stage, or a tumor that appears to invade or "threaten" the mesorectal fascia on preoperative imaging, we also suggest neoadjuvant therapy (Grade 2C). (See 'Relative indications' above.)

-The use of neoadjuvant therapy for a distal cT1-2N0 rectal cancer in an attempt to convert the operation from a needed abdominoperineal resection (APR) into a sphincter sparing procedure is controversial and not yet an accepted standard of care. However, if the patient is a poor surgical candidate or declines APR, initial RT or CRT may be chosen, followed by a restaging evaluation. (See 'T1-2N0 tumors' above.)

•Short-course RT versus long-course CRT

-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 radiotherapy' 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.)

•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 disease-free and overall survival. 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.)

•Total neoadjuvant therapy – Total neoadjuvant therapy (TNT) consists of a course of neoadjuvant (ie, preoperative) oxaliplatin-based chemotherapy and a course of neoadjuvant RT (either long-course 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 total neoadjuvant therapy (TNT) rather than neoadjuvant CRT alone (Grade 2C). In a randomized trial, this approach improved pathologic complete response rates and disease-free survival 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 ECOG performance status (less than 2) (table 10) and are medically fit to tolerate aggressive systemic therapy, we suggest FOLFIRINOX (table 7) rather than FOLFOX or CAPOX (Grade 2C). CAPOX (table 9) or FOLFOX (table 8)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.)

•Management of complete clinical responders

-Patients who achieve a clinical complete response after conventional neoadjuvant therapy with no evidence of residual tumor on digital rectal examination (DRE), rectal MRI, and direct endoscopic evaluation may be considered for an initial nonoperative approach with an experienced multidisciplinary team. However, there is not uniform agreement on whether nonoperative approaches should be considered standard at this time, even among the authors and editors associated with this topic review. Any decision for nonoperative management should involve a careful discussion with the patient as to their risk tolerance. (See 'Avoidance of radical surgery' above.)

-For patients who choose nonoperative management, we repeat DRE, MRI, and endoscopic examination every three months for two years, and then every six months to complete a full five years of surveillance. (See 'Tumor response assessment and follow-up' above.)

●Patients with nonmetastatic disease, deficient mismatch repair – Upfront immunotherapy followed by nonoperative management for clinical complete responders cannot yet be considered a standard approach for rectal cancers with dMMR. However, individuals with dMMR tumors who place a high value on avoiding the long-term morbidity associated with surgery and pelvic RT might choose this non-standard approach if they are willing to accept the uncertainty of long-term outcomes, the small risk of fatal side effects from checkpoint inhibitors, and the need for very close follow-up (every four month pelvic MRI, DRE, sigmoidoscopy with biopsy). (See 'Neoadjuvant immunotherapy for dMMR tumors' above.)

●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 modern 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.