Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy

INTRODUCTION — Surgical resection is the cornerstone of curative therapy for rectal adenocarcinoma. However, surgery alone provides a high cure rate only for patients with early stage (stage I (table 1)) disease.

Many randomized trials have attempted to improve the results of surgery alone through the addition of chemotherapy and radiation therapy (RT), both before and after surgery. RT has emerged as an important component of adjuvant therapy for rectal cancer because of the distinct patterns of failure following resection. In contrast to colon cancer, in which the failure pattern is predominantly distant metastases, the site of first failure in patients undergoing surgery for rectal cancer is equally distributed locally (ie, pelvis) and in distant sites (eg, liver, lung) [1].

The majority of the early trials of combined modality therapy in rectal cancer evaluated postoperative RT with or without chemotherapy. The focus has shifted to preoperative (neoadjuvant) application of combined chemoradiotherapy (CRT). Neoadjuvant rather than adjuvant CRT is preferred for patients with transmural (T3/4 (table 1)) or node-positive tumors, particularly if they are low lying within the rectum. Advantages of this approach include better local control, an increased likelihood of sphincter-saving surgery, a decreased risk of post-treatment bowel dysfunction (soiling, frequent stooling), and a lower risk of chronic anastomotic stricture. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Indications for neoadjuvant treatment'.)

Most recently, a "total neoadjuvant therapy" approach, which includes induction chemotherapy followed by fluoropyrimidine-based concomitant CRT or short-course RT followed by four months of chemotherapy, has emerged as an alternative to initial CRT for patients with large bulky, locally unresectable tumors, those that are clinical N2, or with extramural venous invasion on staging MRI. In some cases, this may permit nonoperative management of locally advanced rectal cancer if a clinical complete response is achieved. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Nonoperative management (watch and wait)'.)

Nevertheless, despite these advances, initial surgery is still utilized in clinical practice, especially for patients whose preoperative local staging evaluation cannot distinguish between clinical (c) T2/3 tumors and proximal cT3N0 (table 1) tumors, for which RT may not be recommended after total mesorectal excision (TME). (See "Pretreatment local staging evaluation for rectal cancer".)

Postoperative (adjuvant) therapy for resected rectal adenocarcinoma in patients who have not received neoadjuvant CRT will be reviewed here. Neoadjuvant treatment approaches for rectal adenocarcinoma, the role of adjuvant chemotherapy in patients who have received neoadjuvant therapy, the preoperative staging evaluation, surgical management of rectal adenocarcinoma, management of rectal squamous cell cancers (which are treated similarly to anal cancers, with definitive CRT), and post-treatment follow-up after definitive treatment are discussed separately.

●(See "Neoadjuvant therapy for rectal adenocarcinoma".)

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

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

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

●(See "Radical resection of rectal cancer".)

●(See "Surgical treatment of rectal cancer".)

●(See "Treatment of anal cancer", section on 'Rectal squamous cell cancers'.)

●(See "Post-treatment surveillance after colorectal cancer treatment".)

STAGE I DISEASE — Patients with resected stage I rectal cancer (table 1) have an excellent prognosis with surgery alone, and they do not need adjuvant therapy.

STAGE II TO III DISEASE FOLLOWING TRANSABDOMINAL SURGERY

Indications and rationale for adjuvant therapy — For most patients with stage II or III rectal cancer (table 1) who go directly to transabdominal surgery, we suggest postoperative combined modality therapy (a combination of fluoropyrimidine-based chemotherapy plus concomitant pelvic radiation therapy [RT]) over surgery alone, even if a total mesorectal excision (TME) was performed.

For patients with margin-negative T3N0 tumors after TME who did not have preoperative chemoradiotherapy (CRT) and who wish to avoid the potential toxicity of postoperative RT, the 12-gene recurrence score may provide additional data on which to base a decision to forego postoperative therapy. However, there is uncertainty about the predictive validity of this test, and many clinicians, including the authors and editors associated with this topic review, do not routinely use it in rectal cancer.

These recommendations are in keeping with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), but others disagree [2]. (See 'Recommendations from expert groups' below.)

Following surgery alone for rectal cancer, local failure is a component of first relapse in less than 10 percent of patients with T1 to T2 adenocarcinomas, in 15 to 35 percent of those with stage T3N0 disease, and in 45 to 65 percent of those with stage T3/4 node-positive disease (table 1) [1,3,4]. Significantly fewer local recurrences (generally <10 percent) are reported in series utilizing TME (figure 1) (4 to 12 percent). The morbidity associated with local failure is substantial, and salvage procedures often require extensive surgery, possibly including pelvic exenteration, which can be (but is not necessarily) curative. (See "Treatment of locally recurrent rectal adenocarcinoma".)

Randomized trials consistently show significantly better local control and longer times to local failure using conventional fractionation adjuvant RT alone (ie, without concurrent radiosensitizers) in patients with resected stage II or III rectal cancer, although a survival benefit has never been clearly shown [5].

By contrast, a series of randomized trials conducted in the 1980s and 1990s established a benefit for fluoropyrimidine-based chemotherapy, with or without RT, after resection of stage II or III (table 1) rectal adenocarcinoma for disease-free survival (DFS), cause-specific survival, or both compared with surgery alone or surgery followed by RT alone [6-14]. However, many of these trials (including the Gastrointestinal Tumor Study Group [GITSG], the North Central Cancer Treatment Group [NCCTG], and the National Surgical Adjuvant Breast and Bowel Project [NSABP] R-01 trials and others [6-11]) used chemotherapy that would be considered inferior by modern standards, and very few of the trials directly compared adjuvant chemotherapy with concomitant CRT.

As an example, the NSABP R-01 trial randomly assigned 555 patients with resected Dukes B and C rectal cancer to one of three arms: observation only, adjuvant chemotherapy only (methyl-CCNU, vincristine, and FU [MOF]), or postoperative RT only (46 to 47 Gy) [8]. No group received postoperative CRT. There was a significant DFS advantage to MOF chemotherapy compared with surgery alone or surgery with RT, but there was no overall survival benefit. Patients receiving postoperative RT had a reduction in local recurrence but no improvement in survival compared with surgery alone.

However, despite these deficiencies, these trials established the benefit of adjuvant therapy, and no subsequent randomized trial exploring refinements in adjuvant therapy has included a control (surgery alone) arm. Largely based on these trials, a 1990 United States (National Institutes of Health) consensus conference recommended postoperative chemotherapy plus pelvic RT (45 to 55 Gy) as a standard treatment after resection of stage II or III rectal cancer [15]. The panel did not specify an optimal regimen but indicated the need for further refinements in the adjuvant regimen, particularly in chemotherapy, to enhance safety. (See 'Chemoradiotherapy portion' below.)

Contribution of adjuvant chemotherapy — A survival benefit for the addition of adjuvant chemotherapy after potentially curative resection of rectal cancer was further shown in a 2012 meta-analysis of 21 trials comparing the outcomes between 4367 patients with resected rectal cancer who did not receive adjuvant chemotherapy and 4854 who did [16]. All of the trials used fluoropyrimidine-based chemotherapy. Compared with no adjuvant chemotherapy, the use of adjuvant chemotherapy was associated with a significant reduction in the risk of disease relapse (hazard ratio [HR] for relapse 0.75, 95% CI 0.68-0.83) and death (HR for death 0.83, 95% CI 0.76-0.91). The contribution of RT was not addressed in this analysis.

Neoadjuvant versus adjuvant therapy — Neoadjuvant rather than adjuvant therapy (long-course CRT or short-course RT alone) is generally a preferred approach for patients with transmural (T3/4 (table 1)) or node-positive tumors, particularly if they are low lying within the rectum, and for those with a positive or threatened mesorectal fascia. Advantages of the neoadjuvant approach include better local control (even in the setting of optimal TME), an increased likelihood of sphincter-saving surgery, a lower risk of post-treatment bowel dysfunction (soiling, frequent stooling), and a lower risk of chronic anastomotic stricture. This approach is consistent with published consensus-based guidelines from the NCCN. However, others disagree. Updated 2017 guidelines for treatment of rectal cancer from the European Society for Medical Oncology (ESMO) suggest that neoadjuvant therapy is appropriate for transmural tumors with >5 mm of extramural invasion, but that initial surgery is preferred for cases with <5 mm of extramural invasion [2]. This subject is discussed elsewhere. (See "Neoadjuvant therapy for rectal adenocarcinoma".)

Patients with locally advanced rectal cancer who undergo neoadjuvant CRT or short-course RT benefit from the addition of systemic chemotherapy, which is typically administered after resection. The benefits of such therapy and the selection of the appropriate regimen in this setting are discussed in detail elsewhere. (See "Adjuvant therapy after neoadjuvant therapy for rectal cancer".)

However, increasingly, "total neoadjuvant therapy," in which preoperative treatment includes not only RT but also four months of systemic chemotherapy (which would otherwise be given after resection), has become an accepted alternative to long-course CRT alone or short-course RT alone for patients with locally advanced rectal cancer who are at high risk for a margin-positive resection (ie, T4 disease or an involved mesorectal fascia), as well as for those with clearly node-positive disease and a low-lying rectal tumor, given the increased compliance with chemotherapy (which increases the ability to deliver the recommended course of chemotherapy), the improved local control, and the ability to consider nonoperative treatment. This subject is discussed in detail elsewhere. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Total neoadjuvant therapy for locally advanced tumors' and "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Nonoperative management (watch and wait)'.)

Choice of regimen — Given the documented benefits of both RT and chemotherapy, most adjuvant therapy regimens for resected rectal adenocarcinoma consist of two components: chemotherapy alone and concomitant CRT using radiation-sensitizing doses of chemotherapy. No one trial has definitively established an optimal adjuvant regimen after resection of stage II or III rectal cancer.

Chemoradiotherapy portion — We suggest concurrent use of a fluoropyrimidine as a radiation sensitizer during postoperative RT rather than RT alone. This recommendation is based on the lack of a survival benefit with adjuvant RT alone in randomized trials and the results of the GITSG and NCCTG trials, which show a survival benefit with combined use of concurrent fluorouracil (FU)-based CRT plus chemotherapy (using regimens that are considered inferior by modern standards) over surgery alone. (See 'Indications and rationale for adjuvant therapy' above.)

We suggest infusional FU rather than bolus FU because of its more favorable side effect profile and better efficacy. Daily oral capecitabine is a reasonable alternative radiosensitizer.

Infusional versus bolus fluorouracil — Both bolus and infusional FU alone represent appropriate choices for adjuvant FU-based chemotherapy in conjunction with postoperative RT. However, many institutions favor infusional FU based on the survival benefit seen in at least one intergroup study and the lower rate of hematologic toxicity using this approach as compared with bolus treatment seen in multiple studies [11,17]. Major problems with infusional FU are the cost, inconvenience, and need for and risks associated with maintaining a central line.

Two large randomized trials have compared infusional FU with bolus FU as adjuvant treatment for rectal cancer:

●The first NCCTG-led intergroup study tested the value of prolonged venous infusion (PVI) FU (225 mg/m² per day for five weeks) versus bolus FU alone (500 mg/m² per day on days 1 to 3 and 36 to 39) during RT [11]. PVI FU was associated with a significant reduction in distant metastases (31 versus 40 percent) and improvements in four-year relapse-free survival (RFS) as well as overall survival (70 versus 60 percent), but there was no difference in local recurrence. Patients receiving PVI FU during RT were at higher risk of severe diarrhea, but the effect did not persist after completion of RT [18].

●The United States intergroup study INT 0144 was designed to investigate the benefit of PVI FU versus bolus FU not only during but also before and after RT. The study randomly assigned 1917 patients to the following groups [17]:

•Group 1 – Bolus FU before (500 mg/m² daily on days 1 through 5 and 29 through 34) and after (450 mg/m² per day) RT, with PVI FU during RT (225 mg/m² per day).

•Group 2 – PVI FU before (300 mg/m² per day for 42 days), after (300 mg/m² per day for 56 days), and during RT (225 mg/m² per day).

•Group 3 – Bolus FU with leucovorin [LV] and levamisole before RT (FU 425 mg/m² per day and LV 20 mg/m² per day, both on days 1 through 5 and 29 through 34), after RT (FU 380 mg/m² per day and LV 20 mg/m² per day on days 29 to 34 and 57 to 62), and during RT (FU 400 mg/m² and LV 20 mg/m² per day on days 1 to 4 during weeks 1 and 5 of RT). Levamisole (150 mg daily on days 1 to 3 and 14 to 16) was administered with each cycle before and after RT.

At a median follow-up of 5.7 years, there were no differences among the groups in three-year DFS or overall survival. Locoregional failure rates were also similar in all groups. Toxicity (including gastrointestinal toxicity) was similar among all groups except that the PVI FU arm had significantly lower rates of grade 3 to 4 hematologic toxicity (4 versus 49 to 55 percent in the bolus arms, respectively).

Orally active fluoropyrimidines — Oral capecitabine (825 mg/m² twice daily, five days per week) is an acceptable substitute for infusional FU during concurrent CRT, particularly for patients for whom port placement is not an option.

The available data from randomized trials support the long-term therapeutic equivalence of daily oral capecitabine and concomitant intravenous FU during RT for neoadjuvant therapy, albeit with a different toxicity profile.

Capecitabine is an orally active fluoropyrimidine prodrug that was designed to mimic continuous infusion FU while avoiding the cost, inconvenience, and risk of maintaining a central line for PVI. The conversion of capecitabine into active FU requires three different enzymes, one of which (thymidine phosphorylase) is present in higher concentrations in tumors (particularly colorectal cancers) than in normal tissue. As a result of this tumor selectivity, significantly higher tumor to plasma ratios of FU are achievable with capecitabine than with intravenous FU [19,20].

The available data, almost exclusively derived from the neoadjuvant setting, support the therapeutic equivalence of daily oral capecitabine and infusional FU during RT for rectal cancer:

●A phase III German trial directly compared CRT (50.4 Gy) with concomitant capecitabine (1650 mg/m² daily in two divided doses on days 1 to 38) versus infusional FU (225 mg/m² daily by continuous infusion) in patients with stage II or III rectal cancer undergoing adjuvant (n = 213) or neoadjuvant (n = 161) therapy [21]. All patients in the capecitabine arm treated in the adjuvant setting received two postoperative cycles of capecitabine (2500 mg/m² daily on days 1 to 14 of each 21-day cycle) before CRT and three additional cycles afterward, while those treated neoadjuvantly received CRT followed by surgery and then five courses of capecitabine at the same dose and schedule. In the adjuvant setting, the FU group received two cycles of bolus FU (500 mg/m² daily on days 1 to 5 every 28 days) both before and after CRT, while those treated in the neoadjuvant setting received CRT followed by surgery and then four courses of the same dose and schedule of postoperative bolus FU.

Patients receiving capecitabine had significantly more hand-foot syndrome overall, but they had less neutropenia. Within the neoadjuvant therapy stratum, early secondary efficacy endpoints favored capecitabine (higher rate of T stage downstaging and pathologic N0 status), although the primary endpoint, overall survival, was not reported. Efficacy results for patients treated in the adjuvant setting were not reported.

●Long-term therapeutic equivalence was also suggested in the NSABP 04 trial, which directly compared infusional FU with capecitabine concurrent with RT in the neoadjuvant setting. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Fluoropyrimidines'.)

Taken together, these results support the view that capecitabine is an appropriate substitute for infusional FU when given concurrently with RT for treatment of rectal cancer in either the preoperative or postoperative setting, albeit with a different toxicity profile. Oral capecitabine is considered an acceptable option during RT (as well as monotherapy after CRT in guidelines from the NCCN [22]).

One concern is that capecitabine metabolism is variable, and systemic exposure to capecitabine correlates poorly with efficacy and toxicity [23]. The variable bioavailability of oral fluoropyrimidines in individual patients raises concerns as to the 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.

For this reason, we continue to prefer infusional FU during RT.

Agents not used

●Leucovorin – Modern radiation-sensitizing fluoropyrimidine regimens do not utilize LV.

LV enhances FU cytotoxicity by interacting with thymidylate synthase to form a stable ternary complex, prolonging inhibition of the enzyme by FU.

The value of modulating the effect of FU with LV during CRT was tested in the United States intergroup trial INT 0114, which randomly assigned 1696 patients with completely resected rectal cancer to postoperative pelvic RT plus one of the following chemotherapy regimens [12]:

•Bolus FU alone (500 mg/m² daily for five days in two monthly courses prior to CRT, 450 mg/m² daily for five days in two monthly courses after CRT, and 500 mg/m² daily for three days during weeks 1 and 5 of RT).

•FU plus LV (FU 425 mg/m² plus LV 20 mg/m² daily for five days on days 1 to 5 and 29 to 33 prior to CRT, CRT with FU 400 mg/m² plus LV 20 mg/m² daily for five days during weeks 1 and 5 of RT, and two additional courses of FU 380 mg/m² plus LV 20 mg/m² daily for five days once per month after CRT).

•FU plus levamisole, a nonspecific immune stimulant that was mainly studied in combination with FU as an adjuvant treatment for patients with resected node-positive colon carcinoma; its use fell out of favor because of toxicity, and the drug is no longer available.

•FU, LV, and levamisole (the same doses and schedule as the FU plus LV arm described above, in conjunction with oral levamisole).

With extended follow-up [24], there was no significant advantage to any of the regimens compared with bolus FU alone (the three-drug regimen was more toxic), and there was no obvious benefit for levamisole in resected rectal adenocarcinoma. Results from this trial that address the impact of FU dosing on outcome for persons with obesity are discussed below. (See 'Chemotherapy dosing for persons with obesity' below.)

●Oxaliplatin – There is a general lack of benefit and enhanced toxicity when oxaliplatin is added as a component of neoadjuvant or adjuvant concomitant fluoropyrimidine-based CRT, and it should not be used concurrently with RT in either of these settings. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Oxaliplatin'.)

The benefit of adding oxaliplatin to adjuvant fluoropyrimidine-based CRT was directly studied in a multi-institutional Chinese trial in which 589 patients with pathologic stage II or III (76 percent) rectal cancer who did not receive neoadjuvant therapy were randomly assigned to postoperative RT (45 to 50 Gy in 25 fractions over five weeks) with either capecitabine alone (1600 mg/m² per day on days 1 to 14 and 22 to 35), or capecitabine (1300 mg/m² daily on days 1 to 14 and 22 to 35) plus oxaliplatin (60 mg/m² weekly, on weeks 1, 2, 4, and 5) [25]. At a median follow-up of 68 months, oxaliplatin did not improve three-year DFS (74.1 versus 76.3 percent), overall survival, or local recurrence, but it increased rates of grade 3 or 4 acute toxic effects (39 versus 29 percent).

Technical aspects of postoperative radiation therapy — 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. Since the anterior structures, which receive a high dose, are not substantially at risk for local failure, the two-field technique results in increased treatment-related toxicity without significant improvement in local control. At our institution, we generally treat patients with a four-field box technique, 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.

The AP-PA fields extend from approximately the lower level of the L5 vertebral body to 4 to 5 cm below the anastomosis (or below the tumor when treating preoperatively) in patients with a low anterior resection (LAR). For patients with an abdominoperineal resection (APR), the fields always extend to include the perineum. There are a substantial number of local recurrences in the perineum, and this area needs to be in the high dose volume. Laterally, the fields extend approximately 1 to 1.5 cm beyond the bony pelvis so that the lateral pelvic soft tissue receives the full radiation dose. The lateral fields have the same cephalad and caudad extent as the AP-PA fields.

Patients are treated in the prone position. The posterior border of the lateral field extends beyond the bony sacrum so that the full dose is delivered to the presacral space, a common site of local failure. Anteriorly, the fields extend to adequately cover the original tumor with at least a 2 cm margin. Blocks can often be used to spare a portion of the femoral neck in the lateral fields.

The bladder should be full during treatment so as to push some of the small intestine out of the radiation treatment volume. When the perineum needs to be treated, a bolus is placed on it so that a full dose will be delivered to the scar in this region. A bolus is a material with a similar density to tissue that is placed directly on the skin surface. The beam then strikes the absorbing surface at the bolus, whose thickness is calculated so that the maximum dose to the target volume occurs closer to the skin surface. If the reaction becomes marked, the bolus can be removed. Perineal reactions do not typically produce major symptoms.

Patients are treated at 1.8 Gy in five fractions per week to a total dose of 45 Gy to these fields. The field size is then reduced, and a boost dose is delivered to the tumor bed. Prior to designing the boost field, a special small bowel radiographic series is obtained to define the exact location of the small bowel with respect to the boost area. Only by knowing the exact bowel position can one design the treatment volumes to minimize excess irradiation of the small intestine.

Great effort is made to avoid doses greater than 45 Gy to any small bowel that is fixed in the pelvis. In this regard, it is helpful to have the surgeon (at the time of the initial surgical procedure) try to move the small intestine out of the pelvis. This can best be accomplished by reperitonealizing the pelvic floor. When this is not possible, a portion of omentum can be mobilized and swung over to cover the pelvic floor, or the uterus can be retroverted to accomplish the same purpose. Some centers have investigated the use of prostheses or artificial mesh, but these are still being investigated. These approaches are most important when treating patients after an APR; after an LAR, the remaining rectum and colon prevent some small bowel from being immobilized deep in the pelvis.

Role of IMRT and proton beam irradiation — Intensity-modulated radiation therapy (IMRT) is an advanced form of three-dimensional conformal radiation therapy (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.

Possible benefits of treatment of rectal cancer with IMRT include radiation dose escalation to the target and reduction in dose to surrounding normal tissues. Dosimetric studies comparing IMRT with traditional techniques in rectal cancer have shown clinically significant reductions in dose to the bowel, as well as the bladder, pelvic bones, and femoral heads, while also achieving superior target coverage, dose homogeneity, and conformality [26,27]. Successful implementation of IMRT in the preoperative (neoadjuvant) management of rectal cancer has been reported from multiple institutions. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Radiation technique'.)

Although fewer data are available, IMRT has also been safely and successfully integrated into the adjuvant treatment of rectal cancer in patients who have not undergone preoperative RT [28-30].

Dosimetric studies report that proton therapy reduces bone marrow, bladder, and small bowel exposure compared with both IMRT and 3D-CRT [31]. There is little clinical experience with the use of proton therapy, and this modality will require further clinical investigation to determine its ultimate benefit.

Adjuvant chemotherapy — We recommend a course of adjuvant chemotherapy in addition to CRT after resection of rectal adenocarcinoma.

For the chemotherapy component of adjuvant therapy, the evidence base for selecting an optimal regimen is sparse. Several regimens are acceptable, extrapolating from experience in adjuvant treatment of colon cancer. These include the de Gramont regimen of short-term infusional FU and LV (table 2) [32], single-agent capecitabine, or an oxaliplatin-based regimen as is used for node-positive colon cancer. In keeping with guidelines from the NCCN [22], we suggest use of an oxaliplatin-containing regimen for those with resected T4 or node-positive tumors and use of a fluoropyrimidine-based regimen for others. However, clinicians should be aware that the evidence that oxaliplatin-containing regimens are better than non-oxaliplatin-containing chemotherapy in the adjuvant setting of rectal cancer is limited. Irinotecan-based regimens should not be used. (See 'Oxaliplatin versus fluoropyrimidines alone' below and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oxaliplatin-based therapy'.)

Oxaliplatin versus fluoropyrimidines alone — For patients with resected node-positive colon cancer, data from the randomized MOSAIC and NSABP C-07 trials indicate the superiority of adding oxaliplatin to an FU plus LV backbone. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oxaliplatin-based therapy'.)

Whether oxaliplatin is beneficial for adjuvant treatment of rectal cancer is not yet established. The available data come from a single trial which examined this question in patients who had all received neoadjuvant CRT.

●The randomized phase II ADORE trial, randomly assigned 321 patients with resected rectal cancer after neoadjuvant CRT to adjuvant FU plus LV or FOLFOX [33]. In the latest report, the FOLFOX group had a significantly higher six-year DFS, although treatment-related toxicity was also higher, and the improvement in six-year overall survival was only of borderline statistical significance (78 versus 76 percent, HR 0.73, 95% CI 0.45-1.19). These data are discussed in detail elsewhere. (See "Adjuvant therapy after neoadjuvant therapy for rectal cancer", section on 'Choice of postoperative regimen'.)

Largely based on these data, updated guidelines from the NCCN [22] include FOLFOX (using a regimen such as that outlined in the table (table 3)) or capecitabine plus oxaliplatin (CAPOX (table 4)) as preferred regimens for the chemotherapy component of adjuvant therapy in rectal cancer.

Duration — For most patients we suggest four months of systemic chemotherapy in conjunction with six weeks of CRT to provide approximately six months of postoperative therapy.

The optimal number of courses of adjuvant therapy is not established. There are no trials directly comparing longer with shorter durations of adjuvant chemotherapy. However, in the adjuvant setting of resected colon cancer, six months of adjuvant therapy represents a standard approach that is supported by randomized trials (at least with FU plus LV) comparing 6 with 4 or 12 months of therapy. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Duration of therapy'.)

Consensus-based guidelines from the NCCN [22] recommend a total of six months of perioperative therapy for treatment of resected rectal cancer. We agree with these guidelines. In the adjuvant setting, we consider this to constitute a five- to six-week course of CRT and four additional months of chemotherapy alone.

Is there a role for irinotecan-based regimens? — We recommend against the use of irinotecan-containing regimens for adjuvant treatment of rectal adenocarcinoma. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Irinotecan'.)

Only one randomized trial has explored the benefit of irinotecan-based adjuvant chemotherapy in conjunction with FU-based CRT for resected rectal cancer [34]. There were 321 patients who were randomly assigned to weekly bolus LV (200 mg/m²) plus FU (450 mg/m²) with or without irinotecan (80 mg/m² weekly); both groups received four weekly infusions followed by pelvic RT concurrent with FU and then five additional months of weekly chemotherapy. There were no differences between the groups in terms of three-year DFS, overall survival, RFS, or local RFS; however, toxicity was higher in the irinotecan arm.

However, additional information is available from the adjuvant treatment of stage III colon cancer, in which three separate trials have shown no benefit for either bolus or infusional irinotecan-containing chemotherapy compared with a fluoropyrimidine alone. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Irinotecan'.)

Sequencing of chemotherapy and radiation therapy — The optimal sequence of adjuvant RT and chemotherapy has not been established conclusively. In a non-study setting, we typically administer two months of chemotherapy followed by six weeks of concomitant fluoropyrimidine-based CRT and then by two months of additional chemotherapy. However, an acceptable alternative is to start with four months of chemotherapy and finish up with concomitant fluoropyrimidine-based CRT.

With the exception of the GITSG study, most trials demonstrating benefit for combined CRT have used a "sandwich" technique, in which one or two cycles of chemotherapy are followed by combined modality therapy and then additional chemotherapy. Historically, this sandwich approach was pursued in order to get the RT planned appropriately without unnecessarily delaying the initiation of adjuvant therapy. However, there are no data indicating a better outcome with early rather than late initiation of RT. This issue was addressed in a Korean trial that randomly assigned 308 patients with resected stage II or III rectal cancer to begin RT (45 Gy in 25 fractions) with either the first or third planned course of LV-modulated FU [35]. At 10 years, there was no significant benefit for early RT in terms of DFS (71 versus 63 percent), overall survival (66 versus 64 percent), or rate of recurrence (27 versus 35 percent), either locoregional or distant.

Chemotherapy dosing for persons with obesity — Most chemotherapy drugs are dosed on the basis of body surface area. Doses for persons with obesity are sometimes calculated based on ideal rather than actual body weight, a practice for which there is no scientific basis. Underdosing of chemotherapy may have adverse clinical consequences for persons with obesity who have rectal cancer, as was shown in the INT 0114 trial [36]. (See 'Agents not used' above.)

Guidelines from ASCO recommend that full weight-based cytotoxic chemotherapy doses be used to treat persons with obesity who have cancer, particularly when the goal of treatment is cure [37]. (See "Dosing of anticancer agents in adults", section on 'Dosing for overweight/obese patients'.)

Treatment-related complications — Although improvements in local control and survival have been achieved with the use of adjuvant combined modality therapy, acute and late treatment-related morbidities have also been observed (see "Radiation proctitis: Clinical manifestations, diagnosis, and management"):

●In a series of 100 patients, compared with those treated with low anterior resection (LAR) alone, patients who received CRT after LAR had more bowel movements per day (median seven versus two) and a greater likelihood of nighttime bowel movements (46 versus 14 percent), occasional incontinence (39 versus 7 percent), and needing to wear a pad to manage soiling (41 versus 10 percent) [38].

●In the intergroup trial described above, 24 percent of patients receiving concurrent pelvic RT and PVI FU experienced severe or life-threatening diarrhea during treatment [11,18]. (See "Overview of gastrointestinal toxicity of radiation therapy", section on 'Risk factors'.)

●In addition to acute toxicity, there may be significant late effects as well. This was illustrated in an analysis of 306 rectal cancer patients treated with postoperative RT from 1981 to 1990, in which the 10-year probability of developing chronic bowel injury was 25 percent [39]. (See "Diagnosis and management of chronic radiation enteritis".)

One of the advantages of neoadjuvant compared with adjuvant therapy for rectal cancer is a decrease in the likelihood of chronic bowel toxicity. As an example, in the seminal German Rectal Cancer Study Group study, which randomly assigned 823 patients with clinically staged T3/4 or node-positive rectal cancer to the same CRT regimen administered either preoperatively or postoperatively, the benefits of preoperative therapy included significantly fewer pelvic relapses, a twofold higher chance of sphincter preservation, and a significantly lower rate of chronic anastomotic strictures (4 versus 12 percent) [40]. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'German Rectal Cancer Study Group trial'.)

Can adjuvant therapy be omitted in any patient?

Patients undergoing total mesorectal excision — While TME lowers the likelihood of local recurrence compared with operations that do not include TME, the available data suggest potential benefit for adjuvant therapy even after TME.

TME is the standard technique of removing perirectal tissue when performing radical rectal cancer surgery (LAR or APR). TME employs a precise, sharp dissection between the visceral and parietal layers of the endopelvic fascia to ensure en bloc removal of the perirectal areolar tissue, including the lateral and circumferential margins of the mesorectal envelope, lymphatics, and vascular/perineural tumor deposits with the primary rectal cancer. (See "Radical resection of rectal cancer", section on 'Total mesorectal excision'.)

The necessity of adjuvant RT in patients undergoing optimal local resection (ie, TME (figure 1)) is controversial. Proponents of eliminating RT quote series that demonstrate a very low local recurrence rate with TME [41,42]. In one such report, the 10-year local recurrence rate was 4 percent in a group of patients who underwent TME without adjuvant therapy for high-risk stage II or III disease over a 13-year period at a single institution [41]. (See 'Recommendations from expert groups' below.)

Opponents of this view quote other data that suggest a higher rate of local recurrence with TME alone when adjuvant therapy is not administered [43-45]. In one of these studies, in which 95 patients with T3N0 rectal cancer underwent TME (79 LAR and 16 APR) without postoperative adjuvant therapy, the five-year rate of actuarial local recurrence was 12 percent [43].

Furthermore, a benefit for RT even among patients undergoing TME was suggested in a Dutch neoadjuvant trial that randomly assigned 1861 patients with resectable rectal cancer to TME alone or short-course preoperative RT (5 Gy daily for five days in the "Swedish style," followed by TME) [45]. The two-year rate of local recurrence was significantly less in the RT group (2 versus 8 percent), although long-term bowel toxicity was prominent using this technique. (See "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Short-course radiotherapy'.)

Other data support the benefit of adjuvant chemotherapy for patients undergoing TME, even if RT is not administered [46]. In a multicenter trial that randomly assigned 276 patients undergoing TME for node-positive rectal cancer to oral tegafur plus uracil (UFT) or no adjuvant chemotherapy [46], the patients receiving UFT had significantly better three-year RFS (78 versus 60 percent) and overall survival (91 versus 81 percent).

T3N0 disease — The need for adjuvant therapy after resection of T3N0 rectal cancers is controversial, and the approach is variable. For most patients treated initially with radical surgery, we recommend combined FU-based chemotherapy and fluoropyrimidine-modulated CRT as the standard approach to treating pathologically staged T3N0 tumors, even if a TME has been performed. For patients with T3N0 disease who did not have a TME, CRT is especially important to minimize the risk of local recurrence. Others disagree with this approach. Updated guidelines for treatment of rectal cancer from the ESMO suggest a selective approach to adjuvant CRT, with pathologic T3N0 disease representing a category for which postoperative CRT is "insufficient and unnecessary" [2]. (See 'Recommendations from expert groups' below.)

The available data on the benefit of adjuvant therapy for resected T3N0 disease are conflicting:

●Some data suggest that a subset of patients with resected T3N0 rectal cancer do well without any adjuvant therapy. A review of the experience at Massachusetts General Hospital included 117 patients with T3N0 rectal cancer who underwent resection with curative intent and received neither neoadjuvant nor adjuvant therapy [47]. For the 25 patients with favorable histologic features (well-differentiated or moderately differentiated histology, extending 2 mm or less into perirectal fat, and without vascular invasion), the 10-year actuarial local control and RFS rates were 95 and 87 percent, respectively. The 10-year actuarial local control and RFS rates were lower (71 and 55 percent, respectively) in the 88 patients with less favorable histologic features.

●Other data support the view that these patients do as well with adjuvant chemotherapy alone as with chemotherapy plus RT [6,7,48,49]. This issue was addressed in a pooled analysis of 3791 patients with rectal cancer enrolled in five randomized trials comparing a variety of adjuvant strategies [49]. For patients with T3N0 disease, the five-year overall survival rate with surgery plus chemotherapy (84 percent) compared favorably with those of patients undergoing surgery with RT and bolus chemotherapy (74 and 76 percent in the combined NCCTG/NSABP and United States intergroup trials, respectively). The five-year DFS rate was 69 percent, compared with 63 and 66 percent in the combined NCCTG/NSABP and United States intergroup trials, respectively.

Use of the 12-gene recurrence score — For patients with margin-negative T3N0 tumors after TME who did not have preoperative CRT and who wish to avoid the potential toxicity of postoperative RT, especially in females who aspire to bear children, the 12-gene recurrence score may provide additional data on which to base a decision to forego postoperative therapy. However, there is uncertainty about the predictive validity of this test, and many clinicians, including the authors and editors associated with this topic review, do not routinely use it in rectal cancer.

Among patients with stage II colon cancer, gene expression tests, such as the 12-gene recurrence score assay (the Oncotype DX colon cancer assay), are used in an attempt to further refine prognostic stratification beyond that possible with conventional clinicopathologic features and assist in decisions about adjuvant chemotherapy. (See "Adjuvant therapy for resected stage II colon cancer".)

Data from The Cancer Genome Atlas (TCGA) project suggest that rectal and colon cancers have similar patterns of genomic alteration [50], implying that recurrence score parameters that have been established for colon cancer might be meaningful for rectal cancer as well. The utility of the 12-gene recurrence score in rectal cancer was addressed in a study of 297 patients who were enrolled in the Dutch TME trial and were mainly treated with surgery alone [51]. Overall, 182 patients died, including 120 who died after a recurrence of rectal cancer.

In the entire cohort, which included patients with stage II and III disease, the recurrence score significantly predicted the risk of recurrence, including distant recurrence and rectal cancer-specific survival, after controlling for stage and resection margin status. The effect was most prominent in stage II patients, in whom the five-year cumulative incidence of recurrence ranged from 11 percent in the low recurrence score group (<30, 49 percent of the total patients with stage II disease) to 27 percent in the intermediate recurrence score group (31 to 40) and 43 percent in the high recurrence score group (≥41).

Several caveats must be considered when interpreting these results:

●This is a relatively small sample size. Furthermore, only 297 of the 583 patients enrolled in the trial were analyzed by this test, introducing the possibility of bias.

●The recurrence score was useful for predicting which stage II patients had a very low incidence of recurrence and, thus, which stage II patients might be candidates for not receiving adjuvant therapy. However, caution is advised against using the recurrence score as a deciding factor to go straight to surgery for clinical stage II patients until prospective trials are performed to test the predictive validity of this strategy. There are no absolutely reliable clinical staging methods that accurately predict node positivity prior to surgery since many positive nodes are <5 mm in diameter. In addition, while magnetic resonance imaging (MRI) and transrectal ultrasound may be relatively accurate at predicting a margin-negative resection, they are not perfect. Preoperative RT is associated with improved outcomes (efficacy and toxicity) when compared with postoperative RT, and it is indicated in patients with node-positive tumors or where a margin-positive resection is a concern. (See "Neoadjuvant therapy for rectal adenocarcinoma" and "Pretreatment local staging evaluation for rectal cancer".)

●The 12-gene recurrence score was created as a prognostic marker. While it may have the ability to better estimate a patient's risk of recurrence, there are no good data suggesting that the recurrence score predicts the value of chemotherapy treatment.

●Whether the results from the Dutch TME trial can be extrapolated to patients who have received preoperative CRT in order to inform decisions about postoperative adjuvant chemotherapy is unclear. Given the lack of data on the utility of the 12-gene recurrence score in these patients, we would not use the test in this setting.

T1-2N1 disease — As with T3N0 disease, the need for adjuvant therapy after resection of T1-2N1 rectal cancers is controversial, and the approach is variable. We recommend fluoropyrimidine-based CRT in addition to adjuvant chemotherapy for all patients with resected node-positive rectal cancer, regardless of the number of involved nodes. Others disagree. Updated ESMO guidelines suggest that the finding of pathologic N1 disease is insufficient and unnecessary as an indicator of the need for postoperative CRT as long as the quality of the TME is adequate [2]. This is not a widely held viewpoint, however. (See 'Recommendations from expert groups' below.)

Patients with stage III rectal adenocarcinoma are a heterogeneous group, with five-year survival rates that range from 30 to 83 percent [48,52]. The American Joint Committee on Cancer (AJCC) classification separates these patients into prognostically distinct A, B, and C categories depending on the depth of tumor invasion and the number of involved lymph nodes (table 1). (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Staging'.)

Similar to the results reported for T3N0 disease, patients with resected T1-2N1 disease may do as well with adjuvant chemotherapy alone as with CRT. In the same pooled analysis described above, the five-year survival rate for patients with T1-2N1 disease (one to three positive lymph nodes) undergoing surgery with chemotherapy (85 percent) compared favorably with those of patients undergoing surgery plus RT and bolus chemotherapy (82 and 83 percent in the combined NCCTG/NSABP and United States intergroup trials, respectively) [49]. The five-year DFS rate was 78 percent, compared with 78 and 75 percent in the combined NCCTG/NSABP and United States intergroup trials, respectively.

Is the 12-gene recurrence score helpful? — The utility of the 12-gene recurrence score in patients with stage III disease was addressed in the analysis of data from the Dutch TME trial (described above) [51]. After controlling for stage and resection margin status, the recurrence score was able to stratify patients with stage IIIA/B disease into prognostically distinct subgroups, but the number of patients in each group was very small, and patients with stage IIIC disease could not be stratified. Further data are needed before this test can be recommended with any degree of confidence in patients with stage III disease.

Recommendations from expert groups — Our recommendations for adjuvant therapy are in keeping with consensus-based guidelines from the NCCN [22]. For the chemotherapy portion of treatment, an oxaliplatin-based chemotherapy regimen is preferred over a fluoropyrimidine-based regimen for patients with pathologic T4 or node-positive tumors.

Others disagree. Updated 2017 guidelines for treatment of rectal cancer from the ESMO recommend that postoperative CRT be used only selectively after primary surgery for patients who have unexpected adverse histopathologic features, including [2]:

●A positive/close circumferential resection margin (CRM, ≤1 mm),

●Perforation in the tumor area or pathologic T4b disease (table 1),

●An incomplete TME,

●Extranodal tumor deposits (N1c disease),

●pN2 disease if the TME is of poor quality or in the presence of a low tumor within 4 cm of the anal verge, or accompanied by extracapsular spread close to the mesorectal fascia,

●Extensive extramural vascular invasion/perineural invasion close to the mesorectal fascia,

●CRT may also be used for other cases with a high risk of local recurrence if preoperative RT has not been given.

By contrast, CRT is insufficient and unnecessary for pT3N0 disease, a CRM >2 mm, pT4a above the peritoneal reflection, pN1 disease, as long as there is a good quality smooth intact mesorectum. The following features were described as "borderline sufficient" for adjuvant CRT: pN2 in the mid/upper rectum if good mesorectal quality, CRM 1 to 2 mm, or circumferential obstructing tumors.

Regarding chemotherapy, a specific recommendation is not made for use of adjuvant chemotherapy in these patients [2]. The guidelines emphasize that after surgery alone for rectal cancer, trials and a meta-analysis indicate a survival and DFS benefit for adjuvant FU-based chemotherapy, but the magnitude of benefit is smaller than what it is for colon cancer, and few of the studies mandated TME surgery. Furthermore, few data are available on the benefit of an oxaliplatin-containing regimen in the absence of neoadjuvant CRT. The decision on postoperative chemotherapy should be risk balanced, taking into account both the predicted toxicity for a particular patient and the risk of relapse, and it should be made jointly by the individual and the clinician.

T2 RECTAL CANCER AFTER LOCAL EXCISION — Patients with early clinically staged T1 rectal cancers who have nonaggressive features can be treated with local excision, including the transanal, transsphincteric, and posterior parasacral approaches. Local excision permits removal of both the tumor and the adjoining rectal tissue in one specimen without tumor fragmentation and allows assessment of inked margins, histologic differentiation, vascular involvement, and depth of invasion. This approach is usually reserved for patients with well-differentiated T1 lesions that are less than 3 cm in diameter, are located in the middle to distal rectum, and lack lymphovascular invasion. (See "Surgical treatment of rectal cancer", section on 'Local excision'.)

Although more radical surgery is preferred, selected patients (ie, those with comorbid illness, refusal of major resection) with incompletely resected early rectal cancers deeper than T1 may be treated with local excision; in such cases, we suggest postoperative chemoradiotherapy (CRT), with or without chemotherapy, if the patient can tolerate it. If this approach is chosen, close post-treatment surveillance is mandatory. Furthermore, all patients undergoing local excision must be closely followed indefinitely, as almost one-third of local recurrences occur more than five years after resection.

Although more radical surgery is preferred patients with comorbid illness, or those who refuse major resection who have incompletely resected early rectal cancers deeper than T1 may be treated with local excision if used in conjunction with radiation therapy (RT) and/or chemotherapy, which may be administered prior to or following local excision:

●An early prospective study of 26 patients with T2/3 rectal cancer less than 4 cm in diameter, within 10 cm of the dentate line, and treated with local excision (transanal, transsphincteric, or transcoccygeal approach) and adjuvant CRT identified a local recurrence in two patients (8 percent) with a mean follow-up of 40.5 months [53]. This is comparable to the rate of local recurrence in 22 patients (9 percent) with T0/1 rectal cancer treated with local excision alone.

●Subsequent reports have been small, with varied surgical techniques, and frequently involved surgical margins [54-59]; not surprisingly, results are variable, with a pooled local recurrence rate of 14 percent after adjuvant RT [60]. Two studies consisting of patients with clear resection margins concluded that local recurrence rates after CRT were low (6 percent) but the sample size (n = 27) was too small to draw any meaningful conclusions [61,62].

●Additional support for this approach is provided by several trials noting relatively low rates of local recurrence (5 to 7 percent) and favorable rates of disease-free as well as overall survival, with rectal preservation rates of over 60 percent in patients treated with neoadjuvant CRT followed by local excision for cT2 disease [63-66]. Notably, this strategy is generally not recommended outside clinical trials except for elderly fragile patients at high surgical risk. (See "Transanal endoscopic surgery (TES)", section on 'T1-3N0 rectal cancer following neoadjuvant therapy'.)

Additional information should be forthcoming from the currently accruing phase III TESAR trial, which is a randomized comparison between radical surgery versus adjuvant CRT after local exclusion of early rectal cancer, including cT2 tumors no larger than 3 cm, well/moderate differentiated and without lymphatic or venous invasion [60].

ADJUNCTIVE THERAPY — The benefits of diet and exercise, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin D, and coffee consumption on cancer outcomes are discussed separately. (See "Adjunctive therapy for patients with resected early stage colorectal cancer: Diet, exercise, NSAIDs, and vitamin D" and "The roles of diet, physical activity, and body weight in cancer survivors".)

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

●General principles

•Surgical resection is the cornerstone of therapy for rectal adenocarcinoma, but it provides a high likelihood of cure only for patients with stage I disease. Such patients do not need adjuvant therapy. (See 'Stage I disease' above.)

•Neoadjuvant therapy is generally preferred over initial surgery for patients with clinically staged transmural (ie, T3/4 (table 1)) or node-positive tumors, particularly for distal tumors, and those that threaten the mesorectal fascia. Advantages include better local control, a greater likelihood of sphincter-saving surgery, and fewer chronic anastomotic strictures. This approach is consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), but others disagree. Updated 2017 guidelines for treatment of rectal cancer from the European Society for Medical Oncology (ESMO) suggest that neoadjuvant therapy is appropriate for transmural node-negative tumors with >5 mm of extramural invasion, but initial surgery is preferred for cases with <5 mm of extramural invasion. (See 'Neoadjuvant versus adjuvant therapy' above and "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Indications for neoadjuvant treatment'.)

●Patients with stage II or III disease undergoing initial surgery

•For most patients with stage II or III rectal cancer (table 1) who go directly to transabdominal surgery, we suggest postoperative combined modality therapy over surgery alone, even if a total mesorectal excision (TME) was performed (Grade 2B). (See 'Indications and rationale for adjuvant therapy' above.)

For patients with margin-negative T3N0 tumors after TME who did not have preoperative chemoradiotherapy (CRT) and who wish to avoid the potential toxicity of postoperative RT, the 12-gene recurrence score may provide additional data on which to base a decision to forego postoperative therapy. However, there is uncertainty about the predictive validity of this test, and many clinicians, including the authors and editors associated with this topic review, do not routinely use it in rectal cancer. (See 'Use of the 12-gene recurrence score' above.)

These recommendations consistent with NCCN guidelines, but others disagree with these indications for postoperative therapy. (See 'Recommendations from expert groups' above.)

•Given the documented benefits of both RT and chemotherapy, most adjuvant therapy regimens for resected rectal adenocarcinoma consist of two components: chemotherapy alone and concomitant CRT using radiation-sensitizing doses of chemotherapy. No trial has definitively established an optimal adjuvant regimen after resection of stage II or III rectal cancer.

-For most patients, we suggest concurrent use of a fluoropyrimidine as a radiation sensitizer during postoperative RT rather than RT alone (Grade 2C). (See 'Chemoradiotherapy portion' above.)

-During CRT, we suggest continuous infusion FU (225 mg/m² per day) during the entire course of RT rather than bolus FU (Grade 2B). (See 'Infusional versus bolus fluorouracil' above.)

Oral capecitabine (825 mg/m² twice daily, five days per week) is an acceptable substitute for infusional FU during concurrent CRT, particularly for patients for whom port placement is not an option. (See 'Orally active fluoropyrimidines' above.)

-For most patients, we suggest a course of adjuvant chemotherapy in addition to CRT after resection of stage II or III rectal cancer (Grade 2B). (See 'Contribution of adjuvant chemotherapy' above.)

For patients who can tolerate it, we suggest an oxaliplatin-containing regimen (oxaliplatin plus short-term infusional FU and leucovorin [FOLFOX] (table 3), or capecitabine plus oxaliplatin [CAPOX] (table 4)) rather than a fluoropyrimidine alone (Grade 2B). (See 'Adjuvant chemotherapy' above.)

For less fit patients, options include the de Gramont regimen of short-term infusional FU and leucovorin (table 2), or single-agent capecitabine. (See 'Oxaliplatin versus fluoropyrimidines alone' above and "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Treatment protocols for small and large bowel cancer".)

The optimal number of chemotherapy courses is not established. For most patients, we suggest four months of systemic chemotherapy in conjunction with six weeks of CRT to provide approximately six months of perioperative therapy (Grade 2C). (See 'Duration' above.)

•The optimal sequence of adjuvant RT and chemotherapy has not been established conclusively. We typically administer two months of chemotherapy followed by six weeks of fluoropyrimidine-based chemoradiotherapy and two additional months of chemotherapy. An acceptable alternative is to start with four months of chemotherapy followed by chemoradiotherapy. (See 'Sequencing of chemotherapy and radiation therapy' above.)

●T2N0 rectal cancer undergoing local excision – Although more radical surgery is preferred, select patients (ie, those with comorbid illness, refusal of major resection) with incompletely resected early rectal cancers deeper than T1 may be treated with local excision; in such cases, we suggest postoperative RT and/or chemotherapy if the patient can tolerate it (Grade 2C). If this approach is chosen, close post-treatment surveillance is mandatory. (See 'T2 rectal cancer after local excision' above.)

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