Rectal and colon adenocarcinoma originate from the same epithelial cell types and share the same histologic features. Unlike the colon, the rectum lacks a peritoneal lining, and the tight confines of the pelvis pose a challenge to surgical resection with clear margins. These features may explain the higher local recurrence rates seen in rectal cancer compared with colon cancer. Prior to the advent of multimodality treatment of rectal cancer, local recurrence rates of 5% to 10% for stage I, 25% to 30% for stage II, and >50% for stage III tumors were reported.¹ Pelvic radiation therapy offers a protective effect against local recurrence, and over the past decades preoperative (neoadjuvant) timing has prevailed. The effects of radiation on tumor eradication can be potentiated with concurrent chemotherapy, particularly with fluorouracil-based chemotherapy. However, surgical management with a total mesorectal excision (TME) remains as the key feature of modern rectal cancer care.

Preoperative radiation allows for tumor oxygenation through the intact blood supply. Preoperative treatment is better tolerated than postoperative treatment, as demonstrated in the German Rectal Cancer Study Group study in which 89% of patients randomized to preoperative chemoradiation completed treatment, but among patients randomized to postoperative treatment only 50% of patients received a full dose of chemotherapy and only 54% received full-dose radiotherapy. The relatively high complication rate after rectal cancer surgery is likely to explain this gap in compliance. The advantage of postoperative chemoradiation is that a true tumor stage is available from the surgical specimen, so the indication for this treatment is more accurately determined. Surgical resection may be less challenging in a pelvis that has not been preoperatively radiated, though this has been hard to prove. Some studies have shown that perineal wound healing in abdominoperineal resection (APR) patients is more challenging after any radiation treatment. A major criticism of our reliance on radiation is the long-term side effects of pelvic radiation, which are well documented. As it is not clear that pelvic radiation achieves a survival benefit, a legitimate argument can be made to more closely examine the long-term quality of life implications of pelvic radiation. Furthermore, a more finely tuned selective approach to using radiation has been hampered by our inability to accurately clinically stage patients upon diagnosis. While much progress has been made in this regard, particularly with advances in MRI technology, results of such research is frequently confounded by the fact that neoadjuvant radiation or chemoradiation is commonly administered and frequently downstages the primary tumor, eliminating the gold standard of histopathology of the primary tumor.

In this chapter, the various approaches to neoadjuvant and adjuvant multimodality treatment of rectal cancer are summarized, with an attention to data from randomized controlled trials. Outcomes of local recurrence, primary tumor response to neoadjuvant treatment, overall survival, disease-free survival, surgical complications, and bowel, bladder, and sexual functions are examined. This chapter focuses on curative radical surgery for rectal cancer and does not address treatment approaches in patients with metastatic disease, nor does it address the use of local excision (transanal excision, transanal endoscopic microsurgery (TEM), or transanal minimally invasive surgery (TAMIS)) as a curative approach to early-stage rectal cancers.

Preoperative Short-Course Radiation

Short-course radiation refers to daily administration of a 5-Gy dose over a 5- to 7-day time frame. This protocol is not administered with chemotherapy. The protocol in the Stockholm Rectal Cancer Study administered 25 Gy over 5 to 7 days in fractions of 5 Gy.^2,3 The fields included the anus, rectum, perineum, inguinal nodes, and obturator foramina and extended up to the second lumbar vertebra (L2). Patients underwent surgical resection 1 to 7 days after radiation. In an older EORTC randomized trial, a total of 34.5 Gy was delivered in 15 daily doses of 2.3 Gy each.⁴ These fields also extended up to L2. Patients in this study underwent surgery at a mean of 11 days after radiotherapy. Of note, 5% of radiated patients had a complete pathologic response. In the Lyon R90-01 randomized trial comparing a short versus long interval-to-surgery after preoperative radiation, a higher dose (39 Gy, hypofractionated in 3-Gy doses) was used, but the field did not extend above the lumbosacral junction. All patients in this trial were able to complete radiotherapy.⁵ Of note, a complete or near-complete pathologic response was shown in 26% of patients who had a long rest period group (median time to surgery 46 days) compared to 10% of patients who had a short rest period group (median time to surgery 13 days).

In the Swedish Rectal Cancer Trial, 25 Gy was administered in 5 fractions with fields including the anal canal, the rectal tumor, mesorectal and presacral lymph nodes, internal iliac vessels, and lumbar lymph nodes up to L5.⁶ Patients were radiated with three beams or with a four-beam box technique in supine or prone. The authors discuss the concern that high fractional doses could be more toxic, but using their three- or four-beam technique, no severe toxicity was seen. The MRC-CR07 NCIC C016 trial had a short-course radiotherapy arm; the target volume was the sacral promontory superiorly, 3 to 5 cm below the inferior tumor extent inferiorly, and 1 cm lateral to the bony true pelvis laterally.⁷ Radiotherapy consisted of 5 Gy for 5 consecutive days, followed by surgery 7 days later.

Long-Course Chemoradiation

Long-course chemoradiation can be administered preoperatively or postoperatively, but typically the term refers to neoadjuvant treatment in order to distinguish this approach from short-course preoperative treatment. As described in the German Rectal Cancer Study Group study, this regimen consisted of 50.4 Gy, delivered five times per week in 1.8 Gy fractions (28 total) with three or four fields.^8,9 Fluorouracil (FU) was administered during the first and fifth weeks of radiotherapy as a 120-hour continuous infusion of 1000 mg/m²/day. Surgery occurred 6 weeks after chemoradiation. In the Polish Colorectal Study Group trial, which compared preoperative short-course radiation to preoperative long-course chemoradiation, the regimen was the same as that described in the German Rectal Cancer Study Group study.¹⁰ Surgery occurred 4 to 6 weeks after chemoradiation.

In the NSABP-R03 trial from the United States which compared preoperative and postoperative chemoradiation, long-course preoperative chemoradiation consisted of a 6-week course of induction chemotherapy with weekly FU 500 mg/m², followed by 50.4 Gy of radiation during which two cycles of FU were administered at a dose of 325 mg/m² for 5 days during the first and fifth weeks of radiation.¹¹ Surgery was performed 8 weeks after treatment completion. Radiation consisted of 45 Gy in 25 fractions using a four-field technique with a 5.4-Gy boost in 3 fractions. In MRC-CR07 NCIC CTG C016 trial, postoperative chemoradiation consisted of monthly (370 to 425 mg/m² on days 1 to 5) or weekly (370 to 425 mg/m² once per week) FU with 45 Gy in 25 fractions.⁷ The modern radiation treatment approach for both short- and long-course radiation brings standard fields down to the level of the sacral promontory.

Long-course preoperative chemoradiation has been emphasized as the preferred modality for patients who have threatened circumferential margins, since this approach seems to be more efficacious at downsizing the tumor compared with short-course radiation, as seen in the next section.

Tumor Response to Neoadjuvant Treatment

A complete pathologic response was seen in 8% of the 405 patients who had preoperative chemoradiation in the German Rectal Cancer Study Group study.^8,9 In the Polish trial, which enrolled 312 patients, long-course chemoradiation came with the benefit of higher complete pathologic response rates (16.1% vs. 0.7%) and positive circumferential margins were more common in the short-course radiation group (12.9% vs. 4.4%; p = 0.017).¹⁰ NSABP-R03, which included induction chemotherapy in the preoperative arm, did not have a markedly higher complete pathologic response rate compared to other trials (15%).¹¹ In prospective studies, a more prolonged wait time of 8 to 10 weeks may increase the proportion of patients who show a complete pathologic response.

Local Recurrence

All of the large randomized trials have shown a reduction of local recurrence with preoperative radiotherapy compared with surgery. The Stockholm Rectal Cancer Study Group study randomized 849 patients to preoperative radiation (25 Gy over 5 to 7 days) versus surgery alone.^2,3 Over half of these patients required an APR and cancer stage was split almost evenly between Dukes A, B, and C. The tumor distance from the anal verge was not reported. Patients undergoing preoperative radiation had significantly more postoperative complications (26% vs. 19%; p < 0.01) but showed a decrease in the rate of local recurrence with preoperative short-course radiation (hazard ratio 0.51; p < 0.01). In a subgroup analysis by Dukes’ stage, the benefit appeared to be driven by Dukes’ B tumors (hazard ratio 0.4; p < 0.001), with a marginally significant benefit in Dukes’ C tumors (hazard ratio 0.65; p =0.068).

In the Swedish Rectal Cancer Trial, preoperatively radiated patients had fewer local recurrences (11% vs. 27%; p < 0.001) after a 5-year follow-up.⁶ In curatively treated patients, the rates were 9% versus 23% (p < 0.001). This study randomized 1168 patients to short-course preoperative radiation (25 Gy in 5 fractions) versus surgery alone. Only patients under 80 years were eligible.

Like the Swedish trial, the Dutch Colorectal Study Group study randomized patients to preoperative short-course radiation versus surgery alone, but added intensive TME training for surgeons, which included workshops, instructional videotapes, and supervision of the first five TME procedures at each hospital in the Netherlands.¹² The majority (1530 of 1861) of randomized patients were treated in 84 Dutch hospitals. Overall, 1805 patients were included in the study. Adjuvant chemotherapy and/or radiation was not included in the protocol but was administered in 85 patients despite negative margins (a major protocol violation). Twenty-eight percent of patients had a low tumor (≤5 cm from the anal verge), and 27% of patients underwent APR. Patients with either positive margins or tumor spillage at surgery comprised 23% of all patients. At 2 years, local recurrence was 2.4% in the radiotherapy group versus 8.2% in TME-alone group (p < 0.001). Notably, the local recurrence rate in the patients randomized to TME alone was over three times lower than what was seen in the Swedish trial (27%), likely related to the TME training that occurred in the Dutch trial. In a multivariable Cox analysis adjusting for stage and tumor height, radiotherapy remained an independent protective factor against local recurrence (hazard ratio 3.41; p < 0.001) among patients who had macroscopic resection of the tumor (n = 1748). At a median follow-up of 11.6 years, the 10-year cumulative incidence of local recurrence was 5% in the radiotherapy group and 11% in the surgery-alone group (p < 0.0001). In the early analysis, the benefit of radiotherapy was not seen among tumors that were 10.1 to 15 cm from the anal verge (1.3% vs. 2.8%; p = 0.17). With long-term follow-up (median 11.2 years), the effect of radiotherapy increased as the distance from the anal verge increased (p = 0.03); however, when only patients with a negative circumferential margin were included, there was no significant interaction between tumor distance from the anal verge and radiotherapy (p = 0.62), suggesting that in patients who had an optimal oncologic resection radiotherapy had an equally protective effect at all tumor heights. Patients with stage I and IV tumors derived no protective effects of radiotherapy against local recurrence, and in longer-term follow-up there was no significant effect on patients with stage II tumors also. This study showed that with a more standardized approach to an oncologic rectal dissection (TME), local recurrence was still improved with preoperative radiotherapy. The Dutch investigators searched aggressively for subgroups that benefited from radiotherapy with the finding that patients with stage III tumors had the most to gain.

The German Rectal Cancer Study Group study randomized patients between 1994 and 2002 to preoperative or postoperative long-course chemoradiation.^8,9 Patients were staged with endorectal ultrasound and computed tomography (CT) of the abdomen and pelvis in order to exclude stage I and IV cancers. Patients over 75 years old were excluded. Among the 799 patients who were analyzed, low tumors (<5 cm from the anal verge) were overrepresented in the preoperatively treated group. Despite this imbalance, fewer local recurrences were seen in patients assigned to preoperative chemoradiation compared with patients assigned to postoperative chemoradiation (6% vs. 13%; p = 0.006) at 5 years. In an analysis by actual treatment, at 10 years local recurrence occurred in 6.8% of patients who had preoperative chemoradiation and 10.5% of patients who had postoperative chemoradiation (p = 0.02). The median time to local recurrence was 30.7 months in the 22 patients who had preoperative chemoradiation, 18.7 months in the 21 patients who had postoperative chemoradiation, and 15.1 months in patients who did not have any chemoradiation (p = 0.05). The authors also found that in the long-term, 72% of local recurrences were associated with distant metastases, and they concluded that in the long-term there is only a small absolute benefit (3%) in local control favoring the preoperative chemoradiation group. A subgroup analysis showed that the strongest difference in hazard ratios between preoperative and postoperative chemoradiation was in patients who had intersphincteric or abdominoperineal resections (hazard ratio 2.24, p = 0.03). When tumors were stratified by stage (0, 1, and 2 vs. 3 and 4) and tumor distance from the anal verge (≥5 and <5 cm), no difference in hazard ratios was observed for these subgroups.

Roh et al¹¹ in the NSABP-R03 study randomized patients with stage II or III rectal cancer to preoperative or postoperative chemoradiation. The trial did not meet target accrual numbers. A complete pathologic response was seen in 15% of patients who had preoperative chemoradiation, and patients were more likely to be node negative with preoperative treatment (66.7% vs. 52.5%; p = 0.04) likely due to downstaging. However, the incidence of locoregional recurrence was the same: 10.7% in each treatment arm.

In the Polish Colorectal Study Group study only patients with a clinical T3 or T4 tumor were included.¹⁰ The 4-year actuarial cumulative incidence of local recurrence was 10.6% in the short-course group and 15.6% in the long-course chemoradiation group, but this difference was not statistically significant (p = 0.21). With only 312 patients enrolled, however, this study was likely underpowered to detect a difference.

The MRC CR07/NCIC C016 study randomized patients to preoperative short-course radiation (n = 674) versus selective postoperative chemoradiation (n = 676) for patients with positive circumferential margins (12% in this arm).⁷ The median patient age was 65 and over 70% were men. Local recurrence was less frequent in the preoperative radiotherapy group (hazard ratio 0.39; p < 0.0001) with an absolute difference in 3-year local recurrence of 6.2% (4.4% vs. 10.6%). Subgroup analyses found no significant difference between groups stratified by circumferential margin involvement. When stratified by tumor distance from the anal verge, each subgroup showed a significantly lower rate of local recurrence in the preoperative radiotherapy arm: 1.2% versus 6.2% (hazard ratio 0.19) for tumors at 10 to 15 cm, 5.0% versus 9.8% (hazard ratio 0.5) for tumors at 5 to 10 cm, and 4.8% versus 10.4% (hazard ratio 0.45) for tumors at 0 to 5 cm. A subgroup analysis by stage found that patients with stage I tumors showed no difference in local recurrence between groups, while patients with stage II and III tumors had significantly lower local recurrence rates if they were treated preoperatively (hazard ratios 0.29 and 0.46, respectively).

Overall Survival and Disease-Free Survival

Randomized controlled trials comparing neoadjuvant radiation therapy versus surgery alone have examined the impact on overall survival. Earlier studies published in the 1990s show an improvement in overall survival in radiated patients but later studies cannot detect this difference, possibly due to improvement in surgical technique, which impacts both arms of the trials. The Stockholm Rectal Cancer Study Group study found no difference in overall survival between groups at a median of 53 months but a significant improvement in disease-free survival in the radiation group (hazard ratio 0.77; p < 0.05).² However, preoperative radiation caused a significantly greater morbidity and higher postoperative mortality (8% vs. 2%; p > 0.01) compared with patients who had surgery alone. In patients >75 years of age, postoperative death occurred in 16% of irradiated patients compared with 2% in nonirradiated patients. In the EORTC rectal cancer study, conducted between 1976 and 1981, 466 patients were randomized to preoperative radiation or surgery alone.⁴ The mean follow-up was 75 months. Of these patients, 81% underwent APR and 41% had tumors that were <5 cm from the anal verge. The 5-year survival was not different between groups, even when curatively treated patients were analyzed. However, in a subgroup of patients <55 years old (n = 103), the 5-year survival with radiation was 80% in the preoperative radiation group compared to 48% in the surgery-alone group.

The Swedish Rectal Cancer Trial did find a significant difference in overall survival with preoperative short-course radiation with a 3- or 4-beam technique versus surgery alone.⁶ After 5 years follow-up time, the overall survival rate was significantly higher in the preoperative radiation group compared with the surgery-alone group (58% vs. 48%; p = 0.004). Cancer-specific survival was also significantly better in the preoperative radiation group compared with those who received surgery alone (74% vs. 65%, p = 0.002). Patients who underwent radiotherapy were more likely to have a Dukes’ A or B tumor, thought to be a result of downstaging; however, in a Cox regression model, radiotherapy was still associated with survival after adjusting for stage. In this large randomized controlled trial, there was no increase in postoperative mortality in the preoperative radiation group. The administration of adjuvant chemotherapy was not described in this study.

Patients in the Dutch TME trial comparing preoperative short-course radiation to TME alone had similar overall survival (82% vs. 81.8%; p = 0.84).¹² Overall cancer recurrence was no different between groups at 2 years (16.1% vs. 20.9%; p = 0.09). In long-term follow-up the overall cancer recurrence was significantly lower in the irradiated group (26% vs. 32%; p = 0.03); however, overall survival was the same in both groups (48% vs. 49%) and cancer-specific death was also the same (28% vs. 31%; p = 0.2). Among patients with negative circumferential resection margins, a subgroup analysis showed that the radiated stage III patients had significantly better survival (50% vs. 40%, p = 0.032), but radiated stage I and II patients did not have a survival benefit. With the lack of survival benefit seen in this trial that focused on proper surgical technique, questions emerged about the overall utility of radiation therapy.