Chapter 111: Multimodality Treatment of Rectal Cancer

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.

The MRC CR07/NCIC C016 study also found no difference in overall survival between groups. There was an improvement in 3-year disease-free survival for the patients receiving preoperative radiotherapy (hazard ratio 0.76; p = 0.013).⁷ Patients in both groups had equivalent rates of adjuvant chemotherapy administration, with over 80% of stage III patients receiving adjuvant treatment. Those with TNM stage III disease and a negative resection margin, however, had a better 10-year survival with preoperative radiation compared to TME alone.

In the German Rectal Cancer Study Group study comparing preoperative and postoperative chemoradiation, overall survival at 5 years was not different between treatment arms: 76% in the preoperative group and 74% in the postoperative treatment group (p = 0.8).⁸ Five-year disease-free survival was also not different between groups: 68% in the preoperative group and 65% in the postoperative group (p = 0.32). The median follow-up in this study was 46 months. Long-term follow-up was reported at a median of 134 months; 10-year survival was not different between groups in either the intention-to-treat analysis (59.6% vs. 59.9%, p = 0.85) or in analysis by patients’ actual treatment (60.1% vs. 59.3%; p = 0.61).⁹ Disease-free survival was also not different in an intention-to-treat (68.1% vs. 67.8%; p = 0.65) and actual treatment (68.5% vs. 67.5%; p = 0.54) analysis.

Roh et al¹¹ in the NSABP-R03 study randomized 267 patients with stage II or III rectal cancer to receive preoperative or postoperative chemoradiation. The trial had a goal of 900 patients and was terminated in 1999, 6 years after it was opened. The primary endpoints were disease-free survival and overall survival. Adjuvant chemotherapy consisted of four cycles of 5-fluorouracil. There was no difference in overall survival (74.5% vs. 65.6%; p = 0.065). However, disease-free survival at 5 years was significantly improved in the preoperative chemoradiation group (64.7% vs. 53.4%; p = 0.011).

In the Polish Rectal Cancer Trial comparing short-course to long-course preoperative radiation, the 4-year overall and disease-free survival was the same in both groups.¹⁰ Patients were followed for a median of 48 months. Three percent of patients in each group died during either preoperative radiation treatment or within 30 days of surgery. The crude incidence of distant metastasis was 31.4% in the short-course group and 34.6% in the long-course group.

Adjuvant Chemotherapy

The EORTC 22921 uses a 2 × 2 randomized design comparing preoperative long-course radiotherapy, preoperative long-course chemoradiation, preoperative radiotherapy followed by postoperative chemotherapy, and preoperative chemoradiation followed by postoperative chemotherapy.¹³ Patients under 80 years of age with resectable T3 or T4 rectal tumors were enrolled between 1993 and 2003 in nine European countries and Israel. Patients who had adjuvant chemotherapy did not have better overall survival than patients who did not have adjuvant chemotherapy (10-year survival 51.8% vs. 48.4%). Disease-free survival at 10 years was also no different in patients who had postoperative chemotherapy versus observation (hazard ratio 0.91; p = 0.29). This trial also illustrated the magnitude of the problems posed by a plan to administer postoperative adjuvant chemotherapy to rectal cancer patients: 27% of patients assigned to postoperative chemotherapy did not initiate treatment and only 43% of patients received the planned dose.

A phase II open-label randomized trial from Korea, known as ADORE, compared patients with stage II and III rectal cancer who had undergone preoperative 5-FU-based chemoradiation and TME resection.¹⁴ Patients were randomized to four cycles of adjuvant 5-FU and leucovorin (n = 160) or eight cycles of adjuvant 5-FU, leucovorin and oxaliplatin (FOLFOX) (n = 161). In contrast to the EORTC trial, compliance with adjuvant regimens was excellent. Adjuvant chemotherapy was completed in 95% of patients randomized to 5-FU, and in 97% of patients randomized to FOLFOX. A three-year disease-free survival favoring the FOLFOX group was demonstrated (71.6% vs. 62.9%; hazard ratio 0.66; p = 0.047). A subset analysis showed this survival benefit in stage III but not stage II cancers. There were no differences in grade 3 or 4 hematologic or nonhematologic adverse events. Despite these encouraging findings, this relatively small study was not considered definitive due to the phase II study design.

Sphincter Preservation

The Lyon R90-01 randomized trial was designed to evaluate whether sphincter preservation rates differ between short and longer intervals from preoperative radiation to surgery.⁵ A 2-week interval was compared to a 6 to 8 week interval. Patients were T2 or T3 with any N stage, and at the time of diagnosis, the surgeon determined whether the patient would be eligible for sphincter preservation. Patients received 39 Gy delivered in 13 fractions. There were 29 centers involved in the study with 201 patients, over half with T3 disease, and a median distance of 5.7 cm from the anal verge. The higher rate of sphincter preservation seen in the long-interval group was not statistically significant (75.5% vs. 67.7%). Among patients who had sphincter preservation, the rate of anastomotic complications was the same in both groups (17% vs. 18%). In the German Rectal Cancer Study Group study, surgeons were asked to judge whether an APR was indicated prior to treatment, and this status was assigned to 28% of patients in the preoperative arm and 20% of patients in the postoperative chemoradiation arm.^8,9 Ultimately, patients who underwent preoperative chemoradiation were more likely to undergo sphincter-sparing surgery (39% vs. 19%; p = 0.004). The NSABP-R03 trial did not find differences in the rate of sphincter-sparing surgery (47.8% vs. 39.2%; p = 0.23) comparing preoperative to postoperative chemoradiation; however, this study did not meet accrual targets and may have been underpowered.¹¹ In the Polish Rectal Cancer Trial, which compared short-course radiotherapy to preoperative chemoradiation, the primary endpoint of the trial, sphincter preservation, was no different between groups.¹⁰ In this trial, a high percentage of all patients who had initial sphincter preservation (21%) ultimately went on to require a permanent stoma.

Short-Term Complications

Preoperative chemoradiation has been shown to cause fewer grade 3 or 4 acute (27% vs. 40%; p = 0.001) and long-term (p = 0.01) toxic effects compared to postoperative chemoradiation;^8,9 however, this difference was not seen in all studies. For example, in the NSABP-R03 study, more grade 4 diarrhea (24%) was seen in patients on preoperative chemoradiation compared to postoperative chemoradiation (13%).¹¹ In the Polish Rectal Cancer Study, there was a significantly higher rate of early radiation toxicity in the long-course group compared with the short-course group (18.2% vs. 3.2%, p < 0.001).¹⁰ Beyond this relatively small trial, however, controlled data on the side effect profile of short- versus long-course radiation is lacking.

Specific toxicity effects stratified by gender were examined using data from the German Rectal Cancer Study Group.¹⁵ Women were found to have higher hematologic and acute organ toxicity than men in both groups. However, overall survival was higher in women than men (62.7% vs. 58.4%; p = 0.066). Patients who were free from acute toxicity actually had the lowest overall survival (p = 0.027), suggesting that acute toxicity after chemoradiation may actually be associated with improved long-term outcome.

In the German Rectal Cancer Study Group study, postoperative complications were no different between preoperative and postoperative chemoradiation groups.^8,9 The rates of delayed perineal wound healing were similar (10% in the preoperative group vs. 8% in the postoperative; p = 0.1). In the Dutch trial, short-course radiation was associated with acute side effects in 26% of patients, with only patients (<1%) with grade 3 toxicity; 19% of patients developed grade 1 toxicity, and 7% had grade 2 or 3 toxicity.¹² Most toxicities were gastrointestinal in nature. Radiation slightly increased the estimated blood loss (EBL) during surgery, driven by higher EBLs in patients who underwent low anterior resection. In contrast to the German trial, there was a higher rate of perineal wound complications in APR patients who had undergone radiation (29% vs. 18%; p = 0.008). In a subset analysis, there was a trend toward more perineal wound complications in those patients who had undergone radiation of the anus (31% vs. 18%; p value not reported). The proportion of postoperative complications was higher in irradiated patients overall (48% vs. 41%; p = 0.008), a difference that was considered “slight” by investigators. Postoperative mortality was no different between radiated and nonirradiated patients (3.5% vs. 2.6%).

Anastomotic Leak

In the Dutch trial, clinical anastomotic leaks were not more common in irradiated versus nonirradiated patients who had undergone LAR (11% vs. 12%).¹² No differences were observed in MRC CR07 trial (9% in the preoperative radiation group vs. 7% in the selected postoperative chemoradiation group).⁷ Most patients who had sphincter-sparing surgery (83% in the preoperative radiotherapy group and 78% in the selective postoperative chemoradiation group) had diverting stomas. In the German Rectal Cancer Study Group study, the rate of anastomotic leak was also the same in both groups (11% in the preoperative chemoradiation group and 12% in the postoperative chemoradiation group; p = 0.77).⁸

Bowel Function

Peeters et al¹⁶ examined the quality of life and functional outcomes at a median of 5.1 years from surgery in patients who participated in the Dutch trial, comparing short-course XRT followed by TME to TME alone. A survey response rate of 84% was noted. Patients with known recurrent disease were not surveyed. Of the 362 (60.6%) patients without a stoma, irradiated patients had more bowel movements per day (3.69 vs. 3.02; p = 0.011), increased daytime and nighttime fecal incontinence (62% vs. 38%; p = 0.001), increased need to wear a pad for incontinence (56% vs. 33%, p = 0.001), mucus discharge (27% vs. 15%; p = 0.005), and anal bleeding (11% vs. 3%; p = 0.004). The authors emphasize that patient reported soiling once a week or less was included as "fecal incontinence," accounting for the high reported rates. Severe incontinence (daily episodes) was seen in 14% of irradiated patients versus 5% of nonirradiated patients. Despite these differences, the median scores for perceived overall health on a visual analog scale (0 to 100) were not significantly different between irradiated and nonirradiated patients without a stoma (83.0 vs. 80.5; p = 0.374).

In a multivariable regression analysis of patients from the Dutch trial, among patients who had been irradiated, excessive blood loss (>1400 cc) independently predicted incontinence at 24 months, and excessive blood loss and tumor height independently predicted incontinence at 5 years.¹⁷ Measured factors that were not significant included age, sex, history of childbirth, BMI, duration of surgery, colon J pouch reconstruction, temporary stoma, and anastomotic leak. No risk factors for fecal incontinence were identified among the patients who were not irradiated.

Patients who participated in the MRC CR07/NCIC C016 trial were evaluated for quality-of-life and functional outcomes.¹⁸ At baseline, quality of life, as measured by a Medical Outcomes Study Short-Form 36-item questionnaire (SF-36) and EORTC Quality of Life Questionnaire Colorectal 38-item questionnaire (EORTC CR-38), was equivalent in those who had received preoperative short-course radiation and those who had up-front TME surgery followed by selective postoperative chemoradiation. Surveys were administered every 3 months for the first year, then every 6 months for 3 years. At 2 years, a 49% questionnaire response rate was reported. When the defecation subscale of the EORTC CR-38 was analyzed, there were no differences in bowel problems between the groups. An exploratory analysis of the seven items in the subscale showed unintentional release of stools was significantly worse in the preoperatively radiated groups (53.2% vs. 37.3%; p = 0.007); however, with regard to levels of severity, the major difference was attributed to patients reporting “a little” as opposed to “quite a bit.” Overall physical function at 2 years was the same in both groups.

In a small study, Pietsch et al¹⁹ prospectively compared patients with mid to low rectal cancers who underwent long-course concurrent 5-FU/irinotecan chemoradiation with patients who had undergone surgery alone. Patients were surveyed at 3 to 6 months after restoration of intestinal continuity. The study was small (12 vs. 27 patients), but patients showed no differences in stool frequency, impaired discrimination, fecal urgency, clustering, or Jorge–Wexner incontinence scores. Manometric data measured before and after treatment showed changes after surgery, but not between patients who had preoperative chemoradiation and those who had surgery alone.

A study of 104 patients who underwent low anterior resection for rectal cancer showed that male sex, level of anastomosis, and short-course radiation were independently associated with worse St. Mark’s incontinence scores at a median of 34 months follow-up.²⁰ Patients were interviewed on the telephone. When patients were stratified by low and high anastomoses (defined as ≤6 or > 6 cm), patients with higher anastomoses had worse incontinence scores if they had undergone preoperative radiation (p = 0.003).

Patients treated with long-course chemoradiation was evaluated in long-term follow-up by Hoerske et al.²¹ Of note, nearly 25% of their patients participated in the German Rectal Cancer Study Group study. Among the 114 long-term survivors, anorectal dysfunction (not defined by the authors) was significantly more common in patients who had chemoradiation than in those who did not (14% vs. 0.8%; p < 0.001). EORTC QLQ-C30 and CLQ-CR38 were administered at a median of 13 years from the start of primary treatment, with an 85% response rate. Compared to surgery alone, patients who had chemoradiation had worse social functioning scores (15 point difference; p < 0.05), and worse defecation problems (30.6 vs. 19.2; p = 0.04) than those who had surgery alone. However, global health status scores were not different. Of note, this study did not distinguish between preoperative and postoperative chemoradiation.

In a study from Geneva, Allal et al²² assessed quality of life in patients before and 1 year after long-course chemoradiation. Sixty patients who were participants in radiotherapy clinical trials were surveyed, 43 of whom had restoration of intestinal continuity. Functional outcomes were measured with the QLQ-C30 and C38 instruments. Among 36 respondents without stomas, defecation problems improved over 1 year by 11 points (p = 0.0024) and constipation improved by 11 points (p = 0.046). This study points out that poor function after neoadjuvant chemoradiation can improve with time.

Urinary Function

Peeters et al¹⁶ did not find any differences in urinary function among participants of the Dutch TME trial at 5-year follow-up. However, high levels of urinary incontinence were seen, with approximately 39% of patients in both groups reporting incontinence, and 57% of the patients wearing pads. Marijnen et al²³ evaluated the same group of patients in the short- to medium-term and found no differences in voiding problems between groups, but noted that patients who underwent APR had more problems than patients who underwent LAR (p = 0.007). In long-term follow-up study by Hoerske et al,²¹ urinary function was not statistically significantly different in patients who had long-course chemoradiation compared with no neoadjuvant treatment. Patients were surveyed at a median of 8.8 years after treatment. Data from the MRC CR07 trial showed no differences in the micturition subscale of the EORTC QLQ-CR38.¹⁸

Sexual Function

Male sexual function is known to be adversely affected by rectal resection alone. For example, Allal et al²² assessed quality of life in patients before and 1 year after long-course chemoradiation. Among men, there was a significant increase in sexual dysfunction with median scores increasing from 17 to 83 (p = 0.0045). Problems with female sexual functioning without stomas were found to increase, but changes were not statistically significant.

Survey data from Stephens et al¹⁸ using patients in the MRC-CR07 trial found that male sexual dysfunction was negatively affected by surgery (baseline score 28.4 vs. 3 months postoperative score 59.3; p < 0.001; higher scores indicate worse functioning) with no differences between preoperative radiation and postoperative selective chemoradiation groups. At 6 months, male sexual function was slightly worse in the preoperatively radiated groups (65.9 vs. 56.0; p = 0.004), but the difference was considered minor (<10 points) compared to the impact of surgery (approximately 30 points). Only 21% of women completed the sexual function questions, so analyses of female sexual function were not reported from this randomized controlled trial. In a long-term follow-up study by Hoerske et al²¹ of patients who had long-course chemoradiation or no neoadjuvant treatment, female sexual problems were not statistically significantly different between groups, but worse male sexual problems (mean score 73.6 vs. 47.3; p = 0.02) were seen in patients with preoperative chemoradiation. Patients were surveyed at a median of 8.8 years after treatment. The ACCORD-PRODIGE 2 study randomized patients to neoadjuvant chemoradiation with either capecitabine or combination capecitabine and oxaliplatin.²⁴ Erectile dysfunction was reported by 35% of men prior to treatment and by 71% at 3 years, with no differences between the study arms of the trial.

Marijnen et al²³ reported sexual function in patients who participated in the Dutch TME trial, as measured by an ad hoc questionnaire. Before treatment about 80% of men and 50% of women were sexually active, with no differences between groups. After surgery, both men and women reported a decline in sexual activity, which was worse in the radiated group. At 24 months, among patients who were previously sexually active, 72% of irradiated women compared with 90% of nonirradiated women were active (p = 0.01), and 67% of irradiated men compared with 76% of nonirradiated men were active (p = 0.06). At 24 months, male and female LAR patients were slightly more sexually active (75% and 90%, respectively) than male and female APR patients (63% and 72%, respectively; p = 0.03 and p = 0.01). In male patients who underwent LAR, radiation adversely affected erection and ejaculation, but all patients showed significant deteriorations over time. In male patients who underwent APR, scores for erection and ejaculation disorders were worse compared with LAR patients, and no differences were seen in radiation groups. Women reported similar scores for vaginal dryness or pain with intercourse in both treatment groups when stratified by APR versus LAR, despite worse overall sexual functioning in the irradiated group.

Back/Hip Pain

Analyses from the Stockholm I trial found an increased rate of hip fractures in irradiated patients, but this difference was not seen in the Dutch trial, attributed to better planning of radiation fields.¹⁶ In the Dutch study, back or buttock aches or pains, pain in one or both legs, hip stiffness or pain, or walking difficulties were commonly reported, but not more frequently in the radiated group.

Overall Health

Marijnen et al²³ found that overall perceived health, as measured by the Rotterdam Symptom Check List, a validated cancer-specific questionnaire, improved after treatment, but did not significantly differ in patients who had preoperative short-course XRT compared to TME surgery alone, as measured serially over 24 months. At 3 months, physical symptoms were worse in the preoperatively radiated patients, but this difference normalized from 6 months onward.

In the survey of patients who underwent chemoradiation by Allal et al,²² quality of life and functional outcomes were assessed with the QLQ-C30 and QLQ-C38 instruments. After 1 year, significant improvement in future perspective (43 points), emotional function (25 points), and global quality of life (8 points) was reported. GI symptoms of constipation and diarrhea were found to have improved.

Long-Term Complications

Long-term follow-up of a cohort of patients from Germany found an increased rate of small bowel obstruction (13% vs. 4.9%; p = 0.049) and ureteric stricture (4% vs. 0%; p = 0.036) in patients who had undergone long-course chemoradiation, preoperatively or postoperatively, compared with patients who had not had chemoradiation.²¹ Irradiated patients had an increased relative risk of small bowel obstruction (risk ratio 2.49 (95% CI 1.48 to 4.19)) compared to nonirradiated patients after 14-year follow-up from the Swedish Rectal Cancer Trial.²⁵ The cumulative incidence of admissions for obstruction was 13.9% in radiated patients and 5.5% in nonirradiated patients. The relative risk of operative intervention for small bowel obstruction was also increased in the radiated group (risk ratio 7.42 (95% CI 2.23 to 24.7)). In a U.S. registry-based study of Medicare patients treated between 1986 and 1999, admission for small bowel obstruction was found to be more likely in radiated versus nonirradiated patients at 5 years (18% vs. 11%; p < 0.001).²⁶ Furthermore, 6.6% of irradiated patients required surgery compared with 3.2% of patients in the nonirradiated group (p < 0.001). Patients who had preoperative irradiation were less likely to require admission for SBO than postoperatively irradiated patients (14% vs. 20%; p < 0.001).

Preoperative short-course or long-course radiation or chemoradiation offers a clear benefit to the patient in terms of local recurrence, with a likely 50% risk reduction. Despite efforts to identify lower risk subgroups that could be spared chemoradiation, such as stage I and II disease, T3 tumors without threatened circumferential margins, or upper third rectal cancers, subgroup analyses of large randomized trials for the most part suggest that a local recurrence benefit is seen in all these subpopulations, with the exception of stage I patients. An overall survival benefit for patients is unlikely; however, in both the Dutch TME and the MRC CR07 NCIC trials, stage III patients were found to have a survival benefit. Adjuvant chemotherapy has also not been shown to improve cancer-specific or overall survival, and confusion remains about whether patients should receive adjuvant chemotherapy on the basis of their pretreatment clinical nodal stage versus pathologic nodal stage.

Much work has gone into understanding the impact of preoperative radiation or chemoradiation on short- and long-term complications. Neoadjuvant treatment is certainly better tolerated than postoperative chemotherapy or chemoradiation. Anastomotic healing does not appear to be significantly worse in preoperatively irradiated patients. Perineal wound healing is likely to be worse in radiated patients, although this assessment is challenging due to the wide variation in severity of this complication after APR. A truly critical component of understanding what improves the patient’s overall outcome pertains to long-term functional outcomes. Bowel function is adversely affected by preoperative radiation compared to no radiation, as was comprehensively shown by secondary analyses of surviving patients from the Dutch Rectal Cancer Trial and supported by other studies; however, despite these findings, overall quality of life is frequently found to be similar in both groups. Patients who are radiated clearly have a higher long-term risk of small bowel obstruction, including surgical management of this condition. Urinary function does not appear to be affected by radiation, but rigorous instruments were not used in most studies. Male sexual function probably deteriorates as a result of radiation, but this is difficult to demonstrate and may well be outweighed by the adverse impact of surgical resection. Female sexual function is generally a poorly studied outcome, but probably adversely affected by radiation therapy. A closer investigation of sexual function is warranted, with an attention to validated surveys and pretreatment evaluation.

Future Advancements in Multimodality Treatment

Intensive investigations have improved our abilities to substantially decrease the risk of local recurrence over the past decades, but distant recurrence continues to be responsible for death in a substantial fraction of patients (30% to 40%). Given the superiority of combination chemotherapy (5-FU or capecitabine with oxaliplatin) compared to 5-FU alone in the adjuvant treatment of colon cancer, clinical studies have addressed whether this combination can be used in the neoadjuvant setting for rectal cancer patients. Combination chemotherapy with concurrent radiotherapy was studied in two trials, ACCORD-PRODIGE 2 from France²⁴ and STAR-01 from Italy,²⁷ with an increased rate of toxicity due primary to diarrhea. In both trials, the rate of complete pathologic response was the same. In the STAR-01 trial, tumor regression was the same in both groups,²⁴ but in PRODIGE 2, the rate of complete or near-complete response was higher in the combination group (39.4% vs. 28.9%; p = 0.008).²⁷ Clinical outcome at 3 years was reported in the PRODIGE 2 study: there was no difference in local recurrence, disease-free survival, or overall survival.

A phase II study from the United Kingdom examined induction of capecitabine and oxaliplatin combination chemotherapy administered in advance of chemoradiation with long-course concurrent capecitabine and 54-Gy radiation, followed by surgical resection 6 weeks later.²⁸ Only patients with “poor-risk” disease, as assessed by MRI, were enrolled. Of the 105 patients enrolled, 5% died during neoadjuvant chemotherapy. Grade 3–5 diarrhea was seen in 10% of patients, which is a lower proportion than seen in the PRODIGE and STAR trials that administered oxaliplatin during radiotherapy. Rates of tumor response were high in patients who had TME surgery, with a complete pathologic response in 20% of patients and 76% showing some form of downstaging. Despite this effect, only a modest 5-year progression-free survival of 64% and overall survival of 75% were achieved. Neoadjuvant approaches that incorporate oxaliplatin merit further examination in long-term follow-up, but a large benefit seems unlikely on the basis of current data.

The MERCURY study has attempted to define a low-risk group of patients by MRI criteria in order to spare these patients from exposure to radiation therapy.²⁹ Further work is needed to identify low-risk subgroups of patients with MRI or even molecular testing. Hopefully, such an approach could avoid the widespread use of radiation in the treatment of rectal cancer and spare patients' long-term complications without compromising overall control of the disease.

An emerging approach uses neoadjuvant chemotherapy alone, without radiation. The premise of this treatment modality is to address the risk of metastatic disease early during treatment with a stronger chemotherapy regimen such as FOLFOX. With current long-course chemoradiation, for example, it may be 3 to 4 months before patients receive adjuvant chemotherapy for node-positive disease (assuming adjuvant chemotherapy offers a benefit), and even longer if the patient suffers major complications or has a poor performance status after radical surgery. At Memorial Sloan-Kettering Cancer Center, a single-arm prospective study was performed to examine outcomes in patients treated with neoadjuvant FOLFOX/bevacizumab with selective radiation in the nonresponders.³⁰ Resectable patients without threatened circumferential margins, and with clinical T3 disease located between 5 cm and 12 cm from the anal verge, were treated with FOLFOX and bevacizumab (four cycles) followed by FOLFOX (two cycles) and then restaged. If there was a clinical response, patients proceeded to TME. During the study, this was the pathway followed by 30 of 32 enrolled patients. If there was not clinical response, chemoradiation was administered; this occurred in 2 of 32 patients, both of whom did not tolerate FOLFOX/bevacizumab. A complete pathologic response was seen in 8 of 32 patients (25%), no local recurrence was found at 4 years, and the 4-year disease-free survival was 92% for this group, suggesting that neoadjuvant chemotherapy without radiation is a viable approach. The PROSPECT study, currently ongoing, will compare a neoadjuvant chemotherapy regimen without bevacizumab to traditional long-course chemoradiation and will hopefully clarify whether this new multimodal regimen can be utilized.³¹