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 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.
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.
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.
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.