The investigation of the potential role of radiotherapy in rectal cancer was prompted by the unacceptable risk of local recurrence following conventional surgery when total excision of the mesorectum was not performed. This risk varied between 15% and 50% (1). In addition, when local recurrence occurred, it was associated with significant morbidity and was almost always fatal (1,2).
Prior to the Dutch Total Mesorectal Excision (TME) trial which examined the role of short-course preoperative radiotherapy (SCPRT) (25 Gy in five fractions over five to seven days), in addition to TME, many studies examining the role of preoperative radiotherapy in addition to conventional surgery had already been performed and in excess of 6500 patients were randomized into such studies (3).
Early trials employed an anterior- and posterior-field arrangement intended to treat the primary tumor, internal and common iliac, inferior mesenteric, and para-aortic lymph nodes up to the vertebral level L1/2. First described by Kligerman in 1972, the Yale, Veterians Administration Surgical Oncology Study Group (VASOG) 2, University of Bergen, European Organization for Research and Treatment of Cancer (EORTC), and Stockholm I trials all used variants of this technique known as the chimney or the inverted T (4-8). Of these studies, only the Stockholm I (n = 272) (25 Gy in five fractions over five to seven days) and the EORTC (n = 410) (34.5 Gy in 15 fractions over 19 days) trials used biologically equivalent doses of 30 Gy or more and showed a significant reduction in the rate of local recurrence [relative hazard 0.49; 95% confidence interval (CI) 0.36-0.69; P < 0.01 for Stockholm I and five-year local recurrence 15% vs. 35%; P = 0.001 for the EORTC] (level 1b evidence). The Stockholm I study also demonstrated the potential tox-icity of wide-field irradiation with both a higher postoperative complication (26% vs. 19%; P < 0.01) and 30-day mortality rate (8% vs. 2%; P < 0.01) in irradiated patients (9).
A second group of trials including the VASOG 1, Medical Research Council (MRC) 1 and 2, Toronto, and International Cancer Research Fund (ICRF) trials used a rectangular pair of parallel-opposed fields to treat the pelvis with no "chimney" component (10-14). Again the VASOG 1, MRC 1, and Toronto studies used biologically effective doses of less than 30 Gy and failed to show a significant reduction in local recurrence. The MRC 2 trial (n = 279) (40 Gy in 20 fractions over four weeks) showed a reduction in local recurrence in the irradiated arm (36% vs. 46%; P = 0.04) but there was no difference in either postoperative or late complications (12). The International Cancer Research Fund (ICRF) trial (n = 468) (15 Gy in three fractions over five days) is the only trial of preoperative radiotherapy to show a significant reduction in local recurrence using a biologically equivalent dose of less than 30 Gy (17% vs. 24%; P = 0.04). Postoperative mortality was however, increased in the irradiated arm (9% vs. 4%; P < 0.05). Thromboembolic and cardiovascular complications were also more common in irradiated patients (13% vs. 3%; P < 0.001). The occurrence of both reduced local recurrence and increased complications at a lower equivalent dose than used in the either MRC 2 or the EORTC trial is difficult to explain, particularly as irradiated volume used is smaller than that used in the EORTC trial. However, the median age of patients was five years older than those in the EORTC trial. The importance of patient selection for preoperative radiotherapy strategies will be discussed next.
The North West England Trial (n = 284) (20 Gy in four fractions) employed a unique clinical target volume comprising solely of the primary tumor and the mesorectal lymph nodes (15).
Overall, there was no significant difference in the rate of recurrence between the two arms; however, despite the use of the smallest clinical target volume in any reported randomized trial to date, there was a reduction in local recurrence in the 143 patients (53%) who had a curative resection following radiotherapy (12.8% vs. 36.5%; P = 0.0001).
The Stockholm II (n = 557) and Swedish Rectal Cancer (n = 1168) trials form a final group (8,16). These trials used a three- or four-field technique to treat the posterior pelvis and randomized to surgery preceded by 25 Gy in five fractions over five days or surgery alone. Both studies demonstrated reduced local recurrence at five years (0% vs. 21%; P < 0.01 and 11% vs. 27%; P < 0.001 respectively) without increased postoperative mortality. In addition, patients receiving radiotherapy in the Swedish Rectal Cancer trial had an overall survival improvement at five years (58% vs. 48%; P = 0.004).
Two recent meta-analyses of randomized, controlled trials including the most significant trials described before have been published. One of these analyses included trials of both pre-operative and postoperative radiotherapy and identified 28 trials with a total of 8000 patients (3) (evidence level 1a). This demonstrated a highly significant reduction in local recurrence for both preoperative (P = 0.00001) and postoperative radiotherapy (P = 0.002). There was no statistically significant overall survival advantage for radiotherapy, but there was a reduction in the numbers of patients dying of rectal cancer for patients receiving preoperative radiotherapy (45% vs. 50%; P = 0.0003). This was counterbalanced by an excess number of preoperatively irradiated patients dying within one year of treatment (8% vs. 4%; P < 0.0001) the excess being mainly due to cardiovascular events. The second analysis was restricted to studies of preopera-tive radiotherapy and did not have access to individual patient data (17). A similar advantage for the addition of preoperative radiotherapy to surgery was demonstrated in terms of local recurrence (P < 0.01), cancer-related mortality (P < 0.01) and in addition overall survival at five years (P = 0.03).
As evident in the previous discussion of preoperative studies, both meta-analyses support the use of a biologically equivalent dose in excess of 30 Gy in order to impact on the rate of local recurrence. In addition, an analysis of the radiotherapy dose and fractionations employed in trials of both of pre- and postoperative radiotherapy has revealed that a dose of 15 to 20 Gy higher is likely to be required in the postoperative setting to achieve a reduction in the rate of local recurrence of similar magnitude to that achieved by preoperative treatment (18).
Postoperative chemoradiotherapy has been widely employed in North America on the basis of two studies. In a four-arm study, the Gastrointestinal Study Group randomized 227 patients to surgery only, postoperative radiotherapy (4000-4800 Gy over 4.5-5.5 weeks), postoperative chemotherapy (5-fluorouracil and methyl-CCNU), and postoperative chemotherapy and radiotherapy. There was a significant prolongation in the time to tumor recurrence with combination therapy (P < 0.009) (19). The second study randomized 204 patients to either postoperative radiotherapy (45-50.4 Gy in 25-28 fractions over 5-5.5 weeks) or to both postoperative radiotherapy and chemotherapy (5-fluorouracil and methyl-CCNU). Both local recurrence (13.5% vs. 25%; P = 0.036) and distant recurrence (28.8% vs. 46%; P = 0.011) occurred less frequently with combined treatment (20) (evidence level 1b). Radiotherapy was delivered in both these studies with an anterior and posterior field technique to the pelvis only and significantly in the combined arm further adjuvant chemotherapy was administered in addition to 5-fluorouracil given during chemoradiation.
Two randomized studies have specifically examined the question of the optimal timing of radiotherapy. In the Uppsala study, 471 patients were randomized to either SCPRT (25.5 Gy in five fractions over one week) or postoperative radiotherapy (60 Gy over seven to eight weeks). SCPRT was associated with a lower rate of local recurrence (13% vs. 22%, P = 0.02) (21). In a more recent German study, 421 patients with resectable rectal cancer were randomized to pre-operative chemoradiation (50.4 Gy/28 fractions with continuous 5-fluorouracil infusion in the first and final weeks of radiotherapy) or postoperative chemoradiation (55.4 Gy/31 fractions with identical chemotherapy). The superiority of the preoperative approach was again suggested with improved local recurrence rates (6% vs. 13%; P = 0.006) and late toxicity (12% vs. 24%; P = 0.01) (22) (evidence level 1b).
TME has become a standard practice in the United Kingdom following recognition of the importance of achieving wide circumferential resection margins (CRM) around the tumor to reduce the risk of local recurrence (23,24). Despite the survival advantage seen with SCPRT in the Swedish Rectal Cancer trial, the local recurrence rates associated with TME in single-center series (3-6%), prompted questioning of the additional benefit of SCPRT (25,26).
To resolve whether SCPRT was still justified prior to TME surgery, the Dutch Colorectal Cancer Group randomized 1861 patients to TME with or without SCPRT. Early results of this trial showed that the addition of radiotherapy significantly reduced the risk of local recurrence at two years (2.4% vs. 8.2%; P < 0.001) (27) (level 1b evidence). Although this benefit was achieved without an increase in perioperative mortality (4.0% vs. 3.3%), patients receiving radiotherapy had more frequent perineal complications following abdominoperineal resection (29% vs. 18%; P = 0.008) (28). In addition, irradiated patients were significantly slower to recover from defecation problems (P = 0.006) and experienced more sexual problems (P = 0.04 male; P < 0.001 female) than patients with TME only in the two years following surgery (29).
Subgroup analysis of the Dutch TME trial suggests a statistically significant benefit in terms of local recurrence at two years from SCPRT in patients with midrectal tumours (5-10 cm from the anal margin) (1.0 vs. 10.1%; P < 0.001), patients whose CRM is greater than 1 mm (0% vs. 14.9%; P = 0.02 for CRM of 1-2 mm and 0.9% vs. 5.8%; P < 0.0001 for CRM >2 mm) and patients with lymph node involvement (4.3% vs. 15%; P < 0.001) (27,30). Conversely, there was no significant benefit from either SCPRT or postoperative radiotherapy if the CRM was 1 mm or less (9.3% vs. 16.4%; P = 0.08). The relative reduction in local recurrence for patients undergoing abdominoperineal resection was not as great as for those undergoing anterior resection [4.9% vs. 10.1% for abdominoperineal resection (n = 248); 1.2% vs. 7.3% for anterior resection (n = 577)]. However, such subgroup analysis should be interpreted with caution until both long-term efficacy data from the Dutch trial is published and further data are available from the MRC CR07 trial that randomizes patients to SCPRT or selective postoperative chemoradia-tion in the presence of an involved CRM.
In summary, radiotherapy for rectal cancer has evolved considerably since the 1960s. The superiority of a three- to four-field irradiation technique confined to the posterior pelvis to a biologically equivalent dose of greater than 30 Gy prior to surgery is suggested by the available evidence. However, surgery for rectal cancer has also evolved, and despite the use of modern techniques, SCPRT is still associated with increased postoperative and late complications, and relatively small benefits may be restricted to certain subgroups. Individualized treatment protocols based on the preoperative stage would therefore seem attractive.
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