Local recurrence of rectal cancer following preoperative irradiation. Preoperative irradiation of rectosigmoid carcinoma including its regional lymph nodes. Randomized study on preoperative radiotherapy in rectal carcinoma. Stockholm Colorectal Cancer Study Group. [Comparison of surgical therapy and combined irradiation in rectal cancer--first report, effect of irradiation on the tumor. Study Group of Surgical Therapy and Combined Irradiation in Rectal Cancer]. Preoperative irradiation in operable cancer of the rectum: report of the Toronto trial. Improved sphincter preservation in low rectal cancer with high-dose preoperative radiotherapy: the lyon R96-02 randomized trial. Randomised trial of surgery alone versus radiotherapy followed by surgery for potentially operable locally advanced rectal cancer. Medical Research Council Rectal Cancer Working Party. Final results of a randomized trial on the treatment of rectal cancer with preoperative radiotherapy alone or in combination with 5-fluorouracil, followed by radical surgery. Trial of the European Organization on Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. Combination preoperative radiation and endocavitary hyperthermia for rectal cancer: long-term results of 44 patients. Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Adjuvant preoperative radiotherapy for locally advanced rectal carcinoma. Results of a prospective, randomized trial. Long-term results of a randomised trial of short-course low-dose adjuvant pre-operative radiotherapy for rectal cancer: reduction in local treatment failure. Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: assessment of acute toxicity and treatment compliance. Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group. The evaluation of low dose pre-operative X-ray therapy in the management of operable rectal cancer; results of a randomly controlled trial. A comparison of nonoperative vs. preoperative radiotherapy in rectal carcinoma. A 10-year randomized trial. Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a randomized multicenter trial in western Norway. Long-term results of the Lyons R90-01 randomized trial of preoperative radiotherapy with delayed surgery and its effect on sphincter-saving surgery in rectal cancer. Preoperative radiation and surgery for cancer of the rectum. Veterans Administration Surgical Oncology Group Trial II. Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group.
The authors investigated local recurrence of rectal cancer in patients' groups preoperatively irradiated (40-50 Gy) or treated by surgery alone. In advanced disease both treatment groups were administered postoperative chemotherapy, too. Local recurrence was observed in 30.2% in patients treated by surgery alone, while it dropped to 11.65% in the patients' group subjected to radiation therapy prior to surgery (p < 0.05). Impairment of degree of differentiation resulted in an enhanced number of recurrences in both groups, even if they appeared later in irradiated patients. nan A population based prospective randomized trial on preoperative radiotherapy in operable rectal cancer was conducted in Stockholm, Sweden. Five hundred fifty-seven patients from 12 institutions were included with histologically proven, clinically resectable rectal adenocarcinoma. Patients planned for local excision or previously irradiated to the pelvis were excluded.
                A total of 272 patients were allocated to preoperative irradiation with 25 Gy in five cycles during 5-7 days to the rectum and the pararectal tissues (RT+ group) and 285 patients were allocated to surgery only (RT- group). The median follow-up time was 50 months. No patient was lost to follow-up. Surgery was considered curative in 479 patients (86%).
                Locoregional recurrence occurred in 10% of the patients in the RT+ group versus 21% in the RT- group (p < 0.01). Among the curatively operated patients, distant metastases occurred in 19% in the RT+ group versus 26% in the RT- group (p = 0.02). The overall survival was improved in the irradiated patients (p = 0.02). Postoperative complications were more common after irradiation but were usually mild. The postoperative mortality was low in both groups.
                Preoperative short-term, high-dose radiotherapy as given in this trial reduces the risk of local and distant recurrence and improves survival after curative surgery for rectal carcinoma. In order to establish the best protocol for the treatment of rectal cancers, a cooperative study on preoperative radiation therapy was conducted by 44 institutions in eastern Japan. A total of 166 cases that did not receive preoperative chemotherapy were analyzed, and the following conclusions were obtained. A comparison between two groups of patients, one that had received preoperative irradiation and the other that had not, revealed remarkable tumor regression in the former along with reduction of in rectal stenosis, condition of the border of the lesion, bleeding, constriction and central excavation. There were no significant differences between the two groups in terms of lymph node metastasis. Histological examination based on the criteria established by Oboshi and Shimosato showed radiation effects better than grade II b in 32.1% primary tumors and in 33.3% of metastatic lymph nodes within the radiation field. No significant differences in the incidence of side effects or complications were noted between the two groups. The authors have studied the value of preoperative radiotherapy in 125 patients with cancer of the rectum. The patients were divided into two groups, control (no irradiation) and experimental (irradiation), and according to Dukes' pathological stage. The crude survival indicated no difference between the two groups, but analysis by stage and group demonstrated that for patients with a Dukes' stage C lesion, 500 rads of cobalt-60 gamma irradiation a few hours before excision of the lesion approximately doubles the probability of survival at 5 years. The prospect of surgical cure is three times higher in cancers arising above the peritoneal reflection than in those arising below it. If the practice of abdominoperineal resection is to continue the authors recommend that preoperative irradiation become a routine procedure. The potential advantage of high-dose preoperative radiotherapy to increase tumor response and improve the chance of sphincter preservation for low rectal cancer remains controversial. The aim of this trial was to evaluate the role of escalating the dose of preoperative radiation to increase sphincter-saving procedures.
                Patients with rectal carcinoma located in the lower rectum, staged T2 or T3, Nx, or M0 with endorectal sonography, and not involving more than two-thirds circumference, were randomly assigned to one of two groups: preoperative external-beam radiotherapy (EBRT; 39 Gy in 13 fractions over 17 days) versus the same EBRT with boost (85 Gy in three fractions) using endocavitary contact x-ray.
                Between 1996 and 2001, 88 patients were enrolled onto the study. A significant improvement was seen in favor of the contact x-ray boost for complete clinical response (24% v 2%) and for a complete or near-complete sterilization of the operative specimen (57% v 34%). A significant increase in sphincter preservation was observed in the boost group (76% v 44%; P =.004). At a median follow-up of 35 months, there was no difference in morbidity, local relapse, and 2-year overall survival.
                A dose escalation with endocavitary irradiation provides increased tumor response and sphincter preservation with no detrimental effect on treatment toxicity and early clinical outcome. Survival rates after surgery for rectal cancer remain at about 40% at 5 years from diagnosis. The aim of this study was to find out whether local recurrence rate could be reduced and survival increased by a moderately high dose of preoperative radiotherapy in patients with locally advanced, but otherwise operable, carcinoma of the rectum.
                We carried out a prospective randomised trial of surgery alone (n = 140) versus surgery preceded by 40 Gy radiotherapy (n = 139) given in 20 fractions of 2 Gy over 4 weeks. The patients, from 20 regional centres throughout the UK, were enrolled between 1981 and 1989, and followed up for a minimum of 5 years or to death.
                217 patients died, 114 of 140 allocated surgery alone and 103 of 139 allocated preoperative radiotherapy: median survival times were 24 months and 31 months, respectively. The hazard ratio for overall survival was 0.79 (95% CI 0.60-1.04, p = 0.10). At 5 years' follow-up 65 patients allocated surgery alone and 50 who received preoperative radiotherapy had local recurrence (hazard ratio 0.68 [0.47-0.98], p = 0.04); the corresponding numbers of patients with distant recurrence were 67 and 49 (hazard ratio 0.66 [0.46-0.95], p = 0.02). There was a significant benefit of radiotherapy on disease-free survival (hazard ratio 0.76 [0.58-1.0], p = 0.05). There was no increase in postoperative or late complications in the radiotherapy group.
                Our results provide further evidence that preoperative radiotherapy can reduce the rate of local recurrence of rectal cancer in patients with locally advanced disease. However, survival results are still equivocal, and so we must await the results of a meta-analysis of all radiotherapy trials from which precise and definitive results, particularly for survival, may be obtained. To improve surgical results of potentially operable rectal cancer, the European Organization on Research and Treatment of Cancer conducted a two-arm randomized clinical trial to compare the efficiency of preoperative administration of radiotherapy, with or without 5-fluorouracil before radical surgery. Two hundred forty-seven eligible patients were admitted from November 1972 through April 1976. The overall survival observed in the group treated with preoperative radiotherapy appears to be better than in the group of patients where preoperative combined modality was administered. Five-year survival is 59% versus 46% with a marginal statistical significance of P = 0.06. Although the combined modality arm had a higher incidence of side effects and postoperative deaths, it had a greater effect than the radiotherapy-alone arm in controlling the disease process, mainly distant metastases to the liver with a result bordering on statistical significance (P = 0.07). The incidence of nonmalignant and intercurrent deaths were higher in the combined modality group, whereas deaths due to malignancy were higher in the radiotherapy-alone group. Observing more stringent selection in disease and patients' criteria, side effects and intercurrent deaths can be effectively reduced with further improvement in adjuvant therapy results. Long-term results of 122 patients with advanced rectal cancer who were randomly treated with three different methods from July 1984 to July 1986. Of 122 patients, 44 were treated with endocavitary 915 MHz microwave applicators combined with 10 MeV X-ray or 60CO followed by surgery (group A), 38 with preoperative radiation (group B) and 40 with surgery (group C) as a control group. The temperature on the surface of the applicator touching the middle of the caudad to cephaladic extent of disease was 45-50 degrees C for 45 min twice a week for 6-8 sessions. Radiation dose was 30 Gy or 40 Gy/4 weeks. Of cases with stages 0 and A, 45.5% (20/44) were in group A, 23.7% (9/38) in group B and 12.5% (5/40) in group C (chi 2 test p < 0.05 and p < 0.01, respectively). Five-year survival rate was 66.7% (24/36) in group A, 50% (14/28) in group B and 40.5% (15/37) in group C. Percentage of survival at 5 years was 73.7% (14/19) for 40 Gy plus heat, 57.1% (8/14) for 40 Gy alone, 58.8% (10/17) for 30 Gy plus heat, and 42.9% (6/14) for 30 Gy alone. Data suggest a survival advantage for patients treated with preoperative radiation combined with endocavitary hyperthermia. From 1980 to 1985, 471 patients with resectable rectal and rectosigmoid cancer were randomly allocated to receive either preoperative short-term high-dose irradiation (25.5 Gy in one week) for all patients or prolonged postoperative radiotherapy (60 Gy in seven to eight weeks) only for patients with a Dukes B or C lesion. After a minimum follow-up of five years, the local recurrence rate was statistically significantly lower after preoperative than after postoperative radiotherapy (13 percent vs. 22 percent; P = 0.02). No difference in overall survival was noted (P = 0.5). To evaluate possible late side effects on the bowel, urinary bladder, or skin after surgery and additional preoperative or postoperative radiotherapy, all patients included in the randomized trial, together with 58 patients from a preceding pilot study with the same preoperative regimen, were studied in a prolonged follow-up program. The hospital files of all patients were re-examined. Of the patients who were carefully examined, 176 had a survival exceeding five years and 19 had a survival exceeding 10 years. Overall, 7 percent (33/464) either were operated upon or have had a radiologic diagnosis of small bowel obstruction: 14/255 (5 percent) after preoperative irradiation, 14/127 (11 percent) after postoperative irradiation, and 5/82 (6 percent) after surgery alone. The cumulative risk of developing a bowel obstruction was significantly increased after postoperative radiotherapy. Among the 98 patients alive after preoperative irradiation, significant morbidity from the bowel was noted in 11 patients, from the urinary bladder in two, and from the skin in six. In the postoperatively treated group of 34 patients, the bowel, urinary bladder, and skin morbidity were significant in five, two, and five patients, respectively. Corresponding morbidity in 44 nonirradiated patients was seen in five, one, and two patients, respectively. It is concluded that preoperative, short-term, high-dose radiotherapy decreases the local recurrence rate relative to postoperative radiotherapy, with no indications of increased late morbidity after a follow-up of 5 to 10 years. A prospective, randomized clinical trial was conducted by the Northwest Rectal Cancer Group to study the effects of preoperative radiotherapy given one week before surgery in locally advanced (tethered or fixed) rectal carcinoma.
                A total of 284 patients were entered into the trial between 1982 and 1986; 141 were allocated to receive surgical treatment alone, and 143 were allocated to receive preoperative radiotherapy. A 10 x 10 x 10 cm volume in the posterior pelvis, centered on the tumor, was irradiated at a dose of 20 Gy, divided into four daily fractions of 5 Gy each.
                No differences were observed in any of the clinicopathologic variables in the two arms of the trial; there were no striking down-staging effects in the irradiated tumors. After a minimum follow-up period of 96 months, the overall and cancer-related mortality rates were similar in both arms of the study (P = 0.21 and P = 0.09, respectively). There was a highly significant reduction in local recurrences in the irradiated group (12.8 percent x-ray therapy vs. 36.5 percent surgery; P = 0.0001). The majority of local recurrences after preoperative radiotherapy occurred inside the radiotherapy field (10 cases; 7 percent), with only six cases (5 percent) outside the field. No significant difference was observed in the rates of distant metastasis between the two treatment groups (P = 0.73).
                Although there is no statistically significant survival benefit in the whole series, there is a survival benefit for the subset of patients considered by the surgeon to have undergone a curative operation. We recommend that this form of adjuvant therapy should be offered to all patients with locally advanced rectal cancer who are to undergo radical surgery. A prospective randomised multicentre trial compared pre-operative radiotherapy followed by surgery with surgery alone for rectal cancer < or = 12 cm from the anal verge. Of 468 patients (mean age 67 years, range 31-94, 273 males) who met the entry criteria, 228 were randomised to radiotherapy (3 x 5 Gy over 5 days within 2 days of operation) followed by surgery, and 239 to surgery alone. Randomisation was unknown in 1 patient. Follow-up to death or 5 years was achieved in 454 (97%) patients. 31 (7%) of the 468 patients died within 30 days of operation (radiotherapy and surgery 21 [9%], surgery alone 10 [4%]; P < 0.05). Cardiovascular and thromboembolic complications were more common after radiotherapy and surgery (30, 13%) than after surgery alone (8, 3%; P < 0.005). Of the 280 patients who had curative surgery, 52% of those who had radiotherapy and surgery and 56% of those who had surgery alone survived 5 years (P = 0.88). 395 patients attended outpatients clinics at least once. Local treatment failure was identified during follow-up in 82 patients [31/185 (17%) radiotherapy and surgery; 51/210 (24%) surgery alone; P < 0.05]. It occurred in 33 of the 258 patients who had a curative resection and attended outpatients [radiotherapy and surgery, 11/120 (9%), surgery alone, 22/138 (16%); P = 0.08]. Long-term survival was unaffected, but long-term local recurrence was reduced by the addition of low-dose radiotherapy to surgery. Peri-operative mortality was, however, increased. The European Organisation for Research and Treatment of Cancer (EORTC) 22921 four-arm randomised trial questioned the value of preoperative chemoradiation (XRT-CT) versus preoperative radiation (XRT) and the value of additional postoperative chemotherapy (CT) versus none in T3-T4 M0 resectable rectal cancer patients. We report on the preoperative toxicity, treatment compliance and early deaths (all deaths up to 30 days after surgery) of the two treatment modalities in patients who were entered into trial before January 2001. In the XRT Group (group A), patients received 45 Gy, 25 fractions over 5 weeks. In the XRT-CT Group (group B), two 5-day courses of CT were added to the first and fifth weeks of XRT. For each CT course: 5-fluorouracil (5-FU) 350 mg/m2/day and Leucovorin (LV) 20 mg/m2/day were given. 398 and 400 patients started treatment in groups A and B, respectively. Grade 2+acute diarrhoea occurred in 17.3 and 34.3% of patients in groups A and B, respectively (P<0.005). The other side-effects remained unchanged or were only marginally increased. The compliance with RT was 98.5 and 95.5% in groups A and B, respectively. In group B, 78.7 and 71.1% of the patients received 95-105% of the planned CT doses at the first and second courses, respectively. 6 patients died preoperatively, 2 from toxicity in group B. 8 patients (1%) died within the 30 days after surgery in both groups. At the doses recommended in the protocol, the addition of 5-FU-LV to preoperative XRT slightly increased the amount of acute toxicity. However, the compliance with the radiation protocol or the feasibility of surgery did not decrease. 824 patients with operable rectal carcinoma were randomly allocated to be treated by surgery alone, 2000 rad in 10 daily fractions and 500 rad as a single fraction. No difference has been demonstrated in the actuarial survival rates to 5 years. The local recurrence-free and metastasis-free rates are similar in all groups. There is also no evidence that the pre-operative radiotherapy benefited patients in subgroups by Dukes' stage. The complication rates were also similar in the three treatment groups. From 1978 to 1980, 68 patients with rectal cancer were randomly allocated to either preoperative irradiation plus surgery or surgical treatment without any preoperative measures. The primary aim of the trial was to investigate the 5-year survival rate in both groups; a secondary aim was to analyze the local recurrence rate and finally the anatomopathologic tumoral classification after surgery. All patients were followed at least 8 years. The preoperative irradiation group (Group A) was submitted to 4000 cGy for 4 weeks and surgery was performed 1 week after irradiation. All tumors were classified anatomically and pathologically according to Broders' and Dukes' classifications. The results indicated that there is a significant difference in the five-year survival rates in both groups: group A had a corrected survival rate of 80 percent; group B (nonirradiated) had a corrected survival rate of 80 percent; group B (nonirradiated) had a corrected survival rate of 34.4 percent. The local recurrence rate was 2.9 percent in group A and 23.5 percent in group B. Regarding tumor regression, before radiotherapy 64.6 percent of the tumors were Broders' Grades 3 and 4; after radiotherapy these were reduced to 20.5 percent. As to Dukes' classification, 26.4 percent of the tumors were type C in group A and, in group B, 47 percent were considered as Dukes' C. A randomized, multicenter clinical trial was conducted in Western Norway to study the effectiveness of preoperative radiation therapy in operable rectal cancer, given at a dosage of 3150 cGy in 18 fractions, 2 to 3 weeks before radical surgery. Three hundred nine patients were entered into the trial between May 1976 and December 1985. After radiation no tumor was seen in 4.5% of the patients. There was no increased morbidity or mortality at surgery. The 5-year survival for evaluable patients was 57.5% in the control group and 56.7% in the radiotherapy group. For patients operated on for cure the 5-year survival was 60.9% and 64.2% in the control group and radiotherapy group, respectively. Radiation significantly delayed both local and distant recurrences in patients in the radiation group who had curative resection from 13.3 months in controls to 27.1 months. The local recurrence rate in the corresponding groups was 21.1% and 13.7%, respectively. We conclude that higher preoperative radiation doses should be used in new trials as a higher dosage may transform the observed positive effects into a survival benefit. nan In a prospective randomized trial, 361 male patients with histologically proven adenocarcinoma of the rectum, judged preoperatively to require abdominoperineal resection (APR), were treated by surgery alone or were given 3,150 rads of preoperative radiotherapy. Surgical resection was done on 320 patients, 262 having "curative" APR. Only moderate symptoms from radiotherapy were noted and postoperative complications and 30-day mortality were similar in both groups. Five-year survival for curative APR was the same in both groups (50% for both treated and control patients). The incidence of positive lymph nodes in the resected specimens was 35% in treated and 41% in controls. In the first preoperative radiotherapy trial conducted by the group, 5-year survival in patients undergoing "curative" APR was 47% in treated versus 34% in control groups. Additionally, the difference in positive lymph nodes in the resected specimens was substantially greater in the first trial (26% in treated versus 44% in controls). Neoadjuvant chemoradiotherapy does not alter anal sphincter preservation or postoperative complications compared with short-course radiotherapy alone in patients with clinical stage T3 or T4 resectable rectal cancer. The aim of this study was to compare survival, local control and late toxicity in the two treatment groups.
                The study randomized 312 patients to receive either preoperative irradiation (25 Gy in five fractions of 5 Gy) and surgery within 7 days or chemoradiation (50.4 Gy in 28 fractions of 1.8 Gy, bolus 5-fluorouracil and leucovorin) and surgery 4-6 weeks later. The median follow-up of living patients was 48 (range 31-69) months.
                Early radiation toxicity was higher in the chemoradiation group (18.2 versus 3.2 per cent; P < 0.001). The actuarial 4-year overall survival was 67.2 per cent in the short-course group and 66.2 per cent in the chemoradiation group (P = 0.960). Disease-free survival was 58.4 versus 55.6 per cent (P = 0.820), crude incidence of local recurrence was 9.0 versus 14.2 per cent (P = 0.170) and severe late toxicity was 10.1 versus 7.1 per cent (P = 0.360) respectively.
                Neoadjuvant chemoradiation did not increase survival, local control or late toxicity compared with short-course radiotherapy alone. From 1980 to 1987, 849 patients with clinically resectable rectal adenocarcinoma were randomized into a controlled clinical trial to evaluate the role of preoperative radiotherapy.
                Patients were given either 25 Gy during 5 to 7 days before surgery or underwent surgery alone.
                At a median follow-up time of 107 months (range, 62-144 months) the incidence of pelvic recurrence among 684 "curatively" operated patients was significantly lower among those who also received radiotherapy (P < 0.001) in all Dukes' stages. No significant difference was observed between the treatment groups with regard to frequency of distant metastases or overall survival. The time to local recurrence or distant metastasis and survival was significantly prolonged in the irradiated group. However, the postoperative mortality was 8% in the radiotherapy group compared with 2% in the surgery only group (P = 0.01).
                Preoperative short term radiotherapy reduced the incidence of pelvic recurrences and prolonged survival related to rectal cancer compared with surgery alone. The postoperative morbidity was significantly higher in the irradiated group.
Optimal PRT improves LR, OA mortality, but no increase in sphincter sparing procedure. CRT further increases local control. If the objective is to increase the incidence of sphincter sparing surgery, endocavitary boost showed the most promise. Strategies with the potential to improve outcomes, especially OAS and spincter sparing while reducing acute and late toxicities (rectal and sexual function) are needed to guide future strategy designs.