Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish rectal cancer trial

Birgisson H, Pahlman L, Gunnarsson U, Glimelius B. Journal of Clinical Oncology 23:8697-8705, 2005.

Introduction

Radiation therapy and/or chemotherapy combined with surgery typically comprise the standard treatment for early to intermediate stage rectal cancer. Pre-operative treatment is often better tolerated than post-operative treatment, and thus is preferred at some centers. The Swedish Rectal Cancer Trial was designed to evaluate the benefit of pre-operative radiation therapy utilizing 5 Gy x 5 to 25 Gy, followed by resection 1 week later. The benefit of radiation therapy has been demonstrated in several trials, including this one, but the therapy is not without risk. This article presents the long-term toxicity data of the previously published Swedish Rectal Cancer Trial.

Materials/Methods

• Median duration of follow-up was 14 years
• 1,147 patients were randomized between 1987 and 1990 to surgery with or without pre-operative radiation, to a total dose of 25 Gy in 5 Gy fractions completed 1 week prior to surgery
• No patients received chemotherapy
• The radiation treatment target volume included the primary tumor, anal canal, mesorectal/presacral nodes, internal iliac vessel nodes, lumbar lymph nodes up to L5, and the obturator foramen
• The target volumes were defined by bony landmarks, and patients were treated either via a 3-field technique in the prone position or a 4-field technique in the supine position
• Most centers used 5 16MV photons, but 1 center used 60 Co
• 181 patients were treated without any shielding of normal tissues
• Patients were matched to the Swedish Hospital Discharge Register for main and secondary diagnoses
• Admissions for primary treatment and for relapses occurring within 3 months of treatment were omitted from the analysis

Results

• 239 out of 1,147 patients were treated with noncurative intent
• Out of 6,496 patient admissions, 3,442 were included for analysis
• The number of survivors at 5 and 10 years were higher in irradiated group, so the number of patients eligible for admission was higher in that group
• 73% of patients analyzed were at admitted for inpatient care at least once
• There was no statistically significant difference in number of hospital admissions between the 2 groups, but there was in increase in relative risk (RR) for patients receiving radiation (RR=1.64; 95% CI 1.21 to 2.22) for early admissions (< 6 months following primary treatment)
• In the first 6 months, a significant increase in RR was seen among irradiated patients for infections and gastrointestinal diagnoses, and a trend for increased RR was seen among irradiated patients for endocrine and cardiovascular diagnoses
• Trends for increased RR were seen in the irradiated group for late admissions for infectious and gastrointestinal diagnoses and for fractures; for gastrointestinal diagnoses, the RRs were significantly increased in the irradiated group for bowel obstruction (RR 1.88, 95% CI 1.10 to 3.20) and abdominal pain (RR 1.92, 95% CI 1.14 to 3.23)

Authors' Conclusions

• Patients receiving radiation therapy patients had an increased risk of hospital admission in the first 6 months following primary therapy.
• There was no difference in late admissions overall, but for specific diagnoses, patients receiving radiation were at greater risk for unspecified infections, bowel obstruction, abdominal pain, and nausea.
• The study endpoint was limited to admissions, so the incidence of other significant symptoms such as sexual/urinary tract issues, enteritis, proctitis, and incontinence is not known. These side effects can be significant for patients undergoing radiation for rectal cancer treatment.
• Late effects after 14 years not known, although with a median age at treatment of 70 years, this may not be a significant issue.

Clinical Implications/Criticisms

• The authors note that 5 Gy per fraction is quite a high amount, but the total dose overall was reduced to minimize toxicity. The field sizes however, were larger than those typically used today, particularly with regard to the upper border. The authors maintain that with today's radiation fields and blocking techniques, more small bowel is excluded from treatment, possibly decreasing treatment-associated morbidity.
• While the study is interesting from the standpoint of long-term follow-up and significant toxicity requiring hospitalization, the results may not be comparable to what we see today in the era of combined chemotherapy and radiation.
• Given the improved outcome previously reported by the authors of this study using this pre-operative treatment paradigm, this particular radiation regimen may be a valid option for those patients who could not tolerate an extended course of pre-operative chemoradiation.
• As this trial has shown an increase in gastrointestinal diagnoses for those patients receiving pre-operative radiation, steps should be taken to minimize the dose to the small bowel and other normal tissues in patients receiving pre-operative radiotherapy.