The NSABP-R-04 trial randomly assigned 1,608 patients with clinically staged T3 or T4 or clinical node-positive adenocarcinoma within 12 cm of the anal verge in a 2 × 2 factorial design to one of the following four treatment groups:
- Intravenous continuous infusion (IVCI) 5-FU with radiation therapy.
- Capecitabine with radiation therapy.
- IVCI 5-FU plus weekly oxaliplatin with radiation therapy.
- Capecitabine plus weekly oxaliplatin with radiation therapy.
The primary objective of this study is locoregional disease control.
Preliminary results, reported in abstract form at the 2011 American Society of Clinical Oncology annual meeting, demonstrated that there was no significant difference in the rates of pCR, sphincter-sparing surgery, or surgical downstaging between the 5-FU and capecitabine regimens or between the regimens with and without oxaliplatin. However, similar to the other studies, patients treated with oxaliplatin had significantly higher rates of grade 3 and 4 acute toxicity (15.4% vs. 6.6%, P < .001).[Level of evidence: 1iiD]
The German CAO/ARO/AIO-04 trial randomly assigned 1,236 patients with clinically staged T3 to T4 or clinical node-positive adenocarcinoma within 12 cm from the anal verge to receive either concurrent chemoradiation with 5-FU (week 1 and week 5) or concurrent chemoradiation with 5-FU daily (250 mg/m2) and oxaliplatin (50 mg/m2). In contrast to the previous studies, a significantly higher rate of pCR was achieved in patients who received oxaliplatin (17% vs. 13%, P = .038). There was no significant difference in rates of overall grades 3 and 4 toxicity, however, diarrhea and nausea and vomiting were more common among those treated with oxaliplatin. The 5-FU schedules in this study differed between the two arms, which may have contributed to the difference in outcomes noted. Longer follow-up will be necessary to determine the effect on the primary endpoint of the study, DFS.[Level of evidence: 1iiD]
The acute side effects of pelvic radiation therapy for rectal cancer are mainly the result of gastrointestinal toxicity, are self-limiting, and usually resolve within 4 to 6 weeks of completing treatment. Of greater concern is the potential for late morbidity following rectal cancer treatment. Patients who undergo aggressive surgical procedures for rectal cancer can have chronic symptoms, particularly if there is impairment of the anal sphincter. Patients treated with adjuvant radiation therapy appear to have increased chronic bowel dysfunction, anorectal sphincter dysfunction (if the sphincter was surgically preserved), and sexual dysfunction than those who undergo surgical resection alone.[41,42,43,44,45,46,47]
A Cochrane review highlights the risks of increased surgical morbidity as well as late rectal and sexual function in association with adjuvant therapy. Improved radiation planning and techniques may minimize these acute and late treatment-related complications. These techniques include:[48,49,50]
- The use of high-energy radiation machines.
- The use of multiple pelvic fields.
- Prone patient positioning.
- Customized patient molds (belly boards) to exclude as much small bowel as possible from the fields and immobilize patients during treatment.
- Bladder distention during radiation therapy to exclude as much small bowel as possible from the fields.
- Visualization of the small bowel through oral contrast during treatment planning so that when possible, the small bowel can be excluded from the radiation field.
- The use of three dimensional or other advanced radiation planning techniques.