Adjuvant strategies for rectal cancer in BC

The optimal management of rectal cancer continues to evolve, and recent studies have addressed the dual pattern of recurrence of the disease: local recurrence within the pelvis and distant metastases. In conjunction with careful preoperative imaging, improved surgical techniques, and accurate pathological staging, significant improvements have been achieved in the results of rectal cancer management. The traditional approach to adjuvant treatment of stage II (node-negative tumors that penetrate into the perirectal fat) and stage III (node-positive tumors) rectal cancer in North America is postoperative chemoradiation. In contrast, in Europe the favored approach for therapy is preoperative radiation with greater emphasis on preoperative imaging, total mesorectal excision, and accurate pathological reporting of circumferential margins. The preoperative approach appears to offer some advantages in terms of controlling pelvic disease and overall survival, but has the disadvantage that preoperative assessment of the tumor is not as reliable as postoperative staging. Some patients who may not have needed postoperative adjuvant treatment do receive preoperative treatment.

Preoperative radiation

A meta-analysis of 3722 patients comparing preoperative radiation with surgery confirmed that preoperative radiation reduced local recurrences (odds ratio [OR] = 0.49; P <0.001) as well as improved survival (OR = 0.85; P = 0.03).[1] It is important to distinguish between the two major indications for preoperative radiation: to reduce the risk of pelvic recurrence in patients with resectable cancers or to reduce the bulk of unresectable tumors or those in the low rectum when sphincter-preserving surgery is contemplated.

A trial from Sweden of patients with resectable rectal cancer showed that a 1-week course of preoperative treatment was at least as effective in reducing pelvic recurrence as prolonged high-dose postoperative treatment.[2] Subsequently, the Swedish Rectal Cancer Trial showed that a short-course preoperative radiation regimen—using five fractions of 5 Gy given over 5 days followed by surgery—reduced pelvic recurrence and improved 5-year survival rates compared to surgery alone.[3] The more recent Dutch rectal cancer trial[4] showed that a similar short course of preoperative treatment significantly reduced the risk of local recurrence after total mesorectal excision compared to surgery alone, although the recurrence rates in both arms of the trial were commendably low. The short-course treatment probably sterilizes microscopic disease that may be left in the pelvis, although there is no statistically significant downstaging of macroscopic disease. Note that surgery should be performed within a week of completion of the radiation therapy, before any significant inflammatory reaction has developed.

Although the Swedish and Dutch trials included all patients with resectable rectal cancer, and some benefit was seen in all stages of disease, the maximum benefit is seen in those with disease that has breached the muscularis propria (stage II) or involved regional lymph nodes (stage III). When endorectal ultrasound with an appropriate rectal probe and/or MRI is available, imaging is recommended to identify lower-risk patients for whom preoperative treatment may be unnecessary. Concurrent chemotherapy cannot be integrated into the short-course schedule without incurring excessive toxicity, but our present practice is to offer 6 cycles of postoperative chemotherapy with 5-fluorouracil and folinic acid (5FU-FA) at monthly intervals to patients with stage II or stage III tumors.

For patients with unresectable disease or disease in the low rectum, preoperative treatment aims to maximize the potential for a curative (R0) resection of the tumor, and in some cases to maintain sphincter function. A recent German trial[5] has compared preoperative radiation and chemotherapy with a similar regimen given postoperatively. The investigators found that for patients thought to require an abdominoperineal resection at their initial preoperative assessment, the rate of sphincter-sparing surgery increased from 18% in those randomized to postoperative treatment to 35% in those who had preoperative treatment. In this case the goal is to achieve a clinically significant reduction in tumor bulk. A 5-week course of radiation is usually combined with continuous low-dose infusion of 5-fluorouracil (5FU). Reassessment is recommended 4 to 6 weeks after the treatment is finished, by which time the acute inflammatory reaction associated with the treatment should have subsided and the tumor should be smaller. Surgery is recommended in the 6- to 10-week period after the completion of radiation, before any significant fibrosis has developed. Additional cycles of postoperative chemotherapy may be offered to suitable patients.

Postoperative radiation and chemotherapy
A few randomized trials have shown that adjuvant 5FU chemotherapy with postoperative radiation reduced rates of local recurrence and improved overall survival compared with surgery alone or surgery and radiation. Based on these studies and evolving data from postoperative chemotherapy for colon cancer, the National Institutes of Health issued a consensus statement in 1990 that recommended adjuvant therapy for stages II and III rectal carcinoma. Adjuvant treatment consisted of delivery of pelvic radiation at a dose of 45 Gy to 55 Gy and 5FU-based chemotherapy, with two cycles of chemotherapy being given during radiation as a bolus over 4 successive days. One approach to improve the efficacy of postoperative chemoradiation is the use of 5FU by protracted intravenous infusion during radiation. This leads to an improved overall survival, although local pelvic recurrence was not significantly reduced.[6] An intriguing recent study that examined the timing of postoperative radiation suggests that giving the radiation with the first cycle of chemotherapy confers an advantage in disease-free survival.[7]

Adjuvant chemotherapy
The principal aim of adjuvant chemotherapy is the reduction of distant metastases and a consequent improvement in overall survival. However, the radio-sensitizing effect of some chemotherapeutic agents is a clear advantage since it enhances the effects of radiation therapy. The standard drug used for adjuvant chemotherapy of rectal cancer is 5FU with folinic acid (5FU-FA). A potential advance in chemoradiation is the substitution of capecitabine, an oral formulation of 5FU, for intravenous 5FU. This not only simplifies the administration of chemotherapy, but the unique mechanism of selective activation of capecitabine by the enzyme thymidine phosphorylase in tumor cells leads to a higher concentration of the active drug in tumors.[8] In addition, radiation has been shown to up-regulate thymidine phosphorylase in tumor cells.[9]

In additional to 5FU, two other classes of drugs have useful activity in colorectal cancer. First, irinotecan, a topoisomerase inhibitor, has been shown to improve the survival of patients with metastatic colorectal cancer, and studies that examine its role in the adjuvant setting are in progress.[10] Second, oxaliplatin is another active drug in the metastatic setting, and is now undergoing testing as an adjuvant treatment.[11]

Competing interests
None declared.

John Hay, MB, FRCPC and Amil Shah, MDCM, FRCPC, FACP 

Dr Hay is a radiation oncologist at the BC Cancer Agency Vancouver Cancer Centre. Dr Shah is a medical oncologist and chair of the GI Tumor Group at the BC Cancer Agency in Vancouver, BC.