Adjuvant Therapy for Rectal Cancer: Results and Controversies

In this excellent article, Dr. Minsky examines the current state of knowledge about adjuvant therapy for resectable rectal cancer, as well as ongoing research in this area. Reasonable recommendations for the management of patients with rectal cancer are made based on data obtained from clinical trials.

Postoperative adjuvant combined-modality therapy is recognized as the standard of care for T3-4 N0 M0 or T1-4 N1-3 M0 rectal cancer. Attempts to improve adjuvant therapy by investigating novel drugs, techniques, and technologies are appropriately judged by the success of these strategies in avoiding acute or delayed treatment-related morbidity, by their ability to prevent local or distant failure, and, ultimately, by the achievement of improvements in survival when compared with standard therapy.

Role of Mesorectal Dissection

Surgery is the keystone of rectal cancer therapy. Surgical therapy that includes a sharp mesorectal dissection appears to decrease the risk of pelvic failures. Only in the mid-1990s were data on series of patients treated with this surgical technique published.

Mesorectal dissection is not used by all surgeons performing rectal cancer surgery. Additional data on local failure rates, surgical morbidity, and quality of life need to be collected as the technique becomes more commonly used. It may be possible to identify subsets of patients whose chance of pelvic and/or distant failure is low enough with sharp mesorectal dissection that they can avoid adjuvant therapy.

Adjuvant Therapy Trials

Many postoperative adjuvant trials currently underway are investigating how to increase overall and relapse-free survival by optimizing chemotherapy administration in conjunction with standard radiotherapy (50.4 to 54.0 Gy in 28 to 30 fractions).

Two randomized trials comparing preoperative to postoperative combined-modality therapy have been mounted in North America. One trial closed because of poor accrual, although the other, the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-03 trial, remains open. The primary end points of this trial are to determine disease-free and overall survival using preoperative chemoradiotherapy, but important information will also be obtained regarding local recurrence rates, primary tumor response, and downstaging to neoadjuvant therapy, as well as rates of sphincter preservation. It may then be possible to justify the use of preoperative chemoradiotherapy in certain patients based on randomized controlled trials, rather than single-institution series.

Sphincter Preservation and Function

Sphincter preservation is an important benefit that has been reported with the use of conventionally fractionated neoadjuvant radiotherapy or chemoradiotherapy in a number of single-institution series. Several such series have cited an approximate 75% decrease in the rate of abdominoperineal resections in patients who received neoadjuvant therapy, although a preliminary report from the NSABP R-03 trial showed a lower rate of sphincter preservation that this with neoadjuvant treatment.[1] The skills of a specialized surgeon may be required to optimize sphincter preservation in patients given preoperative chemoradiotherapy.

The use of preoperative irradiation may decrease treatment-related morbidity through another means. In patients in whom adjuvant therapy is indicated because of locoregionally advanced disease, giving preoperative radiotherapy or chemoradiotherapy decreases the volume of small bowel irradiated. If a sphincter-sparing procedure is performed, the proximal limb of bowel brought down to the anastomosis may not have received the same dose of radiation as the tumor.

Changing the timing of the adjuvant therapy may lead to improved small-bowel function during and after therapy, and may also result in decreased rates of anastomotic strictures. Coloanal anastomosis function in patients irradiated before surgery has been reported to be quite good, and may be superior to that in patients who were irradiated postoperatively.[2,3]

Intensive, Short-Course, Preoperative Radiation

Another strategy using preoperative irradiation has been explored in a series of randomized protocols mounted in Scandinavia over the past 2 decades. Intensive, short-course, preoperative radiotherapy (25 Gy in 5 fractions) has been compared to postoperative therapy and to surgical therapy in thousands of patients. The radiotherapy technique and exclusion criteria have evolved over these serial protocols.

Current techniques (just as in conventionally fractionated irradiation) include three or four portals to treat the pelvis, customized shielding, and treatment energies high enough to avoid unacceptable dose inhomogeneities. By using these techniques, and by restricting enrollment to patients under 80 years old, the high postoperative mortality seen in early protocols has decreased to levels comparable to those in unirradiated patients. Moreover, a randomized trial has demonstrated statistically significant improvements in both local control and survival with these new techniques, compared to surgery alone.[4] This is the first randomized trial to show a survival advantage for the use of preoperative radiotherapy as the sole adjuvant treatment in rectal cancer.

It has been demonstrated that tumor regression does occur with this brief radiotherapy regimen, but it is unclear whether or not any improvement in sphincter sparing can be obtained. If indicated, patients who have received preoperative radiotherapy can be given postoperative fluorouracil (5-FU)-based chemotherapy with leucovorin or levamisole (Ergamisol) without any undue difficulty.[personal communication, B. Glimelius, 1998]

A current Dutch trial (CKVO 95-04) will answer the question of whether or not local control and survival is improved by intensive, short-course radiotherapy prior to surgery that includes a sharp mesorectal dissection. An examination of the morbidity and mortality associated with this therapy should also be possible. Hopefully, mature data from a completed Scandinavian trial that randomized 2,200 patients with Dukes’ stage B and C colorectal carcinoma to surgery alone or surgery and 5-FU based chemotherapy will define the magnitude of benefit of adjuvant postoperative chemotherapy in patients with rectal cancer who received preoperative, short-course radiotherapy.

The morbidity associated with the use of a brief, intensive course of preoperative radiotherapy has been studied. Even with careful technique, there is a higher risk of venous thromboembolism, fracture of the femoral neck or pelvis, and postoperative fistulas, compared with surgery alone.[5] Although this preoperative regimen has been shown to contribute to improved local control and survival, it is not necessarily suitable for all patients. For many debilitated patients, systemic adjuvant therapy is inappropriate because of medical contraindications. In such cases, preoperative radiotherapy may be inappropriate as well, due to an increased risk of perioperative mortality.

Intensive, short-course, preoperative radiotherapy differs enough in intent and side effects that a randomized controlled trial will be required to compare it to conventionally fractionated, preoperative chemoradiotherapy in order to assess its impact on overall survival, disease-free survival, and other important end points.

Summary

Aggressive preoperative systemic and locoregional staging is proper procedure before administering any preoperative adjuvant therapy. This is necessary to rule out distant metastatic disease and to identify patients who are unlikely to require the systemic component of adjuvant therapy.

Mature data from well-controlled trials comparing preoperative treatment of any sort to standard postoperative combined-modality therapy are still lacking. Any patient being considered for intensive, short-course preoperative radiotherapy should be made aware of possible side effects that differ from those commonly encountered with conventionally fractionated radiotherapy. Patients should also be told about the possibly lower rate of sphincter preservation associated with this treatment compared to conventionally fractionated neoadjuvant radiotherapy. Preoperatively irradiated patients who have risk factors for distant metastatic spread should receive postoperative adjuvant 5-FU-based systemic therapy.

References:

1. Hyams DM, Mamounas EP, Petrelli N, et al: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: A progress report of the National Surgical Adjuvant Breast and Bowel Project protocol R0-3. Dis Colon Rectum 40:131-139, 1997.

2. Wagman R, Minsky BD, Cohen AM, et al: Sphincter preservation with preoperative radiation therapy and coloanal anastomosis: Long term follow-up. Int J Radiat Oncol Biol Phys, 1998 (in press).

3. Kollmorgen CF, Meagher AP, Pemberton JH, et al: The long-term effect of adjuvant postoperative chemoradiotherapy for rectal cancer on bowel function. Ann Surg 220:676-682, 1994.

4. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-7, 1997.

5. Holm T, Singnomklao T, Rutqvist LE, et al: Adjuvant preoperative radiotherapy in patients with rectal carcinoma. Cancer 78:968-976, 1996.