Commentary (Staley): Are We Overtreating Some Patients With Rectal Cancer?

The authors have presented a comprehensive review of rectal cancer, challenging clinicians to consider whether some patients are being overtreated with any modality including surgical resection, chemotherapy, and/or radiotherapy. Tables 2 and 3 provide an excellent overview of suggested criteria for deciding between polypectomy/observation and radical resection for a cancer confined to a rectal polyp. Before any surgical resection is proposed, the surgeon should review all pertinent pathologic slides with an experienced pathologist. Furthermore, any polyp with invasive cancer that has been completely excised and needs further surgical resection should be marked with India ink by the gastroenterologist to guide accurate surgical resection. If this is not done in a timely manner, the surgeon may not be able to identify the polypectomy site, and a more extensive operation may be required to make sure all disease is removed. Unique Complexities
Compared to the treatment of colon cancer, there are unique complexities associated with the treatment of rectal cancer, including the morbidity of surgical resection as related to continence and bowel function, the possibility of a colostomy (which affects the patient's quality of life), and the potential side effects of chemotherapy and radiation therapy (which often persist over a lifetime). Concerns over local recurrence and survival can trigger emotional responses by both the clinician and the patient that favor overtreatment of rectal cancer. We are challenged as clinicians to strive to improve treatment of this disease and to individualize appropriate therapy to minimize overtreatment. One obvious issue that is frequently overlooked is the anatomically defined boundary between the colon and rectum. By endoscopy, the rectum is anatomically defined from the anal verge to approximately 15 to 18 cm. In most clinical trials, rectal carcinoma has been defined as a tumor below the peritoneal reflection. Thus, it is important for surgeons to precisely describe the location of the tumor in relation to the peritoneal reflection at the time of surgical resection so that patients will receive appropriate postoperative treatment. Two Key Factors
Over the past 30 years, there has been a significant improvement in overall survival and decreased local recurrence in patients with rectal carcinoma. Two important factors that have contributed to this improvement have been the concept of total mesorectal excision (TME), introduced by Heald et al in 1979, and the demonstrated benefit of postoperative chemoradiation for stage III disease in 1990. TME is defined as the sharp dissection of the lymph node-bearing mesorectum with preservation of the autonomic nerves. Studies using this technique with proctectomy demonstrated a reduction in local recurrence to 3% to 7%. Proponents of TME questioned the need for postoperative radiation with such a low local recurrence rate. The Dutch trial in 1996 randomized 1,861 patients to TME vs TME and radiation therapy to examine this question.[1] There was a significant decrease in local recurrence from 8.2% to 2.4% in favor of TME and radiation therapy. TME should be a standardized technique in any surgical resection of rectal cancer. In 1990, a National Cancer Institute Consensus Conference concluded that combined-modality therapy should be the standard postoperative adjuvant treatment for patients with T3 and/or N1/2 rectal cancer. However, pathologic evaluation of rectal specimens treated with surgery alone demonstrated that 17% to 20% of patients had positive margins, most of which involved the circumferential margin.[2] A significant number of these patients with positive margins would go on to develop local recurrence.[ 2] Also, approximately 30% of patients needed an abdominoperineal resection and permanent colostomy for clearance of their rectal tumors. In order to decrease positive surgical margins, improve local recurrence, and potentially increase sphincter preservation, a neoadjuvant treatment strategy was developed for rectal cancer. Preoperative Chemoradiation
The potential advantages of the preoperative approach includes decreased tumor seeding, less acute toxicity due to a smaller radiation field, lower rates of bowel injury from radiation, increased radiosensitivity to more oxygenated cells, and enhanced sphincter preservation. The primary disadvantage of preoperative chemoradiation is possible overtreatment of patients due to inadequate preoperative staging and also potential increased wound complications. Because the staging accuracy of endoscopic ultrasound (EUS) approaches 91%, the number of stage I/II patients being overtreated with preoperative chemoradiation is very small. Multiple studies have demonstrated that rectal EUS should be the standard of care for preoperative staging of rectal cancer. Early studies using infusional fluorouracil (5-FU)-based chemoradiation demonstrated a 90% sphincter preservation rate with only 10% of patients requiring abdominoperineal resection. Investigators saw a profound decrease in positive surgical margins (to 3%) and a pathologic complete response of 15%. Of note, residual nodal disease was found in 28% of patients, indicating that chemoradiation does not sterilize all pelvic nodal disease. Although improved sphincter preservation was demonstrated, the oncologic results remained in question. In 1999, a study examined the results of 193 patients who underwent either a proctectomy/coloanal anastomosis or abdominoperineal resection.[ 3] Neither local recurrence nor overall survival were compromised by sphincter preservation. More importantly, no study has ever shown an increased cancer recurrence or decreased survival rate in appropriate selected patients undergoing continence- preserving procedures vs abdominoperineal resections. Further advantages of neoadjuvant chemoradiation include improved postoperative quality and number of bowel movements compared to those patients who underwent postoperative chemoradiation. Two US prospective randomized trials comparing preoperative vs postoperative chemoradiation were closed due to poor accrual. It was obvious that most clinicians felt so strongly about a particular treatment strategy, that randomization was not acceptable. European Studies
The Europeans have had better luck at these randomized trials. The Swedish Rectal Cancer Trial, although it used a short course of chemoradiation, showed a significant benefit of preoperative treatment in local recurrence and overall survival.[4] A German trial using more traditional chemoradiation showed a significant advantage in patients undergoing preoperative chemoradiation, with improved local recurrence, anastomotic stricture rate, and sphincter preservation (39% vs 19%). Although significant improvement in overall survival has not been demonstrated, the improvements in local recurrence and sphincter preservation, representing significantly improved quality of life, should not be underestimated in rectal cancer. Traditionally, a distal margin of 2 cm at the time of surgical resection was necessary to clear microscopic disease. A study by Moore et al investigated the adequacy of a 1-cm distal margin in 94 patients who had sphincter preservation surgery after preoperative chemoradiation.[5] When divided into two groups of distal margins less than and greater than 1 cm, there was no statistically significant difference in local recurrence or overall recurrence-free survival between groups. These data suggested that for patients with locally advanced rectal cancer undergoing resection and preoperative chemoradiation, distal margins less than 1 cm do not seem to compromise the oncologic outcome. Technically resecting patients with low rectal tumors with a smaller distal margin will allow for more sphincter preservation surgery and less overtreatment with abdominoperineal resection. US Studies
The Eastern Cooperative Oncology Group (ECOG) 1297 trial recently examined the role of infusional 5-FU with escalating doses of oxaliplatin (Eloxatin) in the treatment of locally advanced rectal carcinoma. A maximum tolerated dose of 85 mg/m² of oxaliplatin every 2 weeks for three cycles was demonstrated. Interestingly, the ECOG researchers found a complete pathologic response rate of 29% and a microscopic residual disease rate of 21%, representing a dramatic overall response rate of 50%. This response seemed to be dose-dependent, with those patients treated in levels 2 and 3 having an overall complete and microscopic residual response of 70%. This regimen will be tested in an upcoming ECOG phase II trial. Two major rectal trials are about to open throughout the United States. ECOG 3201 will determine the optimal adjuvant chemotherapy treatment for rectal cancer. This trial will allow both preoperative and postoperative chemoradiation in this trial at the physician's discretion. The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial will examine the role of oral 5-FU-based chemoradiation in the treatment of rectal cancer, and these patients will also be allowed to enter into the adjuvant ECOG 3201 study. Through novel trials in rectal cancer, we look forward to continued improvement in both survival and quality of life for patients with rectal cancer.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Kapitejin E, Kranenbarg K, Steup WH, et al: Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Eur J Surg 165:410-420, 1999.
2. Nagtegaal ID, Marijnen C, Kranenbarg EK, et al: Circumferential margin involvement is still an important predictor of local recurrence in rectal cancer: Not one millimeter but two millimeters is the limit. Am J Surg Path 26:350- 357, 2002.
3. Gamagami RA, Liagre A, Chiotasso P, et al: Coloanal anastomosis for distal third rectal cancer: Prospective study of oncologic results. Dis Colon Rectum 42:1272-1275, 1999.
4. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336:980- 987, 1997.
5. Moore HG, Riedel E, Minsky B, et al: Adequacy of 1 cm distal margin after restorative rectal cancer resection with sharp mesorectal excision and preoperative combinedmodality therapy. Ann Surg Oncol 10:80-85, 2003.