ABSTRACT: The treatment for patients with locally advanced, resectable rectal cancer has evolved over the years. Various combinations and sequences of chemotherapy, radiation therapy, and total mesorectal excision (TME)-based surgery are the mainstay of current therapy. Preoperative combined chemoradiation, followed by surgery, is now the preferred treatment strategy, with the majority of patients receiving either infusion fluorouracil(Drug information on fluorouracil) (5-FU) or capecitabine(Drug information on capecitabine) (Xeloda) with radiation. Clinical trials with oxaliplatin(Drug information on oxaliplatin) (Eloxatin)-based neoadjuvant chemoradiation have not shown improvement in the pathologic complete response rate (pCR) compared with 5-FU; however, final data addressing local recurrence rates and disease-free survival are pending. The use of adjuvant chemotherapy following preoperative chemoradiation and surgery has not been optimally defined. Some studies have shown that patients who obtained significant pathologic downstaging after chemoradiation and surgery have improved survival with the use of adjuvant chemotherapy. Since FOLFOX (folinic acid, 5-FU, and oxaliplatin) is the preferred adjuvant chemotherapy regimen for stage III colon cancer based on randomized clinical trial results, FOLFOX is also recommended for rectal cancer patients as an adjuvant therapy approach.
The most significant advances in surgical management of the rectal cancer patient in the last three decades have come about because of an enhanced appreciation of the importance of patterns of cancer spread, anatomical planes, neural innervations, and negative surgical margins.[4-8] This has led to development of surgical approaches, specifically total mesorectal excision (TME) and autonomic nerve preservation (ANP), that have resulted in improved local control as well as improved functional results.[9-11] In addition, because of advances in imaging and pathologic assessment, we have an improved ability to identify preoperatively the need for neoadjuvant therapy and postoperatively the need for adjuvant therapy. This has facilitated our ability to better tailor therapy for the individual patient and determine the sequence of treatments, namely surgery up front with post-operative adjuvant therapy as pathologically determined vs neoadjuvant therapy based on pretherapy assessment including physical exam, histology, and imaging. Clearly, the goal and challenge has been and continues to be optimal treatment rather than undertreatment or overtreatment of a particular rectal cancer patient.
Surgical Technique and Pathologic Assessment
The technique of operating in embryologic planes between the fascia propria of the mesorectum (which envelops the mesorectum and mesorectal lymph nodes) and the parietal fascia (which overlies important pelvic structures such as autonomic nerves) is referred to as sharp mesorectal excision. It decreases the likelihood of a positive circumferential margin (CRM), shown to be a predictor of local recurrence and poor survival,[1,4-8,12] and is used in performing a TME. Subsequent to TME's popularization, introduction of TME techniques into surgical training programs led to a decrease in local recurrence and improved survival in several European populations.[13-15] In conjunction with ANP, sharp mesorectal excision has also led to decreased rates of postoperative genitourinary dysfunction.
Parallel to advances in surgical technique, there have been advances in pathologic grading of adequacy of rectal cancer resection into the mesorectal plane (a good plane of surgery achieved), intramesorectal plane (a moderate plane of surgery achieved), and lastly the muscularis propria plane (a poor plane of surgery achieved, based on grading of the resected specimen). The plane of surgery achieved is an important prognostic factor, given that surgery in the mesorectal plane lowers local recurrence rates.[2,16] This finding further underscores the important role of optimal surgical technique.
Although laparoscopic surgery for colon cancer is now well accepted, with proven oncologic equivalency and superior earlier postoperative recovery relative to open surgery, its acceptance in rectal cancer surgery has not been universal, in part because of isolated reports documenting higher but nonsignificant rates of CRM involvement and a trend toward worse male sexual function following a laparoscopic anterior resection. However, despite differences in CRM rates, 3- and 5-year follow-up have not demonstrated a difference in local and distant recurrence, nor in overall or disease-free survival rates, between laparoscopic resection and open rectal cancer resection.[18,19] Clearly, larger sample studies with longer follow-up are needed to fully address this important issue. Nevertheless, at the present time, although there might be short-term postoperative benefits to laparoscopic rectal cancer resection, an oncologic benefit has yet to be demonstrated. However, because of the earlier postoperative recovery with the laparoscopic approach, it is conceivable that a laparoscopic resection may lead to an increase in patient compliance with postoperative adjuvant therapies.
Despite advances in surgical technique, there are cases of locally advanced rectal cancer in which surgery as the sole treatment may lead to a positive CRM, resulting in an increased risk of local failure and a poorer survival outcome. These include fixed cancers invading local structures and abutting pelvic sidewalls. In these cases, neoadjuvant therapy, in the form of chemoradiation (CMT), chemotherapy, or radiation alone (as reviewed later in this article), is indicated in an attempt to shrink the bulk of disease and enhance the likelihood of obtaining a negative CRM while preserving anal sphincters. The bigger challenge is determining the need for neoadjuvant therapy for disease that is nonfixed yet at increased risk of local failure, such as node-positive (N+) disease or disease involving/abutting the mesorectal fascia. Conventional treatment for locally advanced, clinically resectable (T3 and/or N+) rectal cancer is neoadjuvant CMT. However, our current ability to accurately identify N+ disease is limited, leading to overtreatment of perhaps 18% of patients, as shown in the German CAO/ARO/AIO-94 trial, or undertreatment of 20% to 30% of N+ rectal cancer, as shown by a consortium of high-volume centers. Contrast-enhanced MRI shows promise, with reported improved sensitivity and specificity for detection of metastatic lymph nodes.
Similarly, preoperative high-resolution MRI and expert radiological interpretation may help oncologists select rectal cancer patients likely to have a good outcome with surgery alone.[23-25] However, there are a number of limiting factors—including the ability of high-resolution MRI to determine the proximity of the rectal cancer to the mesorectal fascia, the likelihood of positive CRM, and the need for downstaging with preoperative CMT; in addition, a positive CRM is not always reliably predicted, and preoperative CMT is sometimes erroneously omitted. Neoadjuvant systemic chemotherapy alone has been explored, with promising results as will be discussed.
Neoadjuvant Chemoradiation, Radiation, or Chemotherapy Alone?
The conventional treatment for locally advanced, clinically resectable (T3 and/or N+) rectal cancer is preoperative CMT. When 5-FU is used concurrently with radiation, continuous infusion (CI) of capecitabine (Xeloda) is the conventional treatment.[26,27] The National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial compared preoperative CMT with CI 5-FU vs capecitabine (with or without oxaliplatin [Eloxatin]). Compared to those treated with CI 5-FU, patients randomized to capecitabine had similar rates of pathologic complete response (pCR, 22% vs 19%, respectively), sphincter-sparing surgery (63% vs 61%, respectively), and grade 3+ diarrhea (11%).
Local recurrences can occur late in rectal cancer. Patients who receive postoperative CMT have an increase in local recurrence and a decrease in survival after 5 years. The Intergroup postoperative rectal adjuvant trial INT 0114 in patients with T3-4 and N+ disease showed rates of local control and survival continue to decrease beyond 5 years. At 7 years, the local recurrence rate was 17% and survival was 56%, vs 14% and 64%, respectively, at 5 years. In contrast, in patients who received preoperative CMT in the German CAO/ARO/AIO-94 trial there was a decrease in survival at 10 years vs 5 years (74% vs 60%) but no change in local recurrence (6%).
The two randomized trials of preoperative vs postoperative CMT for clinically resectable T3-4 Nany rectal cancer (NSABP R0-3) and the German CAO/ARO/AIO-94 trial reported opposite results. In the German trial, patients who received preoperative therapy had a significant decrease in local recurrence (6% vs 15%, P = .006), acute toxicity (27% vs 40%, P = .001), and chronic toxicity (14% vs 24%, P = .012), and among 194 patients judged by the surgeon pretreatment to require abdominoperineal resection, there was a significant increase in sphincter preservation (39% with preoperative therapy vs 20% with postoperative treatment, P = .004). There was no difference in survival (74% vs 76%, respectively). The results were updated with a median follow-up of 11.2 years. At 10 years the local control benefit of preoperative therapy was still superior to that of postoperative therapy (cumulative incidence of local relapse, 6% vs 10%, respectively), and the survival was equivalent (60% for both groups).
Compared with postoperative therapy, patients who received preoperative therapy in the NSABP R-03 trial had a significant improvement in 5-year disease-free survival (65% vs 53%, P = .011) and a borderline significant improvement in 5-year overall survival (75% vs 66%, P = .065). There was no difference in 5-year local recurrence (11% for both groups). There was a corresponding higher incidence of grade 4+ toxicity (33% vs 23%), but grade 3+ toxicity was lower (41% vs 50%). Lastly, based on a prospective office assessment by the operating surgeon, there was no improvement in sphincter preservation (48% vs 39%).
Results of the NSABP trial should be interpreted with caution since only 267 of the 900 planned patients were accrued, thereby limiting the statistical power to detect differences. The German trial met its accrual goals, and based on the positive results, preoperative CMT remains the standard of care.
Preoperative 5 Gy × 5 or chemoradiation?
There are two randomized trials of short-course radiation vs CMT. Bujko et al randomized 316 patients with cT3 rectal cancer.[32,33] All tumors were above the anorectal ring, TME was performed for distal tumors, and there was no radiation quality-control review. There were no significant differences in local control or survival. The incidence of positive radial margins was lower following CMT than with short-course radiation alone (4% vs 13%, P = .017). A similar trial was reported by Ngan et al. A total of 326 patients with T3Nany rectal cancer (56% were N0) were randomized. In contrast to the trial by Bujko et al, patients received postoperative adjuvant chemotherapy. There were no significant differences in 3-year local recurrence (8% vs 4%) or 5-year survival (74% vs 70%).
These trials challenge the role of long-course CMT in selected patients, but they need to be examined in perspective. Neither was limited to N+ disease, and both require longer follow-up.
Selective use of radiation
Given the improvements in systemic chemotherapy, there may be an opportunity to use preoperative radiation more selectively. In a prospective trial reported in abstract form, Cercek et al treated 32 patients with ultrasound-staged uT2N1 or uT3N0-1 rectal cancer by preoperative assessment who were treated with neoadjuvant FOLFOX (folinic acid, 5-FU, and oxaliplatin) + bevacizumab(Drug information on bevacizumab) (Avastin). Pelvic radiation was reserved for patients who progressed preoperatively or who following surgery had either pT4, pN2, or positive margins. Of the 30 patients who underwent low anterior resection, none required radiation, the pCR rate was 27%, and 2 required postoperative radiation. This approach remains investigational and will be examined in an Intergroup phase II/III trial.