Prior to the publication of the German CAO/ARO/AIO 94 trial, the conventional adjuvant approach for patients with clinically resectable, ultrasonographically diagnosed T3 (uT3) and/or node-positive rectal cancer was initial surgery and, if pathologically confirmed T3 (pT3) and/or node-positive, postoperative combined chemotherapy plus radiation. The German trial confirmed that compared to postoperative therapy, the preoperative approach was associated with significantly lower local recurrence rates, less acute and chronic toxicity, and an increased incidence of sphincter preservation. Standard treatment for clinically diagnosed T3 (cT3) and/or node-positive disease is now preoperative chemoradiotherapy followed by surgery and 4 months of postoperative adjuvant chemotherapy.
Given this shift to preoperative therapy, clinical staging to accurately identify both T stage and N stage is critical. Imaging techniques to assess the extent of the primary tumor include computed tomography (CT), magnetic resonance imaging (MRI), 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET), and transrectal ultrasound. In the United States, ultrasound plus CT or MRI are commonly used, whereas in many European countries, high-resolution MRI is preferred. High-resolution MRI also allows for identification of patients likely to have close or positive radial margins if they have undergone initial surgery and therefore are selected to receive preoperative therapy. The UK-based Mercury Trial also uses MRI to select for the intensity of preoperative therapy.
The overall accuracy in predicting T stage is approximately 50% to 90% with transrectal ultrasound and 50% to 70% with CT or MRI. FDG-PET may be more accurate than CT for identification of metastatic disease.[5,6] High-resolution MRI is helpful in predicting patients who will have negative margins at surgery. FDG-PET is not as accurate.
The identification of positive lymph nodes is more difficult. The overall accuracy in detecting positive pelvic lymph nodes with the above techniques is approximately 50%. The accuracy of MRI is similar to that of CT in this setting; however, it is improved with the use of external and/or endorectal coils. Both CT and MRI can identify lymph nodes measuring ≥ 1 cm, although enlarged lymph nodes are not pathognomonic of tumor involvement. The accuracy of MRI may be further enhanced with the use of superparamagnetic iron oxide particles. Likewise, the accuracy of ultrasound for the detection of involved perirectal lymph nodes may be augmented if combined with fine-needle aspiration.
The ability to accurately predict the pathologic stage following preoperative chemoradiotherapy with MRI,[10,11] ultrasound,[12,13] FDG-PET, or physical exam remains suboptimal. Tumor regression grade may help predict lymph node–positive disease. However, patients in this situation would have already received preoperative chemoradiotherapy.
Is Pelvic Radiation Required for Node-Negative Rectal Cancer?
The 1990 National Cancer Institute (NCI) Consensus Conference recommendation for postoperative combined-modality therapy was based on trials where neither total mesorectal resection (TME) nor examination of ≥ 12 nodes was required. Retrospective data suggest that there may be a subset of patients with pT3, N0 disease who may not require adjuvant therapy. Nissan and associates reported results in 100 patients with uT2/3, N0 disease who underwent TME alone and had at least 12 nodes examined. In the subset of 49 patients with pT3, N0 disease, the overall local recurrence rate was 4%. For the total group, local recurrence was significantly higher in those with lymphatic vessel invasion (32% vs 6%, P = .006) and an elevated (> 5.0 ng/mL) preoperative carcinoembryonic antigen (21% vs 0%).
The sixth edition of the American Joint Commission on Cancer (AJCC) staging system subdivides stage III into IIIA (T1-2, N1), IIIB (T3-4, N1), and IIIC (T any, N2). The prognostic validity of this change was supported by both the pooled analysis of Intergroup and National Surgical Adjuvant Breast and Bowel Project (NSABP) postoperative trials and the retrospective analysis of the American College of Surgeons National Cancer Database (NCDB). The 5-year survival by stages IIIA, B, and C in the pooled analysis was 81%, 57%, and 49%, and in the NCDB was 55%, 35%, and 25%, respectively.
These data provided further evidence that patients with upper rectal cancers who undergo a TME, have at least 12 nodes examined, and have stage pT3, N0 disease likely do not need the radiation component of chemoradiotherapy. The approximately 3% to 4% benefit in local control with radiation may not be worth the risks, especially in women of reproductive age. However, the subset of patients with pT3, N0 tumors with either adverse pathologic features and/or fewer than 12 nodes examined should still receive postoperative chemoradiotherapy.
Although the appropriate number of nodes is defined in the AJCC staging system, the location of pelvic nodes is not. Leibold and associates treated 121 patients with preoperative chemoradiotherapy and found that the incidence of metastatic disease was higher among patients with positive nodes in the proximal pelvis compared with positive nodes anywhere in the pelvis (46% vs 32%). Of note, the proximal nodes are above the superior border of the radiation field (L5/S1) since they are located along the apical and midportion of the inferior mesenteric artery.
Potential Overtreatment With Preoperative Therapy
In the German trial, 18% of patients who were clinically staged as cT3, N0 preoperatively and underwent initial surgery without preoperative therapy had pT1-2, N0 disease. Therefore, those patients would have been overtreated if they had received preoperative therapy. Although it is not ideal, preoperative therapy is still preferred to performing surgery first because even after preoperative chemoradiotherapy (which downstages tumors), 22% will have lymph node–positive disease at the time of surgery. In patients who undergo surgery alone, this number is as high as 40%. These patients will then require postoperative chemoradiotherapy, which, compared with preoperative chemoradiotherapy, has inferior local control, higher acute and chronic toxicity, and if a low anastomosis is performed, inferior functional results. Clearly, the development of more accurate methods to identify lymph node–positive disease including imaging techniques and/or molecular markers is essential as more patients are being treated with preoperative combined-modality therapy.
Preoperative Short-Course Radiation vs Chemoradiation
Twelve modern randomized trials of preoperative radiation therapy (without chemotherapy) have been conducted. All use low to moderate doses of radiation. Most of the trials showed a decrease in local recurrence, and in five of the trials this difference reached statistical significance. Although in some trials a subset analysis revealed a significant improvement in survival, the Swedish Rectal Cancer Trial is the only one that reported a survival advantage for the total-treatment population. With 13-year follow-up, survival is still significantly improved (38% vs 30%, P = .008) in this group. The local recurrence rate in lymph node–positive patients who underwent surgery alone was 46%, illustrating the inferior results of surgery prior to the adoption of TME.
The updated results of the Dutch CKVO 95-04 trial revealed that 5-year local recurrence with TME is 11% but was still significantly decreased to 6% with preoperative radiation. Furthermore, local recurrence in patients with positive nodes who underwent surgery alone was 21%. Therefore, despite undergoing a TME, node-positive patients still require chemoradiotherapy. The challenge is the identification of positive nodes to allow proper selection of patients for preoperative therapy.
Sphincter Preservation With Preoperative Radiation
From the viewpoint of sphincter preservation, the advantage of preoperative therapy is to decrease the volume of the primary tumor. When the tumor is located in close proximity to the upper part of the anorectal sphincter, a decrease in tumor volume may allow the surgeon to perform a sphincter-conserving procedure that would not otherwise be possible. However, if the tumor directly invades the anorectal sphincter, sphincter preservation is unlikely even when a complete response is achieved.
If the degree of downstaging needs to be adequate to enhance sphincter preservation, which regimen (short-course or combined-modality therapy) is preferred? An analysis of 1,316 patients who received a short course of radiation revealed that downstaging was most pronounced when the interval between the completion of radiation and surgery was at least 10 days. In the Dutch CKVO 95-04 trial, where the interval was 1 week, there was no downstaging.
When the goal of preoperative therapy is sphincter preservation, conventional radiation doses and techniques are recommended. These include multiple-field techniques to a total dose of 45 to 50.4 Gy at 1.8 Gy/fraction. Surgery should be performed 4 to 8 weeks following the completion of radiation. Unlike the intensive short-course radiation regimen, this conventional design allows for two important events to occur. First is the recovery from the acute side effects of radiation, and second is adequate time for tumor downstaging.
Data from the Lyon R90-01 trial of preoperative radiation suggest that an interval > 2 weeks following the completion of radiation increases the chance of downstaging. Most series recommend a 4- to 8-week interval. Whether increasing the interval between the end of intensive short-course radiation and surgery to > 4 weeks will increase downstaging is not known. This question is being addressed in the ongoing Stockholm III trial.
Although preoperative chemoradiotherapy may adversely affect sphincter function, the impact is most likely less than that of postoperative chemoradiotherapy. Functional results continue to improve up to 1 year after surgery. Functional data from the German trial are pending.
Bujko and colleagues performed a randomized trial of two preoperative approaches. A total of 316 patients with cT3 rectal cancer were randomized to 5 Gy × 5 followed by surgery (at a median of 8 days) vs conventional preoperative chemoradiotherapy (50.4 Gy plus bolus fluorouracil(Drug information on fluorouracil) [5-FU]/leucovorin daily × 5 at weeks 1 and 5) followed by surgery (at a median of 78 days). All tumors were above the anorectal sphincter, and TME was performed for distal tumors.
Compared with 5 Gy × 5, patients who received chemoradiotherapy had a significantly lower incidence of positive circumferential margins (4% vs 13%) but no significant difference in local failure (14% vs 9%) or 4-year survival (66% vs 67%). Furthermore, although a significantly higher pathologic complete response (pCR) rate (16% vs 1%) was noted, the incidence of sphincter preservation was not increased (58% vs 61%). It must be emphasized that the numbers of patients (316) were small for a randomized trial, surgeons were not encouraged to modify the operation based on the response to preoperative therapy, and no centralized radiation quality review was conducted. The German trial did have centralized quality control, and it was found that the treatment center, schedule, and gender were independent prognostic factors for local control. Results of similar randomized trials from Australia and Europe are pending.
Similar to the German trial, patients underwent a pretreatment clinical assessment by the operating surgeon. In the subset of patients who were thought to require an abdominoperineal resection (APR), sphincter preservation was achieved in 21% of those who received chemoradiotherapy and 26% of those who received short-course radiation. The absence of a difference in sphincter preservation rate may have been related to a lack of the surgeon’s commitment to the concept of sphincter preservation. Since modification of the surgical approach following preoperative therapy is contrary to traditional oncologic teaching, sphincter-preserving surgery in a patient who would normally require an APR requires a surgeon who is comfortable with this change. The German trial controlled for this bias as the randomization was stratified by surgeon.