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Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4078-4084 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.2968 Predictors of Recurrence in Patients With T2 and Early T3, N0 Adenocarcinoma of the Rectum Treated by Surgery Alone
From the Departments of Surgery, and Pathology and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Address reprint requests to W. Douglas Wong, MD, Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-1067, New York, NY 10021; e-mail: wongd{at}mskcc.org
Purpose Treatment of rectal cancer with neoadjuvant radiotherapy has been shown to reduce local recurrence and improve overall survival. The role of chemoradiotherapy in patients with T2, N0 and early T3, N0 rectal cancer, treated by radical surgery with total mesorectal excision, remains controversial. The aim of this study was to identify predictors of recurrence in this group of patients to enhance treatment selection. Patients and Methods One hundred patients with primary T2-3, N0 adenocarcinoma of the rectum, uniformly treated by surgery alone, were studied. The pathology slides available for 97 patients were rereviewed. Three patients with incomplete data sets were excluded. Clinical and survival data were obtained from a prospective computerized database and updated from hospital and office charts. The study end points were disease-free survival, disease-specific survival (DSS), time to pelvic recurrence (PR), and distant recurrence. Results Complete follow-up was available for all study patients. Median follow-up was 79.5 months (range, 57.7 to 105.9 months). During this time period 30 patients (31.9%) died as a result of disease and 64 patients (68.1%) remained alive and disease free. Five-year DSS was 73%. The cumulative risk for PR was 8% at 5 years and 10% at 8 years. Lymphovascular invasion, preoperative serum carcinoembryonic antigen (CEA > 5 ng/mL) level, and age older than 70 years were all associated with adverse outcome. Conclusion Patients with T2-3, N0 rectal cancers and either lymphovascular invasion or elevated CEA levels have reduced survival and a higher incidence of PR, and should be considered for future randomized trials.
Major advances in rectal cancer management, such as total mesorectal excision (TME) and preoperative radiation therapy have improved rates of cure, sphincter preservation, local control, disease-specific survival (DSS), and pelvic recurrence.1-7 Preoperative radiotherapy has become the standard of care for all rectal cancers in many medical centers. Elsewhere, a more selective treatment approach based on preoperative staging by endorectal ultrasound (ERUS) or magnetic resonance imaging is practiced; locally advanced or node-positive disease is often treated with preoperative radiation or chemoradiotherapy. This selective approach is supported by the National Institutes of Health Consensus Conference8 and by several prospective randomized trials.9,10 However, selection criteria for the preoperative therapeutic protocol are still controversial.11 Although 30% of T2 and early T3, N0 (Dukes' B) patients die as a result of disease, some surgeons believe that adjuvant chemoradiotherapy before or after radical surgery adds little to local control or survival.12 Many clinical variables correlate with outcome in colorectal cancer (CRC). Elevated serum carcinoembryonic antigen (CEA > 5 ng/mL),13 lymphovascular invasion (LVI),14-16 high histologic grade, mucin production,17 and signet-ring cell variant18 are associated with poorer prognosis. The College of American Pathologists (CAP) rigorously categorizes CRC prognostic markers into four classes. Class I includes the most important variables based on scientific evidence: T stage (pT), regional lymph node metastasis (pN), LVI, residual tumor, and CEA more than 5 ng/mL.19 However, this and other reports make no distinction between colon and rectal cancers. Few studies have been validated in homogeneous cohorts of rectal cancer patients. Some investigators correlate the molecular markers p5320 or K-RAS21 with outcome. Currently, however, none of these prognosticators are used in clinical practice. Our study was intended to assess the influence of clinical variables on outcome for a cohort of rectal cancer patients treated only by radical surgery (low anterior resection or abdominoperineal resection [LAR/APR]) with TME.
The Memorial Sloan-Kettering Cancer Center (MSKCC) Colorectal Cancer database maintains prospectively recorded demographic, treatment, pathologic, and outcome data for more than 7,500 CRC patients treated at our institution. Of these, we identified 1,468 of 2,149 with rectal adenocarcinoma who received no neoadjuvant therapy; 494 had pT2, N0 or pT3, N0 disease; 166 of 494 underwent resection from 1992 to 1995. Fourteen died as a result of noncancer-related causes, 55 were lost to follow-up or treated adjuvantly at outside institutions, and three had pathology slides unavailable for review at the time of analysis, leaving 94 with complete clinical and pathologic data. Our study is based on these 94 patients. All underwent complete curative resection (American Joint Committee on Cancer/International Union Against Cancer R0) and were observed prospectively. Only those who died as a result of disease or had at least 5 relapse-free years of complete follow-up were included. Follow-up, primarily obtained from the institution database, was updated by clinical chart review, tumor registry information, physician records, patient correspondence, and telephone interviews. Pathology reports and all available slides were reviewed critically to confirm the diagnosis. Permanent section hematoxylin-eosin slides were reviewed without knowledge of clinical characteristics or outcome. A tumor was considered a primary lesion if located 0 to 12 cm above the anal verge. Macroscopic margins were assessed at surgery and microscopic margins were assessed histopathologically. Complete resection was defined as absence of gross residual disease after surgical excision. Primary study end points included time to first local recurrence and distant metastasis, disease-free survival, and disease-related mortality. Clinicopathologic factors including age, sex, mural penetration, LVI, perineural invasion, histologic grade, and preoperative serum CEA were correlated with study end points.
Treatment Scheme
Statistics Rate of recurrence or death was estimated using the Kaplan-Meier product limit method.23 Univariate influence of prognostic factors on study end points was analyzed with the log-rank test.24 Multivariate analysis based on Cox proportional hazards regression model was used to associate covariates with time-dependent end points. Statistical analysis was performed using the SPSS statistical package (SPCC Inc, Chicago, IL), and JMP software (SAS Institute, Cary, NC). P < .05 was considered significant.
Tumor and Patient Characteristics Ninety-four patients were included. The median age was 67 years (range, 28 to 85 years); the male-to-female ratio was 2:1. Preoperative serum CEA levels were recorded in 79 of 94 patients (84.0%), with mean (± standard deviation) serum CEA = 8.1 ± 13.7 ng/mL. Review of histology slides confirmed initial T stage in all T2 (n = 45; 47.9%) and T3 (n = 49; 52.1%) tumors. All were graded as moderately differentiated, with the exception of four well-differentiated tumors. All patients were node negative (N0) on pathologic rereview. Median number of lymph nodes removed at surgery was 12 (range, four to 56). All resections were complete, with microscopically negative circumferential and distal margins. Distance from the distal margin was measured on original pathologic examination and recorded for 84 of 94 patients (89.4%). Median distance from the surgical margin was 2.5 cm (range, 1.0 to 11.0 cm). LVI was present in eight of 94 (8.5%); perineural invasion was present in two of 94 (2.1%; Table 1).
Follow-Up and Survival Median follow-up was 79.5 months (range, 57.7 to 105.9 months). During this time, 30 patients (31.9%) died as a result of disease; 64 patients (68.1%) remained alive and disease free. Median DSS for the entire group was not reached. Five-year DSS was 72%. Cumulative risk for pelvic recurrence was 8% at 5 years and 10% at 8 years. There were 49 patients with pT3, N0 rectal adenocarcinoma. At time of last follow-up, 16 had either local (n = 2; 4.1%) or distant (n = 14; 28.6%) recurrence, 16 (32.6%) had died as a result of disease, and 33 (67.4%) were disease free. Five-year recurrence-free survival (RFS) and DSS for pT3, N0 disease was 67.1% and 71.4%, respectively (Table 2).
All patients were staged clinically (digital rectal exam plus proctoscopy) before treatment by surgery alone. Deep or bulky T3 tumors were treated with neoadjuvant chemoradiotherapy and excluded. Comparison of pT2, N0 and pT3, N0 lesions for RFS and DSS rates showed no statistically significant difference (5-year RFS, 73.3% v 67.1%; P = .80; 5-year DSS, 73.3% v 71.4%; P = .92).
Class I Prognostic Markers
Abnormal preoperative CEA (5 ng/mL) was present in 29 patients (36.7%). This was associated with increased recurrence (Fig 1C) and tumor-related mortality (Fig 1D). Of 79 patients with recorded preoperative CEA, four had pelvic recurrences; all were associated with abnormal levels. In those with elevated CEA, risk of pelvic recurrence was 13% at 5 years and 21% at 8 years, versus 0% in those with normal preoperative CEA (P = .004; Fig 2B). The combined influence of serum CEA and LVI on DSS and DFS was evaluated. Of 79 patients with recorded preoperative CEA, 45 (57.0%) had normal CEA and no LVI, 31 (39.2%) had either elevated CEA or LVI, and three (3.8%) had both elevated CEA and LVI. The 5-year DFS of these groups was 80%, 58%, and 33% respectively (P = .02); 5-year DSS was 82%, 64%, and 33% respectively (P = .04).
Other Prognostic Markers
The number of regional nodes assessed in a pathologic specimen as part of curative-intent resection is of prognostic importance. Therefore, the relationship between number of regional nodes, local control, distant recurrence, and disease-specific outcome was examined. We found no statistically significant association between the number of nodes (< 12 v Female sex is associated with better outcome in rectal cancer. In our study 31.9% of patients were females. The 5-year DFS was 80% for females and 69% for males; 5-year DSS was 80% and 69%, respectively. Cumulative risk of pelvic recurrence was 4% and 9%, respectively. None of these differences achieved statistical significance. Median age at time of surgery was 67 years. There were 62 patients (66.0%) age 70 or younger, and 32 patients (34.0%) older than 70. Five-year DFS was 77% and 56% (P = .03), and DSS was 79% and 59% for these two age groups, respectively (P = .02). On multivariate analysis, the only independent predictor of DFS was abnormal preoperative CEA (risk ratio, 3.1; 95% CI, 1.2 to 8.1; P = .01). The only independent predictor of tumor-related mortality was CEA (risk ratio, 2.9; 95% CI, 1.1 to 7.6; P = .02).
Preoperative radiotherapy improves survival and reduces pelvic recurrence in rectal cancer patients.3 Postoperative chemoradiotherapy improves local control and survival in patients with T3-4 primary tumors and those with node-positive disease.7,8,25-27 TME significantly reduces pelvic recurrence.10 However, the benefit of adjuvant chemoradiotherapy in patients with small, mobile rectal cancers treated by radical surgery with TME is probably low. Our study was undertaken to identify potential prognostic markers to refine patient selection for adjuvant therapy. We evaluated class I prognostic markers identified by CAP19 in our group of 94 patients. Staging was done clinically by digital rectal examination and proctoscopy before operation; ERUS was not performed routinely at MSKCC during the study period. Patients with early T2 lesions treated by transanal excision were excluded, as were those with tethered or fixed bulky (cT3) tumors treated with preoperative chemoradiotherapy. This study therefore comprises a select group with pT2, N0 and early pT3, N0 moderately and well-differentiated rectal adenocarcinoma. We found no statistically significant difference between pT2, N0 and pT3, N0 rectal cancers in terms of local and distant RFS or DSS. This can be explained by the fact that only patients with early T3 rectal cancers who did not undergo neoadjuvant or adjuvant treatment were included.
Local and distant recurrence rates for pT3, N0 rectal adenocarcinoma treated by surgery alone were 4.1% and 28.6%, respectively. At the time of last follow-up, 16 of 49 patients (32.6%) had died as a result of disease; 33 remained disease free. Five-year RFS and DSS for pT3, N0 disease was 67.1% and 71.4%, respectively. These results compare favorably with other published clinical trial data. In the Swedish Rectal Cancer Trial, locoregional recurrence in intermediate-risk Dukes' B rectal cancer treated by surgery alone was considerably higher than that observed in our study ( Residual tumor and pN stage were not evaluated, given that only node-negative and R0 patients were included. The two remaining class I markers, preoperative abnormal CEA and LVI, were analyzed. Abnormally elevated preoperative serum CEA (> 5 ng/mL) is a powerful prognostic marker of survival in CRC,29 but it has not been studied in the context of treatment selection. In their 358-patient study, Wanebo et al30 reported that in Dukes' C patients, median time to recurrence was 13 months with preoperative CEA more than 5 ng/mL, and 28 months if less than 5 ng/mL. Davey et al31 studied the prognostic value of CEA in patients with recurrent or inoperable disease, reporting that only those with CEA levels of less than 30 ng/mL responded to radiotherapy. Harrison et al13 studied retrospectively 572 node-negative CRC patients undergoing curative-intent resection; on multivariate analysis, only pT stage and CEA were found to be independent predictors of survival, and abnormal preoperative CEA was associated with poor outcome. Wollmark et al32 analyzed data from the National Surgical Adjuvant Breast and Bowel Project prospective randomized trials, demonstrating correlation between preoperative CEA and Dukes' stage. Treatment failure was predicted by CEA, however, independent of stage. To the best of our knowledge, previous studies have not analyzed the combined effect of preoperative CEA and LVI on outcome after curative-intent resection. The potential to stratify risk for recurrence and disease-specific mortality on the basis of these factors is intriguing. However, the inherent limitations of a retrospective analysis conducted on patients referred to a cancer center with analysis of selected subsets must be recognized. The possible impact of small subset sample size on the CIs of these estimates, and the bias it introduces, is understood. Nevertheless, when one considers the difference in cumulative risk for pelvic recurrence between patients with and without LVI, the P value of .006 suggests that this prognostic factor has clinical meaning. The smaller but statistically significant P values for comparisons, including a number of patients with both elevated CEA and LVI, reflect inherent bias. Nonetheless, these differences are provocative, and merit additional study. Our results support the findings of others evaluating CRC in various stages. All pelvic recurrences were in patients with elevated preoperative CEA, suggesting that this group may benefit from the addition of preoperative chemoradiotherapy. Increased rates of distant recurrence and tumor-related mortality in the setting of elevated CEA may be addressed by chemotherapy. Consideration of adjuvant therapy in this setting is further supported by the observation that tumor response to radiation is predicted by serum CEA31 in patients with advanced disease. LVI is a well-established prognostic marker. Penetration of tumor into the small vessels of the submucosa is a predictor of nodal metastasis in early CRC.33-36 Involvement of extramural veins is associated with increased risk for liver metastasis and adverse outcome.37,38 Willett et al39 studied 117 T3, N0 rectal cancer patients, showing that well-differentiated tumors with radial extension of less than 2 mm into the perirectal fat, without LVI, were associated with a 10-year DFS of 87%, compared with a 10-year DFS of 55% for patients with one or more positive prognostic factors. In another study from the same group,40 64 American Joint Committee on Cancer stage I patients who underwent APR had high recurrence rates. Willett et al39 concluded that radiation therapy and chemotherapy should be reconsidered for stage I lower rectal carcinoma, specifically those tumors invading the muscularis propria and with blood vessel invasion or LVI. In our study, LVI was associated with significantly reduced 5-year DFS (36%) and DSS (37%), and a high rate of pelvic recurrence (32%). Adjuvant chemoradiotherapy should be considered strongly for these patients. Although LVI is not always readily apparent in the initial biopsy, every effort should be made to obtain a representative specimen in maximize relevant prognostic data preoperatively and facilitate treatment planning. Other significant predictors of survival might be considered when selecting optimal treatment.41-43 Perineural invasion was classified by CAP as a class III marker. In our study, only two of 94 tumors (2.1%) showed perineural invasion. Histologic grade was classified by CAP as a class II marker. In our study, four tumors (4.3%) were well differentiated; 90 were moderately differentiated. Because of the low positivity rate of these two markers, we did not perform an outcome analysis. At MSKCC, treatment for the rectal cancer patient currently is based on the findings of ERUS, digital rectal and proctoscopic examinations, and computed tomography scanning. Our approach to uT2, N0 and early T3, N0 lesions includes radical surgery (LAR/APR) with TME. Postoperative chemoradiotherapy is administered to select patients with nodal metastasis not identified by preoperative ultrasound. On the basis of this study, patients with LVI or elevated preoperative CEA may be candidates for neoadjuvant therapy. Our results emphasize the importance of both as prognostic factors, supporting their inclusion as discriminating variables in future randomized clinical trials.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests. Local recurrence was defined as the first clinically, radiologically, or pathologically evident tumor of the same histologic type, within or contiguous to the previously treated tumor bed, 3 or more months after primary therapy. Nodal recurrence was defined as pathologically confirmed metastases to regional draining lymph nodes. Distant metastasis was defined as clinical or radiologic evidence of systemic disease spread outside the primary tumor basin. Outcome was classified according to site of first disease recurrence (locoregional and/or distant). Clinical outcomes studied were locoregional recurrence, distant recurrence, disease-free survival (DFS), and DSS. Time to recurrence and DSS were calculated from the date of the primary operation. Patients who died as a result of rectal cancer were considered to have died as a result of disease and were included in disease-related mortality calculations. Those who died as a result of other causes (were free of disease) were considered to be alive without evidence of disease and were lost to follow-up. Thus, patient status at last follow-up was regarded as a censored event for DSS estimates. Follow-up was calculated from the time of first primary rectal cancer operation to the date of last follow-up. 
; n = 8), and without lymphovascular invasion (+; n = 86), P = .01. (B) Disease-specific survival of patients with lymphovascular invasion (
12), local or distant DFS, or DSS (P > .05 for all comparisons). 
23%), whereas 5-year DSS was comparable to that of our pT3, N0 patients (
