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Originally published as JCO Early Release 10.1200/JCO.2004.08.173 on April 5 2004 © 2004 American Society of Clinical Oncology. Impact of T and N Stage and Treatment on Survival and Relapse in Adjuvant Rectal CancerA Pooled AnalysisFrom the Radiation Oncology Department, Mayo Clinic Cancer Center, Scottsdale, AZ; Statistics, Mayo Clinic Cancer Center, Rochester, MN; Radiation Oncology, University of North Carolina, Chapel Hill, NC; Radiation Oncology, Kansas City Community Clinical Oncology Program, Kansas City, MO; Medical Oncology, Allegheny General Hospital, NSABP Operations and Biostatistical Center, Pittsburgh, PA; Abramson Cancer Center at the University of Pennsylvania, Philadelphia; and Oncology, Mayo Clinic Cancer Center, Rochester, MN; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Radiation Oncology, University of Virginia, Charlottesville, VA; Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston TX; Medical Oncology, St Vincent's Comprehensive Cancer Center, New York, NY; Radiation Oncology, Massachusetts General Hospital, Boston, MA. Address reprint requests to Leonard L. Gunderson, MD, Mayo Clinic Cancer Center, Scottsdale, 13400 E Shea Blvd, Scottsdale, AZ 85259; e-mail: gunderson.leonard{at}mayo.edu
PURPOSE: To determine survival and relapse rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies. PATIENTS AND METHODS: Data were pooled from 3,791 eligible patients enrolled onto North Central Cancer Treatment Group (NCCTG) 79-47-51, NCCTG 86-47-51, US Gastrointestinal Intergroup 0114, National Surgical Adjuvant Breast and Bowel Project (NSABP) R01, and NSABP R02. Surgery alone (S) was the treatment arm in 179 patients. The remaining patients received adjuvant treatment as follows: irradiation (RT) alone (n = 281), RT + fluorouracil (FU) ± semustine bolus chemotherapy (CT; n = 779), RT + protracted venous infusion CT (n = 325), RT + FU ± leucovorin or levamisole bolus CT (n = 1,695), or CT alone (n = 532). Five-year follow-up was available in 94% of surviving patients, and 8-year follow-up, in 62%. RESULTS: Overall (OS) and disease-free survival were dependent on TN stage, NT stage, and treatment method. Even among N2 patients, T substage influenced 5-year OS (T1-2, 67%; T3, 44%; T4, 37%; P < .001). Three risk groups of patients were defined: (1) intermediate (T1-2/N1, T3/N0), (2) moderately high (T1-2/N2, T3/N1, T4/N0), and (3) high (T3/N2, T4/N1, T4/N2). For intermediate-risk patients, those receiving S plus CT had 5-year OS rates of 85% (T1-2/N1) and 84% (T3/N0), which was similar to results with S plus RT plus CT (T1-2/N1, 78% to 83%; T3/N0, 74% to 80%). For moderately high-risk lesions, 5-year OS ranged from 43% to 70% with S plus CT, and 44% to 80% with S plus RT plus CT. For high-risk lesions, 5-year OS ranged from 25% to 45% with S plus CT, and 29% to 57% with S plus RT plus CT. CONCLUSION: Different treatment strategies may be indicated for intermediate-risk versus moderately high- or high-risk patients based on differential survival rates and rates of relapse. Use of trimodality treatment for all patients with intermediate-risk lesions may be excessive, since S plus CT resulted in 5-year OS of approximately 85%; however, 5-year disease-free survival rates with S plus CT were 78% (T1-2/N1) and 69%(T3/N0), indicating room for improvement.
In the 1990 National Institutes of Health Colorectal Cancer Consensus Conference Statement,1 it was noted that the Modified Astler-Coller (MAC) staging system2 was commonly used within the United States, but a plea was made for more standard use of the tumor-node-metastasis (TNM) system.3 Staging classifications for large bowel cancers depend on the depth of primary tumor invasion and the presence or absence of nodal or distant metastasis.1–4 Although the original Dukes' system (A, B, C)4 is useful in predicting survival outcome after surgical resection, categories of patients within each stage have markedly different outcomes.1,2,4–16 The TNM system applies to both clinical and pathologic staging, has a more precise definition of the degree of primary tumor extension for lesions confined to the bowel wall, and defines node involvement by the number of nodes involved (N1, N1-3; N2,  N4). The sixth edition of the American Joint Committee on Cancer TNM system has been refined by the addition of substaging for TNM system stage II and stage III lesions based on differential survival and relapse rates found within TNM stages II and III colon and rectal cancer (Dukes' classification B and C).3 A prior analysis of pooled data from three randomized adjuvant rectal cancer trials was performed to determine whether the trends toward improved survival and disease control seen in patients with intermediate- versus high-risk lesions in single institution analyses13,15,16 could be confirmed in multi-institutional phase III trials.17–22 Data were merged from North Central Cancer Treatment Group (NCCTG) 79-47-51 (N = 200), NCCTG 86-47-51 (N = 656), and US Gastrointestinal Intergroup (INT) 0114 (N = 1,695). All patients received postoperative irradiation, and 96% were randomized to receive concomitant and maintenance chemotherapy. In that analysis,17 three risk groups of patients were defined by rates of relapse and survival. For intermediate-risk patients (T1-2/N1, T3/N0), 5-year overall survival (OS) rates were 74% and 81%, respectively, and 5-year disease-free survival (DFS) rates were 66% and 74%, respectively. With moderately high-risk patients (T4/N0, T3/N1, and T1-2/N1), 5-year OS ranged from 61% to 69%. For patients with high-risk lesions (T3/N2, T4/N1-2), 5-year OS ranged from 33% to 48%. Although results by treatment method were not part of that analysis, the authors suggested that different treatment strategies may be indicated for intermediate- versus moderately high- or high-risk patients in view of differential survival and rates of relapse. The purpose of the current pooled analysis was to determine survival rates by T and N stage and treatment method in five randomized phase III North American rectal adjuvant studies. Data from National Surgical Adjuvant Breast and Bowel Project (NSABP) R0123 and NSABP R0224 were combined with data from the three North American randomized phase III rectal adjuvant trials that were included in the prior pooled analysis.17–22
Eligibility criteria of the five studies were similar, and have been previously reported.18–24 In each trial, eligible patients had primary tumor extension beyond the muscularis propria, nodes negative (T3-4/N0), primary tumor confined to the rectal wall, nodes positive (T1-2/N1-2), or both high-risk features (T3-4/N1-2). All patients received adjuvant treatment after surgical resection, except for the surgery-alone arm of NSABP R01.23 The primary aims of the current pooled analysis were to describe and compare outcomes by T and N substage and method of treatment. Subgroups of particular interest were the intermediate-risk subsets of patients (T1-2/N1 and T3/N0) compared with the moderately high-risk patients (T1-2/N2, T3/N1, T4/N0) and high-risk patients (T3/N2 and T4/N1-2) that had been defined in the prior rectal cancer pooled analysis.17 Data describing the number of assessable patients, and treatment methods in each of the five randomized phase III trials are presented in Table 1. NCCTG 79-47-51 included 200 assessable patients randomly assigned to receive pelvic irradiation alone or combined with concurrent fluorouracil (FU) and systemic FU plus methyl lomustine (CCNU).18 NCCTG 86-47-51 included 656 assessable patients randomized in a 2 x 2 factorial design to receive either bolus or protracted venous-infusion FU (PVIFU) during radiation, or the addition of methyl CCNU to FU as maintenance chemotherapy, given before and after the concurrent chemoradiation.19 In INT 0114, 1,695 assessable patients were randomly assigned to one of four FU-based chemotherapy regimens (FU ± leucovorin or levamisole) as part of a combined chemoradiation regimen.20–22 NSABP R0123 was a three-arm trial with a surgery-alone control arm (n = 179) and single-modality adjuvant arms of pelvic irradiation alone (n = 182) or chemotherapy alone (n = 183). In the subsequent NSABP R02 trial,24 patients were randomly assigned to received either chemotherapy alone (n = 349) or combined with pelvic irradiation (n = 347). All assessable randomized patients in the five separate trials were included in the current pooled analysis.
Patient Population and Pooled Data Available raw data from the five randomized trials were reviewed by the primary author (L.L.G.) and Mayo Clinic Cancer Center statisticians (D.J.S., C.A.) to determine what data items were consistently available. Surgery and pathology parameters included degree of rectal wall invasion, invasion of or adherance to adjacent organs or structures, and number of involved nodes; number of total nodes was available except in NCCTG 79-47-51. Chemotherapy data included agent, dates, and objective status. Radiation therapy data included site, dose, number of fractions, and elapsed days. Follow-up information included relapse status (date, site) and survival status (alive, dead, date). Five-year follow-up information was available in 94% of surviving patients and 8-year follow-up information was available in 62%. All patients were censored at 8 years post–random assignment. Patient demographics included age, sex, and performance status. Patient age ranged from 20 to 99 years, with a median of 61 years. There were 2,360 male patients and 1,416 female patients. Performance status (PS) was PS 0 in 2,616 patients; PS 1 in 1,049 patients; PS 2 in 50 patients; PS 3 in 1 patient; unknown in 5 patients; and missing in 70 patients.
Statistical Considerations Analyses of treatment effects within patient risk groups are presented as descriptive only. This is due to the large time span these trials included (1979-1992) and to possible changes in patient populations due to differences in patient selection and treatment. Formal testing indicated between-trial heterogeneity for the same treatment regimen in different studies.
Results by T and TN Stage Survival. The impact of both T stage and TN stage on OS and DFS was evaluated (Fig 1, Table 2). The 5-year OS ranged from 37% to 79%, and the 5-year DFS, from 30% to 73%. P values shown in Table 2 reflect comparisons either between the three T stages (T1-T2, T3, T4), or reflect pair-wise comparisons between the adjacent TN stages of patients, (the impact of N substage within the separate T stages: T1-2/N1 v T1-2/N2; T3/N0 v T3/N1, T3/N2; T4/N0 v T4/N1, T4/N2). OS and DFS vary as a function of both T stage and N substage within T stage (Table 2A). As in the prior pooled analysis,16 there was a progressive decrease in overall survival at 5 years with increasing T stage (T1-2, 75%; T3, 60%; T4, 47%; P < .001), and the addition of substaging by N0, N1, and N2 resulted in overlapping outcomes among T stages. OS rates at 5-years in patients with both T1-2/N1 and T1-2/N2 lesions were 79% and 67%, respectively. With T3 lesions, there was a steady decrease in survival with N0, N1, and N2 substages; whereas with T4 lesions, there was no difference in outcome between the N1 and N2 substages of disease. Although the overall group of T1-2 patients had improved survival when compared with T3 or T4 patients, the N0 subset of T3 and T4 patients had 5-year survival rates similar to T1-2/N1 (79%) or T1-2/N2 (67%) patients, at 75% (T3/N0) and 65% (T4/N0).
Disease relapse. The impact of both T and TN stage on local and distant disease relapse is presented in Table 2. Local relapse and distant metastasis rates were a function of both T stage and TN stage. The trends were similar to those observed in the survival analyses. Increasing T stage (T1-2, T3, T4) was associated with a steady increase in rates of both local (7% v 12% v 16%; P < .001) and distant relapse (22% v 34% v 41%; P < .001). However, when T stage was subdivided by respective N substage, there was an overlap in local relapse rates. For example, T3/N0 patients had similar local relapse rates as T1-2/N1 and T1-2/N2 (range, 7% to 9%), and T4/N0 patients had similar local relapse rates as those with T3/N1 and T3/N2 (range, 12% to 14%). A similar difference between T stage and TN stage was observed in the analyses of distant relapse rates. There was a steady increase in distant relapse rates with each combination of TN stage (15% v 31%, T1-2/N1 v N2, P < .001; T3/N0-2 [range, 20% to 47%], P < .001; T4/N0-2 [range, 28% to 53%] P = .002). For T3/N0 patients, the rate of distant relapse (20%) was between the rate seen in T1-2/N1 (15%) and T1-2/N2 (31%) patients. Patients with T4/N0 and T1-2/N1 lesions had a similar distant relapse rate (28% and 31%, respectively) and a somewhat lower distant relapse rate than patients with T3/N1 (37%) or T4/N1 lesions (39%). The highest distant relapse rates were seen in the patients with the highest combination of TN stage T3/N2 (47%) and T4/N2 (53%).
Results by N Stage and NT Stage
Survival. OS and DFS are shown as a function of N stage and NT stage (Fig 2, Table 3). The impact of T substage within N stage is similar to the impact of N substage within T stage with regard to a steady decrease in both OS and DFS (Table 3). Both the N stage and NT stage variably impact survival rates (5-year OS by N stage: N0, 74%, N1, 64%, N2, 48%; P < .001). Within each N stage, the progressive increase in T substage (T1-2, T3, T4) resulted in a decrease in survival (Fig 2). However, a subset of 355 patients with N1 disease (N1/T1-2) had OS and DFS similar to or exceeding that observed in N0/T3 and N0/T4 patients (5-year OS: N1/T1-2, 79%; N0/T3, 75%; N0T4, 65%). For patients with N2 lesions, the favorable 5-year OS of 67% with N2/T1-2 lesions (n = 226) was in marked contrast to the OS with N2/T3 (44%) or N2/T4 lesions (37%); P < .001. For N2T1-2 lesions, the 5-year survival of 67% was more similar to that of some patients with N0 and N1 lesions (N2/T1-2, 67%; N0/T4, 65%; N1/T3, 62%). Disease relapse. The impact of N stage and NT stage on disease relapse is shown in Table 3. Within N stage, an increase in T substage was associated with an increase in both local and distant relapse for N0 patients (N0/T3 v N0/T4) that did not achieve statistical significance. For N1 and N2 patients, an increase in T substage was associated with a statistically significant increase in distant relapse rates (P < .001), but the increase in local relapse rates achieved statistical significance only for the N1 patients (P < .001).
Survival and Relapse Rates by Stage of Disease
Results by Treatment Method and TN Stage of Disease Five-year OS by treatment method is shown in Figure 3 for each of the six treatment methods evaluated. Surgery alone and adjuvant radiation alone had inferior survival when compared with the other four treatment methods (P < .001). These differences are also demonstrated in Tables 5, 6, 7, 8, 9, 10, 11, and 12, for most TN stages of disease.
For each of the six treatment methods previously described, survival and relapse rates at 5-years were analyzed in descriptive fashion as a function of both TN and NT stage. Tables 5 through 10 show 5-year OS by TN (y-axis) and NT stage (x-axis) for each treatment method. For many of the treatment methods, there is a steady decrease in OS, with a progressive increase in both TN and NT stage. Patients were separated into three risk groups (intermediate, moderately high, high-risk) for analysis of survival (Table 11) and relapse rates (Table 12) by TN stage and treatment method. Intermediate-risk lesions. For patients with intermediate-risk lesions (T1-2/N1, T3/N0), surgery (S), followed by adjuvant chemotherapy (CT) had 5-year OS of 85% and 84% (Table 11). The trimodality treatment arms (radiotherapy [RT] + bolus CT, RT + protracted venous infusion CT, RT + bolus CT) had similar results with a 5-year OS range of 74% to 83%. With regard to DFS, surgery + CT had a 5-year DFS of 78% with T1-2/N1 lesions, but for T3/N0 lesions, 5-year DFS fell to 69% (Table 11). For the trimodality arms, 5-year DFS ranged from 75% to 78% for patients with T1-2/N1 lesions and from 63% to 75% for those with T3/N0 lesions. Local relapse rates with T1-2/N1 lesions ranged from 5% to 7% with adjuvant treatment; for T3/N0 lesions, LR was 11% with S plus CT, versus a range of 5% to 10% with trimodality methods (Table 12). Distant relapse rates for treatment arms without CT ranged from 25% to 41%, versus a range of 13% to 20% for CT arms (Table 12).
Moderately high-risk lesions.
For patients with moderately high-risk lesions (T1-2/N2, T3/N1, T4/N0), 5-year OS ranged from 20% to 80% by treatment method (Table 11), and 5-year DFS ranged from 20% to 70% (Table 11). S plus CT had a 70% 5-year OS for patients with T4/N0 lesions, but for T1-2/N2 and T3/N1 lesions, OS was less favorable at 43% and 52%, respectively. For the trimodality arms, 5-year OS was
High-risk lesions.
For patients with high-risk lesions (T3/N2, T4/N1-2), 5-year OS and DFS ranged from 0% to 57% by treatment method (Table 11). The 5-year OS and DFS exceeded 50% in only one of the 18 combinations of TN stage and treatment method. Local relapse was usually
Patterns and Rates of Relapse After Curative Resection Patterns of relapse after surgery alone for primary rectal cancer have been previously defined in clinical, reoperative and autopsy series.2,5–8 The rate of local (pelvic) relapse after "curative resection" is related both to the degree of tumor extension beyond the rectal wall and to nodal spread. For patients with a single high-risk factor of either direct tumor extension beyond the wall, nodes negative (T3/N0), or positive nodes but primary tumor confined to the wall (T1-2/N1-2), local relapse rates published in older surgical series vary from 20% to 40%.2,5–8 For patients with both positive nodes and extension beyond the wall (T3-4/N1-2), the risk of pelvic relapse was nearly additive (40% to 65% in clinical series and 70% in a reoperative series).2,5–8 When lesions extend beyond the muscularis propria, the amount of uninvolved perirectal tissue on microscopic review (circumferential or radial margin) may be equally or more important than the degree of extrarectal extension in determining the risk of local relapse.29 If lesions with surgical adherence to unresected structures have the sites of adherence marked by the surgeon, the pathologist can then determine whether the margins of resection are either narrow or microscopically involved. The rate of systemic metastases seems to be significantly higher for patients with both high-risk pathologic factors (extension beyond rectal wall and positive nodes; T3-4/N1-2), as opposed to those with only a single risk factor (T3-4/N0, T1-2/N1). In published data from adjuvant rectal cancer patients irradiated at either Massachusetts General Hospital (MGH)13 or the Mayo Clinic,16 the incidence of subsequent systemic relapse was approximately 20% with T3-4/N0 and T1-2/N+ lesions versus 40% to 60% with T3-4/N+ lesions.
Impact of TN and NT Stage on Relapse and Survival When results in the current pooled analysis were evaluated by N stage and NT stage (substaging within N stage based on the amount of primary disease extension or T stage), there was, again, variable survival and disease relapse by both N stage and by NT stage. Single-institution analyses from the Mayo Clinic16 and MGH13 had previously suggested that N1-2/T1-2 patients treated with postoperative irradiation alone or combined with chemotherapy had outcomes similar to N0/T3 and N0/T4 patients; however, the patient numbers in each stage subset were small. In the current analysis, 581 patients had N1-2/T1-2 lesions, 1,060 patients had N0/T3 lesions, and 111 had N0/T4 lesions. The 79% 5-year OS rates observed for the N1/T1-2 patients (n = 355) in the current analysis was similar to that for N0/T3 patients (75% 5-year OS). It was also similar to results found in a "patterns of care" analysis.30 The 67% 5-year survival seen with N2/T1-2 patients (n = 226) in the current analysis was higher than expected confirming findings in the earlier rectal pooled analysis.17 For the N2/T1-2 patients, 5-year OS was similar to that for patients with N0/T4 or N1/T3 lesions at 67% (N2/T1-2) v 65% (N0/T4) and 60% (N1/T3). Results by N2 stage were rarely available before the earlier pooled analysis,17 and results by T sub-stage within the N2 group (ie, T1-2/N2, T3/N2, T4/N2) were nonexistent.
Risk Analysis, Implications for Patient Information, and Staging In the current pooled analysis of survival and relapse rates by TN stage (Table 4), patients were separated into four risk groups (low-, intermediate-, moderately high-, and high-risk). The percentages listed for low-risk patients were based on single-institution2,5–16,31–33 or "patterns of care" analyses,30 since the low-risk patients (T1-2N0) were not eligible for the trials included in this analysis because of low relapse risks and excellent survival (approximate 90% 5-year OS). The 5-year OS, DFS, and relapse rates for the intermediate-, moderately high-, and high-risk patients are data from the current pooled analysis. For patients with intermediate-risk lesions (T1-2/N1, T3/N0), 5-year OS was 79% and 75%; those with moderately high-risk lesions (T1-2/N2, T3/N1, T4/N0) had a 5-year OS range of 60% to 67%, and patients with high-risk lesions (T3/N2, T4/N1-2) had 5-year OS of 37% to 44%. The 5-year DFS by risk group had similar trends: intermediate-risk, 73% and 65%; moderately high-risk, 48% to 58%; high-risk, 30% to 36%. The advantage of TN substaging over MAC staging in predicting both survival and disease relapse rates for node-positive patients is seen for MAC C1 and C2 stages (T1-3/N+) in the pooled analysis data (Table 4) but not with MAC C3 (T4/N+). For patients with T1-2 and T3 lesions, those with N1 disease (1 to 3 nodes involved) have statistically improved survival (Table 2) and lower rates of disease relapse (Table 2) when compared with their N2 counterparts (4 or more nodes involved). For patients with T4/N+ lesions, the number of involved nodes (N1 versus N2) did not affect either survival or the rate of local relapse, but did have an impact on the rate of distant metastasis (Table 2).
Substaging Within American Joint Committee on Cancer TNM System Patients with T1-2/N1-2 disease should receive a more favorable discussion regarding prognosis. Accurate data from large numbers of patients are now available to discuss the prognosis of T1-2/N1 and T1-2/N2 patients relative to other substages of disease. For patients with N2 disease, information from the current and prior pooled rectal cancer analyses shows that N2 disease does not by itself confer poor prognosis. Sub-staging by T stage influenced survival in the current analysis (5-year OS: N2/T1-2, 67%; N2/T3, 44%; and N2/T4, 37%; P < .001; 5-year DFS: 58% v 36% and 30%, P < .001). Therefore, placement of all N2 patients within AJCC IIIC substage does not reflect the markedly different prognosis of N2 patients found in the current and prior pooled rectal cancer analyses.17
Impact of Method of Treatment on Survival and Relapse At the present time, most clinicians concur that patients with low-risk lesions (T1-2/N0) are best managed with surgical resection alone, except for those with select lesions that may be amenable to less extensive treatment. Such patients are usually not referred for adjuvant treatment unless surgical resection margins are compromised. More controversy exists for patients with intermediate-risk lesions (T1-2/N1, T3/N0), who have been candidates for all of the trials included in the current pooled analysis and were included in the mandate for combined chemoradiotherapy in the 1990 National Institutes of Health consensus statement.1 It has been suggested for several decades that properly selected patients with T1-2/N1-2 or T3/N0 lesions may have relatively low risks of local and distant relapse with surgery alone.52,53 This may include those with upper rectal T1-2/N1 lesions who have only a few positive nodes adjacent to the primary lesion or those with negative nodes and minimal extension beyond the muscularis propria (T3/N0) who have adequate radial or circumferential resection margins.54,55 One of the challenges is adequate pathological evaluation of specimens to provide the necessary information concerning patient prognosis. The other challenge is to have enough data to determine what constitutes an adequate radial or circumferential resection margin. Collection of radial or circumferential margin data was encouraged in NCCTG 86-47-51 and INT 0114, but the percentage of patients with such information was so low that it could not be evaluated.19,20–22 In the current pooled analysis, patients with T1-2/N1 and T3/N0 lesions had a 5-year OS of 85% and 84% when treated with surgery followed by chemotherapy (S plus CT) as a single adjuvant (Tables 7 to 11). These results were similar to those achieved with trimodality combinations of surgery and chemo-radiation which resulted in a 5-year OS range of 78% to 83% for T1-2/N1 lesions and 74% to 80% for T3/N0 lesions (Table 11). An evaluation of 5-year OS data suggests that use of trimodality postoperative chemoradiation for all patients with T1-2/N1 and T3/N0 lesions may be excessive treatment. However, since this is a descriptive analysis of results across different trials and eras, definitive conclusions cannot be made regarding the necessity of adjuvant radiation. When 5-year DFS and relapse rates were evaluated (Tables 11 and 12), S plus CT had good results for patients with T1-2/N1 lesions with DFS of 78%, local relapse (LR) of 5%, and distant relapse of 16% (trimodality treatment: DFS range, 75% to 78%; LR range, 5% to 7%). For patients with T3/N0 lesions, however, 5-year DFS fell to 69% with S+CT and LR increased to 11% (distant relapse similar at 18%). For trimodality treatment, the 5-year DFS range with T3/N0 lesions was 63% to 75%, and LR ranged from 5% to 10%. The DFS and relapse data suggests that further improvements in outcome should be feasible, even for patients with "intermediate risk" rectal cancers. Such improvements in outcome might be achieved with the use of preoperative chemo-radiation in properly selected patients (T3 or N+ on the basis of endoscopic ultrasound), by the addition of new agents to current "standard regimens" or with the evaluation of targeted therapy based on molecular markers.
For patients with moderately high-risk lesions (T1-2/N2, T3/N1, T4/N0), the current analysis of results by treatment method showed definite room for improvement in outcome. Five-year OS ranged from 43% to 70% with S+CT and 44% to 80% with S plus RT plus CT. It was uncommon to have 5-year DFS In the high-risk patients (T3/N2, T4/N1-2 lesions), 5-year OS and DFS were less than 50% for most combinations of TN stage and treatment method (5-year OS range of 25% to 45% with S plus CT and 29% to 57% with S plus RT plus CT). Local relapse ranged from 0% to 33% with trimodality treatment, and distant relapse ranged from 22% to 78% even in CT arms, demonstrating much room for improvement in both therapy and outcomes.
Future Treatment Implications For carefully selected patients with intermediate risk lesions, it may be appropriate to evaluate surgery alone or plus postoperative chemotherapy if careful pathology evaluation suggests a low risk of LR after a confirmed total mesorectal excision by an experienced surgeon.53,56–58 However, initiation of new trials that evaluate radiation as a component of treatment for select intermediate-risk patients should be done with caution, using stringent surgical and pathological guidelines,54–57 since preoperative radiation reduced LR rates when combined with total mesorectal excision (8% v 2%, P < .001) in a Dutch phase III trial.56
Patients with T1-2/N1 and T3/N0 lesion are still appropriate candidates for adjuvant chemoradiotherapy. Trials evaluating adjuvant preoperative chemo-radiation would be reasonable for patients with distal lesions, in whom down-staging would improve the chance for rectal preservation and reanastamosis.59–65 Postoperative chemo-radiation trials should include patients without indications for preoperative treatment who have an inadequate evaluation of nodes (< 10 to 15 nodes examined by pathology)21 and those at higher risk for local relapse based on amount of primary tumor extension beyond the muscularis propria ( For patients with moderately high- or high-risk lesions, the high rates of both local and distant relapse support continuing use of both concurrent chemo-radiation and adjuvant chemotherapy or other systemic therapy. Further testing of the sequencing of chemo-radiation and surgery66,67 will probably not be indicated, since the completed German preoperative versus postoperative phase III trial resulted in an improvement in both sphincter preservation and local control for patients randomized to receive the preoperative chemoradiotherapy.68,69 Evaluation of preoperative chemoradiotherapy combined with more aggressive chemotherapy (ie, irinotecan or oxaliplatin) or targeted therapy (vascular endothelial growth factor or epidermal growth factor receptor inhibitors)70–74 is indicated in these patients in view of the modest efficacy of postoperative adjuvant therapy.
The authors indicated no potential conflicts of interest.
Oral Presentation at the 39th Annual Meeting of the American Society of Clinical Oncology in Colorectal Cancer Session, Chicago, IL, June 1, 2003. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
22% with trimodality treatment (eight of nine instances; range, 0% to 33%); with other treatment methods, however, LR exceeded 22% in three of nine instances (range, 0% to 50%). Distant relapse was commonly less than 50% with CT arms (range, 22% to 78%) and was 
