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Originally published as JCO Early Release 10.1200/JCO.2005.02.0826 on December 19 2005 © 2006 American Society of Clinical Oncology. Postoperative Surveillance in Patients With Colorectal Cancer Who Have Undergone Curative Resection: A Prospective, Multicenter, Randomized, Controlled TrialFrom the Gastroenterology, Surgical and Oncology Departments, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona (IDIBAPS), Barcelona; Oncology and Gastroenterology Departments, Hospital de Terrassa, Terrassa; and Gastroenterology and Oncology Department, Hospital General de Vic, Vic, Catalonia, Spain. Address reprint requests to Antoni Castells, MD, Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Villarroel 170, 08036 Barcelona, Catalonia, Spain; e-mail: castells{at}clinic.ub.es
Purpose: Although systematic postoperative surveillance of patients with colorectal cancer has been demonstrated to improve survival, it remains unknown whether a more intensive strategy provides any significant advantage. This prospective, multicenter, randomized, controlled trial was aimed at comparing the efficacy of two different surveillance strategies in terms of both survival and recurrence resectability. Patients and Methods: Patients with stage II or III colorectal cancer were allocated randomly to either a simple surveillance strategy including clinical evaluation and serum carcinoembryonic antigen monitoring, or an intensive strategy in which abdominal computed tomography or ultrasonography, chest radiograph, and colonoscopy were added. Results: A total of 259 patients were included: 132 were observed according to the simple strategy and 127 were observed according to the intensive strategy. Both groups were similar with respect to baseline characteristics and rate and type of tumor recurrence. After a median follow-up of 48 months, there was no difference in the probability of overall survival in the whole series (hazard ratio [HR] = 0.87; 95% CI, 0.49 to 1.54; P = .62). However, the intensive strategy was associated with higher overall survival in patients with stage II tumors (HR = 0.34; 95% CI, 0.12 to 0.98; P = .045) and in those with rectal lesions (HR = 0.09; 95% CI, 0.01 to 0.81; P = .03), mainly due to higher rate of resectability for recurrent tumors. Colonoscopy was responsible for the detection of the highest proportion (44%) of resectable tumor recurrence in the intensive arm. Conclusion: A more intensive surveillance strategy improves the prognosis of patients with stage II colorectal cancer or those with rectal tumors. Inclusion of regular performance of colonoscopy seems justified up to the fifth year of follow-up, at least.
Colorectal cancer (CRC) is the second-leading cause of cancer mortality in Western countries.1 Prognosis of these patients mainly depends on the tumor stage at diagnosis. Indeed, although more than two thirds of patients undergo radical surgery, up to 30% to 50% of patients with stage II to III tumors will develop tumor relapse as locoregional recurrence, distant metastasis, or metachronous colorectal lesions after 5 years of follow-up.2 This high risk of disease recurrence makes postoperative surveillance advisable, given that early treatment of tumor relapse seems to be critical to improve patients' prognosis.3-7 In that sense, several nonrandomized studies3,7-10 and four meta-analyses6,11-13 suggested that systematic follow-up of patients with CRC increases the rate of resectable tumor recurrence and improves survival. Although there is general agreement about the usefulness of postoperative surveillance, no consensus has been reached so far with respect to the most effective strategy. Indeed, follow-up schedules are highly heterogeneous regarding both procedures (clinical history, physical examination, carcinoembryonic antigen [CEA] monitoring, imaging techniques, and colonoscopy) and the frequency with which they are carried out.14,15 The lack of a uniform strategy is mainly due to the scarce number of randomized trials.16-21 Despite this fact, the American Society of Clinical Oncology expert panel concluded that there was enough evidence to recommend the inclusion of periodic serum CEA testing and clinical evaluation in any surveillance strategy in patients with CRC who have undergone curative resection, as well as colonoscopy every 3 to 5 years to detect metachronous lesions.14,15 Conversely, the panel also concluded that there was no convincing information on the effectiveness of the remaining investigations.14,15,22 Similarly, the contribution of colonoscopy to early detection of locoregional tumor recurrence and, consequently, to the overall effectiveness of surveillance strategies, is still under debate.19 This prospective, multicenter, randomized controlled trial was aimed at establishing the efficacy of two different surveillance strategies in patients with CRC who have undergone curative resection with respect to both survival and detection of resectable tumor recurrence. The working hypothesis of this study was that imaging techniques and colonoscopy did not add any benefit with respect to the simplest strategy based on clinical evaluation and serum CEA monitoring only.
All patients undergoing curative resection for newly diagnosed CRC in any participating center (Hospital Clinic of Barcelona, Barcelona; Hospital de Terrassa, Terrassa; and Hospital General de Vic, Vic, Spain) from January 1997 to December 2001 were considered for inclusion in this study. Exclusion criteria were TNM stage I or IV tumors, lack of an adequate staging to rule out distant or residual disease, history of familial adenomatous polyposis, personal history of inflammatory bowel disease, inability to be monitored by the surveillance program, and no consent to participate in the study. Baseline evaluation of patients included history, physical examination, and laboratory analyses including serum CEA concentration measured by an enzymatic immunoassay method. Complete colon study was achieved with colonoscopy to determine the presence of synchronous lesions. If colonoscopy of the entire bowel could not be performed before resection, a postoperative colonoscopy was warranted. Chest radiograph and abdominal computed tomography (CT) or ultrasonography were performed preoperatively. Immediately after surgery, patients were stratified according to center, tumor location (colon/rectum), and TNM stage (II/III); thereafter, patients were randomly allocated to either simple or intensive surveillance strategies by means of sealed envelopes containing computer-generated random numbers. Random assignment was centralized at the Hospital Clinic. The study protocol was approved by the institutional ethics of research committee of each participating center, and informed consent was obtained from each patient. Patients in both simple and intensive surveillance groups underwent regular clinical review, including history, physical examination, and laboratory analyses (CBC, liver function tests, and serum CEA concentration). Patients in the intensive strategy also underwent abdominopelvic CT (in those patients in whom primary tumor was located at rectum) or abdominal ultrasonography (in those patients in whom primary tumor was located at colon), chest radiograph, and colonoscopy (Table 1). The protocol required patients in the simple surveillance strategy to undergo these radiologic and endoscopic procedures only when tumor relapse was suspected according to any clinical or blood test abnormality. However, patients with hereditary nonpolyposis colorectal cancer or synchronous colorectal neoplasm who were allocated to the simple strategy underwent colonoscopy at 1 and 3 years of follow-up because of their high risk for metachronous lesions (Table 1).3,23
The therapeutic protocol was identical in both surveillance groups, and included postoperative adjuvant chemotherapy (fluorouracil and leucovorin) in all patients, and pre- or postoperative radiation therapy in patients with rectal cancer, in accordance with standard schedules.24 Tumor relapse was suspected on the basis of any suggestive clinical, radiologic, or endoscopic finding, or a confirmed CEA increment higher than 25% of previous value and above the normal upper limit.25 The first method suggesting tumor relapse in those patients with confirmed recurrence was registered as responsible for its detection. When tumor relapse was suspected from results of two procedures simultaneously, the following criteria were arbitrarily used to define the first method indicating tumor relapse: when clinical manifestation and CEA increase concurred, the first method was considered responsible; when CEA increase and imaging or endoscopic alteration concurred, the first method was considered responsible; when clinical manifestation and imaging or endoscopic alteration concurred, the first method was considered responsible. Work-up investigations included laboratory analyses, chest radiograph, colonoscopy, and/or abdominopelvic CT. Positron emission tomography was considered in patients with confirmed serum CEA increase in whom imaging techniques and colonoscopy did not identify tumor recurrence. Tumor relapse was histologically confirmed and classified as distant metastasis, locoregional recurrence (tumor growth restricted to the anastomosis or the region of primary operation), or metachronous lesion. Repeat operations were considered curative when all visible tumor tissue was removed and subsequent microscopy examination confirmed tumor-free surgical margins.
Statistical Methods
Continuous variables were expressed as mean ± standard deviation, and the length of follow-up was expressed as median and range. Differences in qualitative variables were evaluated by means of Results of both survival and tumor recurrence analyses were adjusted for potential confounding factors by using a multivariate approach. Cox proportional hazards modeling was used to determine the influence of patients' baseline characteristics (age, preoperative CEA levels, tumor stage, tumor location, and risk of metachronous lesions) on overall survival. Conversely, a logistic regression analysis was performed to evaluate the influence of these covariables on the proportion of resectable tumor recurrence. Considering the small sample sizes in some particular subgroup analyses, a limited number of covariates were used to adjust for these parameters. A cost-minimization analysis was performed to establish the most efficient strategy with respect to the detection of resectable tumor recurrence. Costs were calculated for each patient considering all procedures performed during the scheduled follow-up or as a result of additional work-up for any suspected recurrence. Costs were established according to Hospital Clinic current billing, without considering any change during the study (no discount rate was applied) or differences among centers. Neither the cost of primary tumor therapy nor indirect costs, such as time lost from work or transportation charges, were factored into the analysis.28 All P values were two sided. A P value of less than .05 was considered to indicate a statistically significant difference.
During the study period, 270 patients were included. Eleven patients (4%) were excluded after random assignment because of inadequate initial assessment of tumor stage (eight had distant metastases and three had a stage I tumor). Consequently, 259 patients constitute the basis of this study. One hundred twenty-seven patients were allocated to the intensive surveillance strategy and 132 patients were allocated to the simple surveillance arm (Fig 1). At baseline, both groups were similar (Table 2).
No patient was lost during follow-up. The median follow-up was 49 months (range, 24 to 87 months) in the intensive strategy group and 45 months (range, 21 to 86 months) in the simple strategy group. Compliance with both surveillance strategies was 95% and 97%, respectively, with no significant deviation in any specific method (data not shown).
Overall Survival
When the survival analysis was performed after patients were stratified according to the TNM stage, the intensive strategy was associated with a higher overall survival in those with stage II lesions (intensive strategy, 81.6 ± 2.1 months; simple strategy, 70.9 ± 4.0 months; P = .02; Fig 3). No difference was found in patients with stage III tumors (intensive strategy, 66.4 ± 4.0 months; simple strategy, 62.3 ± 4.6 months; P = .44; Fig 3). After we adjusted for potential confounding factors, the intensive strategy maintained its advantage in patients with stage II tumors (HR = 0.34; 95% CI, 0.12 to 0.98; P = .045), but not in those with stage III lesions (HR = 0.71; 95% CI, 0.34 to 1.47; P = .35).
Similarly, when the analysis was performed according to the location of primary tumor, the intensive strategy was associated with a higher overall survival in patients with rectal lesions (intensive strategy, 84.1 ± 2.3 months; simple strategy, 67.1 ± 4.9 months; P = .01; Fig 4). No difference was found in patients with tumor located at the colon (intensive strategy, 71.3 ± 2.9 months; simple strategy, 70.8 ± 3.3 months; P = .85; Fig 4). After we adjusted for potential confounding factors, the intensive strategy maintained its advantage in patients with rectal tumors (HR = 0.09; 95% CI, 0.01 to 0.81; P = .03), but not in those with lesions located at the colon (HR = 0.85; 95% CI, 0.45 to 1.61; P = .62). There were no differences when patients were stratified according to the participating center or the risk of metachronous lesions (data not shown).
Tumor Recurrence Tumor recurrence was detected in 35 patients (27%) allocated to the intensive strategy and in 34 patients (26%) allocated to the simple strategy (P = .74; Table 3); there was no difference in the probability of tumor recurrence (P = .82).
There were no differences between surveillance strategies with respect to time to relapse (P = .39) and type of recurrence (P = .81; Table 3). However, the intensive surveillance strategy was associated with a higher proportion of resectable tumor recurrence. Indeed, 18 patients (51%) in the intensive strategy group underwent curative resection again, whereas only 10 patients (29%) from the simple strategy group underwent curative resection again (P = .06). After we adjusted for potential confounding factors, this superiority was confirmed (OR = 2.85; 95% CI, 1.04 to 7.87; P = .04). When the analysis was performed after stratifying patients according to the TNM stage, the intensive strategy was associated with a higher proportion of resectable tumor recurrence with respect to the simple strategy in those with stage II lesions (intensive strategy, 11 of 15 [73%]; simple strategy, three of 15 [20%]; P = .003), but not in those with stage III tumors (intensive strategy, seven of 20 [35%]; simple strategy, seven of 19 [37%]; P = 1.0). After we adjusted for potential confounding factors, the intensive strategy maintained its advantage in patients with stage II tumors (OR = 8.88; 95% CI, 1.60 to 49.3; P = .01), but not in those with stage III lesions (OR = 1.10; 95% CI, 0.28 to 4.41; P = .89). Similarly, when the analysis was performed according to location of primary tumor, the intensive strategy was associated with a higher proportion of resectable tumor recurrence in those with rectal tumors (intensive strategy, four of five [80%]; simple strategy, two of 10 [20%]; P = .08), but not in those with tumor located at colon (intensive strategy, 14 of 30 [47%]; simple strategy, eight of 24 [33%]; P = .32). After we adjusted for potential confounding factors, the intensive strategy maintained its advantage in patients with rectal tumors (OR = 29.4; 95% CI, 0.94 to 916.48; P = .054), but not in those located at the colon (OR = 2.22; 95% CI, 0.71 to 6.67; P = .89). The most frequent first method indicating tumor recurrence in the simple strategy group was laboratory analysis (24 patients [71%]: increment of CEA concentration in 22 patients, alteration of liver function tests in one patient, and anemia in one patient), whereas abdominal CT or ultrasonography (31%), colonoscopy (26%), and laboratory analysis (23%) were responsible for detecting tumor recurrence in the intensive strategy group (Table 4). However, when only resectable tumor recurrences were considered, colonoscopy was responsible for the detection of highest proportion (44%) in the intensive strategy (Table 4). This differential performance remained in those subsets of patients in whom the intensive strategy achieved a higher detection rate of resectable tumor recurrence (ie, those with stage II tumors and rectal lesions; Table 4). Finally, colonoscopy-detected tumor relapse accounted for the highest resectability rate. This fact was due mainly to the detection of metachronous lesions (the type of tumor relapse associated with the highest resectability rate); these were detected more frequently in those subsets of patients who benefit from an intensive surveillance strategy (Tables 4 and 5).
To ascertain whether the efficacy of each individual surveillance procedure varied throughout the follow-up, tumor recurrence and those amenable to curative-intent surgery were analyzed in each period of time in patients observed according to the intensive strategy (Table 6). As shown, the resectability rate was lower in the first 2 years than in the last 3 years (  2 test; P = .001 for trend).
Finally, the cost minimization analysis demonstrated that although overall cost of follow-up was higher in the intensive strategy group (300,315  ) than in simple strategy group (188,630), the intensive surveillance strategy was more efficient when resectability was considered. In fact, the cost per resectable tumor recurrence was 16,684 in the intensive surveillance group and 18,863 in the simple surveillance arm.
The results of this randomized controlled trial suggest that, although no difference on overall survival was observed in the whole series, patients with CRC who have undergone curative resection may benefit from a more intensive surveillance strategy. This assumption is based on the fact that the intensive strategy increased the proportion of resectable tumor recurrences in the whole series as well as in some subsets of patients; more importantly, it increased the probability of overall survival in patients with stage II lesions or rectal tumors. To our knowledge, this is the first study in which it was possible to identify a more effective follow-up strategy in subgroups of patients based on baseline tumor location or stage exclusively. The strength of this investigation relies on several factors. First, its prospective and randomized design, along with the use of relevant prognostic factors as stratification criteria, allowed us to ensure an unbiased allocation of patients to the two groups, thus favoring the analysis in subsets of patients. Second, patients were observed for a long period of time, with no patients lost to follow-up and no deviation from the proposed protocol. Third, the simple surveillance strategy included the only two methods universally accepted (ie, clinical evaluation and CEA monitoring),14,15,22 whereas other procedures included in the intensive strategy are those most widely available. Fourth, evaluation of individual surveillance methods both overall and in each period of follow-up provided the opportunity to identify specific flaws of the evaluated strategies. We are aware, however, of some limitations of this study. First, sample size was calculated on the basis of a noninferiority hypothesis between strategies and, accordingly, the study could be underpowered to find a difference smaller than 15% in the 5-year survival rate.6,11,27,28 Nevertheless, this potential drawback could be circumvented because it was possible to discriminate the prognosis of subgroups of patients. Furthermore, it is important to consider that all randomized trials published so far16-21 failed to demonstrate a benefit in terms of overall survival—a fact only established in meta-analyses.6,11-13 Second, the relatively low number of events in some subsets of patients precludes the determination of the number of patients we needed to observe in each specific period of time, which would have allowed a more precise evaluation of the efficacy of individual methods. Nevertheless, to address this relevant issue, the number of tumor recurrences and the corresponding resectability rate were provided according to the first method indicating tumor relapse and year of detection. Finally, locoregional recurrence rate is higher than expected in a series in which colon cancer predominated. This circumstance might be explained by the potential misdiagnosis of some intramural relapses, which could actually correspond to metachronous lesions (an explanation that would also justify the high resectability rate obtained in these patients). The prognostic advantage observed in specific subsets of patients deserves some comments. Indeed, our results show that patients with stage II tumors or tumors located at the rectum benefited from a more intensive strategy, whereas those with stage III lesions or lesions located at the colon apparently did not achieve any gain. Although it is difficult to explain these results unequivocally, the type of recurrence detected in both strategies may contribute to elucidate this opposing performance. With respect to the stage of primary tumor, the intensive strategy detected double the number of metachronous lesions than the simple strategy in patients with stage II tumors, whereas no difference was observed in patients with stage III lesions. Although the limited number of events prevents us from reaching definitive conclusions, it is tempting to hypothesize that the better prognosis of patients with stage II tumors favors the appearance of second neoplasms, which benefit from an early detection and adequate surgical treatment. Explanation of the intensive strategy advantage in patients with rectal tumors is more challenging because of the lower number of events. However, in addition to considering that the only metachronous lesion was detected in the intensive strategy group, the fact that the resectability rate of both metastases and locoregional recurrences was higher in these patients than in those observed according to a simple scheme reinforces that an intensive strategy allowed earlier relapse detection. Contribution of individual surveillance methods to the overall benefit was analyzed considering both the proportion of tumor recurrences detected and the resectability rate achieved by each procedure. In this analysis, whereas CEA monitoring was responsible for the detection of the vast majority of relapses in the simple strategy group, abdominal imaging, colonoscopy, and chest radiograph contributed almost equally to their identification in the intensive strategy. However, when only curative-intent surgery was considered, colonoscopy constituted the most common method of detecting tumor relapse and, concurrently, the patients with recurrences detected during colonoscopy had the highest number of resectable tumors. These results reinforce the inclusion of this procedure in CRC surveillance strategies, as it has been previously proposed,3,15,22 whereas the addition of other techniques (ie, abdominal CT, ultrasonography, or chest radiograph) would be based on the overall benefit rather than on the specific individual data. In addition to assessment of the most useful methods to be included in a surveillance strategy, there is a need to delineate the most convenient timing to perform these procedures. With respect to colonoscopy, the American Society of Clinical Oncology expert panel concluded that there were sufficient data to recommend colonoscopy every 3 to 5 years to detect new colorectal lesions, but did not recommend routine annual performance of colonoscopy for all patients.15 Results of our study suggest that colonoscopy maintained its benefit in terms of resectability of recurrent tumors at least up to the fifth year; unfortunately, the most adequate interval cannot be extrapolated from these data. Conversely, analysis of the efficacy of the whole intensive surveillance method in each follow-up period indicates that it performed significantly poorer in terms of resectability of recurrent tumors in the first 2 years with respect to the years 3 to 5, thus suggesting the need to improve surveillance strategies at early stages. However, the real impact of such a policy on the prognosis of these patients is uncertain because the low resectability rate may actually reflect a more aggressive tumor behavior. In conclusion, the results of this study indicate that a more intensive surveillance strategy improves the prognosis of patients with stage II CRC or those with rectal tumors, and reinforces the convenience of including regular performance of colonoscopy. More importantly, the lack of benefit observed in patients with stage III colon cancer, mainly because the surveillance strategy did not result in improvement in the patients’ outcomes in the first 2 years, warrants the evaluation of different approaches based on either new methods, such as routine performance of positron emission tomography or shorter intervals among procedures in the early follow-up.
The authors indicated no potential conflicts of interest.
Supported by grants from the Agència d'Avaluació de Tecnologia Mèdica of the Generalitat de Catalunya (2/6/96), from the Instituto de Salud Carlos III (Grants No. RC03/02 and RC03/10), and from the Ministerio de Ciencia y Tecnología (Grant No. SAF 04-07190). F.R.-M. received a research grant from the Hospital Clínic and the Instituto de Salud Carlos III, and V.P. received a grant from the Institut d'Investigacions Biomèdiques August Pi i Sunyer. Presented in part at the Annual Meeting of the American Gastroenterological Association, Chicago, IL, May 16, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Jeffery GM, Hickey BE, Hider P: Follow-up strategies for patients treated for non-metastatic colorectal cancer [Cochrane Database System Review]. Oxford, United Kingdom, Cochrane Library, CD002200, 1, 2002 13. Figueredo A, Rumble RB, Maroun J, et al: Follow-up of patients with curatively resected colorectal cancer: A practice guideline. BMC Cancer 3:26, 2003[CrossRef][Medline] 14. Desch CE, Benson AB III, Smith TJ, et al: Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 17:1312, 1999 15. Benson AB III, Desch CE, Flynn PJ, et al: 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 18:3586-3588, 2000 16. Pietra N, Sarli L, Costi R, et al: Role of follow-up in management of local recurrences of colorectal cancer: A prospective, randomized study. Dis Colon Rectum 41:1127-1133, 1998[CrossRef][Medline] 17. 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Eur J Surg Oncol 28:418-423, 2002[CrossRef][Medline] 22. Pfister DG, Benson AB III, Somerfield MR: Clinical practice. Surveillance strategies after curative treatment of colorectal cancer. N Engl J Med 350:2375-2382, 2004 23. Jarvinen HJ, Aarnio M, Mustonen H, et al: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829-834, 2000[CrossRef][Medline] 24. Boland CR, Sinicrope FA, Brenner DE, et al: Colorectal cancer prevention and treatment. Gastroenterology 118:S115-S128, 2000[CrossRef][Medline] 25. Bast RC Jr, Ravdin P, Hayes DF, et al: 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1865-1878, 2001 26. Rothmann M, Li N, Chen G, et al: Design and analysis of non-inferiority mortality trials in oncology. Stat Med 22:239-264, 2003[CrossRef][Medline] 27. 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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
