- Email: [email protected]
Colorectal Cancer Follow-up in 2005
Surg Oncol Clin N Am 15 (2006) 175–193
Colorectal Cancer Follow-up in 2005 Thomas Anthony, MDa,b a
Division of Surgical Oncology, Department of Surgery, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA b VA North Texas Health Care System, 4500 South Lancaster Road, Dallas, TX 75216, USA
Monitoring patients after the completion of cancer therapy through carefully designed follow-up programs may have several benefits, including early recognition of other treatable disease through more frequent medical contact, better tracking of treatment results, and improved psychologic support. The main goal, however, is to improve survival. The survival benefit of a follow-up program for a population of cancer patients depends on the likelihood of recurrence, the availability of sensitive and specific tests to identify recurrences at a treatable stage, the availability of a curative retreatment options, an aggressive application of retreatment whenever possible, and the minimization of morbidity and mortality associated with retreatment. Whether the goal of improving survival rates through careful follow-up can be achieved for patients who had colorectal cancer (CRC) is the subject of considerable controversy. At first glance, CRC appears to present an ideal opportunity for demonstrating the merits of follow-up: approximately half of all patients treated for CRC will experience disease recurrence; tests exist that can identify recurrences while retreatment is still possible; curative retreatment options exist and are well described in the literature and can be applied with modest morbidity and mortality. Unfortunately, it has been very difficult to demonstrate that all of these elements, when applied to the follow-up of colorectal cancer, result in a measurable improvement in survival. This article reviews the available level-I data concerning the overall role of follow-up in colorectal cancer to identify individual tests that may help to identify recurrences, to address issues related to cost and the impact on quality of life, and to review current societal recommendations concerning colorectal cancer follow-up.
E-mail address: [email protected] 1055-3207/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2005.08.004 surgonc.theclinics.com
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Level-I studies of colorectal cancer follow-up: randomized, controlled trials and meta-analyses Six randomized, controlled trials have been undertaken that have compared different colorectal cancer (CRC) follow-up strategies. Each trial was undertaken in an attempt to define the survival benefit of intensive follow-up compared with less intensive follow-up. The following discussion highlights the heterogeneous follow-up strategies used and summarizes the principal findings of each study in their attempt to answer the general question of the value of CRC follow-up. The first reported randomized, controlled trial comparing CRC follow-up programs was reported in 1995 by Ohlsson and colleagues [1]. These authors randomized 107 patients undergoing curative-intent resection for colorectal cancer between ‘‘no-follow-up’’ (n ¼ 54) and intensive follow-up (n ¼ 53). Adjuvant therapy was not used. The intensive follow-up regimen consisted of a physical examination, rigid proctoscopy, carcinoembryonic antigen (CEA) and liver function studies, fecal hemoglobin, and chest radiography every 3 months for 2 years and then every 6 months for 2 years, with a final evaluation at 5 years. Additionally, patients underwent endoscopic visualization of their anastomosis or complete colonoscopy and a CT of the pelvis (if the patient had undergone abdominoperineal resection). The no-follow-up group underwent periodic fecal hemoglobin tests, and patients were given written and verbal instructions to return for symptoms. No statistical difference in the 5-year survival rate was noted between these two groups although there was a weak trend toward improved survival in the intensely followed group (67% at 5-year survival for the no-follow-up group versus 75% for the intensely followed group, P ¼ .26). The small sample of this study made the identification of a survival advantage unlikely, unless it were dramatic, but the trend toward improved survival was intriguing, especially considering individual patients who underwent retreatment. Five of 20 patients who had recurrence who were in the intensive follow-up arm underwent surgical retreatment; these included two anastomotic recurrences, the resection of two intra-abdominal, nonanastomotic recurrences, and resection of one ovarian metastasis. No liver or lung resections were performed. Only the two patients undergoing resection for intra-abdominal nonanastomotic recurrence were long-term survivors. Thus, only two of 53 (3.7%) patients benefited from the use of an intensive follow-up program. Later in 1995, Makela and colleagues [2] reported the results of a trial in which 106 patients who had undergone radical resection of CRC were randomized to either conventional (n ¼ 54) or intensive follow-up (n ¼ 52). Adjuvant therapy was not used. All patients were seen every 3 months for 2 years and then every 6 months for the next 3 years. At each visit, the patient’s history was taken, and an examination, a complete blood count, a fecal occult blood and CEA tests, and chest radiography were performed.
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Intensive follow-up was defined by the use of more endoscopic follow-up and the use of liver imaging (ultrasonography every 6 months and yearly CT). These authors reported no difference in 5-year survival based on follow-up. The intensely followed group had a 5-year survival rate of 59% versus 54% with conventional follow-up (P ¼ .5). Forty-three patients developed recurrence, and eight underwent reoperation (five in the intensive group and three in the conventional group). Among these patients, three were long-term survivors (one in the conventional arm and two in the intensive arm). Thus, two patients (3.8%) benefited from intensive follow-up. Interestingly, although the recurrence rates were higher in this study (Dukes’ A for example had 36% rate of recurrence), careful follow-up appeared to have no impact on survival. An increase in the recurrence rate should have increased the likelihood that a survival advantage would be identified with more intensive follow-up. The fact that it did not raises the possibility that either the follow-up used was truly ineffectual (at least compared with the conventional follow-up), that retreatment was not performed as often as it could have been, or alternatively, that the sample size was insufficient. The lack of positive results and the difficulty of interpreting studies with small sample sizes led to several additional trials of larger size. The largest prospective randomized trial of the impact of follow-up strategies for patients who had colorectal cancer on survival was reported in 1997 by Kjeldsen and colleagues [3]. These authors randomized 597 patients who had complete surgical resections of CRC to more frequent (n ¼ 290) or less frequent (n ¼ 307) follow-up visits. The two groups were stratified both by the site of disease (rectum or sigmoid versus other colonic sites) and by Dukes’ staging. No information was provided on the use of adjuvant therapy among participants. In the arm of the study with more frequent follow-up, patients were examined at 6, 12, 18, 24, 30, 36, 48, 60, 120, 150, and 180 months. The patients who underwent less frequent followups were seen at 60, 120, and 180 months. Each visits consisted of the same tests: a history, a clinical examination, gynecologic examination, digital rectal examination, a fecal hemoglobin test, colonoscopy, chest radiography, hemoglobin level, erythrocyte sedimentation rate, and liver enzymes. Radiologic examination of the liver was not performed, and CEA was not used. Although recurrent disease was identified earlier (and more frequently while patients were asymptomatic) and re-resections and metastectomies were performed more often in the more frequently seen group of patients, there was no difference in 5-year survival between the two groups (70% versus 68% at 5-year survival for frequent and less frequent examination, respectively). Ten (3.4%) patients in whom disease recurrence was identified and retreated (five local recurrences and two patients who had distant metastases and three with metachronous disease) remained free of disease in the group followed more frequently compared with two (0.6%) patients (one patient who had local recurrence and one metachronous disease) in the less frequently examined group. Examination at 6-month (versus more
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frequent) intervals and the lack of routine carcinoembryonic antigen measurement or liver imaging probably decreased the likelihood of identification of a survival benefit for the more intensely followed patients. In 1998, Pietra and colleagues [4] reported the first randomized, controlled trial to suggest a benefit to more intensive follow-up. These investigators randomized 207 patients who had undergone curative resection for Astler-Coller stages B1–2 or C1–2 colorectal cancer to either an intensive follow-up (104 patients) or a less intensive follow-up (103 patients). This study concentrated specifically on the detection, rates of re-resection, and survival based on two follow-up strategies. The distinction in follow-up was defined by more frequent visits and the inclusion of yearly CT in the intensely followed arm. Patients with rectal cancer received postoperative irradiation, but adjuvant therapy was not used in patients who had colon cancer. The results of this study suggest that local recurrences are detected earlier and are more often asymptomatic in patients who are followed more intensely. This finding led in turn to greater rates of resectability (65% versus 10%, in favor of the more intensely followed patients) and ultimately to more surviving patients in the intensely followed population. Five-year survival rates were 73% in the intensively followed group and 58% in the less intensely followed group (P % .02). In the intensely followed group, 26 local recurrences were identified. Seventeen patients underwent re-resection, and of these, eight patients (7.6% of the more intensely followed cohort) were long-term survivors. In the group less intensely followed, only two of 20 recurrences were re-resected, and neither of these patients was a long-term survivor. The lack of mention of other sites of recurrence, the limited of use of adjuvant therapy, and the coincidently high rates of local recurrence (15% for colon and 37% for rectal tumors) make the interpretation and generalization of the results of this study difficult. Also in 1998, Schoemaker and colleagues reported the results of a randomized trial of CRC follow-up [5]. A total of 325 patients who had undergone surgical resection for CRC were randomized to either standard (n ¼ 158) or intensive follow-up (n ¼ 167). The use of adjuvant therapy was not reported. Intensive follow-up included yearly chest radiography, CT of the liver, and colonoscopy. Clinic visits, liver function studies, fecal occult blood tests, and CEA tests were performed with the same frequency in both study arms. Isolated CEA elevations were not acted on. A nonsignificant improvement in survival was noted for patients followed with these additional tests (76% versus 70% at 5-year survival, respectively, P ¼ .20). A total of 26 (8%) patients were found to have isolated liver disease. Although many of these patients were found in the asymptomatic state in the intensively followed group, similar proportions of patients underwent surgical resection regardless of follow-up strategy (4/12 in the standard follow-up group and 3/14 in the intensive follow-up group). Only one of seven patients (a patient in the intensive follow-up arm) who underwent liver resection survived longterm. Eight patients (2.5%) were found to have isolated lung disease (four in
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each arm). Four of these eight patients underwent resection, with a single long-term survivor (this patient had been in the intensive follow-up arm). Colonoscopy identified a total of eight cancers, five of which were treatable (three in the standard arm and two in the intensive arm). Three of these patients remained alive, two from the intensive follow-up arm and one from the standard arm. Therefore, in terms of long-term survival after retreatment, a net of three patients (3/167 ¼ 1.8%) experienced increased survival that could be attributed directly to follow-up program intensity as measured by the use of yearly chest radiography, liver CT, and colonoscopy. Although this trial was well done and carefully analyzed, there were several flaws. First, the lack of adjuvant therapy complicates the ability to generalize these results to populations treated in such a manner. Second, CEA was drawn, but isolated increased values of CEA were not acted on. Basing further testing on CEA is among the more common strategies recommended for follow-up [6,7]. Finally, although recurrent disease was more often found in the asymptomatic state in patients undergoing more intensive follow-up, similar proportions of patients underwent surgical retreatment. Previous studies have suggested a greater rate (3 fold, on average) of resections among patients with asymptomatic disease [8]. If surgical retreatment is not pursued aggressively, increased follow-up intensity is unlikely to be of benefit. The most recent randomized trial comparing colorectal cancer follow-up programs was reported in 2002 by Secco and colleagues [9]. These authors divided their patients who had undergone surgery for colorectal cancer into those at high risk for recurrence (adenocarcinoma of the low rectum, splenic flexure Dukes-Kirklin B2 or T3 tumors, Dukes’ stage C, a preoperative CEA level of R7.5 ng/mL, poorly differentiated tumors, or tumors containing mucin or signet-ring cells) versus those at low risk (all others). Patients in the high-risk category were then randomized to undergo intensive or minimal follow-up. Patients in low-risk follow-up also were randomized between two strategies: a low-intensity follow-up plan versus a minimal follow-up plan. Based on the modulated intensity of follow-up and recurrence-risk stratification, the authors reported improved survival at 5 years for patients followed with more intensive follow-up for both highand low-risk patients. High-risk patients undergoing intensive follow-up had a 5-year survival rate of 50% versus 32% for those at a similarly high risk but who were followed minimally. The difference in 5-year survival for the low-risk patients was of a similar magnitude (80% for the intensively followed group and 60% for the minimal follow-up group). There are several concerns with this study. First, similar to the study by Pietra and colleagues [4], the authors report high rates of local recurrence (39% for high-risk patients and 17% for low-risk patients) and high rates of overall disease recurrence (local or metastatic disease, 69% for high-risk patients and 36% for low-risk patients). These high rates of recurrence by themselves increase the yield of any follow-up program but cannot be extrapolated to lower risk populations (including those treated with adjuvant therapy).
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Furthermore, despite an apparently large difference in survival, the number of actual patients benefiting from the identification of recurrence, resection of recurrent disease, and long-term survival after resection is small (7/192 [3.6%] in the risk-adapted follow-up groups versus 3/145 [2.1%] in the minimal follow-up groups) and is of similar magnitude to other studies. This raises the possibility that factors other than the follow-up program itself may have been responsible for the observed survival differences. Based on the above review, it is clear that if there is a survival benefit to more intensive follow-up after treatment of colorectal cancer, it is likely to be relatively small. Given the likelihood of only a small survival benefit and the relatively small size of most randomized, controlled studies, it is not surprising that most have shown no benefit from more intensive follow-up. The number of individual patients required to identify a 10% survival increase from 65% to 75% between two programs of follow-up is in excess 1000 patients in each arm. This number exceeds the number of patients accrued in any single study. Based on the desire to identify the value of follow-up, the likelihood of a potentially small but clinically meaningful benefit, and the underpowered nature of individualized randomized, controlled trials, combining individual study information into a single pooled sample and reanalyzing the effect of follow-up are appealing. Several meta-analyses that have taken this approach have been published [10–13]. With minor variations, each meta-analysis has reached similar conclusions in terms of the efficacy of intensive follow-up in improving survival (Table 1). There are a number of difficulties, however, with meta-analysis methodology when applied to the randomized, controlled trials of colorectal cancer follow-up. As mentioned previously, the value of a follow-up program is based on three factors: the rate of recurrence, the rate of identification of treatable disease recurrence, and survival after treatment. Variation in any of these three factors can result in differences in outcome, but only when rates of recurrence and survival after treatment are constant and a follow-up program results in an increased rate of identification of treatable disease can improved outcome be attributed directly to the follow-up program. A variation in recurrence rates (in these six trials recurrence rates varied from 19%–57% [4,9]), the use or disuse of adjuvant therapy (only one trial used adjuvant therapy [4]), and a variation in surgical outcome after retreatment are all potential confounders of the relationship between survival and follow-up intensity and are unaccounted for in the published meta-analyses. Even when focusing specifically on how follow-up intensity was defined, there is significant variation between individual trials. Indeed what was considered intensive follow-up in one study would have been much closer to less intensive follow-up in another (compare [3] with [5]). Combining studies that have such widely varying definitions of intensity makes little sense. Therefore, rather than definitively showing that a particular strategy is beneficial, these meta-analyses provide general support for the principle of colorectal cancer follow-up.
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Table 1 Summary of recent meta-analyses of colorectal cancer follow-up Study
Studies included
Patients (N)
Figueredo et al 2003 [13]
6 randomized trials [1–5,9]
1700
Jeffery et al 2002 [12]
5 randomized, controlled trials [1–5]
1342
Renehan et al 2002 [10]
5 randomized, controlled trials [1–5]
1342
Findings
Comment
Combined relative risk ratio for survival ¼ 0.80 (95% CI, 0.70-0.91) in favor of more intensively followed patients Odds ratio for mortality ¼ 0.67 (95% CI, 0.53-0.84); risk difference for mortality ¼ 0.07 (95% CI, 0.120.02) in favor of intensive follow-up Combined risk ratio for survival ¼ 0.81 (95% CI, 0.70-0.94) in favor of intense follow-up group
Asymptomatic recurrences and re-operations for cure were more common in patients followed intensively. Although there was a survival improvement with increased intensity of follow-up, variability in the tests used and the frequency of these tests did not allow for identification of optimal follow up program. Intense follow-up was most pronounced in four extramural detection studies (not [3]); intense follow-up identified recurrence earlier (average of 8.5 mo).
Furthermore, although more vigorous follow-up appears to be associated with an improved rate of survival, an analysis of the individual randomized, controlled trials suggests that the minority of this benefit actually comes as a result of the identification of recurrence and successful retreatment. Renehan and colleagues [14] have noted recently that, although in meta-analyses there appears to be survival benefit of approximately 10% associated with increased intensity of follow-up, only approximately 2% can be attributed to cure from salvage operations. The authors hypothesize that the remainder of the survival benefit is the result of other factors associated with follow-up, including improved psychologic support, altered lifestyle and diet, or the improved treatment of coincident disease. Ongoing or planned prospective randomized trials based in the United Kingdom and Italy hopefully will shed more light on the magnitude of benefit that can be attributed to intensive follow-up for patients who have CRC [15,16]. Individual tests used in follow-up of colorectal cancer The specific role of an individual test used in follow-up is the early and reliable identification of disease recurrence. These tests should be focused
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on the most likely sites of treatable recurrence. For CRC, the most likely sites of recurrent disease include local recurrence and metastasis to either the liver or lung. Because surgery is the only curative retreatment option currently available for disease at these sites, it is implied that follow-up program participants are fit candidates for the major surgical procedures that would be required to retreat disease in these locations. Furthermore, the majority of recurrences will be manifest within the first 2 years of follow-up; therefore, clustering tests during this period of increased risk makes intuitive sense.
Office visits Questioning the patient regarding symptoms and the performance of a physical examination, looking for signs of recurrence, are important components of a follow-up program. Periodic office visits also facilitate ordering, evaluating, and reviewing additional tests. Patients are often symptomatic at the time of identification of CRC recurrence. Poorly localized abdominal pain, weight loss, increased fatigue, and change in bowel habits are among the more common symptoms of recurrence. The lack of specificity of these symptoms often results in delays in evaluation. Delayed evaluation in turn results in few of these patients having resectable disease when the diagnosis is finally made. Studies suggest that the frequency of resectable disease identification in symptomatic patients is between 1.7 and 7% [3,17,18]. A physical examination of asymptomatic individuals, although rarely helpful in identifying occult colorectal cancer recurrence, can be helpful in the early identification of other disease processes that may benefit from treatment. The role of fecal occult blood testing (FOBT) as an extension of a digital rectal examination has been evaluated in the follow-up of patients who have colorectal cancer [2–5,19,20]. This test is capable of identifying both intraluminal local recurrences and metachronous disease. Most studies, however, have suggested a low sensitivity for this test in the identification of either manifestation of recurrent disease [19–21].
Complete blood counts and liver function tests It is widely believed that the role of the complete blood count (CBC) is very limited in the follow-up of colorectal cancer [6,7]. Two series that have indirectly assessed the role of the CBC and have found very few recurrences identified solely by this test [21,22]. This is not surprising because the reduction in hemoglobin level is nonspecific, and if it occurs at all, it is as a late finding in the course of extraluminal disease recurrence. Although it occurs more commonly with direct intraluminal recurrence, the sensitivity of a reduction in serum hemoglobin in identifying this condition is still quite
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low. Nonetheless, over 50% of physicians use a CBC test as a component of follow-up [23]. The possible role of liver function tests (LFTs) in following up CRC has been evaluated extensively. Unfortunately, many times even with widespread liver disease, LFTs are not elevated. The sensitivity of these tests are, therefore, low, and the rate of resectable disease identified solely by an abnormal liver function test is even lower [1,22,24,25]. Based on low sensitivity and poor ability to identify resectable disease, liver function studies are not routinely recommended [6,7]. Despite the recommendations against their use, liver function tests are still frequently obtained during CRC follow-up. Over 65% of the members of the American Society of Colon and Rectal Surgeons and more than 80% of the members of the Society of Surgical Oncology who responded to a survey on colorectal cancer follow-up practices reported using liver function tests in the first year of follow-up [26]. Carcinoembryonic antigen CEA is a membrane-bound, surface glycoprotein expressed by the majority of colorectal cancers. The CEA test has been in clinical use for more than 30 years, yet there is still considerable controversy concerning its best use in a CRC follow-up program. The CEA is often the first indicator of CRC recurrence. Several studies have suggested that in 33% to 67% of cases of asymptomatic recurrent disease, CEA will be elevated [2,15,27]. Furthermore, CEA elevation often occurs well in advance of other tests showing abnormal results. Estimates have suggested that CEA elevation gives a lead-time of 4 to 6 months compared with other tests [28,29]. On several levels, the CEA test appears to offer promise as a follow-up tool. The CEA test, however, does have significant limitations. First, the rate of falsepositive elevation approaches 20% [27]. Intra-abdominal inflammatory processes, other malignancies, and smoking are among the most common sources of these false-positive elevations [30]. Second, CEA levels appear to be fairly sensitive for hepatic metastasis (70%–80%) but much less sensitive for lung metastasis or local recurrences [27]. Third, CEA only signals disease recurrence and neither localizes the disease nor defines resectability. Additional testing is required for this purpose. Fourth, although several metaanalyses have suggested improvement in survival associated with follow-up programs using the CEA test compared with those in which CEA was not used, these studies have also routinely included other forms of liver imaging [10,11,13]. No randomized trial has shown a survival benefit attributable solely to CEA measurement. Despite these significant limitations, societal guidelines have routinely recommended the use of the CEA test [6,7,13]. This also matches practice patterns across the United States. Vernava and colleagues [31] found that, among members of the American Society of Colon and Rectal Surgeons,
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more than 80% of colorectal surgeons perform CEA measurements at least every 6 months for the first two years of follow-up. Virgo and colleagues [23] found a similar rate of CEA use among members of the Society of Surgical Oncology.
Radiologic examinations Chest radiography Based on a relatively low rate of metastatic disease to the lung and the modest sensitivity for detecting lung metastasis at a resectable stage, most experts feel that chest radiography is of limited value and should not be included routinely in a follow-up program [6,7]. Several series, however, have suggested that chest radiography leads to the identification of resectable disease in 1% to 2% of cases [17,18,22]. It is noteworthy that these trials included only patients who had colon cancer, thus these figures probably underestimate the value of chest radiography and because a greater proportion of rectal cancer patients will develop lung metastasis. Despite recommendations against its routine use, chest radiography is still used commonly in clinical practice; approximately 70% to 80% of clinicians use chest radiography yearly or more often in the follow-up of colorectal cancer [17,22,23]. Specific hepatic imaging: CT and liver ultrasonography Most patients who experience a recurrence of CRC will have liver metastases [32]. CT and ultrasonography are relatively sensitive and specific imaging modalities for identifying hepatic disease in these patients. The major limitations to the routine use of CT and ultrasonography for this purpose are an imperfect sensitivity and specificity, operator dependence for ultrasonography, and increased cost compared with other tests. Several studies have attempted to address directly the value of including CT or ultrasonography in a follow-up program. Although nonrandomized studies have documented reasonably good overall rates of recurrent disease identification and appreciable rates of resectable disease among those with liver recurrence, the results of randomized trials specifically addressing the value of CT or CT and liver ultrasonography to improve survival have been mixed [2,4,5,9,15,33]. Several meta-analyses have found that follow-up strategies that include liver imaging (CT or ultrasonography) and CEA have a statistically improved survival rate compared with strategies that omit routine liver evaluation [10,13]. A recent study has reported the simultaneous use of CT and CEA to detect recurrent disease among stage II or III CRC patients who were treated in a randomized trial of two forms of adjuvant therapy. This study suggests that the combination of CT and CEA is able to identify 90% of the asymptomatic hepatic recurrences, with CT identifying more
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cases of resectable disease than CEA [15]. This high rate of detection of asymptomatic disease suggests that CT and CEA may offer complimentary diagnostic information. CT is used by 30% to 35% of surgeons during the first year of follow-up of CRC [23]. Whether CEA compliments CT and the exact role of CT as a component of routine follow-up await further study. These questions become even more important considering the rapid evolution of CT technology.
Intraluminal follow-up The goal of intraluminal follow-up is to identify intraluminal local recurrence as well as metachronous disease. Because the timeframe for the development of each of these forms of disease is dramatically different, each of these goals will be discussed separately. Local and anastomotic recurrences The rate of anastomotic recurrence after colon cancer resection generally is believed to be too low to justify routine visualization [6]. There have been authors and expert panels, however, who have suggested that follow-up endoscopy may play more of a role after the treatment of rectal cancers because of the higher rates of local recurrence associated with tumors in this location, especially in patients who had American Joint Committee on Cancer stage II or III disease if combined chemotherapy and radiation therapy were not performed [34,35]. There have been two prospective randomized trials that have considered the role of anastomotic visualization or imaging after low anterior resection. Chemoradiation therapy was not used in either study. Ohlsson and colleagues [1] postoperatively visualized the anastomosis of such patients at 9, 21, and 42 months. Full colonoscopy was also performed for these patients at 3, 15, 30, and 60 months. This combination of studies led to the identification of one anastomotic recurrence. Makela and colleagues [2] used flexible sigmoidoscopy at each office visit if the patient had rectal or sigmoid cancer, in addition to yearly colonoscopy. They found one local recurrence. In neither study were increased absolute numbers or increased percentages of resectable anastomotic or loco-regional recurrences identified through heightened anastomotic surveillance compared with the control arm of these studies. Because most local recurrences occur as a result of positive circumferential margins at the time of the original resection, recurrent disease most often begins extraluminally, limiting the value of routine intraluminal evaluation. Endorectal ultrasonography (EUS), which can image the adjacent tissues in the pelvis, may be more valuable than traditional intraluminal evaluations. Several studies have suggested that EUS offers complimentary information to other modalities such as digital rectal examination and
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proctoscopy or CT [36,37]. Most experts have found, however, that EUS by itself has limited value in follow-up because it is difficult to distinguish postoperative changes from local recurrence. One study has looked specifically at the role of ultrasonography-guided biopsy as an adjunct to EUS in the identification of pelvic recurrence in patients who had rectal cancer and underwent sphincter-preserving procedures [38]. This study found that the addition of the biopsy improved sensitivity and specificity to over 90% compared with EUS alone, which had a specificity of only 57%. As the availability and expertise improve, this modality will likely become a more important component of follow-up for patients who had pelvic anastomoses. Identification of metachronous tumors The risk of developing metachronous adenomatous polyps or colorectal cancer after the completion of treatment of the index tumor depends on a number of factors, including the patient’s genetic profile and the length of follow-up considered. Several studies have attempted to define this risk for metachronous polyp and cancer development by performing periodic colonoscopy on cohorts of patients after primary colorectal cancer treatment [39–41]. These studies have uniformly suggested that the rates of polyp and cancer development in patients who have undergone treatment of colorectal cancer are low but exceed those present in the general population. Because screening colonoscopy has been associated with a reduction in colorectal cancer mortality, it follows that the same benefit (and perhaps one even more pronounced) would be present for patients undergoing colonoscopic follow-up after treatment for colorectal cancer. A recent study has preliminarily confirmed this hypothesis. This report suggests a 43% reduction in death rate if one postoperative colonoscopy were performed compared with patients who had completed treatment and did not undergo colonoscopy [42]. Although most clinicians believe that postoperative colonoscopy is warranted, there is some controversy concerning the optimal frequency of colonoscopic evaluation [43]. The most common approach has been to perform colonoscopy within 1 year of the completion of therapy. If the remaining colon is normal or contains only low-risk polyps, colonoscopic evaluation can then occur every 3 to 5 years. Conducting a colonoscopic examination every 3 to 5 years is based on the extrapolation of data from the National Polyp Study, in which colonoscopy at 3-year intervals was found to be as good as colonoscopy at 1 and 3 years in identifying polyps with advanced pathologic features [44]. It is likely however, that colorectal cancer patients are at a higher risk for polyp and cancer development compared with those patients included in the National Polyp Study (patients who had colonoscopically defined and resected adenomas were included in the National Polyp Study), and a case could be made for more frequent
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colonoscopic evaluation. Comparisons of differing frequencies of colonoscopic examination should be a component of future studies of CRC follow-up.
Other studies: positron emission tomography and CT The role of positron emission tomography (PET) and PET combined with simultaneous CT in the follow-up of patients who had colorectal cancer is evolving. Currently, PET is most commonly used as a tertiary test in follow-up. It is used as a staging tool after recurrence has been documented by another modality and further surgical treatment is planned. In this latter circumstance, the role of PET is to rule out disease outside of the intended field of surgery [45,46]. Studies have suggested that PET scanning will alter the surgical plan in approximately 25% of cases, most commonly because greater amounts of disease have been identified [46,47]. Furthermore, patients who underwent PET scans that showed negative results for extrahepatic disease and who undergo liver resection have been reported to have improved survival compared with patients preoperatively staged by other modalities [48]. PET is also used commonly after other studies have suggested the possibility of recurrent disease. Although many tracer agents are available, the majority of PET imaging in oncology has relied on [18F]-2-fluoro-2 deoxyD-glucose and the increased uptake of this tracer in metabolically active tissue. The use of this tracer and PET allows for the functional assessment of areas of increased metabolism. Coupled with the use of whole-body scans, this methodology makes possible an accurate survey of metastatic sites in both usual (liver, lung, and local recurrence) and unusual sites (brain, bone, soft-tissue, and others). Most studies have found accuracy rates for the detection of recurrent and metastatic disease between 80% and 97% [45,49,50]. Although these reported accuracy rates are substantially better than CT alone (indeed the indication for these studies is often rising CEA coupled with a negative CT scan), there is a considerable overlap with other metabolically active tissues, such as inflammatory tissue (from recent surgery or infection), bowel, and urinary tract [46]. On the other hand, mucinous tumors, well-differentiated varieties of colorectal cancer with lower metabolic rates, and tumors treated neoadjuvantly can also be the source of false-negative results [46,50,51]. Combining anatomic imaging with functional imaging theoretically would decrease both false-negatives and false-positives that would occur with PET alone. Several recent reports have suggested increased accuracy using combined PET and CT [46,50]. One study of 100 PET-CT scans has suggested an improvement in specificity from 63% to 100% with dedicated CT interpretation [50]. Although no study to date has used PET or PET-CT as a primary modality for follow-up of CRC,
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perhaps with increasing availability, decreasing cost, and improved tracers, PET will assume a more prominent role.
Other issues Cost and cost effectiveness Although it is likely that there is a benefit to intensive post-treatment follow-up for patients who have had colorectal cancer, the survival benefit is small. The economic question that must be addressed, therefore, is whether the small improvement in survival justifies the expenditure of health care dollars necessary to meet this end. In so far as specific information regarding optimal tests and the timing of those tests to achieve improved survival is unavailable, there can be no direct answer to this question. Several authors, however, have performed theoretical analyses based on limited data and many assumptions [52,53]. These studies have uniformly suggested that, although the benefit may be limited in terms of survival, the cost associated with these benefits have not been extreme. Renehan and colleagues [54] have taken the approach of a cost-effectiveness analysis based on the costs associated with the follow-up strategies used in five of the randomized, controlled trials of colorectal cancer. Using this approach, these authors calculated that the cost for intensive follow-up resulted in a net extra cost of £2479 to £2529 ($4214–$4299) per patient compared with the less intensive follow-up arm. Each life year saved through intensive follow-up was calculated to cost between £3077 and £3402 ($5230–$5783). This is well below the current British National Health System cost acceptability level of £30,000 or the United States standard of $50,000. They further calculated that, given the incremental cost of intensive follow-up relative to less intensive follow-up (as defined by the five studies), the threshold of cost acceptability would be reached when the intensive follow-up regimens resulted in a reduction in absolute mortality of 3% or less. Further progress in this important area awaits completion of adequately powered randomized, controlled trials that have incorporated a cost-effectiveness analysis into the study design. Quality of life and patient satisfaction The impact that participation in follow-up can have on individual patient quality of life and satisfaction with care is variable. Participation in a follow-up program may either provide relief or provoke anxiety. Which effect predominates for a given patient probably depends on a complex interaction among many factors, such as fear of recurrence, patient confidence in the ability of follow-up to identify recurrence, the frequency of follow-up, tests used, economic considerations, and overall attitude toward care. To date, there have been very few studies that assess the impact of a follow-up program on quality of life or patient satisfaction with care. In
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an attempt to address the question of whether participation in follow-up resulted in increased anxiety and a negative impact on quality of life, Stiggelbout and colleagues [24] studied a group of 82 patients enrolled in unspecified follow-up programs in four hospitals in the Netherlands. They found that patient quality of life did not vary based on the timing of the measurement relative to the visit (quality of life was measured 1 week before a visit, 2 weeks after, or at the midpoint between visits), suggesting that participation in follow-up does not have a negative effect on quality of life. This study also explored patient preference for follow-up. These investigators found that for most patients, participation in a follow-up program conveys a sense of security. Over three fourths of patients felt that the advantages of participation in follow-up outweighed the disadvantages. Patients in this study were
Table 2 Summary of societal recommendations and guidelines dealing with colorectal cancer follow-up Society and year of recommendation American Society of Colon and Rectal Surgeons 2004 [6]
American Society of Clinical Oncology 2000 [7]
National Comprehensive Cancer Network (www.nccn.org) (2005)
Cancer Care, Ontario’s program in evidenced-based care 2003 [13]
Recommendations Clinical evaluation should be performed every 3 mo for 2 y followed by 6-mo follow-ups through year 5. CEA should be measured at each visit. Periodic direct visualization of anastomosis or excision site is recommended for patients undergoing either low anterior resection or local excision of rectal cancer. Colonoscopy should be performed preoperatively if possible or within 6 mo of surgery. If no polyps are identified, colonoscopy should be repeated at 3-y intervals Perform history and examination every 3–6 mo for first 3 y and annually thereafter. Administer CEA every 2–3 mo in patients with stages II–III for R2 y. Colonoscopy is recommended pre- or perioperatively and then every 3–5 y. Patients with stage II or III rectal cancer who have not received pelvic radiation should undergo periodic direct rectal imaging (flexible sigmoidoscopy). A history and physical should be obtained every 3 mo for 2 y and then every 6 mo until y 5. For tumors with invasion to or through muscularis propria, measure CEA every 3 mo for 2 y and then every 6 mo through y 5. CT scan may be considered for patients at high risk of recurrence. Perform colonoscopy preoperatively or, if not possible because of obstruction, within 3–6 months, then yearly for 2 y, and then at least every 2–3 y if negative for polyps. In patients who are at high risk of relapse (stages IIb and III), who are fit and willing to undergo investigation for and treatment of recurrence: prompt assessment of symptoms and clinical assessment every 6 mo for 3 y and then annually for 3 y. During these visits, patient may have CEA, chest radiography and liver ultrasounography or CT. Additionally, based on the American Gastroenterologic Association guideline (for stages I–III), colonoscopy should be performed postoperatively if not preoperatively; if high risk polyps are found (R1 cm), repeat colonoscopy yearly; if no polyps are found, repeat colonoscopy every 3–5 y.
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reluctant to switch to a less rigorous follow-up strategy, even if it led to a similar rate of early detection of a recurrence [24]. A single study of health-related quality of life (HRQoL) of patients enrolled in a randomized, controlled trial has been performed [55]. These authors administered the Nottingham Health Profile at a single time during follow-up to 350 patients who had completed therapy for colorectal cancer. They found that patients who underwent more intensive follow-up had a HRQoL that was comparable to their counterparts who were undergoing less rigorous follow-up. They also found that patients followed more intensively had greater confidence that their follow-up would increase their lifespan and in general had more of a positive attitude about follow-up [55]. These preliminary works leave many questions unanswered, including, do particular tests influence quality of life? If the frequency of testing does not influence HRQoL, is it an important determinant of satisfaction? Why do patients prefer more intensive follow-up even if it has a minimal impact on survival? Can patients be satisfied with less frequent follow-up; and most importantly, how can concerns about survival, HRQoL, and satisfaction be integrated to insure an optimal follow-up program? These and other question will require increased research attention in order for further progress to be made. Current recommendations Although the supporting literature for specific tests and timing of those tests is far from ideal, several professional societies that commonly deal with CRC have developed follow-up program recommendations [6,7,13]. These recommendations are summarized in Table 2. Despite varied membership, these recommendations are fairly uniform. All recommend a combination of history, physical examination, CEA, and periodic endoscopic examinations. Ideally, future research will concentrate on comparisons of these recommendations to other possible follow-up strategies. References [1] Ohlsson B, Breland U, Ekberg H, et al. Follow-up after curative surgery for colorectal carcinoma: randomized comparison with no follow-up. Dis Colon Rectum 1995;38(6):619–26. [2] Makela JT, Laitinen SO, Kairaluoma MI. Five-year follow-up after radical surgery for colorectal cancer: results of a prospective randomized trial. Arch Surg 1995;130(10):1062–7. [3] Kjeldsen BJ, Kronborg O, Fenger C, et al. A prospective randomized study of follow-up after radical surgery for colorectal cancer. Br J Surg 1997;84(5):666–9. [4] Pietra N, Sarli L, Costi R, Ouchemi C, et al. Role of follow-up in management of local recurrences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 1998; 41(9):1127–33. [5] Schoemaker D, Black R, Giles L, et al. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998;114(1): 7–14 [comments: 211–3].
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[6] Anthony T, Simmang C, Hyman N, et al. Practice parameters for the surveillance and follow-up of patients with colon and rectal cancer. Dis Colon Rectum 2004;47(6):807–17. [7] Benson AB III, Desch CE, Flynn PJ, et al. 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 2000;18(20):3586–8. [8] Ohlsson B, Palsson B. Follow-up after colorectal cancer surgery [review]. Acta Oncol 2003; 42(8):816–26. [9] Secco GB, Fardelli R, Gianquinto D, et al. Efficacy and cost of risk-adapted follow-up in patients after colorectal cancer surgery: a prospective, randomized and controlled trial. Eur J Surg Oncol 2002;28(4):418–23. [10] Renehan AG, Egger M, Saunders MP, et al. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials [review]. BMJ 2002;324(7341):813. [11] Rosen M, Chan L, Beart RW Jr, et al. Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 1998;41(9):1116–26. [12] Jeffery GM, Hickey BE, Hider P. Follow-up strategies for patients treated for non-metastatic colorectal cancer [review]. Cochrane Database Syst Rev 2002;(1):CD002200. [13] Figueredo A, Rumble RB, Maroun J, et al. Follow-up of patients with curatively resected colorectal cancer: a practice guideline [review]. BMC Cancer 2003;3(1):26. [14] Renehan AG, Egger M, Saunders MP, et al. Mechanisms of improved survival from intensive followup in colorectal cancer: a hypothesis. Br J Cancer 2005;92(3):430–3. [15] Chau I, Allen MJ, Cunningham D, et al. The value of routine serum carcino-embryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer. J Clin Oncol 2004;22(8):1420–9 [comments: 1363–5]. [16] Johnson FE, Virgo KS, Fossati R. Follow-up for patients with colorectal cancer after curative-intent primary treatment. J Clin Oncol 2004;22(8):1363–5. [17] Graham RA, Wang S, Catalano PJ, et al. Postsurgical surveillance of colon cancer: preliminary cost analysis of physician examination, carcinoembryonic antigen testing, chest x-ray, and colonoscopy. Ann Surg 1998;228(1):59–63. [18] Goldberg RM, Fleming TR, Tangen CM, et al for the Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Ann Intern Med 1998;129(1):27–35 [comments]. [19] Ahlquist DA, Wieand HS, Moertel CG, et al. Accuracy of fecal occult blood screening for colorectal neoplasia: a prospective study using Hemoccult and HemoQuant tests. JAMA 1993;269:1262–7. [20] Jahn H, Joergensen OD, Kronborg O, et al. Can Hemoccult-II replace colonoscopy in surveillance after radical surgery for colorectal cancer and after polypectomy? Dis Colon Rectum 1992;35(3):253–6. [21] Graffner H, Hultberg B, Johansson B, et al. Detection of recurrent cancer of the colon and rectum. J Surg Oncol 1985;28(2):156–9. [22] Peethambaram P, Weiss M, Loprinzi CL, et al. An evaluation of postoperative follow-up tests in colon cancer patients treated for cure. Oncology 1997;54(4):287–92. [23] Vernava AM 3rd, Longo WE, Virgo KS, et al. Current follow-up strategies after resection of colon cancer. Results of a survey of members of the American Society of Colon and Rectal Surgeons. Dis Colon Rectum 1994;37(6):573–83. [24] Stiggelbout AM, de Haes JC, Vree R, et al. Follow-up of colorectal cancer patients: quality of life and attitudes towards follow-up. Br J Cancer 1997;75(6):914–20. [25] Rocklin MS, Slomski CA, Watne AL. Postoperative surveillance of patients with carcinoma of the colon and rectum. Am Surg 1990;56(1):22–7. [26] Virgo KS, Wade TP, Longo WE, et al. Surveillance after curative colon cancer resection: practice patterns of surgical subspecialists. Ann Surg Oncol 1995;2(6):472–82 [comments: 467–8].
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[27] Moertel CG, Fleming TR, Macdonald JS, et al. An evaluation of the carcinoembryonic antigen (CEA) test for monitoring patients with resected colon cancer. JAMA 1993;270(8): 943–7. [28] Duffy MJ. Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful? [review] Clin Chem 2001;47(4):624–30. [29] McCall JL, Black RB, Rich CA, et al. The value of serum carcinoembryonic antigen in predicting recurrent disease following curative resection of colorectal cancer. Dis Colon Rectum 1994;37(9):875–81. [30] Anthony T, Fleming JB, Bieligk SC, et al. Postoperative colorectal cancer surveillance [review]. J Am Coll Surg 2000;190(6):737–49. [31] Vernava AM, Longo WE, Virgo KS, et al. Current follow-up strategies after resection of colon cancer. Dis Colon Rectum 1994;37:573–83. [32] Galandiuk S, Wieand HS, Moertel CG, et al. Patterns of recurrence after curative resection of carcinoma of the colon and rectum. Surg Gynecol Obstet 1992;174(1):27–32. [33] Glover C, Douse P, Kane P, et al. Accuracy of investigations for asymptomatic colorectal liver metastases. Dis Colon Rectum 2002;45(4):476–84. [34] Fleischer DE, Goldberg SB, Browning TH, et al. Detection and surveillance of colorectal cancer. JAMA 1989;261:580–5. [35] Desch CE, Benson AB III, Smith TJ, et al. Recommended colorectal cancer surveillance guidelines by the American Society of Clinical Oncology. J Clin Oncol 1999;17(4):1312–21. [36] de Anda EH, Lee SH, Finne CO, et al. Endorectal ultrasound in the follow-up of rectal cancer patients treated by local excision or radical surgery. Dis Colon Rectum 2004;47(6): 818–24. [37] Milsom JW, Lavery IC, Stolfi VM, et al. The expanding utility of endoluminal ultrasonography in the management of rectal cancer. Surgery 1992;112(4):832–40. [38] Hunerbein M, Totkas S, Moesta KT, et al. The role of transrectal ultrasound-guided biopsy in the postoperative follow-up of patients with rectal cancer. Surgery 2001;129(2):164–9. [39] Chen F, Stuart M. Colonoscopic follow-up of colorectal carcinoma. Dis Colon Rectum 1994;37(6):568–72. [40] Cali RL, Pitsch RM, Thorson A, et al. Cumulative incidence of metachronous colorectal cancer. Dis Colon Rectum 1993;36:388–93. [41] Lan YT, Lin JK, Li AF, et al. Metachronous colorectal cancer: necessity of post-operative colonoscopic surveillance. Int J Colorectal Dis 2005;20(2):121–5. [42] Fisher DA, Jeffreys A, Grambow SC, et al. Mortality and follow-up colonoscopy after colorectal cancer. Am J Gastroenterol 2003;98(4):901–6 [comments: 2801–3]. [43] McFall MR, Woods WG, Miles WF. Colonoscopic surveillance after curative colorectal resection: results of an empirical surveillance programme. Colorectal Dis 2003;5(3):233–40. [44] Winawer SJ, Zauber AG, O’Brien MJ, et al for the National Polyp Study Workgroup. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993;328(13):901–6 [comments: 2028–9]. [45] Larson SM, Schoder H, Yeung H. Positron emission tomography/computerized tomography functional imaging of esophageal and colorectal cancer [review]. Cancer J 2004;10(4): 243–50. [46] Selzner M, Hany TF, Wildbrett P, et al. Does the novel PET/CT imaging modality impact on the treatment of patients with metastatic colorectal cancer of the liver? Ann Surg 2004; 240(6):1027–34. [47] Arulampalam TH, Francis DL, Visvikis D, et al. FDG-PET for the pre-operative evaluation of colorectal liver metastases. Eur J Surg Oncol 2004;30(3):286–91. [48] Fernandez FG, Drebin JA, Linehan DC, et al. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 2004;240(3):438–47. [49] Huebner RH, Park KC, Shepherd JE, et al. A meta-analysis of the literature for whole-body FDG PET detection of recurrent colorectal cancer. J Nucl Med 2000;41:1177–89.
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[50] Kamel IR, Cohade C, Neyman E, et al. Incremental value of CT in PET/CT of patients with colorectal carcinoma. Abdom Imaging 2004;29(6):663–8. [51] Whiteford MH, Whiteford HM, Yee LF, et al. Usefulness of FDG-PET scan in the assessment of suspected metastatic or recurrent adenocarcinoma of the colon and rectum. Dis Colon Rectum 2000;43(6):759–67. [52] Ketteniss M, Schutz G, Ulrich B. Costs and efficiency of a tumor follow-up program for the detection of colorectal liver metastases. Int J Colorectal Dis 2001;16(1):28–31. [53] Norum J, Olsen JA. A cost-effectiveness approach to the Norwegian follow-up programme in colorectal cancer. Ann Oncol 1997;8(11):1081–7. [54] Renehan AG, O’Dwyer ST, Whynes DK. Cost effectiveness analysis of intensive versus conventional follow up after curative resection for colorectal cancer. BMJ 2004;328(7431):81. [55] Kjeldsen BJ, Thorsen H, Whalley D, et al. Influence of follow-up on health-related quality of life after radical surgery for colorectal cancer. Scand J Gastroenterol 1999;34(5):509–15.
Colorectal Cancer Follow-up in 2005 Thomas Anthony, MDa,b a
Division of Surgical Oncology, Department of Surgery, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA b VA North Texas Health Care System, 4500 South Lancaster Road, Dallas, TX 75216, USA
Monitoring patients after the completion of cancer therapy through carefully designed follow-up programs may have several benefits, including early recognition of other treatable disease through more frequent medical contact, better tracking of treatment results, and improved psychologic support. The main goal, however, is to improve survival. The survival benefit of a follow-up program for a population of cancer patients depends on the likelihood of recurrence, the availability of sensitive and specific tests to identify recurrences at a treatable stage, the availability of a curative retreatment options, an aggressive application of retreatment whenever possible, and the minimization of morbidity and mortality associated with retreatment. Whether the goal of improving survival rates through careful follow-up can be achieved for patients who had colorectal cancer (CRC) is the subject of considerable controversy. At first glance, CRC appears to present an ideal opportunity for demonstrating the merits of follow-up: approximately half of all patients treated for CRC will experience disease recurrence; tests exist that can identify recurrences while retreatment is still possible; curative retreatment options exist and are well described in the literature and can be applied with modest morbidity and mortality. Unfortunately, it has been very difficult to demonstrate that all of these elements, when applied to the follow-up of colorectal cancer, result in a measurable improvement in survival. This article reviews the available level-I data concerning the overall role of follow-up in colorectal cancer to identify individual tests that may help to identify recurrences, to address issues related to cost and the impact on quality of life, and to review current societal recommendations concerning colorectal cancer follow-up.
E-mail address: [email protected] 1055-3207/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2005.08.004 surgonc.theclinics.com
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Level-I studies of colorectal cancer follow-up: randomized, controlled trials and meta-analyses Six randomized, controlled trials have been undertaken that have compared different colorectal cancer (CRC) follow-up strategies. Each trial was undertaken in an attempt to define the survival benefit of intensive follow-up compared with less intensive follow-up. The following discussion highlights the heterogeneous follow-up strategies used and summarizes the principal findings of each study in their attempt to answer the general question of the value of CRC follow-up. The first reported randomized, controlled trial comparing CRC follow-up programs was reported in 1995 by Ohlsson and colleagues [1]. These authors randomized 107 patients undergoing curative-intent resection for colorectal cancer between ‘‘no-follow-up’’ (n ¼ 54) and intensive follow-up (n ¼ 53). Adjuvant therapy was not used. The intensive follow-up regimen consisted of a physical examination, rigid proctoscopy, carcinoembryonic antigen (CEA) and liver function studies, fecal hemoglobin, and chest radiography every 3 months for 2 years and then every 6 months for 2 years, with a final evaluation at 5 years. Additionally, patients underwent endoscopic visualization of their anastomosis or complete colonoscopy and a CT of the pelvis (if the patient had undergone abdominoperineal resection). The no-follow-up group underwent periodic fecal hemoglobin tests, and patients were given written and verbal instructions to return for symptoms. No statistical difference in the 5-year survival rate was noted between these two groups although there was a weak trend toward improved survival in the intensely followed group (67% at 5-year survival for the no-follow-up group versus 75% for the intensely followed group, P ¼ .26). The small sample of this study made the identification of a survival advantage unlikely, unless it were dramatic, but the trend toward improved survival was intriguing, especially considering individual patients who underwent retreatment. Five of 20 patients who had recurrence who were in the intensive follow-up arm underwent surgical retreatment; these included two anastomotic recurrences, the resection of two intra-abdominal, nonanastomotic recurrences, and resection of one ovarian metastasis. No liver or lung resections were performed. Only the two patients undergoing resection for intra-abdominal nonanastomotic recurrence were long-term survivors. Thus, only two of 53 (3.7%) patients benefited from the use of an intensive follow-up program. Later in 1995, Makela and colleagues [2] reported the results of a trial in which 106 patients who had undergone radical resection of CRC were randomized to either conventional (n ¼ 54) or intensive follow-up (n ¼ 52). Adjuvant therapy was not used. All patients were seen every 3 months for 2 years and then every 6 months for the next 3 years. At each visit, the patient’s history was taken, and an examination, a complete blood count, a fecal occult blood and CEA tests, and chest radiography were performed.
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Intensive follow-up was defined by the use of more endoscopic follow-up and the use of liver imaging (ultrasonography every 6 months and yearly CT). These authors reported no difference in 5-year survival based on follow-up. The intensely followed group had a 5-year survival rate of 59% versus 54% with conventional follow-up (P ¼ .5). Forty-three patients developed recurrence, and eight underwent reoperation (five in the intensive group and three in the conventional group). Among these patients, three were long-term survivors (one in the conventional arm and two in the intensive arm). Thus, two patients (3.8%) benefited from intensive follow-up. Interestingly, although the recurrence rates were higher in this study (Dukes’ A for example had 36% rate of recurrence), careful follow-up appeared to have no impact on survival. An increase in the recurrence rate should have increased the likelihood that a survival advantage would be identified with more intensive follow-up. The fact that it did not raises the possibility that either the follow-up used was truly ineffectual (at least compared with the conventional follow-up), that retreatment was not performed as often as it could have been, or alternatively, that the sample size was insufficient. The lack of positive results and the difficulty of interpreting studies with small sample sizes led to several additional trials of larger size. The largest prospective randomized trial of the impact of follow-up strategies for patients who had colorectal cancer on survival was reported in 1997 by Kjeldsen and colleagues [3]. These authors randomized 597 patients who had complete surgical resections of CRC to more frequent (n ¼ 290) or less frequent (n ¼ 307) follow-up visits. The two groups were stratified both by the site of disease (rectum or sigmoid versus other colonic sites) and by Dukes’ staging. No information was provided on the use of adjuvant therapy among participants. In the arm of the study with more frequent follow-up, patients were examined at 6, 12, 18, 24, 30, 36, 48, 60, 120, 150, and 180 months. The patients who underwent less frequent followups were seen at 60, 120, and 180 months. Each visits consisted of the same tests: a history, a clinical examination, gynecologic examination, digital rectal examination, a fecal hemoglobin test, colonoscopy, chest radiography, hemoglobin level, erythrocyte sedimentation rate, and liver enzymes. Radiologic examination of the liver was not performed, and CEA was not used. Although recurrent disease was identified earlier (and more frequently while patients were asymptomatic) and re-resections and metastectomies were performed more often in the more frequently seen group of patients, there was no difference in 5-year survival between the two groups (70% versus 68% at 5-year survival for frequent and less frequent examination, respectively). Ten (3.4%) patients in whom disease recurrence was identified and retreated (five local recurrences and two patients who had distant metastases and three with metachronous disease) remained free of disease in the group followed more frequently compared with two (0.6%) patients (one patient who had local recurrence and one metachronous disease) in the less frequently examined group. Examination at 6-month (versus more
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frequent) intervals and the lack of routine carcinoembryonic antigen measurement or liver imaging probably decreased the likelihood of identification of a survival benefit for the more intensely followed patients. In 1998, Pietra and colleagues [4] reported the first randomized, controlled trial to suggest a benefit to more intensive follow-up. These investigators randomized 207 patients who had undergone curative resection for Astler-Coller stages B1–2 or C1–2 colorectal cancer to either an intensive follow-up (104 patients) or a less intensive follow-up (103 patients). This study concentrated specifically on the detection, rates of re-resection, and survival based on two follow-up strategies. The distinction in follow-up was defined by more frequent visits and the inclusion of yearly CT in the intensely followed arm. Patients with rectal cancer received postoperative irradiation, but adjuvant therapy was not used in patients who had colon cancer. The results of this study suggest that local recurrences are detected earlier and are more often asymptomatic in patients who are followed more intensely. This finding led in turn to greater rates of resectability (65% versus 10%, in favor of the more intensely followed patients) and ultimately to more surviving patients in the intensely followed population. Five-year survival rates were 73% in the intensively followed group and 58% in the less intensely followed group (P % .02). In the intensely followed group, 26 local recurrences were identified. Seventeen patients underwent re-resection, and of these, eight patients (7.6% of the more intensely followed cohort) were long-term survivors. In the group less intensely followed, only two of 20 recurrences were re-resected, and neither of these patients was a long-term survivor. The lack of mention of other sites of recurrence, the limited of use of adjuvant therapy, and the coincidently high rates of local recurrence (15% for colon and 37% for rectal tumors) make the interpretation and generalization of the results of this study difficult. Also in 1998, Schoemaker and colleagues reported the results of a randomized trial of CRC follow-up [5]. A total of 325 patients who had undergone surgical resection for CRC were randomized to either standard (n ¼ 158) or intensive follow-up (n ¼ 167). The use of adjuvant therapy was not reported. Intensive follow-up included yearly chest radiography, CT of the liver, and colonoscopy. Clinic visits, liver function studies, fecal occult blood tests, and CEA tests were performed with the same frequency in both study arms. Isolated CEA elevations were not acted on. A nonsignificant improvement in survival was noted for patients followed with these additional tests (76% versus 70% at 5-year survival, respectively, P ¼ .20). A total of 26 (8%) patients were found to have isolated liver disease. Although many of these patients were found in the asymptomatic state in the intensively followed group, similar proportions of patients underwent surgical resection regardless of follow-up strategy (4/12 in the standard follow-up group and 3/14 in the intensive follow-up group). Only one of seven patients (a patient in the intensive follow-up arm) who underwent liver resection survived longterm. Eight patients (2.5%) were found to have isolated lung disease (four in
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each arm). Four of these eight patients underwent resection, with a single long-term survivor (this patient had been in the intensive follow-up arm). Colonoscopy identified a total of eight cancers, five of which were treatable (three in the standard arm and two in the intensive arm). Three of these patients remained alive, two from the intensive follow-up arm and one from the standard arm. Therefore, in terms of long-term survival after retreatment, a net of three patients (3/167 ¼ 1.8%) experienced increased survival that could be attributed directly to follow-up program intensity as measured by the use of yearly chest radiography, liver CT, and colonoscopy. Although this trial was well done and carefully analyzed, there were several flaws. First, the lack of adjuvant therapy complicates the ability to generalize these results to populations treated in such a manner. Second, CEA was drawn, but isolated increased values of CEA were not acted on. Basing further testing on CEA is among the more common strategies recommended for follow-up [6,7]. Finally, although recurrent disease was more often found in the asymptomatic state in patients undergoing more intensive follow-up, similar proportions of patients underwent surgical retreatment. Previous studies have suggested a greater rate (3 fold, on average) of resections among patients with asymptomatic disease [8]. If surgical retreatment is not pursued aggressively, increased follow-up intensity is unlikely to be of benefit. The most recent randomized trial comparing colorectal cancer follow-up programs was reported in 2002 by Secco and colleagues [9]. These authors divided their patients who had undergone surgery for colorectal cancer into those at high risk for recurrence (adenocarcinoma of the low rectum, splenic flexure Dukes-Kirklin B2 or T3 tumors, Dukes’ stage C, a preoperative CEA level of R7.5 ng/mL, poorly differentiated tumors, or tumors containing mucin or signet-ring cells) versus those at low risk (all others). Patients in the high-risk category were then randomized to undergo intensive or minimal follow-up. Patients in low-risk follow-up also were randomized between two strategies: a low-intensity follow-up plan versus a minimal follow-up plan. Based on the modulated intensity of follow-up and recurrence-risk stratification, the authors reported improved survival at 5 years for patients followed with more intensive follow-up for both highand low-risk patients. High-risk patients undergoing intensive follow-up had a 5-year survival rate of 50% versus 32% for those at a similarly high risk but who were followed minimally. The difference in 5-year survival for the low-risk patients was of a similar magnitude (80% for the intensively followed group and 60% for the minimal follow-up group). There are several concerns with this study. First, similar to the study by Pietra and colleagues [4], the authors report high rates of local recurrence (39% for high-risk patients and 17% for low-risk patients) and high rates of overall disease recurrence (local or metastatic disease, 69% for high-risk patients and 36% for low-risk patients). These high rates of recurrence by themselves increase the yield of any follow-up program but cannot be extrapolated to lower risk populations (including those treated with adjuvant therapy).
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Furthermore, despite an apparently large difference in survival, the number of actual patients benefiting from the identification of recurrence, resection of recurrent disease, and long-term survival after resection is small (7/192 [3.6%] in the risk-adapted follow-up groups versus 3/145 [2.1%] in the minimal follow-up groups) and is of similar magnitude to other studies. This raises the possibility that factors other than the follow-up program itself may have been responsible for the observed survival differences. Based on the above review, it is clear that if there is a survival benefit to more intensive follow-up after treatment of colorectal cancer, it is likely to be relatively small. Given the likelihood of only a small survival benefit and the relatively small size of most randomized, controlled studies, it is not surprising that most have shown no benefit from more intensive follow-up. The number of individual patients required to identify a 10% survival increase from 65% to 75% between two programs of follow-up is in excess 1000 patients in each arm. This number exceeds the number of patients accrued in any single study. Based on the desire to identify the value of follow-up, the likelihood of a potentially small but clinically meaningful benefit, and the underpowered nature of individualized randomized, controlled trials, combining individual study information into a single pooled sample and reanalyzing the effect of follow-up are appealing. Several meta-analyses that have taken this approach have been published [10–13]. With minor variations, each meta-analysis has reached similar conclusions in terms of the efficacy of intensive follow-up in improving survival (Table 1). There are a number of difficulties, however, with meta-analysis methodology when applied to the randomized, controlled trials of colorectal cancer follow-up. As mentioned previously, the value of a follow-up program is based on three factors: the rate of recurrence, the rate of identification of treatable disease recurrence, and survival after treatment. Variation in any of these three factors can result in differences in outcome, but only when rates of recurrence and survival after treatment are constant and a follow-up program results in an increased rate of identification of treatable disease can improved outcome be attributed directly to the follow-up program. A variation in recurrence rates (in these six trials recurrence rates varied from 19%–57% [4,9]), the use or disuse of adjuvant therapy (only one trial used adjuvant therapy [4]), and a variation in surgical outcome after retreatment are all potential confounders of the relationship between survival and follow-up intensity and are unaccounted for in the published meta-analyses. Even when focusing specifically on how follow-up intensity was defined, there is significant variation between individual trials. Indeed what was considered intensive follow-up in one study would have been much closer to less intensive follow-up in another (compare [3] with [5]). Combining studies that have such widely varying definitions of intensity makes little sense. Therefore, rather than definitively showing that a particular strategy is beneficial, these meta-analyses provide general support for the principle of colorectal cancer follow-up.
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Table 1 Summary of recent meta-analyses of colorectal cancer follow-up Study
Studies included
Patients (N)
Figueredo et al 2003 [13]
6 randomized trials [1–5,9]
1700
Jeffery et al 2002 [12]
5 randomized, controlled trials [1–5]
1342
Renehan et al 2002 [10]
5 randomized, controlled trials [1–5]
1342
Findings
Comment
Combined relative risk ratio for survival ¼ 0.80 (95% CI, 0.70-0.91) in favor of more intensively followed patients Odds ratio for mortality ¼ 0.67 (95% CI, 0.53-0.84); risk difference for mortality ¼ 0.07 (95% CI, 0.120.02) in favor of intensive follow-up Combined risk ratio for survival ¼ 0.81 (95% CI, 0.70-0.94) in favor of intense follow-up group
Asymptomatic recurrences and re-operations for cure were more common in patients followed intensively. Although there was a survival improvement with increased intensity of follow-up, variability in the tests used and the frequency of these tests did not allow for identification of optimal follow up program. Intense follow-up was most pronounced in four extramural detection studies (not [3]); intense follow-up identified recurrence earlier (average of 8.5 mo).
Furthermore, although more vigorous follow-up appears to be associated with an improved rate of survival, an analysis of the individual randomized, controlled trials suggests that the minority of this benefit actually comes as a result of the identification of recurrence and successful retreatment. Renehan and colleagues [14] have noted recently that, although in meta-analyses there appears to be survival benefit of approximately 10% associated with increased intensity of follow-up, only approximately 2% can be attributed to cure from salvage operations. The authors hypothesize that the remainder of the survival benefit is the result of other factors associated with follow-up, including improved psychologic support, altered lifestyle and diet, or the improved treatment of coincident disease. Ongoing or planned prospective randomized trials based in the United Kingdom and Italy hopefully will shed more light on the magnitude of benefit that can be attributed to intensive follow-up for patients who have CRC [15,16]. Individual tests used in follow-up of colorectal cancer The specific role of an individual test used in follow-up is the early and reliable identification of disease recurrence. These tests should be focused
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on the most likely sites of treatable recurrence. For CRC, the most likely sites of recurrent disease include local recurrence and metastasis to either the liver or lung. Because surgery is the only curative retreatment option currently available for disease at these sites, it is implied that follow-up program participants are fit candidates for the major surgical procedures that would be required to retreat disease in these locations. Furthermore, the majority of recurrences will be manifest within the first 2 years of follow-up; therefore, clustering tests during this period of increased risk makes intuitive sense.
Office visits Questioning the patient regarding symptoms and the performance of a physical examination, looking for signs of recurrence, are important components of a follow-up program. Periodic office visits also facilitate ordering, evaluating, and reviewing additional tests. Patients are often symptomatic at the time of identification of CRC recurrence. Poorly localized abdominal pain, weight loss, increased fatigue, and change in bowel habits are among the more common symptoms of recurrence. The lack of specificity of these symptoms often results in delays in evaluation. Delayed evaluation in turn results in few of these patients having resectable disease when the diagnosis is finally made. Studies suggest that the frequency of resectable disease identification in symptomatic patients is between 1.7 and 7% [3,17,18]. A physical examination of asymptomatic individuals, although rarely helpful in identifying occult colorectal cancer recurrence, can be helpful in the early identification of other disease processes that may benefit from treatment. The role of fecal occult blood testing (FOBT) as an extension of a digital rectal examination has been evaluated in the follow-up of patients who have colorectal cancer [2–5,19,20]. This test is capable of identifying both intraluminal local recurrences and metachronous disease. Most studies, however, have suggested a low sensitivity for this test in the identification of either manifestation of recurrent disease [19–21].
Complete blood counts and liver function tests It is widely believed that the role of the complete blood count (CBC) is very limited in the follow-up of colorectal cancer [6,7]. Two series that have indirectly assessed the role of the CBC and have found very few recurrences identified solely by this test [21,22]. This is not surprising because the reduction in hemoglobin level is nonspecific, and if it occurs at all, it is as a late finding in the course of extraluminal disease recurrence. Although it occurs more commonly with direct intraluminal recurrence, the sensitivity of a reduction in serum hemoglobin in identifying this condition is still quite
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low. Nonetheless, over 50% of physicians use a CBC test as a component of follow-up [23]. The possible role of liver function tests (LFTs) in following up CRC has been evaluated extensively. Unfortunately, many times even with widespread liver disease, LFTs are not elevated. The sensitivity of these tests are, therefore, low, and the rate of resectable disease identified solely by an abnormal liver function test is even lower [1,22,24,25]. Based on low sensitivity and poor ability to identify resectable disease, liver function studies are not routinely recommended [6,7]. Despite the recommendations against their use, liver function tests are still frequently obtained during CRC follow-up. Over 65% of the members of the American Society of Colon and Rectal Surgeons and more than 80% of the members of the Society of Surgical Oncology who responded to a survey on colorectal cancer follow-up practices reported using liver function tests in the first year of follow-up [26]. Carcinoembryonic antigen CEA is a membrane-bound, surface glycoprotein expressed by the majority of colorectal cancers. The CEA test has been in clinical use for more than 30 years, yet there is still considerable controversy concerning its best use in a CRC follow-up program. The CEA is often the first indicator of CRC recurrence. Several studies have suggested that in 33% to 67% of cases of asymptomatic recurrent disease, CEA will be elevated [2,15,27]. Furthermore, CEA elevation often occurs well in advance of other tests showing abnormal results. Estimates have suggested that CEA elevation gives a lead-time of 4 to 6 months compared with other tests [28,29]. On several levels, the CEA test appears to offer promise as a follow-up tool. The CEA test, however, does have significant limitations. First, the rate of falsepositive elevation approaches 20% [27]. Intra-abdominal inflammatory processes, other malignancies, and smoking are among the most common sources of these false-positive elevations [30]. Second, CEA levels appear to be fairly sensitive for hepatic metastasis (70%–80%) but much less sensitive for lung metastasis or local recurrences [27]. Third, CEA only signals disease recurrence and neither localizes the disease nor defines resectability. Additional testing is required for this purpose. Fourth, although several metaanalyses have suggested improvement in survival associated with follow-up programs using the CEA test compared with those in which CEA was not used, these studies have also routinely included other forms of liver imaging [10,11,13]. No randomized trial has shown a survival benefit attributable solely to CEA measurement. Despite these significant limitations, societal guidelines have routinely recommended the use of the CEA test [6,7,13]. This also matches practice patterns across the United States. Vernava and colleagues [31] found that, among members of the American Society of Colon and Rectal Surgeons,
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more than 80% of colorectal surgeons perform CEA measurements at least every 6 months for the first two years of follow-up. Virgo and colleagues [23] found a similar rate of CEA use among members of the Society of Surgical Oncology.
Radiologic examinations Chest radiography Based on a relatively low rate of metastatic disease to the lung and the modest sensitivity for detecting lung metastasis at a resectable stage, most experts feel that chest radiography is of limited value and should not be included routinely in a follow-up program [6,7]. Several series, however, have suggested that chest radiography leads to the identification of resectable disease in 1% to 2% of cases [17,18,22]. It is noteworthy that these trials included only patients who had colon cancer, thus these figures probably underestimate the value of chest radiography and because a greater proportion of rectal cancer patients will develop lung metastasis. Despite recommendations against its routine use, chest radiography is still used commonly in clinical practice; approximately 70% to 80% of clinicians use chest radiography yearly or more often in the follow-up of colorectal cancer [17,22,23]. Specific hepatic imaging: CT and liver ultrasonography Most patients who experience a recurrence of CRC will have liver metastases [32]. CT and ultrasonography are relatively sensitive and specific imaging modalities for identifying hepatic disease in these patients. The major limitations to the routine use of CT and ultrasonography for this purpose are an imperfect sensitivity and specificity, operator dependence for ultrasonography, and increased cost compared with other tests. Several studies have attempted to address directly the value of including CT or ultrasonography in a follow-up program. Although nonrandomized studies have documented reasonably good overall rates of recurrent disease identification and appreciable rates of resectable disease among those with liver recurrence, the results of randomized trials specifically addressing the value of CT or CT and liver ultrasonography to improve survival have been mixed [2,4,5,9,15,33]. Several meta-analyses have found that follow-up strategies that include liver imaging (CT or ultrasonography) and CEA have a statistically improved survival rate compared with strategies that omit routine liver evaluation [10,13]. A recent study has reported the simultaneous use of CT and CEA to detect recurrent disease among stage II or III CRC patients who were treated in a randomized trial of two forms of adjuvant therapy. This study suggests that the combination of CT and CEA is able to identify 90% of the asymptomatic hepatic recurrences, with CT identifying more
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cases of resectable disease than CEA [15]. This high rate of detection of asymptomatic disease suggests that CT and CEA may offer complimentary diagnostic information. CT is used by 30% to 35% of surgeons during the first year of follow-up of CRC [23]. Whether CEA compliments CT and the exact role of CT as a component of routine follow-up await further study. These questions become even more important considering the rapid evolution of CT technology.
Intraluminal follow-up The goal of intraluminal follow-up is to identify intraluminal local recurrence as well as metachronous disease. Because the timeframe for the development of each of these forms of disease is dramatically different, each of these goals will be discussed separately. Local and anastomotic recurrences The rate of anastomotic recurrence after colon cancer resection generally is believed to be too low to justify routine visualization [6]. There have been authors and expert panels, however, who have suggested that follow-up endoscopy may play more of a role after the treatment of rectal cancers because of the higher rates of local recurrence associated with tumors in this location, especially in patients who had American Joint Committee on Cancer stage II or III disease if combined chemotherapy and radiation therapy were not performed [34,35]. There have been two prospective randomized trials that have considered the role of anastomotic visualization or imaging after low anterior resection. Chemoradiation therapy was not used in either study. Ohlsson and colleagues [1] postoperatively visualized the anastomosis of such patients at 9, 21, and 42 months. Full colonoscopy was also performed for these patients at 3, 15, 30, and 60 months. This combination of studies led to the identification of one anastomotic recurrence. Makela and colleagues [2] used flexible sigmoidoscopy at each office visit if the patient had rectal or sigmoid cancer, in addition to yearly colonoscopy. They found one local recurrence. In neither study were increased absolute numbers or increased percentages of resectable anastomotic or loco-regional recurrences identified through heightened anastomotic surveillance compared with the control arm of these studies. Because most local recurrences occur as a result of positive circumferential margins at the time of the original resection, recurrent disease most often begins extraluminally, limiting the value of routine intraluminal evaluation. Endorectal ultrasonography (EUS), which can image the adjacent tissues in the pelvis, may be more valuable than traditional intraluminal evaluations. Several studies have suggested that EUS offers complimentary information to other modalities such as digital rectal examination and
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proctoscopy or CT [36,37]. Most experts have found, however, that EUS by itself has limited value in follow-up because it is difficult to distinguish postoperative changes from local recurrence. One study has looked specifically at the role of ultrasonography-guided biopsy as an adjunct to EUS in the identification of pelvic recurrence in patients who had rectal cancer and underwent sphincter-preserving procedures [38]. This study found that the addition of the biopsy improved sensitivity and specificity to over 90% compared with EUS alone, which had a specificity of only 57%. As the availability and expertise improve, this modality will likely become a more important component of follow-up for patients who had pelvic anastomoses. Identification of metachronous tumors The risk of developing metachronous adenomatous polyps or colorectal cancer after the completion of treatment of the index tumor depends on a number of factors, including the patient’s genetic profile and the length of follow-up considered. Several studies have attempted to define this risk for metachronous polyp and cancer development by performing periodic colonoscopy on cohorts of patients after primary colorectal cancer treatment [39–41]. These studies have uniformly suggested that the rates of polyp and cancer development in patients who have undergone treatment of colorectal cancer are low but exceed those present in the general population. Because screening colonoscopy has been associated with a reduction in colorectal cancer mortality, it follows that the same benefit (and perhaps one even more pronounced) would be present for patients undergoing colonoscopic follow-up after treatment for colorectal cancer. A recent study has preliminarily confirmed this hypothesis. This report suggests a 43% reduction in death rate if one postoperative colonoscopy were performed compared with patients who had completed treatment and did not undergo colonoscopy [42]. Although most clinicians believe that postoperative colonoscopy is warranted, there is some controversy concerning the optimal frequency of colonoscopic evaluation [43]. The most common approach has been to perform colonoscopy within 1 year of the completion of therapy. If the remaining colon is normal or contains only low-risk polyps, colonoscopic evaluation can then occur every 3 to 5 years. Conducting a colonoscopic examination every 3 to 5 years is based on the extrapolation of data from the National Polyp Study, in which colonoscopy at 3-year intervals was found to be as good as colonoscopy at 1 and 3 years in identifying polyps with advanced pathologic features [44]. It is likely however, that colorectal cancer patients are at a higher risk for polyp and cancer development compared with those patients included in the National Polyp Study (patients who had colonoscopically defined and resected adenomas were included in the National Polyp Study), and a case could be made for more frequent
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colonoscopic evaluation. Comparisons of differing frequencies of colonoscopic examination should be a component of future studies of CRC follow-up.
Other studies: positron emission tomography and CT The role of positron emission tomography (PET) and PET combined with simultaneous CT in the follow-up of patients who had colorectal cancer is evolving. Currently, PET is most commonly used as a tertiary test in follow-up. It is used as a staging tool after recurrence has been documented by another modality and further surgical treatment is planned. In this latter circumstance, the role of PET is to rule out disease outside of the intended field of surgery [45,46]. Studies have suggested that PET scanning will alter the surgical plan in approximately 25% of cases, most commonly because greater amounts of disease have been identified [46,47]. Furthermore, patients who underwent PET scans that showed negative results for extrahepatic disease and who undergo liver resection have been reported to have improved survival compared with patients preoperatively staged by other modalities [48]. PET is also used commonly after other studies have suggested the possibility of recurrent disease. Although many tracer agents are available, the majority of PET imaging in oncology has relied on [18F]-2-fluoro-2 deoxyD-glucose and the increased uptake of this tracer in metabolically active tissue. The use of this tracer and PET allows for the functional assessment of areas of increased metabolism. Coupled with the use of whole-body scans, this methodology makes possible an accurate survey of metastatic sites in both usual (liver, lung, and local recurrence) and unusual sites (brain, bone, soft-tissue, and others). Most studies have found accuracy rates for the detection of recurrent and metastatic disease between 80% and 97% [45,49,50]. Although these reported accuracy rates are substantially better than CT alone (indeed the indication for these studies is often rising CEA coupled with a negative CT scan), there is a considerable overlap with other metabolically active tissues, such as inflammatory tissue (from recent surgery or infection), bowel, and urinary tract [46]. On the other hand, mucinous tumors, well-differentiated varieties of colorectal cancer with lower metabolic rates, and tumors treated neoadjuvantly can also be the source of false-negative results [46,50,51]. Combining anatomic imaging with functional imaging theoretically would decrease both false-negatives and false-positives that would occur with PET alone. Several recent reports have suggested increased accuracy using combined PET and CT [46,50]. One study of 100 PET-CT scans has suggested an improvement in specificity from 63% to 100% with dedicated CT interpretation [50]. Although no study to date has used PET or PET-CT as a primary modality for follow-up of CRC,
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perhaps with increasing availability, decreasing cost, and improved tracers, PET will assume a more prominent role.
Other issues Cost and cost effectiveness Although it is likely that there is a benefit to intensive post-treatment follow-up for patients who have had colorectal cancer, the survival benefit is small. The economic question that must be addressed, therefore, is whether the small improvement in survival justifies the expenditure of health care dollars necessary to meet this end. In so far as specific information regarding optimal tests and the timing of those tests to achieve improved survival is unavailable, there can be no direct answer to this question. Several authors, however, have performed theoretical analyses based on limited data and many assumptions [52,53]. These studies have uniformly suggested that, although the benefit may be limited in terms of survival, the cost associated with these benefits have not been extreme. Renehan and colleagues [54] have taken the approach of a cost-effectiveness analysis based on the costs associated with the follow-up strategies used in five of the randomized, controlled trials of colorectal cancer. Using this approach, these authors calculated that the cost for intensive follow-up resulted in a net extra cost of £2479 to £2529 ($4214–$4299) per patient compared with the less intensive follow-up arm. Each life year saved through intensive follow-up was calculated to cost between £3077 and £3402 ($5230–$5783). This is well below the current British National Health System cost acceptability level of £30,000 or the United States standard of $50,000. They further calculated that, given the incremental cost of intensive follow-up relative to less intensive follow-up (as defined by the five studies), the threshold of cost acceptability would be reached when the intensive follow-up regimens resulted in a reduction in absolute mortality of 3% or less. Further progress in this important area awaits completion of adequately powered randomized, controlled trials that have incorporated a cost-effectiveness analysis into the study design. Quality of life and patient satisfaction The impact that participation in follow-up can have on individual patient quality of life and satisfaction with care is variable. Participation in a follow-up program may either provide relief or provoke anxiety. Which effect predominates for a given patient probably depends on a complex interaction among many factors, such as fear of recurrence, patient confidence in the ability of follow-up to identify recurrence, the frequency of follow-up, tests used, economic considerations, and overall attitude toward care. To date, there have been very few studies that assess the impact of a follow-up program on quality of life or patient satisfaction with care. In
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an attempt to address the question of whether participation in follow-up resulted in increased anxiety and a negative impact on quality of life, Stiggelbout and colleagues [24] studied a group of 82 patients enrolled in unspecified follow-up programs in four hospitals in the Netherlands. They found that patient quality of life did not vary based on the timing of the measurement relative to the visit (quality of life was measured 1 week before a visit, 2 weeks after, or at the midpoint between visits), suggesting that participation in follow-up does not have a negative effect on quality of life. This study also explored patient preference for follow-up. These investigators found that for most patients, participation in a follow-up program conveys a sense of security. Over three fourths of patients felt that the advantages of participation in follow-up outweighed the disadvantages. Patients in this study were
Table 2 Summary of societal recommendations and guidelines dealing with colorectal cancer follow-up Society and year of recommendation American Society of Colon and Rectal Surgeons 2004 [6]
American Society of Clinical Oncology 2000 [7]
National Comprehensive Cancer Network (www.nccn.org) (2005)
Cancer Care, Ontario’s program in evidenced-based care 2003 [13]
Recommendations Clinical evaluation should be performed every 3 mo for 2 y followed by 6-mo follow-ups through year 5. CEA should be measured at each visit. Periodic direct visualization of anastomosis or excision site is recommended for patients undergoing either low anterior resection or local excision of rectal cancer. Colonoscopy should be performed preoperatively if possible or within 6 mo of surgery. If no polyps are identified, colonoscopy should be repeated at 3-y intervals Perform history and examination every 3–6 mo for first 3 y and annually thereafter. Administer CEA every 2–3 mo in patients with stages II–III for R2 y. Colonoscopy is recommended pre- or perioperatively and then every 3–5 y. Patients with stage II or III rectal cancer who have not received pelvic radiation should undergo periodic direct rectal imaging (flexible sigmoidoscopy). A history and physical should be obtained every 3 mo for 2 y and then every 6 mo until y 5. For tumors with invasion to or through muscularis propria, measure CEA every 3 mo for 2 y and then every 6 mo through y 5. CT scan may be considered for patients at high risk of recurrence. Perform colonoscopy preoperatively or, if not possible because of obstruction, within 3–6 months, then yearly for 2 y, and then at least every 2–3 y if negative for polyps. In patients who are at high risk of relapse (stages IIb and III), who are fit and willing to undergo investigation for and treatment of recurrence: prompt assessment of symptoms and clinical assessment every 6 mo for 3 y and then annually for 3 y. During these visits, patient may have CEA, chest radiography and liver ultrasounography or CT. Additionally, based on the American Gastroenterologic Association guideline (for stages I–III), colonoscopy should be performed postoperatively if not preoperatively; if high risk polyps are found (R1 cm), repeat colonoscopy yearly; if no polyps are found, repeat colonoscopy every 3–5 y.
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reluctant to switch to a less rigorous follow-up strategy, even if it led to a similar rate of early detection of a recurrence [24]. A single study of health-related quality of life (HRQoL) of patients enrolled in a randomized, controlled trial has been performed [55]. These authors administered the Nottingham Health Profile at a single time during follow-up to 350 patients who had completed therapy for colorectal cancer. They found that patients who underwent more intensive follow-up had a HRQoL that was comparable to their counterparts who were undergoing less rigorous follow-up. They also found that patients followed more intensively had greater confidence that their follow-up would increase their lifespan and in general had more of a positive attitude about follow-up [55]. These preliminary works leave many questions unanswered, including, do particular tests influence quality of life? If the frequency of testing does not influence HRQoL, is it an important determinant of satisfaction? Why do patients prefer more intensive follow-up even if it has a minimal impact on survival? Can patients be satisfied with less frequent follow-up; and most importantly, how can concerns about survival, HRQoL, and satisfaction be integrated to insure an optimal follow-up program? These and other question will require increased research attention in order for further progress to be made. Current recommendations Although the supporting literature for specific tests and timing of those tests is far from ideal, several professional societies that commonly deal with CRC have developed follow-up program recommendations [6,7,13]. These recommendations are summarized in Table 2. Despite varied membership, these recommendations are fairly uniform. All recommend a combination of history, physical examination, CEA, and periodic endoscopic examinations. Ideally, future research will concentrate on comparisons of these recommendations to other possible follow-up strategies. References [1] Ohlsson B, Breland U, Ekberg H, et al. Follow-up after curative surgery for colorectal carcinoma: randomized comparison with no follow-up. Dis Colon Rectum 1995;38(6):619–26. [2] Makela JT, Laitinen SO, Kairaluoma MI. Five-year follow-up after radical surgery for colorectal cancer: results of a prospective randomized trial. Arch Surg 1995;130(10):1062–7. [3] Kjeldsen BJ, Kronborg O, Fenger C, et al. A prospective randomized study of follow-up after radical surgery for colorectal cancer. Br J Surg 1997;84(5):666–9. [4] Pietra N, Sarli L, Costi R, Ouchemi C, et al. Role of follow-up in management of local recurrences of colorectal cancer: a prospective, randomized study. Dis Colon Rectum 1998; 41(9):1127–33. [5] Schoemaker D, Black R, Giles L, et al. Yearly colonoscopy, liver CT, and chest radiography do not influence 5-year survival of colorectal cancer patients. Gastroenterology 1998;114(1): 7–14 [comments: 211–3].
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[6] Anthony T, Simmang C, Hyman N, et al. Practice parameters for the surveillance and follow-up of patients with colon and rectal cancer. Dis Colon Rectum 2004;47(6):807–17. [7] Benson AB III, Desch CE, Flynn PJ, et al. 2000 update of American Society of Clinical Oncology colorectal cancer surveillance guidelines. J Clin Oncol 2000;18(20):3586–8. [8] Ohlsson B, Palsson B. Follow-up after colorectal cancer surgery [review]. Acta Oncol 2003; 42(8):816–26. [9] Secco GB, Fardelli R, Gianquinto D, et al. Efficacy and cost of risk-adapted follow-up in patients after colorectal cancer surgery: a prospective, randomized and controlled trial. Eur J Surg Oncol 2002;28(4):418–23. [10] Renehan AG, Egger M, Saunders MP, et al. Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials [review]. BMJ 2002;324(7341):813. [11] Rosen M, Chan L, Beart RW Jr, et al. Follow-up of colorectal cancer: a meta-analysis. Dis Colon Rectum 1998;41(9):1116–26. [12] Jeffery GM, Hickey BE, Hider P. Follow-up strategies for patients treated for non-metastatic colorectal cancer [review]. Cochrane Database Syst Rev 2002;(1):CD002200. [13] Figueredo A, Rumble RB, Maroun J, et al. Follow-up of patients with curatively resected colorectal cancer: a practice guideline [review]. BMC Cancer 2003;3(1):26. [14] Renehan AG, Egger M, Saunders MP, et al. Mechanisms of improved survival from intensive followup in colorectal cancer: a hypothesis. Br J Cancer 2005;92(3):430–3. [15] Chau I, Allen MJ, Cunningham D, et al. The value of routine serum carcino-embryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer. J Clin Oncol 2004;22(8):1420–9 [comments: 1363–5]. [16] Johnson FE, Virgo KS, Fossati R. Follow-up for patients with colorectal cancer after curative-intent primary treatment. J Clin Oncol 2004;22(8):1363–5. [17] Graham RA, Wang S, Catalano PJ, et al. Postsurgical surveillance of colon cancer: preliminary cost analysis of physician examination, carcinoembryonic antigen testing, chest x-ray, and colonoscopy. Ann Surg 1998;228(1):59–63. [18] Goldberg RM, Fleming TR, Tangen CM, et al for the Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Surgery for recurrent colon cancer: strategies for identifying resectable recurrence and success rates after resection. Ann Intern Med 1998;129(1):27–35 [comments]. [19] Ahlquist DA, Wieand HS, Moertel CG, et al. Accuracy of fecal occult blood screening for colorectal neoplasia: a prospective study using Hemoccult and HemoQuant tests. JAMA 1993;269:1262–7. [20] Jahn H, Joergensen OD, Kronborg O, et al. Can Hemoccult-II replace colonoscopy in surveillance after radical surgery for colorectal cancer and after polypectomy? Dis Colon Rectum 1992;35(3):253–6. [21] Graffner H, Hultberg B, Johansson B, et al. Detection of recurrent cancer of the colon and rectum. J Surg Oncol 1985;28(2):156–9. [22] Peethambaram P, Weiss M, Loprinzi CL, et al. An evaluation of postoperative follow-up tests in colon cancer patients treated for cure. Oncology 1997;54(4):287–92. [23] Vernava AM 3rd, Longo WE, Virgo KS, et al. Current follow-up strategies after resection of colon cancer. Results of a survey of members of the American Society of Colon and Rectal Surgeons. Dis Colon Rectum 1994;37(6):573–83. [24] Stiggelbout AM, de Haes JC, Vree R, et al. Follow-up of colorectal cancer patients: quality of life and attitudes towards follow-up. Br J Cancer 1997;75(6):914–20. [25] Rocklin MS, Slomski CA, Watne AL. Postoperative surveillance of patients with carcinoma of the colon and rectum. Am Surg 1990;56(1):22–7. [26] Virgo KS, Wade TP, Longo WE, et al. Surveillance after curative colon cancer resection: practice patterns of surgical subspecialists. Ann Surg Oncol 1995;2(6):472–82 [comments: 467–8].
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