Colorectal cancer follow-up: Useful or useless?

1. Introduction 

Regardless of their fields of specialization, many doctors feel that postoperative cancer screening is essential in colorectal carcinoma patients [1], [2], [3], [4], [5], [6], [7]. Only 2/160 doctors involved in Canadian project did not refer their patients for postoperative colorectal follow-up [8]. However, postoperative colorectal follow-up may be based on not very scientific reasons including “health politics”, “national standards” (intensive follow-ups in Japan, minor follow-ups in Holland) or “class requirements” (maximum care of patients to avoid being accused by the same for incurable non-diagnosed recurrence) [9]. Follow-up procedures should be set by guidelines supported by evidence-based medicine [10] (supports only 4% of medical decisions [11]) or accepted by the scientific community that, as in the case of colorectal cancer, is divided. This is an important debate since about 230,000 patients who undergo radical colorectal cancer every year in Europe and the USA are candidates for follow-up, and what is more about 500,000 patients are followed up every year in the USA [12]. In these patients there is the real risk of creating illusions or of causing dread when recurrence is detected early in patients who are in good health, not to mention the distress resulting from intensive follow-ups or from false positives results. Moreover, we are aware that these diagnostic procedures will mainly involve patients who may not present recurrence, and if they do, in most cases it will be too late for radical second-surgery.

2. Follow-up goals 

The main goal of colorectal follow-up is to improve patient survival by early diagnosis of recurrence during the asymptomatic stage when radical surgical treatment is more viable [12], [13], [14], [15]. In effect, it must be kept in mind that radical second-surgery can be performed only a low percentage of patients (1.7–7%) presenting symptomatic [16], [17], [18]. Other goals of follow-up are to enable early treatment of other bowel lesions (polyps and metachronous cancers), to solve surgery related problems, to provide patients with psychological support, to assess surgical audit and the impact of new therapeutic approaches, and to boost relations’ awareness. Though the secondary goals are easily appreciated, it is the main aim of follow-up that worries us, especially because authors have defined the positive results as “small” [16], [19], [20], [21], [22], “limited” [23], [24], [25], “controversial” [8], [26], [27], “marginal” [9], [28], “little” [29], “low” [30], “uncertain” [31] and “doubtful” [32]. What's more these authors believe further statistically valid studies are essential to solve the “vexata quaestio”.

In order to acquire certain data, we must first decide what exactly what we consider improved survival; in reality it could mean:

Indubitably, all these three aims are important in their own different ways but they have to be differentiated to stratify results correctly, to allow clear comparisons between the various experiences and levels of evidence and correctly oriented guidelines.

3. Current references 

Another noteworthy aspect is that the thousands of retrospective, non-randomized studies on colorectal cancer carried by single organizations have still not provided a definite answer to the question “Is follow-up necessary?” Even if Anthony [16] and Kievet [25] reported that keying in the words “colon and rectal cancer, surveillance, follow-up” to Medline brings up over 2500 articles, the panel of experts of the American Society of Clinical Oncology (ASCO) [36] who had studied follow-up surprisingly concluded that “good-quality trials are desperately needed”. At present we are awaiting crucial evidence from three trials carried out in different countries, the FFCD trial in France, the GILDA trial in Italy and the FACS trial in the UK. The trials compare two-arm study: an intensive protocol versus a minimalist protocol rather than a no-follow-up arm where the difficulties in forming it are clearly described [14], [37]. We believe that today the comparison between intensive and minimalist approaches, rather than no-follow-up, are more realistic as the minimalist approach is essential to meet the secondary goals of follow-up. In 1993, Steele [38] stated that follow-up strategies were “empiric and probably not justifiable” and in 1995 and 2000 Kievit [9], [39] stated that “colorectal cancer follow-up is not evidence-based medicine”. Can we find data in the literature to refute these hypotheses before the results of the three previously mentioned trials are reported? Anthony's systematic review [16] identified only four meta-analyses [40], [41], [42], [43], only two [40], [41] of which he considered useful, and five, by no means recent, randomized studies [34], [44], [45], [46], [47] and, together with other authors [14], [24], [28], [30], [31], [48], [49], [50], he underlined important biases. In an almost contemporary review, Figueredo [19] added only one study [26] to the ones previously illustrated by Anthony [16].

4. Is follow-up useful? 

The first datum that emerges from reviewing the literature shows that follow-up of radically operated colorectal patients is useful (evidence level IB) [16]. Anthony's [16] recent systematic review of two meta-analyses [40], [41] based on 5 randomized studies (1342 patients where 5-year survival is between +2% and +15% in favor of intensive follow-up), reports that intensive follow-up prolongs 5-year survival in a “small but significant” way (Renehan [40]: risk ratio 0.81 in favor of intensive follow-up; Jeffery [41]: Odds Ratio: 0.67 in favor of intensive follow-up). Figueredo [19] obtained similar findings (Risk ratio 0.80 in favor of intensive follow-up) as did Renehan [48] (risk ratio: 0.76 in favor of intensive follow-up) when they analyzed the previously mentioned 6 randomized trials [26], [34], [44], [45], [46], [47]. There are too few randomized trails to clarify the discrepancies in the same meta-analyses that have already been pointed out by other authors [51]. Investigations [4], [16], [28], [30], [52], [53] on 4 of the 5 trials [34], [44], [46], [47] included in the meta-analysis [40], [41] only revealed increased survival trend in patients on intensive follow-up. This increase was minimal at times (+2%) as observed in the study with major weight [46], and certainly had no statistical significance. So much so that all four authors stated that intensive follow-up did not improve survival. Among the five studies included in the meta-analysis, only Pietra [45] reported excellent results in terms of survival (+15% in favor of intensive follow-up). However, his study was defined by Kievit [9] as “outlying”; furthermore its methodology can be criticized [28] and such surprising results (65% vs. 10% R0—resection of recurrent tumors) raise doubts on the quality of the primary surgery [28], [30], [48]. Another randomized preliminary report [26] showed statistical significance, even if the author inexplicably stated that the asymptomatic factor, which has been reported [9], [40], [54] to be the goal of intensive follow-up as it leads to “early diagnosis” and allows curative second surgery, did not influence the increase in radical second surgery.

In his second meta-analysis Renehan [48] calculated a theoretical 10% of lives saved by intensive follow-up (reported also by Ohlsson [55]), but reported that only 2% can be referred for salvage surgery, thus suggesting that other factors may play a decisive role, such as treatment of associated disease, changed life-style (smoking, obesity), counseling.

When the reports in the literature are analyzed as a whole regardless of they way they were devised, doubts are evident. Kievit [9] considered 17,897 patients in 47 studies, not only randomized ones, and reported that whereas 5 studies showed follow-up determined a significantly statistical improvement in survival, 11 others showed no advantage of follow-up, and 31 reported that follow-up was better but did not included statistical evidence.

Regardless of its impact on salvage surgery and mortality benefit, it would seem logical to assume [55] that follow-up could enhance the efficacy of complementary treatment on recurrence diagnosed early during the asymptomatic stage. Controversial results were reported by the “Nordic Gastrointestinal Tumor Adjuvant Therapy Group” [56] in a randomized study where improved survival of only 5 months (median 14 months vs. 9 months) and longer symptom-free interval of only 8 months (median 10 months vs. 2 months) was observed in patients when recurrence was detected in the asymptomatic stage.

Nevertheless, after studying the literature in detail we believe that the topic has not received the consideration it deserves. We focused out attention on 11 recent reviews [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67] and observed that the scientific debate underlines some certain data: (i) chemotherapy is used in metastatic colorectal cancer to improve survival and quality of life; (ii) in the last few years 5FU has been flanked by new efficient drugs (irinotecan, oxaliplatin, capecitabine); (iii) anti-VEGF or EGFR monoclonal antibodies are finding their place; and (iv) radical resection can be achieved after chemotherapy induced down-staging, especially for liver metastases. The authors also investigated other aspects that are still being validated, i.e. which patients benefit most from chemotherapy and what are the best combinations and sequence of drugs? It must be underlined that taking into consideration the vast amount of data, only two reviews [62], [67], what's more reporting a study that is not one of the latest [56], stress the importance of early diagnosis in the asymptomatic stage of metastasis when chemotherapy is considered to be most efficacious.

5. Follow-up timing 

Correct timing is debatable. None of the 6 randomized prospective trials [26], [34], [44], [45], [46], [47] are identical. Nevertheless, we can assert that:

A survey conducted by Vernava [7] in 1994 reported that more than 75% of the members of the American Society of Colon and Rectal Surgeons followed up their patients every 3 or 6 months for the first 2 years, and then every 6–12 months until year 5. It must be underlined that only one meta-analysis [42], that also included non-randomized studies, revealed that the best results were achieved when follow-ups are conducted at least thrice yearly for the first 2 years (evidence level IIB) [16]. Pfister [31] suggests that follow-up should not be extended after year 5 when recurrence is not common, while Kievit [25] reports that follow-up should be stopped at year 3 when the rise in false positives is equivalent to the decrease in recurrence. It must also be kept in mind that follow-up timing is not always respected: about half of the patients [32], [55], [71] become symptomatic between follow-ups, thus they either anticipate the date (in this case follow-up becomes symptom-guided) or wait until the next follow-up thus defeating the purpose of early diagnosis [29], [43], [72]. Besides, it seems logical to assume that minimal surveillance or symptom-guided follow-up are suitable for elderly patients presenting co-morbidities that can interfere with potential treatment for recurrence or for patients who do not fully accept follow-up [19], [73].

6. Physical examination 

Physical examination is routine in follow-up, even if it may not be useful. It picks up recurrence in only 0–6% asymptomatic patients [12], [18], [44], [47], [68] and is even less valuable in surgically treated rectal cancer patients undergoing radiation therapy as rectal exploration cannot distinguish between fibrosis and recurrence. Anthony [16], mentions a “small but significant” advantage of the follow up and underlines the importance of physical examination as unfortunately 16–66% of recurrence is detected in symptomatic patients (evidence level IIA). The usefulness of clinical examination cannot be based solely on diagnosis of recurrence. During the examination patients can talk to their doctors, release their anxiety and thus improve their quality of life [74]. Moreover, it is also essential for those who wish to be informed on the spread of the disease so as to plan family, work or psychological prospects [75]. Some authors [76], [77], [78] agree on the positive effects of this counselling on follow up (evidence level IIB) [29], while others do not. The latter have either not observed the psychological issue in their patients or feel that the minor improvements in terms of quality of life do not justify the costs since this quality is similar in intensive and minimalist follow-ups [17], [34], [79].

7. Paraclinical investigations 

This is the core issue of debate in follow up. In other words which are the most useful examinations, which determine the lowest number of false negatives or positives and how should these examinations be scheduled.

In his meta-analysis of randomized studies Jeffery [41] reported that it was not possible to decide on the best combination of paraclinical investigations. Nonetheless, he revealed a “mortality benefit” comparing multitest follow-up and follow-up with few tests. Kievit's [25] meta-analysis of 267 articles and databases reported that 360 positive follow-up tests are required to achieve purely one long-term survival through follow-up, while Korner [14] recorded 270. Therefore, if on one hand multi-test follow-up seems to be more effective, the low numbers of curative recurrences versus thousands of examinations imply the diagnostic methods possess low sensitivity and specificity.

8. Carcinoembryonic antigen (CEA) 

CEA should be determined because other hematochemical tests, such as tests to detect occult blood in feces, liver function tests and hemoglobin tests, are not advisable [80], [81] (evidence level IIA) [16]. During the 1st years of follow-up CEA determination and physical examination are the most commonly performed examinations by the members of the “American Society of Colon and Rectal Surgeons” and the “American Society of Surgical Oncology” [7], [82]. Moreover, according to Staib [30], CEA determination will become one of the most important procedures in future “ideal” follow-up. These data are confirmed by the fact that the antigen increases in 60–70% of colorectal cancer recurrences [13]. Moreover, the CEA test is considered the most cost-effective approach to detect potentially resectable metastases [18], [83], the first test that most frequently detects recurrence (38–66% of cases) [12], [18], [44], [47], [71], [84], [85], [86], especially in the liver (approximately 80% versus 40% in other sites) [13], [24], [25], [84], [85], [87], and the test that possess major sensitivity and specificity to recurrence (58–89% and 75–98%, respectively) [24] even when presurgery CEA levels were within normal range [24], [36], [88]. In addition, pre-operative CEA levels indicate cases where liver or pulmonary resection can have favorable outcome since lower increases in CEA leads to better surgical results [89], [90], [91]. However, there are conflicting opinions on the impact of CEA on long-term survival. Some authors report it is positive [19], [40], [42], [43], [92], while others do not [34], [47], [84] assessing, among other things, the fleeting effects of “second-look CEA-guided” [4], [72]. It must be pointed out that in spite of earlier ascertained CEA-guided diagnosis [24], [93], this procedure levels do not enable diagnosis of metastases less than 4–10cm in 50% of hepatic resection [12], and moreover CEA tests often determine false positives (between 7% and 16%) [84], [85] and false negatives (approximately 30% [94], [95]). Hence, there is debate on whether this test is useful (evidence level IIB and C) [16], [36] or useless (evidence level IIC) [27].

9. Liver metastases 

One of the main goals of follow-up is early diagnosis of liver metastases. They develop symptoms late [20] and are confined to the liver in about a quarter of patients [4], [96], but above all after surgery can achieve R0 [25] and 5-year survival in between 20% and 40% [4], [9], [12], [18], [96], [97], [98] which is greater than observed for other types of recurrence. Both Jeffery [41] and Figueredo [19] revealed that liver imaging led to mortality benefit, and invalidated the findings reported 20 years ago by Sugarbaker [71] who did not show liver imaging achieved better results than CEA monitoring alone. Nonetheless, there is on-going debate on the methods. A meta-analysis by Kinkel [99] showed no differences in diagnostic accuracy of ultrasononography (US) and computer tomography (CT) in detecting liver recurrence. Other authors recommend routine CT, in particular helical CT [54], [100], [101] that seems to detect a higher percentage of liver recurrence (68–91%) [20], [27], possess major sensitivity and specificity [102], [103] and determine increased overall survival [34] if carried out at 6 month intervals [20] (metastases detected by this method doubled in size in a time interval of 90–1109 days [104]). Other authors report different results [16], [34] using CT: they diagnosed recurrence in more asymptomatic patients, but did not report an increase in curative liver resections and 5-year survival. Similar findings were recently observed by Child [87] in his retrospective study on 211 patients. In this study he stressed the importance of follow-up (CEA and liver imaging), and recorded earlier diagnosis of liver metastases in asymptomatic patients, more cases of second-surgery and improved 3-year survival. Nevertheless, 5-year survival in these patients was the same as in patients who were not followed up. These findings agree with those reported by Kievit [9] in his review of not only randomized studies where he revealed a non-statistical significance between larger liver metastases and low survival. However a statistically significant difference was observed for multiple liver metastases, suggesting that the use of CT to detect early diagnosis of small liver metastases may not necessarily lead to better overall survival. On the contrary, advocates [105], [106] of US underlined it is a non-invasive, low cost procedure and claim there is evidence (even if studies are not randomized) of its usefulness in diagnosing liver metastases. They also reported better compliance compared with other methods [14], similar false versus true-positives ratios to those obtained using CT [25], and stated that US is the most frequently used diagnostic method in clinical practice [73].

These conflicting data promoted Scholefield [29] to propose a “recommendation grade A” for liver imaging in each case as, even when no evidence is present, it is logical to diagnose treatable metastases. On the contrary, Anthony [16], Berman [27] and Desch [36] were more objective and stated that routine use of CT and US to diagnosis liver metastases cannot be recommended (evidence level IIB or A). We still wonder, as do other authors [40], [50], [54], whether earlier diagnosis of non-resectable liver recurrence allows advanced complementary treatment (chemotherapy, thermal ablation) to achieve better results leading to down-staging and radical second-surgery [107] or improved survival and quality of life [4], [108], [109]. However, there is no evidence it does [110].

10. Local recurrence 

Most cases of recurrence are extraluminal and only infiltrate the mucosa later, and only a third of them have an endoluminal component at diagnosis [111]. There are few reports on their treatment in the literature [9], outcome is generally poor and associated with morbidity [112], even if Goldberg [12] reported an estimated a 5-year disease-free interval in 27%, almost reaching the percentage recorded after liver resection for metastasis. As recurrence rarely occurs after colon resection even if not all authors agree [14], periodical pancolonoscopy is not justified during follow-up [16]. Local recurrence is much more frequent (from 3% to over 30%) [13], [113] after rectal cancer surgery, especially in the most advanced cancer stages or when preoperative radio-chemotherapy have not been performed [36]. In these cases flexible proctosigmoidoscopy is recommended [36], [114] (evidence level IIIB) [16]. Yet intensive follow-ups have not shown that endoscopy detects more cases of resectable local recurrence or increases survival [34], [44], [47], [115], with the exception of Pietra's previously mentioned study [45]. Ecoendosonography (EUS) examination hopefully will achieve better results [16], [25], [116], [117] in terms of earlier diagnosis of local recurrence in particular, even if Berman [27] reported low levels of evidence in 2000 (evidence level VD).

The use of CT to diagnose local recurrence is also an issue, as the members of the American Society of Colon and Rectal Surgeons [7] do not perform it routinely in follow-up. In effect, data obtained from randomized studies generally agree that routine CT in intensive follow-up does not improve diagnosis of local curable recurrence [34], [45] mainly due to the fact that number of false positives in rectal cancer can amount to 45% of the cases [27], [71]. However, CT can be decisive in patients presenting symptoms of local recurrence or elevated CEA levels [20], [45]. Chau [54] observed conflicting results in a study that he agreed had “several limitations”, above all because it was non-randomized. He stressed the role of spiral and multidetector CT in following up rectal cancer patients where the method would allow more cases of curative second surgery in asymptomatic patients and improved survival. Routine CT is not recommended here either (evidence level IIB) [16], [27].

It cannot be established whether routine follow-up improves diagnosis and allows radical second surgery of “real” anastomotic recurrence because they are too rare and the prospective trials too limited.

Moreover, it has still not been demonstrated that positron emission tomography (PET), with or without CT, should be routinely used in follow up. Today it is a second-level examination performed when there is an inexplicable rise in CEA [118], [119], [120], when local recurrence is suspected [121], [122], [123], prior to hepatic resection for metastases in order to rule out the presence of other tumors [124], [125], [126], or to assess the efficacy of chemotherapy [127].

11. Metachronous cancers and polyps 

Endoscopic diagnosis of metachronous cancers (frequency 0.6–9% [24], [128], [129], [130]; 1.7% in our experience [33]) is more standardized, as is diagnosis of adenomatosus polyps that are more frequent in patients who have already developed cancer (29.8–56% [111], [128]; 34.8% in our series [33]). Endoscopic follow-up is lifelong and pancolonscopy must be performed immediately after surgery if not performed prior to surgery, and then repeated every 3–5 years [16], [29], [72], [73], [131] (evidence level IB [27], [36]—evidence level IIIA [20]). Endoscopy is recommended after 1 year in polypectomy patients [19], [36]. It has to be underlined that endoscopic complications in operated patients do not exceed those reported in other endoscopic series [19].

12. Pulmonary metastases 

Chest X-ray (CXR) is routine procedure in many follow-ups as this examination is low cost and false positives are uncommon [24] even if data are controversial. The percentage of patients who develop pulmonary metastases from colorectal cancer ranges between 6% and 22%, while the percentage of patients with resectable pulmonary spread is between 1.8% and 12% [34], [44], [47], [132]. Obviously this percentage drops in trials with only surgically treated colon cancer patients [16]. Mean 5-year survival after radical surgery is around 30% [12], [20], [132], [133], [134], and like observed for liver metastases [9], survival is not significantly affected by the size but by the number of metastases. No difference in diagnosis of resectable pulmonary metastases and survival was recorded between intensive follow-up including CXR and routine follow-up [36], [44]. Consequently, even if CXR seems useful in follow-up, there are not sufficient data to recommend its routine use (evidence level IIB [27], [36] or IIC [16]), probably because few patients present recurrence solely in the lungs. CXR should be performed only after increased CEA levels or specific symptoms have been observed.

13. Society guidelines 

Hence, it is clear that intensive follow-up is called for even if we must not expect brilliant results. Moreover, pancolonoscopy should be included in follow-up to diagnose metachronous cancers and polyps, and determination of CEA levels is probably useful. There are no other certainties. The guidelines of prestigious American and European Societies, such as American Society Clinical Oncology (ASCO) [135], National Comprehensive Cancer Network (NCCN) [136], [137] and European Society Medical Oncology (ESMO) [138], [139] confirm these considerations even if these societies agree on some of the elements and disagree on many others in the performing follow-up (Table 1).

Table 1.

Such inconsistency reflects the low level of evidence of the single procedures and, as a result, in France [73] different parameters than those recommended in the “French Guidelines” are generally used.

The follow-up recommended by the German Cancer Society (DKG) [140] differentiates follow-up according to high and low risk of recurrence, in other words in relation to tumor staging, another controversial issue. Back in 1994, Vernava [7] stated that the intensity of the follow-ups carried out by 1663 members of the American Society of Colon and Rectal Surgeons did not vary markedly in relation to TNM staging, whereas a year later Johnson [141] reported that follow-up carried out by 2773 members of the two major surgical societies was influenced by tumor TNM staging. More recently, Boulin [73] reported similar data. Today this controversy cannot be solved by “evidence or recommendations”; “common practice” [19], [20], [142], and not statistics, recommends all high-risk patients be put on more intensive follow-up, and it is evident that most examinations are useless in patients with lower staging who rarely develop recurrence and where there will be many false positives [25]. These considerations were confirmed by Borie [28] in a statistical analysis showing the positive effects of more aggressive follow-up on survival, especially in advanced stage cancer patients (Dukes C versus A and B). Contrastingly, other authors [13], [37], [89], [91], [143] suggested that follow-up should be more aggressive in patients with biologically less advanced tumors where treatment for recurrence may be more favorable.

In our experience [33], [69], [70], [74], [86] the far from brilliant results obtained led us to change our follow-up and make it less intensive after 15 years, tailoring it to the stage of the disease, the reliability of the diagnostic methods, and times of recurrence (Table 2).

Table 2.

14. Cost-benefit 

Evidence suggests that colorectal follow-up should be encouraged, but the cost-benefit question becomes a core issue as results are generally considered “small”. Unfortunately in these days of cost cutting, health systems’ limited financial resources cannot be wasted especially in countries that cannot afford a “rich health policy” where investigations will be conducted only if they can improve survival. Katherine Virgo [144] caused a great stir when she published a study revealing that in the USA 5-year follow-up packages cost between 910 and 26,717 US dollars per patient, and the most expensive one was 28 fold the cheapest one. Audisio [37] reported that the difference in cost between minimal and aggressive 5-year follow-up protocol in Italy amounted to US$ 4800 per patient. In 1996 [115] he calculated the following costs: US$ 3800 per patient for 505 patients over 5 years; US$ 13,580 for each recurrence; almost US$ 60,000 for every recurrence treated for cure and US$ 136,779 for those effectively cured. These findings were similar to those reported by Staib [30] in Germany (126,000 Euros for cured recurrence) who concluded that follow-up would have been “effective” if one-quarter of recurrence, and not only 3.6%, had been “suitable for potentially curative second-surgery”. There is no easy solution to the issue, above all as not only the disease-free and infirmity-free interval should be considered, but also the quality of life, i.e. quality-adjusted life-year (QALY), should be considered. Epstein [145] reports that the cut off for each QALY is $30.000 per patient. Norum and Olsen [22] conducted an interesting theoretical economic analysis and calculated that “low cost” 4-year follow-up (based on history, physical examination and CEA) with a percentage of second-surgery in less than 10% of all patients and a quality of life above 80% of ideal “perfect health,” would not exceed this cut-off. We are faced with a “border-line” situation! The more intensive follow-ups achieving the best results, like the Italian randomized studies [26], [45], or lower diagnostic accuracy requiring more cases of second surgery, or less optimistic, yet perhaps more real [146], quality of life reduced by chemotherapy would certainly exceed the cut-off, unless we consider a higher cut-off such as the normal British value of £30,000 GBP or distinguish between poor and wealthy nations cut-off being is between $50,000 and $100,000 for QALY [147] in the latter. Who can decide which cut off is apt? Is it right to invest the same sums in other fields, such as prevention, rather than spend them for follow-up that has small results? Michel [148] says that systematic population screening influences 5-year survival more than any other factor and Pignone's [149] cost-benefit analysis of colorectal screening calculated that every life-year saved costs between $ 10,000 and $25,000.

Hence, the doubts on follow-up protocols still remain. The only alternative would be to teach patients to recognize symptoms because minimum follow-up with only physical examination but without imaging does not seem to provide any better results than does no-follow-up [30].

15. Conclusions 

In conclusion, after reviewing the data in the literature, the obvious question is whether the small increase in survival after intensive follow-up is a result of inappropriate follow-up methodologies (calling for in-depth research) or the fact that follow-up cannot achieve better results. If the latter be true, less intensive follow-up could achieve what today we call secondary goals of follow-up. Nevertheless, we have to consider that even if the advantages of non-minimalist follow-up were only 2%, about 4600/230,000 radically operated bowel cancer patients in USA and EU would recover; including about 400 in Italy. Who are we to decide if these patients are to be sacrificed on the basis of crude statistical analysis of cost-effectiveness as proposed by “evidence based medicine”? If this were so, the same limited resources in the field of primary and secondary prevention of colorectal cancer should be mandatory for the scientific and medical community. Thus, can we merely agree with Northover [72] that “the process of follow-up, is a good thing, but evidence of that benefit is lacking” and thus ask ourselves, as does Smith [110], “is it really better to know one has incurable metastases earlier than to believe one is well when one feels well?”