Overall survival after resection for colon cancer in a national cohort study was adversely affected by TNM stage, lymph node ratio, gender, and old age

Even though several groups have pioneered radical surgery for colon cancer (complete mesocolic excision and a central tie) with its potential benefits similar to (TME) of rectal cancer surgery, such an approach has not been widely adopted in our country. Therefore, we wanted to examine our background results based on a less standardized approach and potential areas for improvement before embarking on more radical procedures as championed by others [2].

The 5-year overall survival (OS) for all three hospitals was 58.0%. Advanced TNM stage had an adverse influence on outcome, as the results for stage IV versus I–III and stage III versus I–II were significant in the multivariate analysis. For stage III patients, the 5-year OS was 58.1%. In one hospital, the 5-year OS for stage III was worse with 47.8%. In the multivariate analysis, however, when adjusted for hospital, there was no significant survival difference. A recently published international multicenter study of a colorectal population [10] reported an identical OS of 58.8% for patients treated in 2000–2002. Others have found a 5-year OS of 90.7–96.3% for stage II and 64.6–71.7% for stage III using radical surgical procedures [2]. Thus, we consider our figures to show room for improvement, although where improvement may be best realised is debatable.

An advanced stage may theoretically be better treated with more radical surgery even though the presence of skip lesions in rare instances may hardly explain this [11]. Radical or complete mesocolic excision has been shown to increase both the absolute lymph node harvest and prognosis for the patients [2, 3]. However, it has been contested that patients will benefit from more radical surgery in advanced cases [12]. In a Swedish population-based retrospective study [13], a median number of six lymph nodes were detected in the specimens from 1,856 patients operated between 1996 and 2000. The patients in that study had a high local recurrence rate of 11.5%. Locations in the right flexure or left colon were independent risk factors for outcome. There were a very low number of nodes in the specimens from the left colon, whereas in the right flexure tumors, the lymph node count was not inferior. In both instances, the feeding vessel areas were not divided completely, i.e., the inferior mesenteric artery proximally and the root of the medial colic artery. In a population-based study from The Netherlands by Kelder and co-workers, the median lymph node harvest was six and in only 21% of the specimens were 12 or more nodes examined [14]. Thus, we consider that the principle of radical colon surgery may have been violated in these studies when tumors were in those locations. More radical surgery for colon cancer has been recommended in reports from the USA, Europe, and Japan [2, 15, 16]. A retrospective national report based on a small number with supposedly radical colon surgery found that this approach significantly increased survival compared with a much larger and older group subject to a “standard” procedure [17].

The number of lymph nodes may be seen only as a surrogate marker for the extent of surgery without a proper oncologic explanation for the importance of a large harvest [2, 3]. The node count has been correlated to survival both for stage II and III disease [2, 18]. The oncologic explanation is particularly lacking for stage II tumors [12]. The Ontario Cancer Registry study [19] showed better survival with a lymph node harvest of more than ten lymph nodes. Increasing the number even more did not improve survival. In contrast, there is good evidence reported by others that increasing the total number of lymph nodes increases survival significantly [2, 4]. In one study, a mean harvest of more than 28 lymph nodes was reported [2]. Data from the SEER database demonstrated that a cutoff value of 15 was useful, and perhaps, there is an inherent limit to the number of nodes necessary to achieve this effect on survival [20]. Nevertheless, the hypothesis that a larger (negative) lymph node yield is beneficial is contradicted even from highly rated institutions [21]. Only 41% of our patients had more than 12 nodes detected in the specimen. In the univariate analysis, one of the hospitals achieved a significantly better survival with a harvest of more than 12 lymph nodes. However, no significant survival benefit was found with harvest of more than 12 lymph nodes in the multivariate analysis. Several confounding factors may have been present [21, 22]. Many pathologists were involved in this trial even though the specimen handling was supposed to be equal. In a recent study, the pathologist was found to be the dependent factor in lymph node harvest in multivariate analysis, not the operating surgeon [6]. The overall poor lymph node harvest may also indicate that more extensive surgery is one way to improve outcome as found in one of the hospitals. It may be speculated that the poorer outcome in the other two hospitals may have levelled out any benefit by an improved lymph node harvest, i.e., more radical surgery. The power of the study may have concealed such a result [21].

Patients below 75 years were given FLV chemotherapy, and staging was considered important for that reason. For proper staging of colon cancer, the minimum number of lymph nodes needed has been somewhat arbitrarily suggested as 12 by a National Cancer Institute expert panel [15]. Although some authors [14, 18] have concluded with stage migration as an explanation for an increased survival benefit, other studies have shown that detection of positive nodes beyond six or seven lymph nodes examined had no effect on staging [19, 23]. Thus, stage migration is debatable and should not be taken for granted [24]. Patient and tumor factors may also contribute to a variable lymph node presence [18]. Doubtless, a standardized surgical approach in cooperation with a dedicated pathology service is necessary if a minimum number of nodes shall be found and consequently help in outcome assessment. The mean number of lymph nodes in our series was 10.3. Therefore, under-staging was not considered important in our study [24]. The share of stage III tumors equalled that reported by others from large cohorts [12].

Studies have shown that the LNR is an independent and better marker than pN+ for survival [25]. In our study, LNR was highly significant for OS when adjusted for hospitals in the multivariate analysis. Five-year OS varied from 83.5% in LNR group 1, 63.3% in LNR 2, to 18.8% in LNR group 3. According to Wang et al. [26, 27], the prognostic effect of LNR did not depend on the total number of lymph nodes nor on the number of positive nodes. In contrast, Berger et al. [25] found that LNR was not a significant prognostic indicator with less than ten examined nodes but became highly significant for OS and disease-free survival with more than ten lymph nodes harvested. A Mayo Clinic study [21] found a positive correlation between the number of positive lymph nodes and survival but did not analyze the effect of LNR. Fifty-eight percent of our stage III patients had less than 12 lymph nodes examined. Still, we found a significant survival difference of 44.5% between LNR group 2 and 3 and 65.3% between group 1 and 4. A study from New Zealand [22] found that both the absolute number of lymph nodes retrieved up to 16, as well as the LNR, were important for prognosis. The share of stage III compared to stage II cancers in their patients amounted to 54.9%, higher than in most other reports. It seems obvious that a large negative lymph node yield will down-regulate LNR, but the importance of this with regard to outcome may need to be examined in more detail.

Another national report of colon cancer from a single institution found that an emergency operation, some colon locations, blood transfusion of more than two units, old age, and TNM stage were negative predictive factors [28]. No information about lymph node harvest was given. We did not study the effect of blood transfusion, and emergency operations were not separated from the rest partly because they were few, i.e., 15% reported by Sjo et al. [28], and the definition may be debatable. Information about tumor obstruction or perforation would be more appropriate in our opinion. The different colon locations found to be statistically significant (transverse, left flexure, and descending colon) were not so in our multivariate analysis. We suspect that this is partly because they were too few, 20%, to make an impact [28].

Old age was another adverse factor in our study. The overall in-hospital mortality in our series was 5%. Even though the number of urgently operated patients was small in this series, as expected, this small group had a higher mortality of 12.5% compared to 4.5% in the elective patients. Severe co-morbidities in old age may have contributed to these figures as has been reported by others [29]. However, it should be possible to set an optimal target of <3% in elective cases [2]. The average age of our study population was 71 years and that may be older than in series of selected patients. The average age of men and women in our country for those that have reached the age of 62 (earliest OAP retirement age) is 81 and 85 years. To circumvent the analytic problem of age, Sjo et al. [28] used relative survival. Thus, their survival figures improved from 62% actuarial survival to 74% for women and 79% for men. The method is cumbersome, as it necessitates life tables to calculate this for every patient year. Three-year disease-free survival has been shown to parallel overall 5-year survival [30]. However, it requires close follow-up with CT instead of the conventional ultrasonography and chest X-ray examinations. Close follow-up may even result in better treatment of metastases according to Japanese results [31].