Accurate staging of colorectal cancer is essential for appropriate therapeutic planning. The TNM staging system has taken over from the pathological Duke’s staging system, however it provides limited prognostic information regarding the heterogeneous group of patients with stage III disease. Novel prognostic methods based on three different parameters had been investigated: the total number of LNs collected the number of positive LNs retrieved, and the positive LNR.
The aim of our retrospective study was to compare and re-evaluate different approaches for CRC prognosis in our population of patients with stage III disease.
According to the AJCC , stage III CRC is defined by the depth of tumor invasion and the extent of LN involvement in non-metastatic carcinomas. Long-term survival rates depend on and are inversely proportional to the number of LNs involved. Although the TNM system is a reliable therapeutic guide, stage migration, a result of inaccurate TNM staging, has made estimation of future survival rate inconsistent. Furthermore, stage III colorectal cancer is subdivided into A, B, and C according to the number of LNs involved, but this number may vary with the total number of LNs extracted [7, 16, 17].
The total number of LNs retrieved may be affected by factors such as ages, gender, body mass index, surgical technique and the location of the tumor. Right-sided tumors tend to yield a higher number of retrievable LNs than left-sided tumors . The NCI and RCP both recommend a minimum of 12 nodes should be retrieved , but there is no general consensus on the exact number of LNs that must be removed, and surgeons should generally remove as many LNs as possible [11, 19]. Taking into consideration all the variables above that could affect the total number of LNs retrieved, our institution has maintained a high resection number over a period of 20 years (mean 20.8, range 2–88) (Table 1).
Reviewing our data, we did not find by univariate analysis a significant correlation between the total number of LNs resected and the survival rate of the patients (P = 0.46). This is likely to reflect the high standards of lymphadenectomy, with few patients in this population being understaged. Our findings are consistent with another study conducted using Surveillance, Epidemiology and End Results (SEER) data, which included records from four different hospitals .
Because the total number of LNs resected was shown to have poor prognostic value in our population, we investigated the prognostic power of using only the number of positive LNs retrieved for prognostic estimation. This method is currently used for prognostic estimation in the TNM staging system, which classifies colorectal cancer into stage III A, B, or C. According to the AJCC, N denotes the number of positive LNs, and N1 means 1–3 positive LNs collected, while N2 denotes 4 or more positive LNs collected. With regard to this number of positive LN method of prognostication, patients in our population classified as N1 or N2 exhibited approximated 10-year survival rates of 58.4% and 19.2% respectively (P = 0.05) (Figure 2). We divided the total number of LNs retrieved into two groups (0–11 and ≥12 LNs removed) and then subdivided each group into two categories (N1 and N2, respectively) (Table 5). Our analysis confirmed that the number of positive LNs retrieved directly correlated with the total number of LNs collected. However, when we used multivariate analysis on the number of positive LNs collected, along with pLNR, tumor stage, and other factors such as age and gender, the number of positive LNs was not found to be significant (P = 0.35).
Our results are consistent with an analysis by Moug et al. , who compared the number of positive LNs and the pLNR in both univariate and multivariate analysis. pLNR maintained its significance as a prognostic factor in both models, whereas the number of positive LNs was not found to be significant when computed along other factors in the multivariate model (Tables 34).
To overcome any factors that can affect the yield of LNs, we evaluated a ratio-based classification, the positive LN ratio (pLNR). This ratio takes into account both the total number of LNs retrieved and the actual number of positive LNs found. Because it does not rely on one variable, the pLNR overcomes several limitations pertaining to total LN collection, including surgical and pathological techniques, tumor sites, and even the minimum number of LNs that should be dissected . This method has already been used as a prognostic tool for other tumors such as gastric, pancreatic, and breast [12–15].
Multiple cutoff points for pLNR have been have been presented in the literature. Berger et al. used <0.05, 0.05 to 0.19, 0.2 to 0.39 and >0.4 . Our pLNR stratification using 0.4 as the cutoff point is consistent with the work of De Ridder et al. , who used the same threshold. As expected, our univariate analysis showed that patients with stage IIIA had a better 10-years disease-free survival rate (75.8%) than those with stage IIIB (56%) or stage IIIC (no patients survived) (P = 0.01) (Figure 2). It also showed that pLNR had a threshold value of 0.4, with patients having better survival when the ratio was ≤ 0.4 (10-year survival of 60.6%, compared to 0% survival in patients with ratio > 0.4) (P < 0.01) (Figure 4).
Using multivariate analysis, we integrated multiple factors to identify which one would be the best prognostic determinant. We looked at age, gender, stage III (stratified into A, B and C), number of positive LNs retrieved, adjuvant chemotherapy, and pLNR. Stage III, although found to be significant in the univariate model, lost its power when computed alongside pLNR. Moreover, pLNR >0.4 proved to have the most significant prognostic factor (HR = 5.25, CI = 1.2 to 22.1, P < 0.05), showing that pLNR is indeed an independent prognostic factor for survival in patients with stage III CRC.
A limitation of our is that it was a retrospective review and there was some loss of follow-up for a few few patients. Nonetheless, the results confirm previous studies regarding the prognostic power of the LNR in the colorectal disease. We have to note that our manuscript is the first such study to be conducted in the Middle East.