Metastatic lymph node ratio in stage III rectal cancer; prognostic significance in addition to the 7th edition of the TNM classification

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Abstract

Aims

Optimal staging in rectal cancer is indispensable for the decision on further treatment and estimation of prognosis. This study assesses the prognostic capacity of the metastatic lymph node ratio (LNR) in addition to the new TNM classification.

Methods

LNR was determined, in stage III patients from the Dutch TME-trial. Six year median follow up data from the trial database were used to analyse the relation of LNR to overall survival (OS) and local recurrence (LR). The relation of LNR to lymph node yield was assessed and appropriate cut off values of LNR for clinical use were determined.

Results

605 patients were analyzed. 278 underwent pre-operative radiotherapy. 82 patients developed a local recurrence and 289 distant metastases. LNR was an independent risk factor for OS, hazard ratio (HR) 2.10 (95% CI 1.35–3.27) (in addition to age >= 65 years, involved circumferential resection margin (CRM) and new TNM stage) and LR, HR 2.25 (95% CI 1.02–4.56) (in addition to pre-operative radiotherapy and involved CRM). LNR is predictive of OS and LR from a lymph node yield of more than one and more than five respectively. A LNR value of 0.60 offers the best cut off to identify high risk patients (5-years OS was 61 vs. 32%, HR 2.45 (95% CI 1.96–3.08) and 5-years LR rate 12.6 versus 16.3%, HR 1.65 (95% CI 1.03–2.64)).

Conclusions

LNR is an independent risk factor for OS and LR in addition to the 7th edition of the TNM classification. It can aid in predicting prognosis and identifying patients that should be considered for adjuvant treatment.

Introduction

Rectal cancer still poses many challenges to oncologists. Major advantages in surgical technique with complete removal of the mesorectum under vision have led to a significant drop in local failure and improvement of overall survival.1, 2 Also the use of (neo-) adjuvant therapy has contributed to improved prognosis with a tendency towards pre- in stead of post-operative radiation.3, 4, 5

Using TME surgery and pre-operative radiotherapy the problem of local recurrence seems to be contained (5.6% at five years6). However, as in colon cancer, distant recurrences are still a matter of concern and occur in 25–30% of patients at five years.6 Adjuvant chemotherapy can possibly aid, but there is still no strong evidence that its benefits in rectal cancer are comparable to those in colon cancer patients.7, 8, 9, 10 Although there are some studies that show a minor benefit of adjuvant chemotherapy in rectal cancer patients11, 12, 13 a recent European consensus conference failed to reach consensus on its use.14

Optimal patient stratification is important to identify patients who will most likely benefit from adjuvant therapy. In this manner, overall morbidity from cytotoxic regimens will be reduced and health care costs are cut down by targeted delivery of expensive chemotherapeutic drugs.

Currently, the UICC/AJCC TNM staging system15, 16 is considered the most robust tool for prediction of prognosis and for decisions on the delivery of adjuvant treatment. However, some criticism is raised towards the validity of this system17 and the usefulness of other tools such as nomograms is being explored.18

In addition to the UICC/AJCC TNM stage,15 the metastatic lymph node ratio (i.e. the ratio of metastatic to retrieved lymph nodes) was found to be an important independent prognostic factor in various malignancies.19, 20, 21, 22 Also in colon cancer some studies show a strong association of metastatic lymph node ratio (LNR) with disease recurrence and survival.23, 24, 25, 26 In rectal cancer the evidence is still limited.

If the LNR can be considered as a prognostic factor it may also have the advantage to be less dependent on the number of retrieved lymph nodes than N stage. Especially in rectal cancer adequate retrieval of lymph nodes may be troublesome as it is dependent on many factors such as age over 60, obesity, female sex, small tumour size and localisation, poor differentiation grade, the absence of a lymphoid reaction and neo-adjuvant therapy.27, 28, 29

Some questions remain unanswered. To what extent can the LNR be considered a reliable prognostic indicator? What is the effect of lymph node yield on the predictive capacity of LNR? Which LNR cut off values have the best discriminative power? Most importantly, very recently the UICC/AJCC TNM system was updated16 and T stage and N stage were further specified to improve its prognostic capacity. More emphasis is made to the number of retrieved malignant lymph nodes. Considering the inherent correlation between LNR and the number of positive lymph nodes it is not clear whether LNR remains an independent predictor prognosis in addition to this 7th edition of the TNM classification.

The aim of this study is to assess the prognostic capacity of the metastatic lymph node ratio in stage III rectal cancer in addition to the 7th edition of the TNM classification and to identify high risk patients.

Section snippets

Patients and methods

From the database of the Dutch TME-trial, a prospective multicentre randomized trial investigating the value of neo-adjuvant short term radiotherapy applying 5×5 Gy, all UICC/AJCC stage III patients were selected for this study. Inclusion and exclusion criteria for the TME-trial have been published previously by Kapiteijn et al.30, 31.Tumours had to be below the level of S1/S2 with the inferior tumour margin being 15 cm or less from the anal verge as measured during withdrawal of a flexible

Statistics

Overall survival (OS) was calculated from surgery to all cause mortality or end of follow up (censoring). Local recurrence time (LR) was defined from surgery to the time of evidence of tumour within the pelvic or perineal area, or death (censoring) or end of follow up (censoring).

Univariate and multivariate analyses (of all univariate relations with p <= 0.1) were performed using a Cox regression analysis. Since the objective of the multivariate analysis was to assess the independent prognostic

Results

Six hundred and five patients were included in the present analysis. There was a complete registration of lymph node harvest and survival data for all patients. For two patients information on local recurrence was unknown.

Patients had an average age of 63 years (range 26–92). Pre-operative radiotherapy was given to 278 patients. Baseline characteristics are shown in Table 1.

The median number of retrieved lymph nodes was 9 (range 1–47). The median number of malignant lymph nodes was 2 (range

Discussion

The present study investigated the predictive capacity of metastatic lymph node ratio (LNR) in stage III rectal cancer. LNR was, in addition to the updated (7th) edition of the UICC/AJCC TNM staging, an independent prognostic factor for LR and OS. Furthermore we determined the minimum number of retrieved lymph nodes required to ensure that LNR is a prognostic factor (two for prediction of OS and six for prediction of LR rate). Finally a cut off value of 0.60 was calculated for which LNR is most

Conclusions

Accurate staging in rectal cancer is indispensable for a balanced clinical decision on further treatment and an accurate estimation of prognosis. This study shows that in addition to the 7th edition of the UICCC/AJCC TNM classification the metastatic lymph node ratio (LNR) is an independent prognostic factor for overall survival and local recurrence in stage III rectal cancer. LNR is a reliable measure for OS from a lymph node yield of more than one node. For adequate prediction of LR more than

Conflict of interest

The authors state that they have no conflict of interest.

Acknowledgements

Merlijn Hutteman is thanked for his help with the lay out of the figures.

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