Journal of Thoracic Oncology:
TNM Classification and Clinicopathological Factors: What Is Helpful for Adjuvant Chemotherapy Decision after Lung Cancer Resection?
Sculier, Jean-Paul MD, PhD; Berghmans, Thierry MD, PhD; Meert, Anne-Pascale MD, PhD
Service des Soins Intensifs et Urgences Oncologiques, Unité de recherche en oncologie thoracique, Institut Jules Bordet, Centre des Tumeurs de l’Université Libre de Bruxelles (ULB), Brussels, Belgium.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Jean-Paul Sculier, MD, PhD, Institut Jules Bordet, Rue Héger-Bordet, 1, B-1000 Bruxelles, Belgique. E-mail: firstname.lastname@example.org
In the present issue of the Journal of Thoracic Oncology, Matsumura et al.1 reported a retrospective unicentric study assessing the prognostic role of a pathological factor, lymphatic permeation, after non–small-cell lung cancer (NSCLC) resection. Lymphatic permeation was defined by the presence of floating tumor cells in vessels with no supporting smooth muscles or with elastic fibers. The confirmation of the visualization of the lymphatic vessels was confirmed by immunohistochemical staining with anti–D2-40 antibody. Lymphatic permeation was classified as ly0 in case of absence of lymphatic permeation, ly1 in the presence of intratumoral lymphatic permeation, and ly2 in the presence of extratumoral lymphatic permeation. In 1069 patients, lymphatic permeation was detected in 224 (21%), with 134 (12%) ly1 and 90 (9%) ly2. The 5-year overall survival rates of the ly0, ly1, and ly2 groups were 75%, 63%, and 34%, respectively, which were statistically significantly different. In multivariate analyses, ly2 appeared to be an independent poor prognostic factor.
Two questions may arise from those results: Should lymphatic permeation be incorporated in the staging classification? Is lymphatic permeation a potential useful marker for proposing adjuvant chemotherapy? By definition, lymphatic permeation can be today fully assessed only after surgery and requires careful microscopic examination of the removed piece. It is thus a factor to be considered for the pathological staging. This type of factor is not taken into consideration in the present tumor, node, metastasis (TNM) classification,2 mainly because of lack of data, small number of patients, or inconsistent clinical and pathologic results. As pulmonary nodules or visceral pleura invasion,3,4 lymphatic permeation might be a new T descriptor for a further revision of the staging system. Other potential changes are related to the size of the primary tumor, the number of positive descriptors within a T, N, or M category, or the number of metastases. This will nevertheless require the careful collection of adequate data with a sufficient number of cases for allowing multivariate analysis, taking into account all other significant descriptors.5 Data concerning the presence of carcinomatous lymphangitis described in the area of the primary tumor, elsewhere within the lobe of the primary, and involving other areas within the ipsilateral and/or contralateral lung are currently collected in the International Association for the Study of Lung Cancer Staging Project.6
In terms of prognosis, multiple factors have been proposed, including tumor characteristics, patients’ characteristics, tumor metabolic activity, laboratory parameters, and tumor biological markers.7 On the basis of the data available in the huge retrospective study performed for the 7th revision of the TNM system, the International Association for the Study of Lung Cancer staging committee proposed clinical extent of disease and sex as potentially useful prognostic factors for patients with resectable NSCLC. Performance status and squamous cell type were proposed for stage IIB or superior and for stage IIIA, respectively. Considering pathological staging, age and sex were confirmed as important prognostic factors in addition to pathologic TNM category in surgically resected NSCLC.8 Standard uptake value maximum (SUVmax) of the primary tumor measured on fluorodeoxyglucose positron emission tomography scan was also included in the list of recommended prognostic factors.7 The evidence is based on more than 20 studies, all retrospective in nature that have assessed the prognostic value of the primary tumor SUV, a semiquantitative measurement of the tumor metabolic activity. In a literature meta-analysis first published in 20089 and updated in 2010,10 SUV was found to be a potential prognostic factor for survival in the whole group of patients (stages I–IV; hazard ratio, 2.08; 95% confidence interval, 1.69–2.56), as well as for nonmetastatic tumors (stages I–III; hazard ratio, 2.18; 95% confidence interval, 1.83–2.60) (Table 1). To assess the independent value of SUV, the same team performed an individual patient data meta-analysis, the first results of which were presented at the World Lung Cancer Conference 2013. In multivariate analysis, SUV confirmed its prognostic value in addition to age, stage, tumor size, and surgery. Other metabolic criteria are nowadays under investigation in NSCLC, considering the whole tumor burden either by measuring the “metabolic tumor volume” or the “total lesion glycolysis” (TLG). For example, a recent large retrospective study showed that metabolic tumor volume and TLG are independent prognostic factors, at the difference of SUV, in stage III NSCLC,11 and the same conclusion was drawn for TLG in another retrospective study including only stage IV NSCLC.12
In addition, we need predictor factors for determining which patients might benefit from adjuvant chemotherapy. Today, the only factor used is the pathological stage on the basis of multiple randomized trials and meta-analyses.13–18 Some biological markers such as mutS homolog 2 or excision repair cross-complementing 1, although promising in retrospective studies (summarized in Tables 1 and 2), failed mainly because no reproducible cutoff was found to decide which patients should be treated (Table 3). In this optic, anatomical factors such as lymphatic permeation or metabolic factors as measured on the primary tumor by positron emission tomography scan should be assessed in addition to pathological stage by well-designed randomized trials with adequate sample sizes.
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