60 Chapter 4 growth to a larger extend before becoming symptomatic on account of growth into structures as the pleura. Furthermore, we recognized a T3 descriptor with a significantly different (worse) prognosis, namely the mixed type, consisting of tumors with a combination of two T3 descriptors. The mixed subtype is currently not recognized in the TNM-8 classification. In our study, this group consisted of 105 (15.4%) of the 683 patients, mainly comprising a group with tumor diameter larger than 7 cm combined with pleural invasion. This mixed subtype was associated with the worst prognosis of all T3 descriptors (a 5-years OS of 29%, which is even lower than the 41% 5-years OS of stage IIIA NSCLC, and is in fact closer to the 5-years OS of 21% for stage IIIB tumors) 16. Our data suggest that future revisions of TNM should explore larger databases with patients in this category to further validate whether allocating the mixed subtype to pT4 is validated. A possible explanation for the discrepancies between the IASLC results and our results may be a difference in the composition of the study cohorts. The IASLC database of any TN0M0 consisted of a total of 26,722 pathologically staged patients, of whom 22,257 were analyzed and 2,108 were classified as pT3N079. As mentioned, most (79%) of the pT3N0 patients in the IASLC database came from Asia, so approximately 440 of the pT3N0 patients in this database are non-Asian. In contrast, our Dutch database consists of 683 patients. Although the ethnicity in our cohort members is unknown, in 2016 less than 1% of the inhabitants in the Netherlands had an Asian background82. Extrapolation to our study population would result in 5-6 patients with an Asian background. Therefore, our nationwide study population is likely to be more representative for the European/ Western population than the IASLC database. Ethnicity in this context may be an important factor influencing survival outcomes for TNM stages. Adjuvant chemotherapy or radiotherapy could affect the OS; however, detailed information is not available in the IASLC database. Patients with pT3N0 have an indication for adjuvant chemotherapy, as mentioned in the Dutch and European Society for Medical Oncology guidelines83,84. Nevertheless, of the 683 patients only 264 (38.6%) received post-operative chemotherapy. This post-operative chemotherapy was a very strong prognosticator, unrelated to the pT3N0 subtype. An explanation for the relatively low percentage of postoperative chemotherapy may be that it is regularly withheld in frail patients, implying that part of the prognostic impact of chemotherapy may be explained in terms of confounding by indication 85. In addition, the percentage of our patients undergoing postoperative chemotherapy is comparable to that reported in a large observational study where only 40% of 31747 patients in whom chemotherapy was indicated, actually got the planned therapy86. Indication for postoperative radiotherapy in our study population appears mainly restricted to patients within the pleural invasion and mixed subtype, presumably as this group consists mainly of patients with pleural invasion and one of the other T3 descriptors (mostly tumor diameter larger than 7cm). This seems logical, since there
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