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2.3. Statistical analyses

identified in four (5.0%) patients. PET/CT downstaged two of four patients, correctly in all cases, and upstaged one patient correctly. The remaining one was not assessable because of therapeutic interventions for un- confirmed site of disease visualised only on imaging. In terms of detecting synchronous SPCs, CWU and PET/CT differed in 21 (11%) patients. CWU detected SPCs in 12 of these 21 patients: these SPCs were in the oesophagus ( n Z 4), stomach ( n Z 2), thyroid ( n Z 2), or lung ( n Z 4). PET/CT accurately excluded the SPC in the lung in three of the latter four cases. However, PET/ CT failed to detect the four cases of CWU-detected SPC in the oesophagus: this was inaccurate. PET/CT accu- rately detected the remaining one in the lung, the two in the stomach, and the two in the thyroid. Additionally, PET/CT, but not CWU, detected SPCs in the remaining nine patients: the SPCs were in the thyroid ( n Z 3), lung ( n Z 2), colon ( n Z 1), breast ( n Z 1), palatine tonsil ( n Z 1), and epiglottis ( n Z 1). Overall, PET/CT stage and CWU stage were discor- dant in 79 patients (31.9%), for whom a validation was available in 71 patients. PET/CT staging was signifi- cantly more sensitive and accurate than CWU staging (both P < 0.001; Table 2 ). Considering the whole pop- ulation of the study, we hypothesise that the stages would be correct for patients with identical PET/CT and CWU e TNM stages because changes of management were not expected in these patients. The overall accuracy of PET/CT staging was significantly higher than those of CWU staging (87.1% versus 82.0%; P < 0.001). Patients whose CWU-determined stage was upstaged by PET/CT staging had a significantly worse PFS and OS than those whose clinical stage did not change (both P < 0.05) ( Fig. 1 ). Overall, the PET/CT staging led to management changes in 39 (15.7%) of the 248 patients. PET/CT had a significantly higher impact on the CWU-determined management plan in patients who were CWU staged as III e IV than in those who were CWU staged as I e II (21.4% versus 9.8%, P Z 0.014). In 12 patients (4.8%), PET-CT had a high impact on the CWU-determined management plan. In most cases, this was because PET/CT detected distant metastasis and SPCs (details are given in Supplementary Table S3 ). All these lesions were histologically confirmed. PET/CT correctly changed the management of these patients. In 27 (10.9%) patients, PET/CT had a moderate impact on the management plan. This was mainly because PET-CT upstaged the nodal stage. This led to modification of the radiation field and/or dose ( n Z 9) and surgical extent ( n Z 18). The actual disease stage could be validated in 24 patients: PET/CT correctly changed the management in 19 of these patients. PET/CT had a low impact in 206 (83%) patients, predominantly because it concurred with 3.1. Primary outcome

Groups were compared in terms of categorical variables by using the Fisher’s exact test. PET/CT and CWU were compared in terms of the sensitivity and accuracy with which they staged HNSCC by using the McNemar test. The Kaplan e Meier method was used to estimate overall survival (OS) and index cancer progression (progres- sion-free survival [PFS]). OS and PFS were defined as the time between the first day of treatment to the date of death or progression, respectively, or to the last clinical follow-up. Disease progression was defined as the appearance of new lesions or enlargement of the initial primary tumour and/or development of metastatic dis- ease [22] . The log-rank test was used to compare sur- vival rates according to stage and management impact. The Cox proportional hazards model was used to identify the prognostic variables for univariate and multivariate predictions of PFS and OS. The tests were based on the likelihood ratio statistic, and the estimated hazard ratio (HR) and 95% confidence intervals (CIs) were calculated. All statistical analyses were two sided and were performed by using SPSS software, version 22.0. P < 0.05 was deemed to indicate statistical significance. The patient clinical characteristics are presented in Table 1 . PET/CT changed the CWU-based TNM clas- sification of 83 lesions in 79 (31.9%) patients; in two patients, both T and N changed. In the remaining two patients, both N and M changed. In the remaining 169 (68.1%) patients, PET/CT and CWU findings presented identical TNM classification. Of the 79 patients with discordant TNM classification, histopathology was available in 68 (86.0%). In another two and one patient, the TNM classification was confirmed by subsequent imaging and clinical follow-up, respectively. It was not possible to definitively confirm the stage in the remain- ing eight patients. These cases were not included when comparing the PET/CT stage and CWU stage in terms of diagnostic accuracy. The discrepancies of T classification were identified in 24 (30.3%) patients. The extent of the primary tumour was not confirmed in two patients because ICT was performed. There were no false-positive PET/CT results for the detection of primary tumour. However, PET/CT failed to detect 15 of the CWU-staged T1 tumours (15 of 101, 14.8%). The discrepancies of N classification were identified in 55 (69.6%) patients ( Supplementary Table S1 ). The discordant nodal stage was confirmed by his- topathology in 46 and serial imaging in 1. PET/CT classified the N classification more accurately and sensitively than CWU (both P < 0.05, Supplementary Table S2 ). The discrepancies of M classification were 3. Results

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