Patient Selection in Human Papillomavirus Related Oropharyngeal Cancer: The Added Value of Prognostic Models in the New TNM 8th Edition Era.
ABSTRACT: Background: With the growing interest in treatment de-intensification trials for human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC), prognostic models have become essential for patient selection. The aim of this paper is to validate and compare the prognostic ability of the TNM 8th edition and previous published risk group classifications of Ang et al. and Rietbergen et al. and to derive a patient selection classification for de-intensification trials. Materials: Patients with HPV+ OPC treated with curative (chemo)radiotherapy between 2004 and 2017 were classified according to the TNM 8th edition, the model of Ang et al. and of Rietbergen et al. HPV status was determined by p16 immunohistochemistry staining. Overall survival was estimated using the Kaplan-Meier method and groups were compared using the log-rank test. Harrell's C-index was used as measure of discriminative performance. Results: A total of 333 OPC were identified of whom 100 were HPV+. The median follow-up was 63.7 months. The 5-year overall survival (5Y-OS) of stage I, II and III were 91.6, 55.2, and 38.0%. There was a significant difference between stage I vs. II and III. The Harrell's C-index for TNM 8th edition stage was 0.67. Including only HPV+ OPC, the Harrell's C-index for the model of Ang and Rietbergen were both 0.62. We combined the main prognostic factors defining the low risk groups in the three models, stage I, low comorbidity and ? 10 pack years, into one new low risk group to identify patients who may benefit from de-intensification trials. Intermediate risk was defined as stage I with high comorbidity or >10 pack years, high risk as stage II-III. The 5Y-OS were 100, 85.7, and 51.3%. The Harrell's C-index for the new classification model was 0.67. Conclusion: Although TNM 8th edition provides better OS stratification than the 7th edition, it is not performant enough for patient selection, neither are the models from Ang et al. and Rietbergen et al. Therefore, we propose a patient selection classification for de-intensification trials based on the new TNM classification 8th edition, comorbidity and smoking pack years. In addition, this study emphasizes the importance of patient selection and personalized treatment for HPV+OPC.
Project description:Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8th edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7th edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16INK4a or HPV-mRNA), p16INK4a positivity alone or the combination of HPV-DNA/p16INK4a positivity as diagnostic tests.A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16INK4a or HPV-mRNA), 83 (10.5%) were p16INK4a positive and 58 (7.4%) were double positive for HPV-DNA/p16INK4a. ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16INK4a-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria.HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials.
Project description:Background:The 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor-node-metastasis (TNM) staging system was released with major revisions. The purpose of this retrospective study was to investigate differences between the 7th and 8th editions of the AJCC/UICC TNM staging system and to compare the predictability of prognosis between the two staging systems with patients who underwent thyroidectomy for differentiated thyroid cancer (DTC) at a single institution. Methods:A total of 3238 patients underwent thyroid operation from January 2002 to December 2006 at Yonsei University Hospital (Seoul, Korea), of which 2294 with complete clinical data and sustained follow up were enrolled. Clinicopathologic features and TNM staging by applying the 7th and 8th editions of the AJCC/UICC were analyzed retrospectively by the complete review of medical charts and pathology reports of patients. Mean follow-up duration was 132.9?±?27.9?months. Results:A significant number of T3 patients were downstaged to T1 (838, 36.5%) and T2 (122, 5.3%). After applying the 8th edition of the AJCC/UICC TNM staging system, the number of stage?I patients increased significantly from 1434 (62.5%) to 2058 (89.7%), whereas numbers of stage III and IV patients decreased significantly from 644 (28.1%) to 33 (1.4%) and from 199 (8.7%) to 17 (0.7%), respectively. According to Kaplan-Meier survival analyses and values of the Harrell's c-index and integrated area under the curve (iAUC), the 8th edition has significantly better predictive performance for disease-free survival (DFS) and disease-specific survival (DSS) than the 7th edition. Conclusions:A significant population was downstaged after applying the 8th edition of the AJCC/UICC TNM staging system, and the 8th edition provided significantly better accuracy in predicting DFS and DSS in patients with DTC.
Project description:Background: Considerable modifications have been introduced in the new edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system. Based on the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, this study aimed to compare the 7th and 8th editions of the AJCC/UICC TNM staging system for patients with papillary thyroid microcarcinoma (PTMC) and follicular variant papillary thyroid microcarcinoma (FVPTMC). Methods: A Data from 2004 to 2014 of 39,032 patients registered in the SEER database were included. The 7th and 8th editions of the AJCC/UICC staging system were compared in terms of TNM staging, age cutoff, and clinical staging. Patient survival was evaluated using Kaplan-Meier and multivariable Cox proportional hazards models. The American Thyroid Association (ATA) risk stratification system was integrated with the AJCC/UICC staging system for further investigation. Receiver operating characteristic (ROC) curves, Harrell's C-index, Akaike information criterion (AIC), and the Bayesian information criterion (BIC) were used to assess the models' performances. Results: Revised TNM categories, age cutoff, and clinical staging in the 8th edition resulted in reclassification of the overall stage. Applying the 8th edition, 1,278 stage III and 425 stage IV patients were reclassified as stage I; 950 stage III and 459 stage IV patients were reclassified as stage II; 77 stage IV patients were reclassified as stage III; and only 88 patients remained in stage IV. All patients in stage I, according to the 7th edition, remained in this stage when using the 8th edition. Patients classified into higher stages (III and IV) in the 8th edition showed a worse prognosis than those classified into same stages in the 7th edition. The 8th edition proved to be a better model with higher prognostic efficacy survival (higher AUC and C-index, lower AIC and BIC) than the 7th edition. When integrated with the ATA risk stratification system, the 8th edition still showed better discriminative power for patients in the higher risk group. Conclusion: Based on the SEER database, the 8th edition of the AJCC/UICC staging system has better prognostic efficacy than the 7th edition for patients with PTMC and FVPTMC.
Project description:Recently, the 2015 American Thyroid Association (ATA) risk stratification and the 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system were released. This study was conducted to assess the clinical value of the lymph node ratio (LNR) as a predictor of recurrence when integrated with these newly released stratification systems, and to compare the predictive accuracy of the modified systems with that of the newly released systems. The optimal LNR threshold value for predicting papillary thyroid cancer (PTC) recurrence was 0.17857 using the Contal and O'Quigley method. The 8th edition of the AJCC/UICC TNM staging system with the LNR and the 2015 ATA risk stratification system with the LNR were significant predictors of recurrence. Furthermore, calculation of the proportion of variance explained (PVE), the Akaike information criterion (AIC), Harrell's c index, and the incremental area under the curve (iAUC) revealed that the 8th edition of the TNM staging system with the LNR, and the 2015 ATA risk stratification system with the LNR, showed the best predictive performance. Integration of the LNR with the TNM staging and the ATA risk stratification systems should improve prediction of recurrence in patients with PTC.
Project description:The modification of the cancer classification system aimed to improve the classical anatomy-based tumor, node, metastasis (TNM) staging by considering tumor biology, which is associated with patient prognosis, because such information provides additional precision and flexibility.We previously developed an mRNA expression-based single patient classifier (SPC) algorithm that could predict the prognosis of patients with stage II/III gastric cancer. We also validated its utilization in clinical settings. The prognostic single patient classifier (pSPC) differentiates based on 3 prognostic groups (low-, intermediate-, and high-risk), and these groups were considered as independent prognostic factors along with TNM stages. We evaluated whether the modified TNM staging system based on the pSPC has a better prognostic performance than the TNM 8th edition staging system. The data of 652 patients who underwent gastrectomy with curative intent for gastric cancer between 2000 and 2004 were evaluated. Furthermore, 2 other cohorts (n=307 and 625) from a previous study were assessed. Thus, 1,584 patients were included in the analysis. To modify the TNM staging system, one-grade down-staging was applied to low-risk patients according to the pSPC in the TNM 8th edition staging system; for intermediate- and high-risk groups, the modified TNM and TNM 8th edition staging systems were identical.Among the 1,584 patients, 187 (11.8%), 664 (41.9%), and 733 (46.3%) were classified into the low-, intermediate-, and high-risk groups, respectively, according to the pSPC. pSPC prognoses and survival curves of the overall population were well stratified, and the TNM stage-adjusted hazard ratios of the intermediate- and high-risk groups were 1.96 (95% confidence interval [CI], 1.41-2.72; P<0.001) and 2.54 (95% CI, 1.84-3.50; P<0.001), respectively. Using Harrell's C-index, the prognostic performance of the modified TNM system was evaluated, and the results showed that its prognostic performance was better than that of the TNM 8th edition staging system in terms of overall survival (0.635 vs. 0.620, P<0.001).The pSPC-modified TNM staging is an alternative staging system for stage II/III gastric cancer.
Project description:Objective:To investigate the validity of the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system for gastric cancer. Methods:The clinicopathologic data of 7371 patients who were diagnosed with gastric cancer and had 16 or more involved lymph nodes (LNs) were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and retrospectively reviewed. Results:Stage migration occurred primarily during stage III between the 7th and 8th edition TNM staging systems. Stages IIIB and IIIC in the 7th edition staging system were divided in the 8th edition and had obvious differences in survival rates (both P < 0.001). The 8th edition TNM stages IIIC and IV showed similar survival rates (P = 0.101). The prognosis of patients with T4aN3bM0 was not different from that of patients with TxNxM1 (P = 0.433), while the prognosis of patients with T4bN3bM0 was significantly poorer than that of patients with TxNxM1 (P = 0.008). A revised TNM system with both T4aN3bM0 and T4bN3bM0 incorporated into stage IV was proposed. Multivariable regression analysis showed that the revised TNM system, but not the 7th and 8th editions, was an independent factor for disease-specific survival (DSS) in the third step of the analysis. Further analyses revealed that the revised TNM system had superior discriminatory ability to the 8th edition staging system, which was also an improvement over the 7th edition staging system. Conclusion:The 8th edition of the AJCC TNM staging system is superior to the 7th edition for predicting the DSS rates of gastric cancer patients. However, for better prognostic stratification, it might be more suitable for T4aN3bM0/T4bN3bM0 to be incorporated into stage IV in the 8th edition TNM staging system.
Project description:The prognosis of HPV-positive squamous oropharyngeal carcinomas (OPCs) is more favorable than that of HPV-negative OPCs. However, the prognosis of some of these tumors is dismal and to date validated survival predictors are missing in clinical practice. We designed a study on HPV-positive OPCs to determine whether a previously published gene expression tumor classification model,defined through meta-analysis of publicly available datasets (PMCID: PMC6721309), is able to predict survival in an external patient cohort. The 3 gene expression clusters were tested in a validation set of 286 cases and in a refined study population of 235 patients and in both confirmed their prognostic value. Five-year OS was 95% in the low risk cluster Cl1, 80% in the intermediate risk cluster (HR=5.74, p=.0057), and 66% in the high risk cluster (HR=9.28, p=.001). Functional/biological cluster characterization identified potentially targetable pathways in the high risk cluster. This prognostic stratification might be useful for clinical decision making and for planning future trials based on molecular tumor features. Overall design: In our work, we considered a cohort of the HPV positive OPC patients included in the project “Big Data and Models for Personalized Head and Neck Cancer Decision Support (BD2Decide)”, trial registry ClinicalTrial.gov number NCT02832102. Patients were treated in seven European referral cancer centers (Italy, The Netherlands and Germany) with expertise in the multidisciplinary management of head and neck cancer patients. Median follow-up was 46.2 months (95% confidence interval 41.2-50) and data collection was concluded in September 2019 (doi:10.1002/hed.26515). OPC patients with loco-regionally advanced non-metastatic disease treated with curative intent were tested for HPV using p16-immunostaining and HPV DNA PCR and when positive included. HPV status was assessed by p16-immunostaining followed by a HPV DNA PCR test on the p16-immunopositive cases. Patients were treated with multimodal strategies (combinations of surgery, radiotherapy, and chemotherapy). For T1N1M0 and T2N1M0 disease single-modality treatment (surgery or radiotherapy) was allowed. To reduce the bias of confounding variables impacting on outcome, we excluded OPC: i) patients with p16-positive but HPV-DNA-negative OPC; ii) patients receiving unimodal treatment (surgery without post-operative radiation or exclusive radiotherapy without concomitant systemic treatments) for clinical stage T1N>1, T2N>1 and T3-T4 any N disease. TNM7= AJCC/UICC staging system 7th edition; TNM8= AJCC/UICC staging system 8th edition; subset (n=235)= exclusion of 51 HPV-DNA negative (n=14) OPCs and suboptimal treatments (n=37); HPV_molecular_clusters= gene-expression stratification based on Locati et al (PMCID: PMC6721309).
Project description:This study compared the prognostic significance of staging between the American Joint Committee on Cancer 8th edition Tumor, Node, Metastasis (TNM) staging system and the Barcelona Clinic Liver Cancer (BCLC) classification in patients with hepatocellular carcinoma (HCC). The study population comprised patients with liver cancer registered in the Taiwan Cancer Database from 2007 to 2013 and was followed up until December 31, 2016. The study included patients with HCC, with known staging in both TNM and BCLC systems, and with follow-up >1 month. Primary endpoint was overall survival. Univariate and multivariate Cox proportional hazards model were constructed to investigate the significance of staging by two systems. Goodness-of-fit of model was evaluated via Akaike's information criterion (AIC), the lower the better. Among 73,136 patients with newly diagnosed liver cancer, a total of 37,062 patients with HCC (25.6% underwent surgery) were eligible. The mean age and overall survival of this cohort were 63.9?years and 27.2%, respectively. Overall survivals for stages I, II, III, and IV (the TNM system) were 54.5%, 34.9%, 10.3%, and 6.4%, respectively. Overall survivals for stages A, B, C, and D (the BCLC classification) were 54.5%, 29.2%, 9.8%, and 4.0%, respectively. The median follow-up time was 59.4 months. Multivariate Cox proportional hazards model revealed that both systems predicted overall survival, cancer-specific survival, disease-free survival, and local recurrence-free rate well. Values of ?AIC of the BCLC classification and the TNM system were lower for the surgery group and nonsurgery group, respectively. The TNM system (8th edition) predicted long-term outcome better than the BCLC classification in patients with HCC. But in patients treated initially with surgery, the BCLC classification outperformed the 8th edition of the TNM system. IMPLICATIONS FOR PRACTICE: This work demonstrates that the Tumor, Node, Metastasis (TNM) system (8th edition) and the Barcelona Clinic Liver Cancer (BCLC) classification both predict long-term outcome significantly in patients with hepatocellular carcinoma but that the TNM system (8th edition) predicts long-term outcome better than the BCLC classification. For patients treated initially with surgery, BCLC classification outperforms in 8th edition TNM system in predicting long-term outcome.
Project description:Background:Preoperative staging of pancreatic cancer determines the choice of treatment. Magnetic resonance imaging (MRI) plays an important role in preoperative staging of pancreatic cancer. The American Joint Committee on Cancer (AJCC) TNM staging system was revised to its 8th version in 2016, there has been no report correlating the 8th edition of the AJCC TNM staging with preoperative MRI examinations and pathological findings. The purpose of our study is to determine the staging accuracy and evaluate the resectability by using MRI about pancreatic cancer compared with intraoperative or pathological findings according to the 8th edition of the AJCC TNM staging system. Methods:One hundred thirty-two patients with a pathological diagnosis of pancreatic cancer who underwent preoperative MRI were identified. The clinical data, MRI findings and pathological findings were analyzed. Preoperative MRI staging and resectability evaluation were compared with pathological findings. The accuracy of MRI for preoperative T and N staging was evaluated, and the sensitivity, specificity and accuracy of MRI in evaluating the resectability were assessed. All the staging and resectability assessments were according to the 8th edition of the AJCC TNM staging system. Results:Analysis showed that the accuracy of MRI for evaluation of the T and N stages was 82.6% (109/132) and 74.2% (98/132), respectively. The sensitivity and specificity of MRI in assessing the resectability were 94.2% and 71.4%, respectively. Integrating the 8th edition of the AJCC TNM stage, no significant differences were identified between the preoperative MRI and pathological results for the staging of pancreatic cancer (P=0.805). Conclusions:MRI is highly accurate for T staging and moderately accurate for N staging. MRI provides important preoperative evaluation of the stage and resectability of pancreatic cancer based on the 8th edition of the AJCC TNM staging system.
Project description:The eighth TNM edition for gastric cancer was released in 2016 and included major revisions, especially of stage III. The purpose of this study was to evaluate the prognostic value of the new AJCC TNM classification in comparison with the 7th edition for stage III gastric cancer.Clinical and histopathological data on 1,496 patients operated on for stage III GC according to the seventh edition between 2005 and 2013 were analyzed and compared using 7th and 8th classifications. The 2 systems were compared in terms of prognostic performance.The stage shifted for 650 (43.45%) patients: from IIIA to IIIB (2 patient, 0.13%), from IIIB to IIIA (214 patients, 14.30%), from IIIB to IIIC (99 patients, 6.62%), and from IIIC to IIIB (335 patients, 22.39%). Cox regression multivariate analysis showed both the 8th and 7th TNM classification were independent prognostic factors. The 8th edition system had higher linear trend and likelihood ratio ?2 scores, and smaller AIC values compared with those for the 7th edition. However, the performance of the eighth edition did not reveal significant improvement compared to the seventh edition (c-index 0.625 vs. c-index 0.616, p=0.085).The eighth TNM edition may not provide significantly better accuracy in predicting the prognosis of stage III GC. However, to confirm our findings, further studies are warranted.