Harmonized Outcome Measures for Use in Non-Small Cell Lung Cancer Patient Registries and Clinical Practice.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States and globally, and many questions exist about treatment options. Harmonizing data across registries and other data collection efforts would yield a robust data infrastructure to help address many research questions. The purpose of this project was to develop a minimum set of patient and clinician relevant harmonized outcome measures that can be collected in non-small cell lung cancer (NSCLC) patient registries and clinical practice. METHODS: Seventeen lung cancer registries and related efforts were identified and invited to submit outcome measures. Representatives from medical specialty societies, government agencies, health systems, health information technology groups, patient advocacy organizations, and industry formed a stakeholder panel to categorize the measures and harmonize definitions using the Agency for Healthcare Research and Quality's supported Outcome Measures Framework (OMF). RESULTS: The panel reviewed 66 outcome measures and identified a minimum set of 8 broadly relevant measures in the OMF categories of patient survival, clinical response, events of interest, and resource utilization. The panel harmonized definitions for the 8 measures through in-person and virtual meetings. The panel did not reach consensus on 1 specific validated instrument for capturing patient-reported outcomes. The minimum set of harmonized outcome measures is broadly relevant to clinicians and patients and feasible to capture across NSCLC disease stages and treatment pathways. A pilot test of these measures would be useful to document the burden and value of the measures for research and in clinical practice. CONCLUSIONS: By collecting the harmonized measures consistently, registries and other data collection systems could contribute to the development research infrastructure and learning health systems to support new research and improve patient outcomes.

Phase 1b trial of proteasome inhibitor carfilzomib with irinotecan in lung cancer and other irinotecan-sensitive malignancies that have progressed on prior therapy (Onyx IST reference number: CAR-IST-553).

Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function. Patients with stable asymptomatic brain metastases were eligible. Dose escalation utilized a standard 3 + 3 design. Results Overall, 16 patients were enrolled to three dose levels, with four patients replaced. Three patients experienced dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) was exceeded in Cohort 3. The RP2 dose was carfilzomib 20/36 mg/m2 (given on Days 1, 2, 8, 9, 15, and 16) and irinotecan 125 mg/m2 (Days 1, 8 and 15). Common Grade (Gr) 3 and 4 toxicities included fatigue (19%), thrombocytopenia (19%), and diarrhea (13%). Conclusions Irinotecan and carfilzomib were well tolerated, with common toxicities of fatigue, thrombocytopenia and neutropenic fever. Objective clinical response was 19% (one confirmed partial response (PR) in small cell lung cancer (SCLC) and two unconfirmed); stable disease (SD) was 6% for a disease control rate (DCR) of 25%. The recommended phase II dose was carfilzomib 20/36 mg/m2 and irinotecan125 mg/m2. The phase II evaluation is ongoing in relapsed small cell lung cancer.

Model selection and inference for censored lifetime medical expenditures.

Identifying factors associated with increased medical cost is important for many micro- and macro-institutions, including the national economy and public health, insurers and the insured. However, assembling comprehensive national databases that include both the cost and individual-level predictors can prove challenging. Alternatively, one can use data from smaller studies with the understanding that conclusions drawn from such analyses may be limited to the participant population. At the same time, smaller clinical studies have limited follow-up and lifetime medical cost may not be fully observed for all study participants. In this context, we develop new model selection methods and inference procedures for secondary analyses of clinical trial data when lifetime medical cost is subject to induced censoring. Our model selection methods extend a theory of penalized estimating function to a calibration regression estimator tailored for this data type. Next, we develop a novel inference procedure for the unpenalized regression estimator using perturbation and resampling theory. Then, we extend this resampling plan to accommodate regularized coefficient estimation of censored lifetime medical cost and develop postselection inference procedures for the final model. Our methods are motivated by data from Southwest Oncology Group Protocol 9509, a clinical trial of patients with advanced nonsmall cell lung cancer, and our models of lifetime medical cost are specific to this population. But the methods presented in this article are built on rather general techniques and could be applied to larger databases as those data become available.

Real-world analysis of the relationships between smoking, lung cancer stigma, and emotional functioning.

INTRODUCTION: People diagnosed with lung cancer experience high rates of distress, which can be compounded by the stigma of the disease. This study assessed a real-world population to understand patient-reported emotional functioning, types of stigma experienced, and relationship with smoking history. METHODS: Questionnaires using validated survey tools assessing demographics, smoking history, stigma, and quality of life (EORTC QLQ-C30 Emotional Functioning Scale) were analyzed from 539 global participants in the Lung Cancer Registry between November 2019 and July 2022. The associations between smoking history and self-reported internalized and perceived stigma and constrained disclosure of lung cancer diagnosis, as well as the potential impact of stigma on emotional functioning, were examined using multivariable logistic regression models. RESULTS: Among the broad geographic mix of study participants, all types of lung cancer stigma were associated with decreased emotional functioning due to a combination of factors including depression, anxiety, stress, and irritability. Participants who reported a history of current or former smoking experienced higher levels of internalized stigma and perceived stigma. Constrained disclosure about a diagnosis was common, associated with decreased emotional functioning, and not related to a history of smoking. Smoking status itself was not associated with reduced emotional functioning, implicating the role of stigma in distress. CONCLUSIONS: In this study, all types of lung cancer stigma were associated with clinically important decreases in emotional functioning. This impact was not dependent on smoking history. Internalized and perceived stigma were associated with the presence of a smoking history. These findings have implications for proper psychosocial care of people diagnosed with lung cancer.

IASLC Lung Cancer Staging Project: The New Database to Inform Revisions in the Ninth Edition of the TNM Classification of Lung Cancer.

In the past 20 years, the International Association for the Study of Lung Cancer (IASLC) has been working on a global project to revise the TNM classification of lung cancer. The first and second phases of the staging projects proposed recommendations for revision of the TNM classification, which were adopted by the Union for International Cancer Control and the American Joint Committee on Cancer as their seventh and eighth editions of the TNM classifications of lung cancer. For the third phase of the IASLC Staging Project, a new database of lung cancer cases diagnosed between January 2011 and December 2019 has been established. The Staging and Prognostic Factors Committee of the IASLC is in charge of the process of proposing new recommendations. The newly established database consisted of 124,581 cases. The data were obtained from Asia and Australia (56.0%), Europe (24.7%), North America (15.7%), South/Central America (3.4%), and Africa and the Middle East (0.1%). After cases with incomplete data are excluded, 87,043 cases were enrolled in the analysis, of which 52,069 (59.8%) were invasive adenocarcinoma and 15,872 (18.2%) were squamous cell carcinoma. Both clinical and pathologic stages were available in 44,831 (51.5%) cases. Analyses of this database are expected to provide proposals for changing the TNM classification toward the ninth edition, which is scheduled to be in use in January 2024. This newly established global database on lung cancer is described to provide fundamental elements for revisions of the TNM rules for staging lung cancer.

Phase II Trial of Carfilzomib Plus Irinotecan in Patients With Small-cell Lung Cancer Who Have Progressed on Prior Platinum-based Chemotherapy.

INTRODUCTION: The purpose of this study was to evaluate the efficacy and tolerability of carfilzomib plus irinotecan (C/I) in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC who progressed after 1 platinum-containing regimen for recurrent or metastatic disease were eligible. Patients were stratified as: sensitive (SS) (progressive disease > 90 days after chemotherapy) or refractory (RS) (progressive disease 30 to 90 days after chemotherapy) and received up to 6 cycles of C/I; imaging was performed every 2 cycles. The primary endpoint was 6-month overall survival (OS). RESULTS: All 62 patients enrolled were evaluable for efficacy and adverse events. 6-month OS was 59% in the platinum SS and 54% in the platinum RS. The overall response rate was 21.6% (2.7% complete response, 18.9% partial response) in SS (n = 37) and 12.5% (all partial response) in RS (n = 25). The disease control rate was 68% (SS) and 56% (RS). Progression-free survival and OS were 3.6 months (95% confidence interval [CI], 2.6-4.6 months) and 6.9 months (95% CI, 4.3-12.3 months) in SS, and 3.3 months (95% CI, 1.8-3.9 months) and 6.8 months (95% CI, 4.1-11 months) in RS. Twenty-nine (47%) patients experienced ≥ grade 3 adverse events; 8 (12.9%) subjects had grade 4 toxicities. Three treatment-related deaths occurred: myocardial infarction (possible), lung infection (possible), and sepsis (probable). CONCLUSION: In patients with relapsed SCLC, C/I was effective in the treatment of SS and RS. With 4.8% grade 5 toxicity, C/I is a viable option for relapsed patients with SCLC with performance status 0 to 1, particularly in platinum-resistant patients, or subjects who cannot receive immunotherapy.

The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor Descriptors for Non-Small Cell Lung Cancer.

OBJECTIVE: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). METHODS: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. RESULTS: In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobe-specific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for R0, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases. CONCLUSIONS: R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.

Updated lung cancer staging system.

The tumor, node and metastasis classification of malignant tumors is periodically revised. Its seventh edition includes the updated classification for lung cancer, based on the analyses of the International Association for the Study of Lung Cancer international database. It is the largest validation ever carried out to date: 100,869 patients registered in 46 databases from 20 countries. The analysis of this database allowed a detailed study of the impact of tumor size on prognosis, the reclassification of additional tumor nodules, the reclassification of pleural dissemination and the separation of two groups of metastatic disease. These changes led to modifications in stage grouping that better differentiate tumors with different prognosis. This updated classification is also recommended for small-cell lung cancer, and for broncho-pulmonary carcinoids. A new international nodal map with stations and zones, and a histological definition of visceral pleura invasion, have also been proposed.

Outcomes of DA-EPOCH-R induction plus autologous transplant consolidation for double hit lymphoma.

High-grade B cell lymphoma with MYC and BCL2 rearrangements (double hit) has a poor prognosis with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). We report here a treatment algorithm of DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) followed by BEAM (carmustine, etoposide, cytarabine, melphalan) autologous transplant in 36 cases of previously untreated double hit lymphoma (DHL) from 2010 to 2015. A high risk International Prognostic Index (IPI) was present in 42% of cases. At median follow-up of 38 months, the 2-year progression free survival (PFS) and overall survival (OS) were 69% (95% CI 54-84%) and 71% (95% CI 56-86%). Eight cases were refractory to induction with 1-year OS 20%, and no factors were predictive for primary refractory disease. Of 28 responders, 17 proceeded to transplant while 11 were observed, primarily due to age and co-morbidities. By 24-week landmark analysis after diagnosis, the 2-year PFS and OS were both 94% (95% CI 83-100%) vs 79% (95% CI 52-100%) for transplant vs observation (p = .59 for both PFS and OS). There was no significant benefit to consolidative transplant in our series, and primary refractory DHL needs novel approaches.

The IASLC Lung Cancer Staging Project: A Renewed Call to Participation.

Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project.

The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer.

INTRODUCTION: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons. METHODS: Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases. RESULTS: The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage. CONCLUSIONS: The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.

Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group.

PURPOSE A retrospective review of the Southwest Oncology Group (SWOG) database was undertaken to review the incidence and timing of diagnosis of brain metastases in patients undergoing combined-modality therapy for stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Four hundred twenty-two eligible, assessable patients with stage IIIA/B NSCLC were treated on four SWOG protocols. Treatment varied with protocol but consisted of concurrent cisplatin-etoposide and radiation in all patients, with a surgery arm in two of the four protocols. Results Of the 422 total patients, 268 (64%) have experienced disease progression; 54 relapses (20%) were in brain only, 17 (6.5%) were in brain and other sites simultaneously, and 197 (63.5%) were in sites other than brain. Of the 268 patients with disease progression, progression in the brain only, in the brain and other sites, and not in the brain occurred in 20%, 6%, and 74% of patients, respectively. Time from treatment to diagnosis of disease progression in the brain in 71 patients was as follows: during treatment, 16 relapses (22.5%); 0 to 16 weeks after treatment, 17 relapses (24%); 16 weeks to 6 months after treatment, 10 relapses (14%); 6 to 12 months after treatment, 16 relapses (22.5%); and more than 12 months after treatment, 12 relapses (17%). Nonsquamous histology and young patient age were the only significant predictors for increased risk of early relapse with brain metastases. CONCLUSION Brain metastases often develop early in the course of treatment for stage IIIA/B NSCLC. The statistical designs of ongoing trials of prophylactic cranial irradiation in stage III NSCLC have taken this into account.

Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small-cell lung cancer: a phase II Southwest Oncology Group Study (S9504).

PURPOSE: Here we report 5-year survival data from S9504, a Southwest Oncology Group phase II trial evaluating consolidation docetaxel after concurrent cisplatin/etoposide and thoracic radiation therapy in patients with pathologically documented stage IIIB non-small-cell lung cancer. Survival outcomes were compared with a predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. PATIENTS AND METHODS: Treatment consisted of cisplatin 50 mg/m(2) per day on days 1, 8, 29, and 36; etoposide 50 mg/m(2) per day on days 1-5 and 29-33; and concurrent thoracic radiation therapy (total dose, 61 Gy). Consolidation docetaxel (75 mg/m(2) initial dose) started 4-6 weeks after completion of chemotherapy. RESULTS: Concurrent chemotherapy was generally well tolerated, with a low level of radiation-related esophagitis; 2 patients died from pneumonitis. Grade 3/4 neutropenia during consolidation docetaxel was common. At a median follow-up of 71 months, median progression-free survival was 16 months; median survival 26 months; and 3-, 4-, and 5-year survival rates were 40%, 29%, and 29%, respectively. Brain metastasis was the most common site of failure. In the predecessor trial S9019, median survival was 15 months, and 3-, 4-, and 5-year survival rates were 17%, 17%, and 17%, respectively. CONCLUSION: The 5-year survival rate in S9540 of 29% compares favorably with the predecessor trial S9019 and other treatment approaches currently used in this patient population. A phase III trial designed to validate the concept of consolidation docetaxel is presently under way.

Survival analyses in lung cancer.

BACKGROUND: Although survival analyses represent one of the cornerstones in oncology in general, some aspects of the reported survival data in lung cancer patients are still not fully elucidated. METHODS: After having defined several open questions, an evidence based approach was applied in order to answer these questions. Areas of interest were: (I) possible uncertainties in reported survival data; (II) survival surrogates; (III) recommended methods for evaluating progression free survival (PFS) as a surrogate endpoint in future datasets; (IV) postoperative lung cancer recurrence and survival. RESULTS: In recent years, PFS has seen increasing use as a primary endpoint, particularly in phase II trials. This article focuses on the statistical aspects, and particularly on evaluating the ability of PFS to accurately predict the overall survival (OS) outcome. If the data are available from randomized trials, then the evaluation of trial level surrogacy should be carried out, in addition to the methods described in the paper. If it is not a case, the patient-level methods should be applied. Suggestions for "landmark analysis" are also given: (I) classify your cases according to progression status (progressed, progression-free, or unknown) at one or more time points of interest; (II) perform a separate Cox proportional hazards regression analysis for each time point; (III) determine and report the landmark time point where progression status best predicts survival according to the hazard ratios and P values; (IV) calculate the concordance index for each landmark analysis model. The concordance index (or "c-Index") is essentially the probability that for any two randomly selected cases, the case that is predicted to have the worst outcome, does in fact have the worst outcome. CONCLUSIONS: the widening spectrum of diagnostic and treatment in pulmonary oncology imposes the need for an updated knowledge about statistical method that would fit best for the analysed problem.

The IASLC Lung Cancer Staging Project: Methodology and Validation Used in the Development of Proposals for Revision of the Stage Classification of NSCLC in the Forthcoming (Eighth) Edition of the TNM Classification of Lung Cancer.

INTRODUCTION: Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017. METHODS: An international database of 94,708 patients with lung cancer diagnosed in 1999-2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification. RESULTS: Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals. CONCLUSIONS: An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: Small cell lung cancer (SCLC) is commonly classified as either limited or extensive, but the Union for International Cancer Control TNM Classification of Malignant Tumours seventh edition (2009) recommended tumor, node, and metastasis (TNM) staging based on analysis of the International Association for the Study of Lung Cancer (IASLC) database. METHODS: Survival analyses were performed for clinically and pathologically staged patients presenting with SCLC from 1999 through 2010. Prognosis was compared in relation to the TNM seventh edition staging to serve as validation and analyzed in relation to proposed changes to the T descriptors found in the eighth edition. RESULTS: There were 5002 patients: 4848 patients with clinical and 582 with pathological stages. Among these, 428 had both. Survival differences were confirmed for T and N categories and maintained in relation to proposed revisions to T descriptors for seventh edition TNM categories and proposed changes in the eighth edition. There were also survival differences, notably at 12 months, in patients with brain-only single-site metastasis (SSM) compared to SSM at other sites, and SSM without a pleural effusion showed a better prognosis than other patients in the M1b category. CONCLUSION: We confirm the prognostic value of clinical and pathological TNM staging in patients with SCLC, and recommend continued usage for SCLC in relation to proposed changes to T, N, and M descriptors for NSCLC in the eighth edition. However, for M descriptors, it remains uncertain whether survival differences in patients with SSM in the brain simply reflect better treatment options rather than better survival based on anatomic extent of disease.

The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer.

The IASLC Staging and Prognostic Factors Committee has collected a new database of 94,708 cases donated from 35 sources in 16 countries around the globe. This has now been analysed by our statistical partners at Cancer Research And Biostatistics and, in close collaboration with the members of the committee proposals have been developed for the T, N, and M categories of the 8th edition of the TNM Classification for lung cancer due to be published late 2016. In this publication we describe the methods used to evaluate the resultant Stage groupings and the proposals put forward for the 8th edition.

The IASLC Mesothelioma Staging Project: Proposals for the M Descriptors and for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Mesothelioma.

INTRODUCTION: The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to propose evidence-based revisions for the eighth edition of the TNM classification of MPM. METHODS: Data from 29 centers were submitted either electronically or by transfer of existing institutional databases. The M component as it currently stands was validated by confirming sufficient discrimination (by Kaplan-Meier analysis) with respect to overall survival (OS) between the clinical M0 (cM0) and cM1 categories. Candidate stage groups were developed by using a recursive partitioning and amalgamation algorithm applied to all cM0 cases. RESULTS: Of 3519 submitted cases, 2414 were analyzable and 84 were cM1 cases. Median OS for cM1 cases was 9.7 months versus 13.4 months (p = 0.0013) for the locally advanced (T4 or N3) cM0 cases, supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggest a possible difference in OS for single- versus multiple-site cM1 cases. A recursive partitioning and amalgamation-generated survival tree on the OS outcomes restricted to cM0 cases with the newly proposed (eighth edition) T and N components indicates that optimal stage groupings for the eighth edition will be as follows: stage IA (T1N0), stage IB (T2-3N0), stage II (T1-2N1), stage IIIA (T3N1), stage IIIB (T1-3N2 or any T4), and stage IV (any M1). CONCLUSIONS: This first evidence-based revision of the TNM classification for MPM leads to substantial changes in the T and N components and the stage groupings.

The IASLC Mesothelioma Staging Project: Proposals for Revisions of the N Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: Nodal categories for malignant pleural mesothelioma are derived from the lung cancer staging system and have not been adequately validated. The International Association for the Study of Lung Cancer developed a multinational database to generate evidence-based recommendations to inform the eighth edition of the TNM classification of malignant pleural mesothelioma. METHODS: Data from 29 centers were entered prospectively (n = 1566) or by transfer of retrospective data (n = 1953). Survival according to the seventh edition N categories was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Survival was measured from the date of diagnosis. RESULTS: There were 2432 analyzable cases: 1603 had clinical (c) staging, 1614 had pathologic (p) staging, and 785 had both. For clinically staged tumors there was no separation in Kaplan-Meier curves between cN0, cN1 or cN2 (cN1 versus cN0 hazard ratio [HR] = 1.06, p = 0.77 and cN2 versus cN1 HR = 1.04, p = 0.85). For pathologically staged tumors, patients with pN1 or pN2 tumors had worse survival than those with pN0 tumors (HR = 1.51, p < 0.0001) but no survival difference was noted between those with pN1 and pN2 tumors (HR = 0.99, p = 0.99). Patients with both pN1 and pN2 nodal involvement had poorer survival than those with pN2 tumors only (HR = 1.60, p = 0.007) or pN0 tumors (HR = 1.62, p < 0.0001). CONCLUSIONS: A recommendation to collapse both clinical and pN1 and pN2 categories into a single N category comprising ipsilateral, intrathoracic nodal metastases (N1) will be made for the eighth edition staging system. Nodes previously categorized as N3 will be reclassified as N2.

The IASLC Mesothelioma Staging Project: Proposals for Revisions of the T Descriptors in the Forthcoming Eighth Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The current T component for malignant pleural mesothelioma (MPM) has been predominantly informed by surgical data sets and consensus. The International Association for the Study of Lung Cancer undertook revision of the seventh edition of the staging system for MPM with the goal of developing recommendations for the eighth edition. METHODS: Data elements including detailed T descriptors were developed by consensus. Tumor thickness at three pleural levels was also recorded. An electronic data capture system was established to facilitate data submission. RESULTS: A total of 3519 cases were submitted to the database. Of those eligible for T-component analysis, 509 cases had only clinical staging, 836 cases had only surgical staging, and 642 cases had both available. Survival was examined for T categories according to the current seventh edition staging system. There was clear separation between all clinically staged categories except T1a versus T1b (hazard ratio = 0.99, p = 0.95) and T3 versus T4 (hazard ratio = 1.22, p = 0.09), although the numbers of T4 cases were small. Pathological staging failed to demonstrate a survival difference between adjacent categories with the exception of T3 versus T4. Performance improved with collapse of T1a and T1b into a single T1 category; no current descriptors were shifted or eliminated. Tumor thickness and nodular or rindlike morphology were significantly associated with survival. CONCLUSIONS: A recommendation to collapse both clinical and pathological T1a and T1b into a T1 classification will be made for the eighth edition staging system. Simple measurement of pleural thickness has prognostic significance and should be examined further with a view to incorporation into future staging.