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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 lobespecific 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 RO, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between RO 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. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

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.

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.

Introduction Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. Methods A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. Results Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor—T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location—with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. Conclusion We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

Introduction Nodal status is considered to be one of the most reliable indicators of the prognosis in patients with lung cancer and thus is indispensable in determining the optimal therapeutic options. We sought to determine whether the current nodal (N) descriptors should be maintained or revised for the next edition (8th) of the International Lung Cancer Staging System. Methods The new International Association for the Study of Lung Cancer lung cancer database was created from 94,708 patients diagnosed as having lung cancer between 1999 and 2010. Among these, 38,910 and 31,426 patients with non–small-cell lung carcinoma were available for an analysis of the clinical (c)N and pathological (p)N status, respectively. The anatomical location of lymph node involvement was defined by either the Naruke (for Japanese data) or American Thoracic Society (for non-Japanese data) nodal charts. Survival was calculated by the Kaplan–Meier method, and prognostic groups were assessed by a Cox regression analysis. Results The current N0 to N3 descriptors for both the cN and pN status consistently separated prognostically distinct groups. The 5-year survival rates according to the cN and pN status were 60% and 75% (N0), 37% and 49% (N1), 23% and 36% (N2), and 9% and 20% (N3), respectively. The differences in survival between all neighboring nodal categories were highly significant for both the cN and pN status. With regard to pathological staging, additional analyses regarding the prognosis were performed by further dividing N1 into N1 at a single station (N1a) and N1 at multiple stations (N1b); N2 into N2 at a single station without N1 involvement (“skip” metastasis, N2a1), N2 at a single station with N1 involvement (N2a2), and N2 at multiple stations (N2b). The survival curves for N1b and N2a2 overlapped each other, and N2a1 had numerically a better prognosis than N1b, although the difference was not significant. Geographic difference in N-specific prognosis was observed for both c-settings and p-settings. This might have been because of the difference in the used nodal map, surgical technique, and pathologist's handling of the resected specimen. Conclusions Current N descriptors adequately predict the prognosis and therefore should be maintained in the forthcoming staging system. Furthermore, we recommend that physicians record the number of metastatic lymph nodes (or stations) and to further classify the N category using new descriptors, such as N1a, N1b, N2a, N2b, and N3, for further testing.

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. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

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.

8513 Background: Relapsed small cell lung cancer (SCLC) is incurable with limited therapeutic options. This phase II study evaluated efficacy and tolerability of carfilzomib + irinotecan in SCLC pts who progressed after prior platinum-based therapy, based on expected synergy of proteosome inhibitor carfilzomib and topisomerase 1 inhibitor irinotecan. Methods: SCLC pts who progressed after one platinum-containing regimen (no maintenance therapy allowed) for recurrent/metastatic disease were eligible. Pts were stratified by response to platinum-based therapy: sensitive (progressive disease (PD) > 90 days after chemo) versus refractory (PD 30 to 90 days after chemo). Pts were treated with up to 6 cycles of carfilzomib (20/36 mg.m2 D1, 2, 8, 9, 15, 16 q28D) and irinotecan (125 mg/m2 D1, 8, 15 q28D), imaging was performed every 2 cycles. The primary efficacy endpoint was 6-month overall survival (OS). Results: 62 pts enrolled and were evaluable for efficacy and adverse events. The 6-month OS was 59% in the platinum sensitive stratum and 54% in the platinum refractory stratum. Overall response rate: sensitive stratum 21.6% (1.6% CR + 16.4% PR) and refractory stratum 12.5% (all PR). Disease control (SD+PR+CR) was 68% in platinum sensitive and 56% in refractory patients. Progression free survival and OS were 3.6 months (95% CI 2.6 - 4.6) and 6.9 months (95% CI 4.3 - 12.3) in the sensitive stratum, and 3.3 months (95% CI 1.8 – 3.9) and 6.8 months (95% CI 4.1-11) in the refractory stratum. Twenty-nine pts (47%) experienced at least one grade 3 AE and 8 subjects had grade 4 toxicities: decreased neutrophils, leukocytes, and lymphocytes, diarrhea, vomiting, sepsis, hypokalemia, hypocalcemia, and dehydration. There were three treatment related deaths: myocardial infarction (possible), lung infection (possible), sepsis (probable). Conclusions: In previously treated pts with relapsed SCLC, irinotecan and carfilzomib was effective in platinum-sensitive and, notably, platinum-refractory pts with similar toxicity profile. This combination is a viable option in relapsed SCLC, can be considered following progression on immunotherapy (IO) or in subjects who cannot receive IO, and should be further explored in a randomized phase III trial. Clinical trial information: NCT01941316.

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.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.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, p0.0001).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.

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.

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 MO (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. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

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.

Introduction Malignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy. Methods Patients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used. Results Fifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36%, and median progression-free survival was 2.6 months. Conclusion Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib.

BACKGROUND: Southwest Oncology Group 0124 was a large North American phase 3 trial that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with extensive stage small cell lung cancer (SCLC). These results were contrary to Japan Clinical Oncology Group 9511, a phase 3 trial exclusively in Japanese patients. Because 0124 and 9511 used identical treatment regimens and similar eligibility criteria, patient-level data were pooled from both trials, and a common arm analysis was performed to explore potential reasons for the divergent results. METHODS: Patients with documented extensive stage SCLC and adequate end-organ function were randomized to intravenously receive either cisplatin 60 mg/m2 Day 1 + irinotecan 60 mg/m2 Days 1, 8, and 15 every 4 weeks or cisplatin 80 mg/m2 Day 1 + etoposide 100 mg/m2 Days 1-3 every 3 weeks. Demographic and outcome data were compared among 805 patients enrolled in 9511 and 0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status (PS). RESULTS: Of 671 patients in 0124, 651 eligible patients were included, as were all 154 patients from 9511. Significant differences in sex and PS distribution as well as toxicity were seen between trials. There were also significant differences in response rates (87% vs 60%, P

Purpose Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. Patients and Methods Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. Results Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. Conclusion This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

International audience; OBJECTIVE: In the 2003 Supplement for tumor, node, metastasis (TNM) Staging classification it states that TNM staging "applies to all types of carcinoma including small cell carcinoma; however, it does not apply to carcinoids." Despite this caveat, most publications on typical and atypical carcinoids use the TNM staging system for nonsmall cell carcinoma and are able to demonstrate prognostic significance for the different stages. For this reason, as the next TNM Staging proposal is being considered, we sought to investigate the carcinoid cases submitted to the International Association for the Study of Lung Cancer (IASLC) database, as well as the National Cancer Institute Surveillance Epidemiology and End Results (SEER). MATERIALS AND METHODS: In the data collected for the IASLC Staging Project database over the time period 1990 to 2000, there were 513 broncho-pulmonary carcinoids. A total of 1619 broncho-pulmonary carcinoid cases diagnosed over the period 1990-2002 were analyzed from the SEER database, including 1437 surgical cases. Pathologic slides were not available for histologic review. RESULTS: Most of tumors in both the IASLC and SEER databases were Stage I (82% and 78%, respectively), as defined by the IASLC proposals for the 7th edition of TNM staging system. T status was a statistically significant predictor of survival for both the SEER data (p < 0.0001) and the IASLC database (p = 0.0156), though for different reasons. N status showed significant survival correlations in both data sets (p < 0.0001). The effect of M status was significant (p < 0.0001) within the SEER data and not studied in the IASLC cases, which were almost exclusively M0. We found that all three T, N, and M categories as defined for non-small cell lung cancer are generally useful for staging of pulmonary carcinoid tumors. Significant differences in survival for overall stages I versus II versus III/IV were identified in both data sets. Patients with multiple same lobe nodules had a 100% 5-year survival, which may be a reason to reevaluate their status in the IIB category in future analyses. CONCLUSIONS: In summary, the IASLC proposals for the 7th edition of TNM are helpful in predicting prognosis for broncho-pulmonary carcinoid tumors. It is the recommendation of the IASLC Staging project that TNM be applied to broncho-pulmonary carcinoid tumors. A prospective collection of data through an International Registry of Pulmonary Neuroendocrine Tumors planned by the IASLC will allow for further detailed analysis of staging data for broncho-pulmonary carcinoids.

Purpose This phase II study (S0341) evaluated the efficacy and tolerability of single-agent erlotinib in unselected chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) of 2. Exploratory analyses of a number of biomarkers relating to epidermal growth factor receptor pathway activation were also performed. Patients and Methods Patients with stage IIIB (pleural effusion) or stage IV NSCLC with a PS of 2 and no prior chemotherapy or biologic treatment for NSCLC received erlotinib 150 mg daily. Results A total of 81 patients entered the study; 76 were assessable. One complete and 5 partial responses were noted for an overall response rate of 8% (95% CI 3%–16%). Stable disease (SD) was seen in 26 patients (34%) resulting in a disease control rate (DCR = CR/PR/SD) of 42%. Progression free and median survival were 2.1 months (95% CI 1.5–3.1) and 5 months (95% CI 3.6–7.2), respectively. One-year survival was 24% (95% CI 15%–34%). Although treatment was generally well tolerated, grade 3 to 4 toxicity was reported in 30 patients (40%), including fatigue (16%), rash (9%), diarrhea (7%), and anorexia (7%). There was one possible treatment related death (pneumonitis). Conclusions In chemotherapy-naive patients with advanced NSCLC and a PS of 2, single agent erlotinib resulted in an acceptable but significant level of treatment-related side effects. With an overall DCR of 42% and median survival of 5 months, results are comparable to those achieved with chemotherapy in this population. Development of an epidermal growth factor receptor-directed biomarker selection strategy may optimize use of erlotinib in PS 2 patients.

Purpose Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non–small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease. Patients and Methods Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m2 on days 1 and 8 plus etoposide 50 mg/m2 on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m2. Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease. Results Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. Conclusion In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.

Introduction It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. Methods A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. Results It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. Conclusions Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.

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.

For nearly 40 years, there was no generally accepted staging system for malignant pleural mesothelioma. In 1994, members of the International Mesothelioma Interest Group, in collaboration with the International Association for the Study of Lung Cancer, proposed a TNM staging system based on analyses of outcomes in retrospective surgical series and small clinical trials. Subsequently accepted by the American Joint Commission on Cancer and the Union for International Cancer Control for the sixth editions of their staging manuals, this system has since been the international staging standard. However, it has significant limitations, particularly with respect to clinical staging and to the categories for lymph node staging. Here we provide an overview of the development of the International Association for the Study of Lung Cancer malignant pleural mesothelioma staging database, which was designed to address these limitations through the development of a large international data set. Analyses of this database, described in papers linked to this overview, are being used to inform revisions in the eighth editions of the American Joint Commission on Cancer and Union for International Cancer Control staging systems. ispartof: Journal of Thoracic Oncology vol:11 issue:12 pages:2082-2088 ispartof: location:United States status: published

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.

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. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Introduction To evaluate the activity of a nonplatinum-, nonetoposide-containing regimen for patients with extensive stage small cell lung cancer. Methods Patients with untreated extensive stage small cell lung cancer were treated with gemcitabine 1000 mg/m 2 and irinotecan 100 mg/m 2 on days 1 and 8 of a 21-day cycle for a maximum of six cycles. Patients with brain metastases were eligible if asymptomatic or controlled after radiation. Results Eighty-four eligible patients with untreated extensive stage small cell lung cancer with adequate organ function and a performance status of 0–2 were accrued. The median age was 64 years (range, 42–85) and 45 (54%) were women. Six cycles were completed by 28 (33%) patients. Some degree of diarrhea occurred in 57% (grade 3/4, 18%). Other grade 3/4 toxicities were neutropenia (26%), anemia (10%), thrombocytopenia (8%), febrile neutropenia (5%), fatigue (11%), nausea (10%), and vomiting (8%). The response rate was 32% (95% confidence interval: 22%–43%) among the 81 patients with measurable disease. The median survival was 8.5 months (95% confidence interval: 7.0–9.8) with 1- and 2-year survival rates of 26% and 7%, respectively. Salvage therapy data were captured by prospective collection, and only 50% of patients were treated secondarily. Conclusion The overall response rate with the combination of gemcitabine and irinotecan was disappointing, and the median survival rate was lower than expected. Further development of this combination in small cell lung cancer is not recommended.

Nodal status is considered to be one of the most reliable indicators of the prognosis in patients with lung cancer and thus is indispensable in determining the optimal therapeutic options. We sought to determine whether the current nodal (N) descriptors should be maintained or revised for the next edition (8th) of the International Lung Cancer Staging System.The new International Association for the Study of Lung Cancer lung cancer database was created from 94,708 patients diagnosed as having lung cancer between 1999 and 2010. Among these, 38,910 and 31,426 patients with non-small-cell lung carcinoma were available for an analysis of the clinical (c)N and pathological (p)N status, respectively. The anatomical location of lymph node involvement was defined by either the Naruke (for Japanese data) or American Thoracic Society (for non-Japanese data) nodal charts. Survival was calculated by the Kaplan-Meier method, and prognostic groups were assessed by a Cox regression analysis.The current N0 to N3 descriptors for both the cN and pN status consistently separated prognostically distinct groups. The 5-year survival rates according to the cN and pN status were 60% and 75% (N0), 37% and 49% (N1), 23% and 36% (N2), and 9% and 20% (N3), respectively. The differences in survival between all neighboring nodal categories were highly significant for both the cN and pN status. With regard to pathological staging, additional analyses regarding the prognosis were performed by further dividing N1 into N1 at a single station (N1a) and N1 at multiple stations (N1b); N2 into N2 at a single station without N1 involvement ("skip" metastasis, N2a1), N2 at a single station with N1 involvement (N2a2), and N2 at multiple stations (N2b). The survival curves for N1b and N2a2 overlapped each other, and N2a1 had numerically a better prognosis than N1b, although the difference was not significant. Geographic difference in N-specific prognosis was observed for both c-settings and p-settings. This might have been because of the difference in the used nodal map, surgical technique, and pathologist's handling of the resected specimen.Current N descriptors adequately predict the prognosis and therefore should be maintained in the forthcoming staging system. Furthermore, we recommend that physicians record the number of metastatic lymph nodes (or stations) and to further classify the N category using new descriptors, such as N1a, N1b, N2a, N2b, and N3, for further testing.

Introduction Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses. Methods Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review. Results Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review. Conclusions Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer.

Purpose A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non–small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort. Patients and Methods Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21days for three cycles. Results Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%. Conclusion Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.

Background In preclinical models, the proteasome inhibitor bortezomib (PS-341) inhibits the growth of small cell lung cancer (SCLC) by inhibiting the antiapoptotic Bcl-2 signaling pathway. We conducted a phase II trial of PS-341 in previously treated patients with platinum-sensitive and -refractory extensive stage SCLC to determine response rate, toxicity, and survival. Methods Patients with histologically confirmed SCLC, measurable disease, Zubrod performance status 0–1, and previous treatment with platinum-based therapy were enrolled. They were stratified by platinum-sensitivity status: sensitive (relapse >90 days after platinum) or refractory (progression during or ≤90 days after platinum). PS-341 was administered at 1.3 mg/m 2 intravenously on days 1, 4, 8, and 11 every 21 days. Results Of 56 eligible patients, 28 were platinum sensitive and 28 refractory. Twenty-nine patients (52%) had received two or more previous chemotherapy regimens. One platinum-refractory patient had a confirmed partial response. A majority of assessable patients (91%) progressed. Median progression-free survival and overall survival were 1 month and 3 months, respectively. Ten patients (18%) discontinued treatment due to adverse events or side effects. Conclusion Although PS-341 induced a response in a patient with platinum-refractory disease, it has limited single-agent activity in this heavily pretreated cohort. As shown in preclinical models, testing of PS-341 in combination with an apoptotic trigger such as chemotherapy, is a rational clinical approach. A trial of topotecan plus PS-341 has been initiated to test this concept.

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.

Background:: There are no published prospective trials of chemotherapy for advanced bronchioloalveolar carcinoma (BAC), a subtype of non-small-cell lung cancer for which there is no current standard therapy. This phase II study assesses the efficacy and toxicity of 96-h paclitaxel in chemotherapy-naive patients with advanced BAC. Patients and methods:: Patients with histologically confirmed stage IIIB (with pleural effusion) or stage IV BAC were eligible. Treatment consisted of paclitaxel 35 mg/m2/24 h continuously infused over 96 h (days 1–4) every 21 days for up to six courses. Results:: A total of 58 eligible patients were enrolled. The objective response rate was 14% (all partial responses, 9% confirmed); 40% of patients demonstrated stable disease. The median progression-free and overall survivals were 5 and 12 months, respectively. Grade 3 or greater toxicities included neutropenia/granulocytopenia (43%), febrile neutropenia (12%), infection (22%), and stomatitis/pharyngitis (10%); there were five treatment-related deaths. Conclusions:: S9714 represents the first prospective multi-institutional cooperative group trial focusing on treatment outcomes in BAC. Studies targeting this population are feasible, and while first-line paclitaxel administered as a prolonged infusion is active in this setting, toxicities limits the utility of this regimen. S9714 serves as a historical control for BAC patients against which future therapeutic approaches can be compared.

BACKGROUND Recent explorations suggest that women may experience more severe 5-fluorouracil (5-FU)–related toxicity than men. The patient populations from 4 Southwest Oncology Group colorectal carcinoma trials with 5-FU–containing regimens were examined for toxicity differences between the genders. METHODS The current study included 1074 patients from 4 trials. Hypotheses regarding differences in specific toxicities were generated via exploratory analyses on the data from the 2 earlier trials (n = 505 patients), using basic univariate techniques and classification tree methods. Validation of these hypotheses was performed on data from the 2 later trials (n = 569 patients) using logistic regression models for dichotomous toxicity outcomes and rank-sum tests for comparisons of overall toxicity grade. RESULTS 5-FU toxicity was more extensive in women than in men in terms of average maximum toxicity grade (P = 0.005), number of different types of toxicity experienced (P = 0.009), and incidence of severe toxicities (P = 0.02). The incidence of ≥ Grade 2 hematologic toxicity in the 2 later trials was higher in women than in men and women experienced more frequent moderate to severe mucositis compared with men. CONCLUSIONS Differences in 5-FU toxicity profiles between men and women were hypothesized after an exploratory analysis, and then verified by an independent confirmatory analysis using data from the 2 later trials. This process provided substantial evidence for gender differences in specific aspects of 5-FU toxicity that persist across a range of treatment regimens, patient characteristics, and cancer trial settings. Cancer 2005. © 2005 American Cancer Society.

Purpose: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new drugs or new strategies to better use currently available agents. Sequential administration offers an opportunity to increase drug diversity while maintaining dose intensity. On the basis of the data indicating the activity of taxanes as second-line therapy and the lack of efficacy for more than three cycles of platinum-based therapy, this randomized Phase II study tested the concept of planned sequential chemotherapy in advanced NSCLC. Experimental Design: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0–1 and normal organ function were eligible. Therapy: arm 1, carboplatin (area under the curve = 5.5 mg/ml × min day 1) and gemcitabine (1000 mg/m2 days 1 and 8 every 21 days × 3) followed by paclitaxel (225 mg/m2 every 21 days × 3) or arm 2, cisplatin (100 mg/m2 day 1), vinorelbine (25 mg/m2 days 1 and 8 every 21 d × 3) followed by docetaxel (75–100 mg/m2 every 21 days × 3). Results: Two-hundred four patients were accrued, of whom, 178 were eligible and evaluable. Eighty percent of patients were stage IV on arm 1 and 85% on arm 2. Response rates were 21 and 28% on arms 1 and 2, respectively. Median, 1-year and 2-year survivals were 9 months, 34 and 13%, and 9 months, 36 and 8%, on arms 1 and 2, respectively. Conclusions: Sequential therapy, as used in this study, resulted in comparable efficacy to previous Southwest Oncology Group trials of two drug combinations in this population; however, it failed to meet criteria for further study.

Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.

The hypothesis tested was that mutant tumor DNA shed into plasma would show predictive value for monitoring response to therapy in non-small cell lung carcinoma patients. Pretreatment plasma specimens from 25 patients on a phase I trial were evaluated, 12 with paired posttreatment specimens, and 138 patients on the Southwest Oncology Group S0003 trial, 38 with paired posttreatment specimens, for the presence of K-RAS mutations. Thirteen tumor specimens from the phase I trial patients and seven tumor specimens from S0003 patients were also available for comparative analysis of K-RAS mutations in tumor tissue and plasma. All patients were treated similarly with paclitaxel, and carboplatin chemotherapy. DNA was extracted and mutational analyses performed using an RFLP-PCR assay. K-RAS mutations were found in plasma DNA in 5/25 of the phase I patients (20%). Median survival was 10 months in all patients, 11.4 months in the wild-type K-RAS group, and 3.3 months in the mutant K-RAS group (P = 0.056). Point mutations in plasma DNA were identical to mutations found in the tumors, confirming the tumor as the source. In two patients with K-RAS mutations pretreatment, posttreatment plasmas were evaluated: a patient with clinical progressive disease retained the mutant DNA, while in a patient with a complete response (CR), the K-RAS mutation was no longer detectable. In an ongoing analysis of S0003 patients, to date, K-RAS mutations have been found in the plasma of 14 patients (10.1%). In 42 matched pre- and posttreatment specimens from both phase I and S0003 trials, four patients had K-RAS mutations pretreatment that were not detectable posttreatment. Of these, two had a clinical CR or partial response, and the other two had stable disease. It was concluded that detection of tumor DNA in plasma is feasible using molecular techniques and that this approach shows promise for monitoring patient response to therapy.

Purpose Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC. Patients and Methods Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, and etoposide 50 mg/m2 on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m2, both drugs administered on day 1 of a 21 day cycle for three cycles. Results The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%. Conclusion Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.

Introduction. Limited information is available regarding surveillance patterns after head and neck cancer radiotherapy. We cataloged follow-up for a specified patient cohort treated at three neighboring university, community, and Veterans Administration institutions. Methods. One hundred fifteen patients were treated with curative intent between 1994–1998 with definitive or postoperative radiotherapy for newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. One hundred patients had continuous follow-up at their treating institution and were included for analysis. Median follow-up until disease recurrence or censorship was 28.5 months. Results. Median follow-up frequency was 5.7 visits/year and was highly variable. Although visit frequency correlated with disease stage and the presence of high-risk disease features, this association was lost when patients with early recurrences were removed from analysis. Procedure and test utilization closely mirrored visit frequency, resulting in a wide range of estimated yearly charges ($0–15,668/year; median, $1,772/year). Actuarial 3-year overall survival for the study group was 71%. Eighty-six percent (19 of 22) of potentially salvageable locoregional failures were discovered secondary to symptomatic complaint rather than by test results. Disease failure, whether detected by symptom or testing, predicted for poor survival (22% at 24 months after recurrence). Conclusions. Postradiotherapy surveillance for head and neck cancer is inconsistently pursued. A proven correlation between intensive follow-up and improved patient survival is lacking. Surveillance directed by patient symptoms should be investigated as an alternative approach. © 2003 Wiley Periodicals, Inc. Head Neck 25: 000–000, 2003

Colorectal adenomas are the usual precursors to carcinoma in sporadic and hereditary colorectal cancers (CRC).A total of 220 CRC patients (stages 0, I, and II) were randomized prospectively in a double-blind pilot study of calcium chemoprevention by using recurrent colorectal adenomas as a surrogate end point. This trial is still in progress, and we report the preliminary findings on adenoma recurrence rates.Synchronous adenomas were present in 60% of patients, and cancer confined in a polyp was present in 23% of patients. The overall cumulative adenoma recurrence rate was 31% (19% in the first year, 29% for 2 years, and 35% for 3 years). The recurrence rates were greater for patients with synchronous adenomas: 38% at 3 years (P =.01). Lower stage was associated with higher adenoma recurrence rates (P =.04). Factors including age, sex, site of primary cancer, and whether the cancer was confined to a polyp were not significantly associated with differences in adenoma recurrence rates.The substantial adenoma recurrence rate in patients resected of CRC justifies colonoscopic surveillance on a periodic basis. Patients with higher rates of adenoma recurrences, such as CRC with synchronous adenomas, are ideal subjects for chemoprevention trials.

Purpose: To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non–small-cell lung cancer (NSCLC). Results were compared with those of the predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. Patients and Methods: Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33, and concurrent thoracic radiotherapy (total dose of 61 Gy). Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2. Results: Stage subsets (tumor-node-metastasis system) in 83 eligible patients were as follows: T4N0/1, 31 patients (37%); T4N2, 22 patients (27%), and T1–3N3, 30 patients (36%). Concurrent chemoradiotherapy was generally well tolerated, but two patients died from probable radiation-associated pneumonitis. Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively. Conclusion: Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019. Nevertheless, this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach. Phase III trials evaluating the S9504 regimen have been initiated to validate these results.

To investigate the hypothesis that a systemic agent designed to inhibit dihydropyrimidine dehydrogenase (DPD), the first enzyme in the fluoropyrimidine degradative pathway, could improve the effective amount of 5-fluorouracil (5-FU) delivered to a tumor resulting in enhanced response.Eligibility included cytologically or pathologically verified diagnosis of colorectal cancer that recurred during or within 12 months of completion of adjuvant therapy, representing patients generally considered resistant to fluorinated pyrimidine therapy. Stratification was into two cohorts: recurrence while receiving adjuvant therapy, and relapse within 12 months of completing adjuvant therapy. Treatment consisted of 28 days of oral therapy every five weeks with eniluracil and 5-FU administered in a 10:1 ratio. The daily dose of eniluracil was 10 mg/m2 with 5-FU 1 mg/m2, divided into two doses.Twenty-five patients are evaluable for response: 9 relapsed during therapy and 16 relapsed within one year of adjuvant therapy. In the first group, there was one partial response (9%; 95% CI 0-41%); in the second cohort there was one confirmed complete response (5%; 95% CI 0-23%) and one unconfirmed partial response, for an overall response rate of 10%.This regimen lacks significant activity in this target population. Pre-treatment intratumoral DPD expression was not assessed, therefore the mechanism of fluorinated pyrimidine resistance cannot be specifically attributed to elevated DPD levels. Attempting restoration of chemotherapy sensitivity through blockade of enzymes or signal transduction molecules responsible for resistance is rational, provided that tumor target expression is the basis for trial entry.

We compiled and analyzed a database of cooperative group trials in advanced pancreatic cancer to develop historical benchmarks for overall survival (OS) and progression-free survival (PFS). Such benchmarks are essential for evaluating new therapies in a single-arm setting. The analysis included patients with untreated metastatic pancreatic cancer receiving regimens that included gemcitabine, between 1995 and 2005. Prognostic baseline factors were selected by their significance in Cox regression analysis. Outlier trial arms were identified by comparing individual 6-month OS and PFS rates against the entire group. The dataset selected for the generation of OS and PFS benchmarks was then tested for intertrial arm variability using a logistic-normal model with the selected baseline prognostic factors as fixed effects and the individual trial arm as a random effect. A total of 1,132 cases from eight trials qualified. Performance status and sex were independently significant for OS, and performance status was prognostic for PFS. Outcomes for one trial (NCCTG-034A) were significantly different from the other trial arms. When this trial was excluded, the remaining trial arms were homogeneous for OS and PFS outcomes after adjusting for performance status and sex. Benchmark values for 6-month OS and PFS are reported along with a method for using these values in future study design and analysis. The benchmark survival values were generated from a dataset that was homogeneous between trials. The benchmarks can be used to enable single-arm phase II trials using a gemcitabine platform, especially under certain circumstances. Such circumstances might be when a randomized control arm is not practically feasible, an early signal of activity of an experimental agent is being explored such as in expansion cohorts of phase I studies, and in patients who are not candidates for combination cytotoxic therapy. Clin Cancer Res; 20(16); 4176–85. ©2014 AACR.

To assess agreement between transvaginal and translabial ultrasonography for measuring cervical length in the second and third trimesters.Eighty-four obstetric patients at 14-40 weeks' gestation were enrolled. Three images of the cervix were obtained by translabial (3.5-MHz curvilinear transducer) and transvaginal (6.5-MHz endovaginal probe) ultrasonography. The mean cervical length obtained by using each method was used for data analysis. The McNemar chi(2) test was used to assess the difference between techniques in their ability to obtain a measurement. The paired t-test was used to evaluate the differences between the measurements. The mean difference and SD for the differences were used to calculate the limits of agreement. An acceptable difference was defined as less than 0.5 cm.Cervical length measurements were obtained in 84 patients (100%) by using the transvaginal technique and in 80 patients (95%) by using the translabial technique (P =.1). Eighty patients had both transvaginal and translabial measurements for comparison. The mean difference in cervical length was 0.37 cm (P.001; 95% confidence interval [CI] 0. 21, 0.52). The upper and lower limits of agreement were 1.75 cm (95% CI 1.48, 2.02) and -1.01 cm (95% CI -0.74, -1.28), respectively. The differences between the two measurements were within these limits 95% of the time. These limits of agreement were greater than the acceptable difference of 0.5 cm.Transvaginal and translabial techniques should not be used interchangeably for clinical assessment of cervical length because agreement between the methods is not within an acceptable range.

Objective Histologic subtyping has been advocated to select chemotherapy for patients with advanced-stage non-small-cell lung cancer (NSCLC). To determine whether histologic subtype was associated with efficacy for the commonly used antimicrotubule (AMT) agents, paclitaxel, docetaxel, and vinorelbine plus a platinum compound, we examined the Southwest Oncology Group (SWOG) lung cancer database. Methods Data from 4 randomized trials (S9308, S9509, S9806, and S0003) administering an AMT agent plus platinum in patients receiving first-line treatment for advanced-stage NSCLC were analyzed. Overall survival (OS) and progression-free survival (PFS) comparisons were performed using Cox proportional hazard regression, adjusting for sex. Median survival times were estimated by Kaplan-Meier. Results Of 1146 patients included in this analysis, 640 had adenocarcinoma (56%), 220 had squamous cell carcinoma (19%), 121 had large cell carcinoma (11%), and 165 had NSCLC not otherwise specified (NOS) (14%). Median OS times by histologic subtypes were 8.5, 8.4, 8.2, and 9.6 months, respectively, and median PFS times were 4.2, 4.3, 4.3, and 4.6 months, respectively. No difference in OS or PFS was observed by histologic subtype and, specifically, between nonsquamous and squamous histologies. Conclusions This pooled analysis from 4 SWOG trials using an AMT-platinum regimen did not show a difference in survival outcomes by histologic subtype. Because the majority of patients with advanced NSCLC continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted. © 2013 Elsevier Inc. All rights reserved.

Purpose Randomized clinical trials failed to show a survival benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors plus concurrent chemotherapy in patients with metastatic non–small-cell lung cancer (NSCLC), with preclinical data suggesting potential negative interactions. In contrast, pilot trials of the EGFR-targeted antibody, cetuximab, plus chemotherapy suggested enhanced antitumor activity. This randomized phase II trial was designed to select a cetuximab plus chemotherapy regimen for phase III evaluation. Patients and Methods Treatment-naive patients with advanced-stage NSCLC were randomly assigned to receive paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6) every 3 weeks plus concurrent cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) for four cycles followed by maintenance cetuximab or sequential paclitaxel-carboplatin for four cycles followed by cetuximab. Results Of 242 patients enrolled, 224 were eligible and assessable for response (106 and 118 patients in the concurrent and sequential arms, respectively). With a median follow-up time of 32 months, the median overall survival was 10.9 months (95% CI, 9.2 to 13.0 months) for patients receiving concurrent therapy and 10.7 months (95% CI, 8.5 to 12.8 months) for patients receiving sequential therapy (P = .57); 1-year survival rates were 45% (95% CI, 36% to 54%) and 44% (95% CI, 35% to 53%), respectively. Response rates and progression-free survival times were similar in both arms, as was grade 3 rash, whereas sensory neuropathy was higher in the concurrent arm (15% v 5% in the sequential arm; P = .036). Conclusion Although both regimens met the efficacy criterion for continued evaluation, the concurrent regimen of paclitaxel/carboplatin plus cetuximab was chosen.

Purpose Patients with early-stage non–small-cell lung cancer (NSCLC) have a poor prognosis even after complete resection. Earlier studies of preoperative (induction) chemotherapy in resectable NSCLC demonstrated feasibility and encouraging survival data. This randomized phase III trial compared overall survival (OS) for preoperative paclitaxel and carboplatin followed by surgery with surgery alone in patients with early-stage NSCLC. Patients and Methods Patients with clinical stage IB-IIIA NSCLC (excluding superior sulcus tumors and N2 disease) were eligible. Patients were randomly assigned to surgery alone or to three cycles of paclitaxel (225 mg/m2) and carboplatin (area under curve, 6) followed by surgical resection. The primary end point was OS; secondary end points were progression-free survival (PFS), chemotherapy response, and toxicity. Results The trial closed early with 354 patients after reports of a survival benefit for postoperative chemotherapy in other studies. The median OS was 41 months in the surgery-only arm and 62 months in the preoperative chemotherapy arm (hazard ratio, 0.79; 95% CI, 0.60 to 1.06; P = .11.) The median PFS was 20 months for surgery alone and 33 months for preoperative chemotherapy (hazard ratio, 0.80; 95% CI, 0.61 to 1.04; P = .10.) Major response to chemotherapy was seen in 41% of patients; no unexpected toxicity was observed. Conclusion This trial closed prematurely after compelling evidence supporting postoperative chemotherapy emerged. Although OS and PFS were higher with preoperative chemotherapy, the differences did not reach statistical significance. At present, stronger evidence exists for postoperative chemotherapy in early-stage NSCLC.