NCCN Guidelines Insights: Malignant Pleural Mesothelioma, Version 3.2016.

These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Malignant Pleural Mesothelioma (MPM). These NCCN Guidelines Insights discuss systemic therapy regimens and surgical controversies for MPM. The NCCN panel recommends cisplatin/pemetrexed (category 1) for patients with MPM. The NCCN panel also now recommends bevacizumab/cisplatin/pemetrexed as a first-line therapy option for patients with unresectable MPM who are candidates for bevacizumab. The complete version of the NCCN Guidelines for MPM, available at NCCN.org, addresses all aspects of management for MPM including diagnosis, evaluation, staging, treatment, surveillance, and therapy for recurrence and metastasis; NCCN Guidelines are intended to assist with clinical decision-making.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

Non-Small Cell Lung Cancer, Version 6.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

Non-small cell lung cancer, version 1.2015.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.

BACKGROUND: The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. METHODS: A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). FINDINGS: Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. INTERPRETATION: Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. FUNDING: UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Thymomas and thymic carcinomas: Clinical Practice Guidelines in Oncology.

Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.

Non-small cell lung cancer, version 2.2013.

These NCCN Guidelines Insights focus on the diagnostic evaluation of suspected lung cancer. This topic was the subject of a major update in the 2013 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer. The NCCN Guidelines Insights focus on the major updates in the NCCN Guidelines and discuss the new updates in greater detail.

Non-small cell lung cancer.

Most patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced cancer. These guidelines only include information about stage IV NSCLC. Patients with widespread metastatic disease (stage IV) are candidates for systemic therapy, clinical trials, and/or palliative treatment. The goal is to identify patients with metastatic disease before initiating aggressive treatment, thus sparing these patients from unnecessary futile treatment. If metastatic disease is discovered during surgery, then extensive surgery is often aborted. Decisions about treatment should be based on multidisciplinary discussion.

Evaluation of a National Comprehensive Cancer Network Guidelines-Based Decision Support Tool in Patients With Non-Small Cell Lung Cancer: A Nonrandomized Clinical Trial.

Importance: The association of guideline-based decision support with the quality of care in patients with non-small cell lung cancer (NSCLC) is not known. Objective: To evaluate the association of exposure to the National Comprehensive Cancer Center (NCCN) guidelines with guideline-concordant care and patients' decisional conflict. Design, Setting, and Participants: A nonrandomized clinical trial, conducted at a tertiary care academic institution, enrolled patients from February 23, 2015, to September 28, 2017. Data analysis was conducted from July 19, 2019, to April 22, 2020. A cohort of 76 patients with NSCLC seen at diagnosis or disease progression and a retrospective cohort of 157 patients treated before the trial were included. Adherence to 6 NCCN recommendations were evaluated: (1) smoking cessation counseling, (2) adjuvant chemotherapy for patients with stage IB to IIB NSCLC after surgery, (3) pathologic mediastinal staging in patients with stage III NSCLC before surgery, (4) pathologic mediastinal staging in patients with stage III NSCLC before nonsurgical treatment, (5) definitive chemoradiotherapy for patients with stage III NSCLC not having surgery, and (6) molecular testing for epidermal growth factor receptor and anaplastic lymphoma kinase alterations for patients with stage IV NSCLC. Subgroup analysis was conducted to compare the rates of guideline concordance between the prospective and retrospective cohorts. Secondary end points included decisional conflict and satisfaction. Interventions: An online tool customizing the NCCN guidelines to patients' clinical and pathologic features was used during consultation, facilitated by a trained coordinator. Main Outcomes and Measures: Concordance of practice with 6 NCCN treatment recommendations on NSCLC and patients' decisional conflict. Results: Of the 76 patients with NSCLC, 44 were men (57.9%), median age at diagnosis was 68 years (interquartile range [IQR], 41-87 years), and 59 patients (77.6%) had adenocarcinoma. In the retrospective cohort, 91 of 157 patients (58.0%) were men, median age at diagnosis was 66 years (IQR, 61-65 years), and 105 patients (66.9%) had adenocarcinoma. After the intervention, patients received more smoking cessation counseling (4 of 5 [80.0%] vs 1 of 24 [4.2%], P < .001) and less adjuvant chemotherapy (0 of 7 vs 7 of 11 [63.6%]; P = .012). There was no significant change in mutation testing of non-squamous cell stage IV disease (20 of 20 [100%] vs 48 of 57 [84.2%]; P = .10). There was no significant change in pathologic mediastinal staging or initial chemoradiotherapy for patients with stage III disease. After consultation with the tool, decisional conflict scores improved by a median of 20 points (IQR, 3-34; P < .001). Conclusions and Relevance: The findings of this study suggest that exposure to the NCCN guidelines is associated with increased guideline-concordant care for 2 of 6 preselected recommendations and improvement in decisional conflict. Trial Registration: ClinicalTrials.gov Identifier: NCT03982459.

Incorporation of a Molecular Prognostic Classifier Improves Conventional Non-Small Cell Lung Cancer Staging.

INTRODUCTION: Despite adoption of molecular biomarkers in the management of NSCLC, the recently adopted eighth edition of the TNM staging system utilized only clinicopathologic characteristics and validated improvement in risk stratification of early-stage disease has remained elusive. We therefore evaluated the integration of a clinically validated molecular prognostic classifier into conventional staging. METHODS: A novel staging system, the TNMB (with the B denoting biology) system, which integrates a 14-gene molecular prognostic classifier into the eighth edition of the TNM staging system, was developed by using data from 321 patients with NSCLC at the University of California, San Francisco. The TNMB staging system was subsequently validated in an independent, multicenter cohort of 1373 patients, and its implementation was compared with adoption of the seventh and eighth edition staging systems utilizing metrics of reclassification. RESULTS: Compared with staging according to the eighth edition of the TNM system, the TNMB staging system enhanced the identification of high-risk patients, with a net reclassification improvement of 0.33 (95% confidence interval [CI]: 0.24-0.41). It better predicted differences in survival, with a relative integrated discrimination improvement of 22.1% (95% CI: 8.8%-35.3%), and it improved agreement between observed and predicted survival, with a decrease in the reclassification calibration statistic of from 39 to 21. The seventh and eighth editions failed to change the net reclassification improvement (0.01 [95% CI: -0.04 to 0.03] and 0.03 [95% CI: 0.00 to 0.06], respectively) or relative integrated discrimination improvement (2.1% [95% CI: -5.8 to 9.9] and -2.5% [95% CI: -17.6 to 12.4], respectively); in addition, the eighth edition worsened calibration, with an increase in the reclassification calibration statistic from 23 to 25. CONCLUSIONS: Incorporation of a molecular prognostic classifier significantly improved identification of high-risk patients and survival predictions compared with when conventional staging is used. The TNMB staging system may lead to improved survival of early-stage disease through more effective application of adjuvant therapy.

Adjuvant Chemotherapy Guided by Molecular Profiling and Improved Outcomes in Early Stage, Non-Small-Cell Lung Cancer.

INTRODUCTION: Many early stage non-small-cell lung cancer (NSCLC) patients who are not considered candidates for adjuvant treatment according to current guidelines do harbor occult metastasis, and have disease recurrence despite complete resection. Although National Comprehensive Cancer Network (NCCN) guidelines suggest clinicopathologic characteristics to identify high-risk patients for adjuvant intervention, molecular profiling more accurately predicts 5-year survival. Early evidence of clinical benefit from application of this molecular-based management strategy, however, has not been reported. PATIENTS AND METHODS: An internationally validated, prognostic, 14-gene quantitative polymerase chain reaction expression assay was used to stratify risk prospectively in 100 consecutive patients with stage IA, IB, and IIA nonsquamous NSCLC. Kaplan-Meyer estimates, log rank analysis, and Cox regression were used to compare disease-free survival (DFS) between high-risk patients who did or did not elect adjuvant chemotherapy. RESULTS: Forty-eight patients (48%) were deemed high-risk according to molecular testing and 36 (36%) met NCCN high-risk criteria; risk designations were discordant in 34 (34%) of all patients. Estimated 5-year DFS was 48.9% among molecular high-risk patients who did not undertake adjuvant chemotherapy, 93.8% among untreated molecular low-risk patients, and 91.7% in molecular high-risk patients who did undergo chemotherapy (P = .004). In contrast, DFS was only 75.2% in untreated NCCN low-risk patients, and 61.9% in untreated NCCN high-risk patients (P = .183). CONCLUSION: This prospective, nonrandomized study provides initial evidence that high-risk designation according to the 14-gene prognostic assay also predicts benefit from adjuvant chemotherapy for very early stage NSCLC, and further supports the superiority of molecular stratification over current NCCN criteria at identifying high-risk patients.

Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high-dose 131I-MIBG. Patients were 11-62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I-MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I-MIBG was synthesized on-site, by exchange-labeling 131I with 127I-MIBG in a solid-phase Cu2+-catalyzed exchange reaction. 131I-MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I-MIBG therapy. After the first 131I-MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High-dose 131I-MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty-three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I-MIBG uptake on diagnostic scanning, high-dose 131I-MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

Radical pleurectomy/decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma.

OBJECTIVES: We performed a retrospective review of the efficacy and morbidity of radical pleurectomy/decortication and intraoperative radiotherapy followed by external beam radiation therapy with or without chemotherapy for diffuse malignant pleural mesothelioma. METHODS: A total of 32 patients with diffuse malignant pleural mesothelioma were initially evaluated between January 1995 and September 2000. Three patients were excluded from analysis because of unresectable disease. Two patients died postoperatively, and one patient had recurrent disease previously treated at an outside institution. Of the remaining 26 patients included in the analysis, 24 received intraoperative radiotherapy. External beam radiation therapy was generally started 1 to 2 months after resection and delivered by means of 3-dimensional conformal radiation therapy or with inverse treatment planning intensity-modulated radiation therapy. When given, chemotherapy consisted of 2 to 3 cycles of cyclophosphamide, doxorubicin (Adriamycin), and cisplatin initiated 1 to 2 months after completion of radiation. RESULTS: At the time of data analysis, 5 of 26 patients were alive. The median follow-up was 9.7 months (range, 2-67.6 months). The median overall survival and progression-free interval from the time of the operation were 18.1 and 12.2 months, respectively. The Kaplan-Meier estimates of overall survival and freedom from progression at 1 year were 64% and 50%, respectively. The site of failure was mostly locoregional. However, there were 4 abdominal failures and 1 contralateral lung failure. CONCLUSIONS: Radical pleurectomy/decortication with aggressive radiotherapy with or without chemotherapy might offer an alternative treatment option to those who cannot tolerate extrapleural pneumonectomy.

Mechanisms of and potential treatment strategies for metastatic disease in non-small cell lung cancer.

Lung cancer consumes over one million lives in the world every year, with surgical resection playing a dominant role in the curative treatment of lung cancer with nonsmall cell histology. Mortality usually is the result of systemic spread of the disease, with little impact on survival when chemotherapy is applied in the adjuvant or palliative setting. Conventional cytotoxic chemotherapy has reached a plateau in efficacy. The future of treatment lies in the elucidation of the biology of lung cancer and the application of targeted therapies either alone or in combination with chemotherapy. The impact of the first generation of targeted therapies on lung cancer has been modest, with studies suggesting improvement in response rates, but no evidence of improved survival. As we expand our understanding of the mechanisms governing lung cancer progression and metastasis, we will be able to apply the growing armamentarium against this disease with a goal toward prolonging survival and increasing the chance for cure.

Divergent management strategies for typical versus atypical carcinoid tumors of the thoracic cavity.

OBJECTIVES: At our institution, limited surgical techniques are reserved only for suspected typical carcinoids, and nodal dissection and multimodality therapy are frequently used for atypical carcinoids. We describe the results of these differing management strategies based on initial clinicopathologic characteristics. METHODS: Retrospective review of patients treated for thoracic carcinoid from 1995 to 2009. Information was abstracted concerning surgical and nonsurgical treatments, pathology results, and outcomes. Event-free and survival endpoints were compared. RESULTS: The median follow-up was 5.0 years (range, 0.5 to 17.4 y). Fifty-two patients underwent resection. The 5-year event-free survival for typical carcinoid patients was 88.2%. Atypical carcinoids had a tendency for nodal involvement (50% vs. 15%) and greater likelihood for disease recurrence, with a 5-year event-free survival of 50%. CONCLUSIONS: These data support the appropriateness of divergent management strategies for typical versus atypical bronchial carcinoids. We propose the following: (1) nonanatomic resection is acceptable only for peripheral typical carcinoids; (2) extended mediastinal dissection should be limited to central presentations, clinically aggressive, or atypical carcinoids; (3) atypical histology, especially with nodal involvement, is prognostic for recurrence and metastasis; (4) nonsurgical therapies only rarely achieve long-term freedom from disease.

Prognostic molecular assay might improve identification of patients at risk for recurrence in early-stage non-small-cell lung cancer.

INTRODUCTION: Adjuvant chemotherapy improves survival for some patients with NSCLC and is recommended in NCCN guidelines for stage Ib to IIa patients with certain "high-risk" characteristics. An internationally validated, 14-gene expression assay has been shown to better stratify mortality risk in nonsquamous NSCLC than either conventional staging or these high risk clinicopathologic features. PATIENTS AND METHODS: A blinded chart review of 52 patients with prospective molecular risk stratification using the 14-gene test compared recurrence outcomes with a mean follow-up of 15.2 ± 11.7 months of patients with high- or low-risk determined according to either NCCN criteria or the molecular assay. RESULTS: Molecular risk assessment was discordant from NCCN criteria in 14 of 23 patients in stages Ib and IIa (61%). Recurrence was not observed among any of 31 molecular intermediate- or low-risk patients, including 10 NCCN high-risk patients, whereas 2 of 6 recurrences (33%) occurred among NCCN low-risk patients. Recurrences in stages I or IIa were seen in 2 of 18 NCCN high-risk patients (11%; both were stage IIa and both received a high-risk molecular designation), and in 4 of 18 patients (22%) with a high-risk molecular score, including 1 stage Ia and 1 stage Ib patient. CONCLUSION: This small cohort study suggests that a 14-gene prognostic assay more accurately stratifies risk among early-stage NSCLC patients than current NCCN criteria. NCCN guidelines already advocate risk stratification within tumor, node, metastases stages. This molecular assay has clinical utility in better identifying high-risk patients and might improve NCCN adjuvant chemotherapy recommendations.

Lung cancer stigma, depression, and quality of life among ever and never smokers.

PURPOSE: In 2010, lung cancer is expected to be the leading cause of cancer death in both men and women. Because survival rates are increasing, an evaluation of the effects of treatment on quality of life (QOL) is an important outcome measure. In other diseases, stigma is known to have a negative impact on health status and QOL and be amenable to intervention. This is the first study to compare levels of lung cancer stigma (LCS) and relationships between LCS, depression, and QOL in ever and never smokers. METHOD: A total of 192 participants with a self-report diagnosis of lung cancer completed questionnaires online. RESULTS: Strong associations in the expected directions, were found between LCS and depression (r = 0.68, p < 0.001) and QOL (r = -0.65, p < 0.001). No significant differences were found in demographic characteristics or study variables between ever smokers and never smokers. A simultaneous multiple regression with 5 independent variables revealed an overall model that explained 62.5% of the total variance of QOL (F5,168 = 56.015, P < 0.001). CONCLUSIONS: After removing age, gender, and smoking status, depression explained 22.5% of the total variance of QOL (F4,168 = 100.661, p < 0.001). It is expected that depression and LCS would share some of the explanation of the variance of QOL, the correlation between LCS and depression is 0.629 (p < 0.001), however, LCS provides a unique and significant explanation of the variance of QOL over and above that of depression, age, gender, and smoking status, by 2.1% (p < 0.001).

Impact of age and comorbidity on non-small-cell lung cancer treatment in older veterans.

PURPOSE: Because comorbidity affects cancer treatment outcomes, guidelines recommend considering comorbidity when making treatment decisions in older patients with lung cancer. Yet, it is unclear whether treatment is targeted to healthier older adults who might reasonably benefit. PATIENTS AND METHODS: Receipt of first-line guideline-recommended treatment was assessed for 20,511 veterans age ≥ 65 years with non-small-cell lung cancer (NSCLC) in the Veterans Affairs (VA) Central Cancer Registry from 2003 to 2008. Patients were stratified by age (65 to 74, 75 to 84, ≥ 85 years), Charlson comorbidity index score (0, 1 to 3, ≥ 4), and American Joint Committee on Cancer stage (I to II, IIIA to IIIB, IIIB with malignant effusion to IV). Comorbidity and patient characteristics were obtained from VA claims and registry data. Multivariate analysis identified predictors of receipt of guideline-recommended treatment. RESULTS: In all, 51% of patients with local, 35% with regional, and 27% with metastatic disease received guideline-recommended treatment. Treatment rates decreased more with advancing age than with worsening comorbidity for all stages, such that older patients with no comorbidity had lower rates than younger patients with severe comorbidity. For example, 50% of patients with local disease age 75 to 84 years with no comorbidity received surgery compared with 57% of patients age 65 to 74 years with severe comorbidity (P < .001). In multivariate analysis, age and histology remained strong negative predictors of treatment for all stages, whereas comorbidity and nonclinical factors had a minor effect. CONCLUSION: Advancing age is a much stronger negative predictor of treatment receipt among older veterans with NSCLC than comorbidity. Individualized decisions that go beyond age and include comorbidity are needed to better target NSCLC treatments to older patients who may reasonably benefit.