Pulmonary neuroendocrine tumors are a distinct subset of tumors composing approximately 20% of all lung cancers. The major categories of pulmonary neuroendocrine tumors include typical and atypical carcinoids, large cell neuroendocrine carcinoma, and the more common small cell lung cancer. They are classified into different categories in the 2004 World Health Organization system, but share structural and morphologic features. Despite these shared features, their clinical characteristics range from indolent to aggressive, and therefore the approach to treatment depends on the histologic subtype. This article discusses the current understanding of the epidemiology, pathologic characteristics, treatment, and prognosis of this spectrum of diseases.
Lin-Chi Chen, William D. Travis and Lee M. Krug
Saber Amin, Michael Baine, Jane Meza and Chi Lin
Background: Immunotherapy has shown excellent efficacy in various cancers. However, there is a lack of knowledge regarding the significant role of immunotherapy in patients with brain metastases (BMs). The objective of this study was to investigate, using the National Cancer Database, the impact of immunotherapy on the overall survival (OS) of patients with BMs who did not receive definitive surgery of the primary tumor. Patients and Methods: Patients diagnosed with the primary cancer of non–small cell lung cancer, small cell lung cancer, other types of lung cancer, breast cancer, melanoma, colorectal cancer, or renal cancer who had BMs at the time of diagnosis were identified from the National Cancer Database. We assessed OS using a Cox proportional hazards model adjusted for age at diagnosis, sex, race, education level, income level, residential area, treatment facility type, insurance status, Charlson-Deyo comorbidity status, year of diagnosis, primary tumor type, and receipt of chemotherapy, radiation therapy (RT), and/or immunotherapy, because these factors were significantly associated with OS in the univariable analysis. Results: Of 94,215 patients who were analyzed, 3,097 (3.29%) received immunotherapy. In the multivariable analysis, immunotherapy was associated with significantly improved OS (hazard ratio [HR], 0.694; 95% CI, 0.664–0.726; P<.0001) compared with no immunotherapy. Treatment using chemotherapy plus immunotherapy was significantly associated with improved OS (HR, 0.643; 95% CI, 0.560–0.738; P<.0001) compared with chemotherapy without immunotherapy. RT plus immunotherapy was also associated with significantly improved OS (HR, 0.389; 95% CI, 0.352–0.429; P<.0001) compared with RT alone. Furthermore, chemoradiation (CRT) plus immunotherapy was associated with significantly improved OS (HR, 0.793; 95% CI, 0.752–0.836; P<.0001) compared with CRT alone. Conclusions: In this comprehensive analysis, the addition of immunotherapy to chemotherapy, RT, and CRT was associated with significantly improved OS in patients with BMs. The study warrants future clinical trials of immunotherapy in patients with BMs, who have historically been excluded from these trials.
Vivek Verma, Swati M. Surkar, Eric D. Brooks, Charles B. Simone II and Chi Lin
Purpose: Current guidelines recommend chemotherapy (CT) with or without radiotherapy for unresected nonmetastatic gallbladder cancer (GC), with little consensus. However, several small-volume, single-institution studies have documented the efficacy of local therapy for this population. This is the largest study to date evaluating outcomes of chemoradiotherapy (CRT) versus CT alone in unresected nonmetastatic GC. Methods: The National Cancer Database was queried for primary GC cases (2004–2013) receiving CT alone or CRT. Patients receiving resection or lack of CT were excluded, as were those with metastatic disease or unknown M classification. Logistic regression analysis ascertained factors associated with CRT delivery. Kaplan-Meier analysis evaluated overall survival (OS) between both cohorts. Cox proportional hazards modeling determined variables associated with OS. Results: In total, 1,199 patients were analyzed (CRT: n=327, 27%; CT: n=872, 73%). Groups were evenly balanced, with no factor on multivariate logistic regression analysis statistically predicting for receipt of a particular paradigm. Median OS in the CRT and CT groups was 12.9 versus 7.8 months, respectively (P=.001). On multivariate analysis, OS was associated with age and years of treatment (P=.001 each). Notably, receipt of CRT independently predicted for improved OS (P=.001). Conclusions: CRT, compared with CT alone, was independently associated with improved survival in unresected nonmetastatic GC. Although causation is not implied, these results support the necessity for prospective CRT evaluation.
Mary E. Charlton, Amanda R. Kahl, Alissa A. Greenbaum, Jordan J. Karlitz, Chi Lin, Charles F. Lynch and Vivien W. Chen
Purpose: KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression. Cox proportional hazards models assessed relationships between KRAS mutations, tumor location, and risk of all-cause death. Results: Of 22,542 patients, 30% received KRAS testing, and 44% of these had mutations. Those tested tended to be younger, married, and metropolitan area residents, and have private insurance or Medicare. Rates of KRAS testing also varied by registry (range, 20%–46%). Patients with right-sided colon cancer (vs left-sided) tended to be older, female, and black; have mucinous, KRAS-mutant tumors; and have a greater risk of death (hazard ratio [HR], 1.27; 95% CI, 1.22–1.32). KRAS mutations were not associated with greater risk of death in the overall population; however, they were associated with greater risk of death among patients with left-sided colon cancer (HR, 1.19; 95% CI, 1.05–1.33). Conclusions: This large population-based study showed that among patients initially diagnosed with stage IV CRC, right-sided colon cancer was associated with greater risk of death compared with left-sided cancer, and KRAS mutations were only associated with risk of death in left-sided colon cancer. An unexpected finding was that among patients with stage IV disease, right-sided cancer was more commonly seen in black patients versus whites. Future studies should further explore these associations and determine the role of biology versus treatment differences. In addition, use of KRAS testing is increasing, but there is wide geographic variation wherein disparities related to insurance coverage and rurality may warrant further study.
Michael J. Baine, Richard Sleightholm, Beth K. Neilsen, David Oupický, Lynette M. Smith, Vivek Verma and Chi Lin
Background: Despite the fact that stereotactic body radiation therapy (SBRT) is the only recommended first-line therapy for inoperable early-stage non–small cell lung cancer (NSCLC), several thermal ablative procedures (TAPs; defined herein as laser/cryoablation and electrocautery) are available. Studies showing outcomes of these procedures and how they compare with SBRT are scarce. We sought to evaluate the comparative efficacy of SBRT versus TAPs using the National Cancer Database (NCDB). Methods: The NCDB was queried for patients with early-stage NSCLC who did not undergo surgical resection. Treatment-specific inclusion criteria were applied to select for patients receiving either TAPs or SBRT. Univariate logistic regression and Cox proportional hazards modeling were performed, and Kaplan-Meier curves were generated. Serial propensity matches were performed using a modified greedy 8→n matching 1:1 algorithm. Results: A total of 27,734 patients were analyzed; 26,725 underwent SBRT and 1,009 underwent TAPs. Patients who received SBRT were older and more likely to have clinical stage IB (vs IA) disease. Despite this, SBRT was associated with longer median overall survival (mOS; 37.7 vs 33.5 months; P=.001) and 1-, 2-, and 5-year OS rates compared with the TAPs cohort (86.7% vs 83.1%, 67.5% vs 62.7%, and 30.6% vs 26.9%, respectively; P=.001). Upon propensity matching, improved OS with SBRT remained, with a mOS of 40.4 versus 33.4 months and 1-, 2-, and 5-year OS rates of 89.0% versus 82.9%, 69.7% versus 62.7%, and 34.4% versus 26.4%, respectively (P=.003). Conclusions: Despite being associated with more higher-risk factors, SBRT was associated with higher OS compared with TAPs for treatment of nonoperative patients diagnosed with early-stage NSCLC. However, causation cannot be implied owing to the inherent limitations of large heterogeneous datasets such as the NCDB.
Yuefeng Wang, Xinhua Yu, Nan Zhao, Jiajing Wang, Chi Lin, Enrique W. Izaguirre, Michael Farmer, Gary Tian, Bradley Somer, Nilesh Dubal, David L. Schwartz, Matthew T. Ballo and Noam A. VanderWalde
Background: Chemotherapy with or without pelvic radiotherapy (RT) is included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for metastatic anal cancer (MAC), despite limited clinical evidence for RT in this setting. In addition, increasing evidence shows that local therapies, including RT, may increase patient survival for some types of metastatic cancers. The purpose of this study was to evaluate the patterns of care and association between definitive pelvic RT and overall survival (OS) for patients with MAC. Methods: The National Cancer Database was analyzed to evaluate OS of patients with newly diagnosed MAC treated with chemotherapy with or without pelvic RT. Those who did not undergo treatment, treated with surgery, or without baseline variables were excluded. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score–matched analyses. Results: From 2004 through 2015, 437 patients received chemotherapy alone and 1,020 received pelvic chemoradiotherapy (CRT). At a median follow-up of 17.3 months, CRT was associated with improved OS on univariate (P<.001) and multivariate analysis (hazard ratio [HR], 0.70; 95% CI, 0.61–0.81; P<.001). Propensity score–matched analysis demonstrated superior median survival (21.3 vs 15.9 months) and 2-year OS rates (46% vs 34%) with CRT compared with chemotherapy alone (P<.001). Landmark analyses limited to long-term survivors of ≥1, ≥2, and ≥4 years showed improved OS with CRT in all subsets (all P<.05). CRT with therapeutic doses (≥45 Gy) was associated with longer median survival than palliative doses (<45 Gy) and chemotherapy alone (24.9 vs 10.9 vs 15.6 months, respectively; P<.001). The benefit of CRT was present among not only those with distant lymph node metastasis (HR, 0.63; P=.04) but also those with distant organ disease (HR, 0.74; P<.001). Conclusions: In this large hypothesis-generating analysis, patients with newly diagnosed MAC who received definitive pelvic RT with chemotherapy lived significantly longer than those who received chemotherapy alone. Prospective trials evaluating definitive local RT for MAC are warranted.
Bing-Yen Wang, Ping-Yi Lin, Shiao-Chi Wu, Hui-Shan Chen, Po-Kuei Hsu, Chih-Shiun Shih, Chao-Yu Liu, Chia-Chuan Liu and Yao-Li Chen
The prognostic value for the post-chemoradiation therapy (CRT) pathologic stage is uncertain. The purpose of this study was to compare the pathologic stage in patients undergoing esophagectomy with and without preoperative CRT for esophageal squamous cell carcinoma (ESCC). This study retrospectively reviewed the data from 2151 patients with ESCC who underwent esophagectomy with or without preoperative CRT between 2008 and 2011 in Taiwan. Patients were divided into 2 groups. Group A consisted of patients treated with primary surgery without prior treatments (n=1301), and group B consisted of patients receiving preoperative CRT followed by esophagectomy (n=850). In group A, 679 patients received surgery alone, 92 received postoperative chemotherapy, 416 received postoperative chemoradiation therapy, and 114 received postoperative radiation therapy. In group A, the 3-year survival rates by pathologic stage were 82.2% for stage 0, 67.6% for stage I, 50.7% for stage II, 21.5% for stage III, and 14.8% for stage IV (P<.001). In group B, the 3-year survival rates of post-CRT pathologic stages 0, I, II, III, and IV were 59.4%, 46.0%, 40.3%, 19.1%, and 8.2%, respectively (P<.001). In multivariate analysis, the pathologic T, N, and M were all independent prognostic factors in both group A (esophagectomy alone) and B (CRT plus esophagectomy). The current, 7th edition of the esophageal TNM staging system could adequately stratify prognostic groups in patients with squamous cell carcinoma who were treated with preoperative CRT and esophagectomy.
Erin Reid, Gita Suneja, Richard F. Ambinder, Kevin Ard, Robert Baiocchi, Stefan K. Barta, Evie Carchman, Adam Cohen, Neel Gupta, Kimberly L. Johung, Ann Klopp, Ann S. LaCasce, Chi Lin, Oxana V. Makarova-Rusher, Amitkumar Mehta, Manoj P. Menon, David Morgan, Nitya Nathwani, Ariela Noy, Frank Palella, Lee Ratner, Stacey Rizza, Michelle A. Rudek, Jeff Taylor, Benjamin Tomlinson, Chia-Ching J. Wang, Mary A. Dwyer and Deborah A. Freedman-Cass
People living with HIV (PLWH) are diagnosed with cancer at an increased rate over the general population and generally have a higher mortality due to delayed diagnoses, advanced cancer stage, comorbidities, immunosuppression, and cancer treatment disparities. Lack of guidelines and provider education has led to substandard cancer care being offered to PLWH. To fill that gap, the NCCN Guidelines for Cancer in PLWH were developed; they provide treatment recommendations for PLWH who develop non–small cell lung cancer, anal cancer, Hodgkin lymphoma, and cervical cancer. In addition, the NCCN Guidelines outline advice regarding HIV management during cancer therapy; drug–drug interactions between antiretroviral treatments and cancer therapies; and workup, radiation therapy, surgical management, and supportive care in PLWH who have cancer.
Erin Reid, Gita Suneja, Richard F. Ambinder, Kevin Ard, Robert Baiocchi, Stefan K. Barta, Evie Carchman, Adam Cohen, Oxana V. Crysler, Neel Gupta, Chelsea Gustafson, Allison Hall, Kimberly L. Johung, Ann Klopp, Ann S. LaCasce, Chi Lin, Amitkumar Mehta, Manoj P. Menon, David Morgan, Nitya Nathwani, Ariela Noy, Lee Ratner, Stacey Rizza, Michelle A. Rudek, Julian Sanchez, Jeff Taylor, Benjamin Tomlinson, Chia-Ching J. Wang, Sai Yendamuri, Mary A. Dwyer, CGC and Deborah A. Freedman-Cass
As treatment of HIV has improved, people living with HIV (PLWH) have experienced a decreased risk of AIDS and AIDS-defining cancers (non-Hodgkin’s lymphoma, Kaposi sarcoma, and cervical cancer), but the risk of Kaposi sarcoma in PLWH is still elevated about 500-fold compared with the general population in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AIDS-Related Kaposi Sarcoma provide diagnosis, treatment, and surveillance recommendations for PLWH who develop limited cutaneous Kaposi sarcoma and for those with advanced cutaneous, oral, visceral, or nodal disease.