The 50 most-cited articles in Cancer, 2017

Cervical cancer is the fourth most common malignancy diagnosed in women worldwide. Nearly all cases of cervical cancer result from infection with the human papillomavirus, and the prevention of cervical cancer includes screening and vaccination. Primary treatment options for patients with cervical cancer may include surgery or a concurrent chemoradiotherapy regimen consisting of cisplatin-based chemotherapy with external beam radiotherapy and brachytherapy. Cervical cancer causes more than one quarter of a million deaths per year as a result of grossly deficient treatments in many developing countries. This warrants a concerted global effort to counter the shocking loss of life and suffering that largely goes unreported. This article provides a review of the biology, prevention, and treatment of cervical cancer, and discusses the global cervical cancer crisis and efforts to improve the prevention and treatment of the disease in underdeveloped countries. Cancer 2017;123:2404-12. © 2017 American Cancer Society.

BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. METHODS: Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). RESULTS: ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic…

BACKGROUND: As panel testing becomes more common in clinical practice, it is important to understand the prevalence and trends associated with the pathogenic variants (PVs) identified. This is especially true for genetically heterogeneous cancers, such as breast cancer (BC), in which PVs in different genes may be associated with various risks and cancer subtypes. The authors evaluated the outcomes of genetic testing among women who had a personal history of BC. METHODS: A total of 35,409 women with a single diagnosis of BC who underwent clinical genetic testing with a 25-gene panel were included in the current analysis. Women with multiple BCs and men with BC were excluded. The frequency and distribution of PVs were assessed for the overall cohort, among women with triple-negative BC (TNBC) (n = 4797), and by age at diagnosis. RESULTS: PVs were identified in 9.3% of women tested; 51.5% of PVs were identified in genes other than breast cancer 1 (BRCA1) and BRCA2, including checkpoint kinase 2 (CHEK2) (11.7%), ataxia telangiectasia mutated (ATM; ATM serine/threonine kinase) (9.7%),…

Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV-related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here.…

Immune checkpoint inhibitors, including those targeting the programmed cell death 1/programmed cell death ligand 1 and cytotoxic T lymphocyte antigen 4 pathways, are revolutionizing cancer therapeutics. Both activity and toxicities largely stem from unleashing tumor- or host-specific cytotoxic T cells. Many patients seen in routine clinical practice have not qualified for or have been seriously underrepresented in immune checkpoint inhibitor clinical trials. Thus, a major gap in knowledge regarding the safety and efficacy of these agents persists in many populations, even after regulatory approval. To address this challenge, this review aggregates and synthesizes the available preclinical and clinical data surrounding immune checkpoint inhibitor therapy in challenging clinical populations to assist both academic and community oncologists in treatment decision making. Specifically, this review focuses on the safety and activity of immune checkpoint inhibitors in patients with autoimmune disorders, organ transplant patients, patients with chronic viral infections, patients with…

BACKGROUND: Monoclonal antibodies against programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are effective therapies in patients with non-small cell lung cancer (NSCLC). Herein, the authors performed a systematic review investigating differences in the toxicities of PD-1 and PD-L1 inhibitors. METHODS: An electronic literature search was performed of public databases (MEDLINE, Excerpta Medica dataBASE [EMBASE], and Cochrane) and conference proceedings for trials using PD-1 inhibitors (nivolumab and pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, and avelumab) in patients with NSCLC. A formal systematic analysis was conducted with Comprehensive Meta-Analysis software (version 2.2). Clinical and demographic characteristics, response, and toxicity data were compared between both groups. RESULTS: A total of 23 studies reported between 2013 and 2016 were eligible for analysis. The total number of patients evaluated for toxicities was 3284 patients in the PD-1 group and 2460 patients in the PD-L1 group. The baseline patient characteristics of the 2…

BACKGROUND: Stomach cancer was a leading cause of cancer-related deaths early in the 20th century and has steadily declined over the last century in the United States. Although incidence and death rates are now low, stomach cancer remains an important cause of morbidity and mortality in black, Asian and Pacific Islander, and American Indian/Alaska Native populations. METHODS: Data from the CONCORD-2 study were used to analyze stomach cancer survival among males and females aged 15 to 99 years who were diagnosed in 37 states covering 80% of the US population. Survival analyses were corrected for background mortality using state-specific and race-specific (white and black) life tables and age-standardized using the International Cancer Survival Standard weights. Net survival is presented up to 5 years after diagnosis by race (all, black, and white) for 2001 through 2003 and 2004 through 2009 to account for changes in collecting Surveillance, Epidemiology, and End Results Summary Stage 2000 data from 2004. RESULTS: Almost one-third of stomach cancers were diagnosed at a distant stage…

BACKGROUND: Breast cancer (BC) disparities may widen with genomic advances. The authors compared non-Hispanic white (NHW), black, and Hispanic BC survivors for 1) cancer risk-management practices among BRCA carriers and 2) provider discussion and receipt of genetic testing. METHODS: A population-based sample of NHW, black, and Hispanic women who had been diagnosed with invasive BC at age 50 years or younger from 2009 to 2012 were recruited through the state cancer registry. Multiple logistic regression was used to compare cancer risk-management practices in BRCA carriers and associations of demographic and clinical variables with provider discussion and receipt of testing. RESULTS: Of 1622 participants, 159 of 440 (36.1%) black women, 579 of 897 (64.5%) NHW women, 58 of 117 (49.6%) Spanish-speaking Hispanic women, and 116 of 168 (69%) English-speaking Hispanic women underwent BRCA testing, of whom 90 had a pathogenic BRCA mutation identified. Among BRCA carriers, the rates of risk-reducing mastectomy and risk-reducing salpingo-oophorectomy were significantly lower among black women…

BACKGROUND: Extrapulmonary neuroendocrine carcinomas (NECs) are poorly studied and are managed similar to lung NECs, which may not account for differences between the 2 groups of tumors as well as the heterogeneity within extrapulmonary NEC. METHODS: Data from the Surveillance, Epidemiology, and End Results program between 1973 and 2012 were used to estimate the relative percentages of lung NECs and subgroups of extrapulmonary NECs, epidemiological patterns at these sites, and the median and 5-year overall survival rates. RESULTS: Of 162,983 NEC cases, 14,732 were extrapulmonary; of these, 5509 were gastrointestinal (37.44%), 4151 were of unknown primary (28.2%), and 5072 were of other sites (34.4%). Lung NEC had the highest percentage of small cell morphology (95.2%) and gastrointestinal NEC had the least (38.7%), with the rest being other morphologies. Significant differences were noted with regard to median age (range, 48-74 years), percentage of cases of distant stage disease (24%-77%), and incidence according to sex and race. The median survival of patients with lung NEC was…

BACKGROUND: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited. METHODS: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vβ gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients. Differences in liposarcoma subsets also were evaluated. RESULTS: UPS and leiomyosarcoma had high expression levels of genes related to antigen presentation and T-cell infiltration. UPS were found to have higher levels of PD-L1 (P≤.001) and PD-1 (P≤.05) on immunohistochemistry and had the highest T-cell infiltration based on T-cell receptor sequencing, significantly more than SS, which had the lowest…

BACKGROUND: Cannabis is purported to alleviate symptoms related to cancer treatment, although the patterns of use among cancer patients are not well known. This study was designed to determine the prevalence and methods of use among cancer patients, the perceived benefits, and the sources of information in a state with legalized cannabis. METHODS: A cross-sectional, anonymous survey of adult cancer patients was performed at a National Cancer Institute-designated cancer center in Washington State. Random urine samples for tetrahydrocannabinol provided survey validation. RESULTS: Nine hundred twenty-six of 2737 eligible patients (34%) completed the survey, and the median age was 58 years (interquartile range [IQR], 46-66 years). Most had a strong interest in learning about cannabis during treatment (6 on a 1-10 scale; IQR, 3-10) and wanted information from cancer providers (677 of 911 [74%]). Previous use was common (607 of 926 [66%]); 24% (222 of 926) used cannabis in the last year, and 21% (192 of 926) used cannabis in the last month. Random urine samples found similar percentages…

Leptomeningeal metastasis is an uncommon and typically late complication of cancer with a poor prognosis and limited treatment options. Diagnosis is often challenging, with nonspecific presenting symptoms ranging from headache and confusion to focal neurologic deficits, such as cranial nerve palsies. Standard diagnostic evaluation involves a neurologic examination, magnetic resonance imaging of the brain and spine with gadolinium, and cytologic evaluation of the cerebral spinal fluid. Therapy entails a multimodal approach focused on palliation with surgery, radiation, and/or chemotherapy, which may be administered systemically or directly into the cerebral spinal fluid. Limited trial data exist to guide treatment, and current regimens are based primarily on expert opinion. Although newer targeted and immunotherapeutic agents are under investigation and have shown promise, an improved understanding of the biology of leptomeningeal metastasis and treatment resistance as well as additional randomized controlled studies are needed to guide the optimal treatment of this devastating…

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life-threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy-associated HLH (M-HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M-HLH may occur in up to 1% of patients with hematologic malignancies. M-HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M-HLH in adults may…

BACKGROUND: Breast cancer 2 (BRCA2)-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. METHODS: A retrospective analysis of a single-institution cohort of men with castration-resistant, metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001 through 2015, 8081 adult men with prostate cancer who had a consultation and/or underwent treatment at Dana-Farber Cancer Institute provided blood samples and consented to analyses of biologic material and clinical records. A subgroup of 141 men received at least 2 doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These patients were categorized according to the absence or presence of pathogenic germline mutations in BRCA2 based on DNA sequencing from whole blood. The primary outcome was the response rate to…

BACKGROUND: Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. METHODS: Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97)…

BACKGROUND: Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO-7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia. METHODS: This double-blind clinical trial (ONO-7643-04) enrolled 174 patients with unresectable stage III/IV non-small cell lung cancer (NSCLC) and cachexia in Japan. Patients were randomized to daily oral anamorelin (100 mg) or a placebo for 12 weeks. The primary endpoint was the change from the baseline LBM (measured with dual-energy x-ray absorptiometry) over 12 weeks. The secondary endpoints were changes in appetite, body weight, quality of life, handgrip strength (HGS), and 6-minute walk test (6MWT) results. RESULTS: The least squares mean change (plus or minus the standard error) in LBM from the baseline over 12 weeks was 1.38 ± 0.18 and -0.17 ± 0.17 kg in the anamorelin and placebo groups, respectively (P < .0001). Changes from the baseline in LBM, body weight, and anorexia symptoms…

BACKGROUND: The objectives of this study were to determine the age-standardized and age-specific annual US cervical cancer mortality rates after correction for the prevalence of hysterectomy and to evaluate disparities by age and race. METHODS: Estimates for deaths due to cervical cancer stratified by age, state, year, and race were derived from the National Center for Health Statistics county mortality data (2000-2012). Equivalently stratified data on the prevalence of hysterectomy for women 20 years old or older from the Behavioral Risk Factor Surveillance System survey were used to remove women who were not at risk from the denominator. Age-specific and age-standardized mortality rates were computed, and trends in mortality rates were analyzed with Joinpoint regression. RESULTS: Age-standardized rates were higher for both races after correction. For black women, the corrected mortality rate was 10.1 per 100,000 (95% confidence interval [CI], 9.6-10.6), whereas the uncorrected rate was 5.7 per 100,000 (95% CI, 5.5-6.0). The corrected rate for white women was 4.7 per 100,000 (95%…

BACKGROUND: Human papillomavirus (HPV) is a well-established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non-OP) head and neck squamous cell cancers (HNSCCs). METHODS: This retrospective, multi-institution study included OPSCCs and non-OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non-Hispanic, black non-Hispanic, Asian non-Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high-risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan-Meier and Cox proportional hazards models were used to evaluate overall survival (OS). RESULTS: The study population included 239 patients with OPSCC and 621 patients with…

BACKGROUND: Patients with advanced cancer often experience frequent and prolonged hospitalizations; however, the factors associated with greater health care utilization have not been described. We sought to investigate the relation between patients' physical and psychological symptom burden and health care utilization. METHODS: We enrolled patients with advanced cancer and unplanned hospitalizations from September 2014-May 2016. Upon admission, we assessed physical (Edmonton Symptom Assessment System [ESAS]) and psychological symptoms (Patient Health Questionnaire 4 [PHQ-4]). We examined the relationship between symptom burden and healthcare utilization using linear regression for hospital length of stay (LOS) and Cox regression for time to first unplanned readmission within 90 days. We adjusted all models for age, sex, marital status, comorbidity, education, time since advanced cancer diagnosis, and cancer type. RESULTS: We enrolled 1,036 of 1,152 (89.9%) consecutive patients approached. Over one-half reported moderate/severe fatigue, poor well being, drowsiness, pain, and lack of…

BACKGROUND: Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population. METHODS: This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-L2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment. RESULTS: Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overall median progression-free survival was 1.8 months (95% confidence…

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) mutations have been reported in lung adenocarcinomas. Herein, the authors describe the prevalence, clinical features, and outcomes associated with HER2 mutations in 1007 patients in the Lung Cancer Mutation Consortium (LCMC). METHODS: Patients with advanced-stage lung adenocarcinomas were enrolled to the LCMC. Tumor specimens were assessed for diagnosis and adequacy; multiplexed genotyping was performed in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories to examine 10 oncogenic drivers. The LCMC database was queried for patients with HER2 mutations to access demographic data, treatment history, and vital status. An exploratory analysis was performed to evaluate the survival of patients with HER2 mutations who were treated with HER2-directed therapies. RESULTS: A total of 920 patients were tested for HER2 mutations; 24 patients (3%) harbored exon 20 insertion mutations (95% confidence interval, 2%-4%). One patient had a concurrent mesenchymal-epithelial transition factor (MET) amplification. The…

The treatment of locally advanced rectal cancer (LARC) has benefited from improved surgical techniques and from the implementation of neoadjuvant chemoradiotherapy (CRT), which have markedly decreased the rates of local recurrence. However, distant metastatic disease remains the most significant cause of death for these patients. Although adjuvant chemotherapy (ChT) after neoadjuvant CRT and definitive surgery is commonly recommended, the value of adjuvant systemic therapy remains less clear. Trials evaluating adjuvant ChT for rectal cancer have been handicapped by poor compliance rates and inconsistent survival results. Shifting systemic therapy delivery to the neoadjuvant setting has the promise to improve compliance rates, reduce toxicity, and decrease distant relapse rates. Recently, multiple prospective trials have reported on the use of total neoadjuvant therapy (TNT) for patients with LARC, incorporating both ChT and CRT in the neoadjuvant setting. Here, the authors review the promising results from those trials. Because the studies have largely focused on pathologic outcomes…

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT.…

BACKGROUND: Increasing physical activity can improve cognition in healthy and cognitively impaired adults; however, the benefits for cancer survivors are unknown. The current study examined a 12-week physical activity intervention, compared with a control condition, on objective and self-reported cognition among breast cancer survivors. METHODS: Sedentary breast cancer survivors were randomized to an exercise arm (n = 43) or a control arm (n = 44). At baseline and at 12 weeks, objective cognition was measured with the National Institutes of Health Cognitive Toolbox, and self-reported cognition using the Patient-Reported Outcomes Measurement Information System scales. Linear mixed-effects regression models tested intervention effects for changes in cognition scores. RESULTS: On average, participants (n = 87) were aged 57 years (standard deviation, 10.4 years) and were 2.5 years (standard deviation, 1.3 years) post surgery. Scores on the Oral Symbol Digit subscale (a measure of processing speed) evidenced differential improvement in the exercise arm versus the control arm (b = 2.01; P…

BACKGROUND: Reports are limited regarding clinical and pretreatment features that might predict a pathological complete response (pathCR) after treatment in patients with esophageal cancer (EC). This might allow patient selection for different strategies. This study examines the association of a pathCR with pretreatment variables, overall survival (OS), recurrence-free survival (RFS), and patterns of recurrence in a large cohort from a single institution. METHODS: The baseline clinical features of 911 consecutive patients with EC who were treated with trimodality therapy from January 2000 to November 2013 were analyzed. A pathCR was defined as a surgical specimen with no residual carcinoma (primary or nodes). Logistic regressions were used to identify independent baseline features associated with a pathCR. We applied log-rank testing and Cox models to determine the association between a pathCR and the time-to-event outcomes (OS and RFS). RESULTS: Of 911 patients, 218 (23.9%) achieved a pathCR. The pathCR rate was 23.1% for adenocarcinoma and 32.2% for squamous cell carcinoma. A…

BACKGROUND: Neoadjuvant chemotherapy in pure urothelial bladder cancer provides a significant survival benefit. However, to the authors' knowledge, it is unknown whether this benefit persists in histological variants. The objective of the current study was to assess the effect of neoadjuvant chemotherapy on the probability of non-organ-confined disease and overall survival after radical cystectomy (RC) in patients with histological variants. METHODS: Querying the National Cancer Data Base, the authors identified 2018 patients with histological variants who were undergoing RC for bladder cancer between 2003 and 2012. Variants were categorized as micropapillary or sarcomatoid differentiation, squamous cell carcinoma, adenocarcinoma, neuroendocrine tumors, and other histology. Logistic regression models estimated the odds of non-organ-confined disease at the time of RC for each histological variant, stratified by the receipt of neoadjuvant chemotherapy. Cox regression models were used to examine the effect of neoadjuvant chemotherapy on overall mortality in each variant subgroup.…

BACKGROUND: Demoralization refers to a state in which there is a perceived inability to cope, that is associated with a sense of disheartenment and a loss of hope and meaning. This study investigated the co-occurrence versus independence of demoralization with mental disorders and suicidal ideation to evaluate its features as a concept of distress in the context of severe illness. METHODS: In a cross-sectional sample of 430 mixed cancer patients, we assessed demoralization with the Demoralization Scale (DS); the 4-week prevalence of mood, anxiety, and adjustment disorders and suicidal ideation with the standardized Composite International Diagnostic Interview-Oncology (CIDI-O); and depressive symptoms with the Patient Health Questionnaire-9 (PHQ-9). We compared the relative risk (RR) for mental disorders associated with demoralization to that associated with self-reported depression. RESULTS: Clinically relevant levels of demoralization were present in 21% of the patients. Demoralization co-occurred with a mood/anxiety disorder in 7%; 14% were demoralized in absence of any…

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. With the implementation of lung cancer screening, the number and proportion of patients diagnosed with early-stage disease are anticipated to increase. Surgery is currently the standard of care for patients with operable stage I NSCLC. However, promising outcomes with stereotactic body radiation therapy (SBRT) in patients with inoperable disease has led to interest in directly comparing SBRT and surgery in operable patients. Unfortunately, early randomized trials comparing surgery and SBRT closed early because of poor accrual. In this article, the nuances of surgery and SBRT for early-stage NSCLC are reviewed. Furthermore, retrospective and prospective analyses of SBRT in early-stage NSCLC are discussed, and active randomized trials comparing these 2 approaches are described. Cancer 2018;124:667-78. © 2017 American Cancer Society.

BACKGROUND: The objective of this study was to determine the effects of National Comprehensive Cancer Network (NCCN) guideline-adherent initiation of postoperative radiation therapy (PORT) and different time-to-PORT intervals on the overall survival (OS) of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The National Cancer Data Base was reviewed for the period of 2006-2014, and patients with HNSCC undergoing surgery and PORT were identified. Kaplan-Meier survival estimates, Cox regression analysis, and propensity score matching were used to determine the effects of initiating PORT within 6 weeks of surgery and different time-to-PORT intervals on survival. RESULTS: This study included 41,291 patients. After adjustments for covariates, starting PORT >6 weeks postoperatively was associated with decreased OS (adjusted hazard ratio [aHR], 1.13; 99% confidence interval [CI], 1.08-1.19). This finding remained in the propensity score-matched subset (hazard ratio, 1.21; 99% CI, 1.15-1.28). In comparison with starting PORT 5 to 6 weeks postoperatively, initiating PORT…

BACKGROUND: Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. METHODS: Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. RESULTS: Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four…

BACKGROUND: Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. METHODS: The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation…

The accurate prediction of prognosis in patients with soft tissue sarcoma (STS) is a challenging issue. Extreme variability in the clinical and pathological characteristics of this family of tumors hinders the simple stratification of patients into meaningful prognostic cohorts. Precision medicine tools for the prediction of prognosis, such as nomograms, enable personalized computation of outcome based on clinical and pathological characteristics of both patient and tumor. The eighth edition of the American Joint Committee on Cancer staging manual moved from a "population-based" to a "personalized" approach endorsing high-quality nomograms to improve clinician prediction ability in definite patient subgroups. The first nomogram for STS was published in 2002, and this was followed by several prognostic predictors offered to clinicians. Focusing on a specific STS subgroup or site, nomograms can take into consideration highly specific factors relevant only in that particular scenario, thereby maximizing prognostic ability. The objective of this review was to critically evaluate…

When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review presents a concise document and figures as a starting point for evidence-based care for patients with these rare diseases. This framework allows prospective decision making and prioritization of clinical trials. It is hoped that this framework will inspire and focus future clinical research and thus lead to new trials to improve efficacy and reduce toxicity. Cancer…

BACKGROUND: Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality. METHODS: The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching. RESULTS: A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P<.001]), adjuvant chemoradiotherapy (HR,…

BACKGROUND: To reduce oral cancer mortality, an organized, population-based screening program for the early detection of oral premalignancy and oral cancer was designed for high-risk individuals with habits of betel quid chewing, cigarette smoking, or both. The objective of this report was to evaluate the long-term effectiveness of this program in reducing the incidence of advanced disease and deaths from oral cancer. METHODS: A nationwide, population-based screening program for oral cancer has been conducted in Taiwan since 2004. Residents aged ≥ 18 years with oral habits of cigarette smoking and/or betel quid chewing were invited. The standardized mortality ratio method was used to compare the observed numbers of advanced oral cancers and deaths from oral cancer among screening attendees with the expected numbers derived from mortality among nonattendees. An intention-to-treat analysis of the relative rate of reductions in advanced-stage oral cancers and oral cancer mortality also was conducted. RESULTS: The overall screening rate was 55.1%. The relative risk of death from oral…

BACKGROUND: Severe fatigue is a common and distressing symptom affecting approximately one in four survivors of breast cancer. The current study examined the efficacy of Internet-based cognitive behavioral therapy (ICBT) for severe fatigue in survivors of breast cancer compared with care as usual (CAU). METHODS: The authors conducted a parallel-group randomized controlled trial. Severely fatigued, disease-free survivors of breast cancer who had completed cancer treatment at least 3 months previously were eligible. Participants were randomly allocated to ICBT or CAU using computer-generated stratified block randomization. The primary outcome of fatigue severity was assessed at baseline and after 6 months, as were the secondary outcomes of functional impairment, psychological distress, and quality of life. Statistical effects were tested with analyses of covariance (intention-to-treat analysis). RESULTS: Participants were recruited between January 2014 and March 2016 and assigned to ICBT (66 patients) or CAU (66 patients). Compared with the participants who had received CAU, those who…

BACKGROUND Osteoradionecrosis (ORN) of the mandible is a late toxicity affecting patients treated with radiotherapy for head and neck malignancies. To the authors' knowledge, ORN has no standardized grading system and its reporting is based on retrospective findings in heterogeneous patient populations. The rate of ORN in the era of intensity‐modulated radiotherapy (IMRT) still is unknown. METHODS The authors report the incidence of ORN from prospectively collected data regarding 1196 patients who were diagnosed with squamous cell carcinoma of the oropharynx and treated with curative‐intent IMRT, with or without concomitant systemic treatment, from January 2005 to December 2014. Each case of ORN was graded according to its severity. Clinical and dosimetric comparisons were performed between patients with ORN and a matched control cohort of patients without ORN. RESULTS The actuarial rate of ORN of the mandible was 3% at 1 year, 5% at 3 years, and 7% at 5 years. On multivariable analysis, smoking (hazard ratio, 1.9; 95% confidence interval, 1.07‐3.4 [ P = .03]) and T classification…

The identification of driver mutations in melanoma has changed the field of cancer treatment. BRAF and NRAS mutations are predominant in melanoma and lead to overactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Selective inhibitors targeting key effectors of the MAPK pathway have revolutionized the treatment of patients with advanced metastatic BRAF-mutant melanoma. However, resistance to therapy is almost universal and remains a major challenge in clinical care, with the majority of patients progressing within 1 year. Dissecting the mechanisms of resistance to targeted therapies may offer new insights into strategies for overcoming resistance. This review describes the efficacy of therapies targeting the MAPK and PI3K/AKT signaling pathways in melanoma, details the mechanisms contributing to drug resistance, and discusses current approaches to improving outcomes further. Cancer 2017;123:2118-29. © 2017 American Cancer Society.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared. METHODS: Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression. RESULTS: Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control,…

Melanoma has one of the highest somatic mutational burdens among solid malignancies. Although the rapid progress in genomic research has contributed immensely to our understanding of the pathogenesis of melanoma, the clinical significance of the vast array of genomic alterations discovered by next-generation sequencing is far from being fully characterized. Most mutations prevalent in melanoma are simply neutral "passengers," which accompany functionally significant "drivers" under transforming conditions. The delineation of driver mutations from passenger mutations is critical to the development of targeted therapies. Novel advances in genomic data analysis have aided in distinguishing true driver mutations involved in tumor progression. Here, the authors review the current literature on important somatic driver mutations in melanoma, along with the implications for treatment. Cancer 2017;123:2104-17. © 2017 American Cancer Society.

BACKGROUND: When bad news about a cancer diagnosis is being delivered, patient-centered communication (PCC) has been considered important for patients' adjustment and well-being. However, few studies have explored how interpersonal skills might help cancer patients cope with anxiety and distress during bad-news encounters. METHODS: A prospective, experimental design was used to investigate the impact of the physician communication style during a bad-news encounter. Ninety-eight cancer patients and 92 unaffected subjects of both sexes were randomly assigned to view a video of a clinician delivering a first cancer diagnosis with either an enhanced patient-centered communication (E-PCC) style or a low patient-centered communication (L-PCC) style. Participants rated state anxiety and negative affect before and immediately after the video exposure, whereas trust in the physician was rated after the video exposure only. Main and interaction effects were analyzed with generalized linear models. RESULTS: Viewing the disclosure of a cancer diagnosis resulted in a substantial increase in…

BACKGROUND: Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era. METHODS: A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis. RESULTS: The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with…

Because cancer registry data provide a census of cancer cases, registry data can be used to: 1) define and monitor cancer incidence at the local, state, and national levels; 2) investigate patterns of cancer treatment; and 3) evaluate the effectiveness of public health efforts to prevent cancer cases and improve cancer survival. The purpose of this article is to provide a broad overview of the history of cancer surveillance programs in the United States, and illustrate the expanding ways in which cancer surveillance data are being made available and contributing to cancer control programs. The article describes the building of the cancer registry infrastructure and the successful coordination of efforts among the 2 federal agencies that support cancer registry programs, the Centers for Disease Control and Prevention and the National Cancer Institute, and the North American Association of Central Cancer Registries. The major US cancer control programs also are described, including the National Comprehensive Cancer Control Program, the National Breast and Cervical Cancer Early…

BACKGROUND: Depression screening in patients with cancer is recommended by major clinical guidelines, although the evidence on individual screening tools is limited for this population. Here, the authors assess and compare the diagnostic accuracy of 2 established screening instruments: the depression modules of the 9-item Patient Health Questionnaire (PHQ-9) and the Hospital Anxiety and Depression Scale (HADS-D), in a representative sample of patients with cancer. METHODS: This multicenter study was conducted with a proportional, stratified, random sample of 2141 patients with cancer across all major tumor sites and treatment settings. The PHQ-9 and HADS-D were assessed and compared in terms of diagnostic accuracy and receiver operating characteristic (ROC) curves for Diagnostic and Statistical Manual of Mental Disorders, 4th edition diagnosis of major depressive disorder using the Composite International Diagnostic Interview for Oncology as the criterion standard. RESULTS: The diagnostic accuracy of the PHQ-9 and HADS-D was fair for diagnosing major depressive disorder, with areas…

BACKGROUND: The authors evaluated the efficacy, patterns of failure, and toxicity of stereotactic ablative radiotherapy (SABR) for patients with medically inoperable, clinical stage I non-small cell lung cancer (NSCLC) in a prospective clinical trial with 7 years of follow-up. Clinical staging was performed according to the seventh edition of the American Joint Committee on Cancer TNM staging system. METHODS: Eligible patients with histologically confirmed NSCLC of clinical stage I as determined using positron emission tomography staging were treated with SABR (50 grays in 4 fractions). The primary endpoint was progression-free survival. Patients were followed with computed tomography and/or positron emission tomography/computed tomography every 3 months for the first 2 years, every 6 months for the next 3 years, and then annually thereafter. RESULTS: A total of 65 patients were eligible for analysis. The median age of the patients was 71 years, and the median follow-up was 7.2 years. A total of 18 patients (27.7%) developed disease recurrence at a median of 14.5 months (range,…

The metabolic genes isocitrate dehydrogenase 1 (IDH1) and IDH2 are commonly mutated in low-grade glioma and in a subset of glioblastoma. These mutations co-occur with other recurrent molecular alterations, including 1p/19q codeletions and tumor suppressor protein 53 (TP53) and alpha thalassemia/mental retardation (ATRX) mutations, which together help to define a molecular signature that aids in the classification of gliomas and helps to better predict clinical behavior. A confluence of research suggests that glioma development in IDH-mutant and IDH wild-type tumors is driven by different oncogenic processes and responds differently to current treatment paradigms. Herein, the authors discuss the discovery of IDH mutations and associated molecular alterations in glioma, review clinical features common to patients with IDH-mutant glioma, and highlight current understanding of IDH mutation-driven gliomagenesis with implications for emerging treatment strategies. Cancer 2017;123:4535-4546. © 2017 American Cancer Society.

Immunotherapy for metastatic melanoma has a decades-long history, and the relatively recent use of checkpoint inhibitors has revolutionized treatment. Durable and sometimes complete remission of metastatic melanoma is now achievable in some patients who receive checkpoint-blocking therapy. However, it is unclear why some patients fare better than others. This review highlights several molecular indicators of response to checkpoint inhibition in metastatic melanoma, focusing on tumor programmed death ligand 1 expression, major histocompatibility complex class I expression, mutational load in the tumor, and T-cell infiltration into the tumor. In addition, clinical correlates of response, notably vitiligo and other immune-related adverse events, can potentially shed light on the mechanisms by which checkpoint blockade may achieve such great success, particularly in melanoma. The authors propose that microphthalmia-associated transcription factor-a key regulator of melanocyte survival, melanin production, and melanoma transformation-produces a molecular landscape in melanocytes and…

BACKGROUND: High-level MYCN amplification (MNA) is associated with poor outcome and unfavorable clinical and biological features in patients with neuroblastoma. To the authors' knowledge, less is known regarding these associations in patients with low-level MYCN copy number increases. METHODS: In this retrospective study, the authors classified patients has having tumors with MYCN wild-type tumors, MYCN gain (2-4-fold increase in MYCN signal compared with the reference probe), or MNA (>4-fold increase). Tests of trend were used to investigate ordered associations between MYCN copy number category and features of interest. Log-rank tests and Cox models compared event-free survival and overall survival by subgroup. RESULTS: Among 4672 patients, 3694 (79.1%) had MYCN wild-type tumors, 133 (2.8%) had MYCN gain, and 845 (18.1%) had MNA. For each clinical/biological feature, the percentage of patients with an unfavorable feature was lowest in the MYCN wild-type category, intermediate in the MYCN gain category, and highest in the MNA category (P<.0001), except for 11q aberration, for which…

BACKGROUND: The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes. METHODS: The current study included 46,567 patients taken from the National Cancer Data Base who were diagnosed with locally advanced invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx and were undergoing definitive radiotherapy. High-volume facilities (HVFs) were defined as the top 1% of centers by the number of patients treated from 2004 through 2012. Multivariable Cox regression and propensity score matching were performed to account for imbalances in covariates. RESULTS: The median follow-up was 55.1 months. Treatment at a HVF (hazard ratio, 0.798; 95% confidence interval, 0.753-0.845 [P<.001]) and treatment at an academic facility (hazard ratio, 0.897; 95% confidence interval, 0.871-0.923 [P<.001]) were found to be independently associated with improved overall survival in multivariable…

BACKGROUND: Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors. METHODS: Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity. RESULTS: In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the…