bluuebunny/crossref_metadata_2025 huggingface dataset:
Future Directions in the Evaluation and Treatment of Precursor Plasma Cell Disorders
Authors: Manier Salomon , Salem Karma Z. , Liu David , Ghobrial Irene M.
Published: October 2018

Multiple myeloma (MM) is an incurable disease that progresses from a premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) and an intermediate stage of smoldering multiple myeloma (SMM). Recent major advances in therapy with more effective and less toxic treatments have brought reconsideration of early therapeutic intervention in management of SMM, with the goal of reducing progression of the disease before the occurrence of end-organ damage to MM and improving survival. Key to this effort is accurate identification of patients at high risk of progression who would truly benefit from early intervention. In this review, we discuss the current definitions, risk factors, risk stratification, prognosis, and management of MGUS and SMM, as well as new emerging therapeutic options under active investigation.
Current Management Concepts: Primary Central Nervous System Lymphoma, Natural Killer T-Cell Lymphoma Nasal Type, and Post-transplant Lymphoproliferative Disorder
Authors: Batchelor Tracy T. , Thye Lim Soon , Habermann Thomas M.
Published: October 2018

Primary central nervous system lymphoma, natural killer T-cell lymphoma nasal type, and post-transplant lymphoproliferative disorder are uncommon and complex lymphoproliferative disorders. These disorders present with different risk factors, have complex tumor characteristics, and require unique therapeutic interventions. These diseases require a multidisciplinary complex team approach. This article will update current management approaches and concepts.
Functional Imaging Using 18-Fluorodeoxyglucose PET in the Management of Primary Mediastinal Large B-Cell Lymphoma: The Contributions of the International Extranodal Lymphoma Study Group
Authors: Cavalli Franco , Ceriani Luca , Zucca Emanuele
Published: October 2018

Primary mediastinal large B-cell lymphoma (PMLBCL) is recognized as a distinct disease entity. Treatment outcomes appear better than in other diffuse large B-cell lymphoma (DLBCL) types, partly because of their earlier stage at presentation and the younger age of most patients. If initial treatment fails, however, the results of salvage chemotherapy and myeloablative treatment are poor. The need to avoid relapses after initial therapy has led to controversy over the extent of front-line therapy, particularly whether consolidation radiotherapy to the mediastinum is always required and whether the 18-fluorodeoxyglucose (18F-FDG) uptake detected by PET-CT scan can be used to determine its requirements. Functional imaging using PET-CT generally allows distinguishing of residual mediastinal masses containing active lymphoma from those with only sclerotic material remaining. The International Extranodal Lymphoma Study Group (IELSG) conducted the prospective IELSG-26 study, which showed that a five-point visual scale can be used to define metabolic response after immunochemotherapy and that a cut point based on liver uptake discriminates effectively between high or low risk of failure, with 5-year progression-free survival (PFS) of 99% versus 68% and 5-year overall survival (OS) of 100% versus 83%. This study also showed that a baseline quantitative PET parameter, namely the total lesion glycolysis describing the metabolic tumor burden, can be a powerful predictor of PMLBCL outcomes and warrants further validation as a biomarker. The ongoing IELSG-37 randomized study addresses the need for consolidation mediastinal radiotherapy in patients in whom a complete metabolic response (CMR) can be seen on PET scans after standard immunochemotherapy.
Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies
Authors: Calvo Emiliano , Walko Christine , Dees E. Claire , Valenzuela Belén
Published: October 2018

The complex nature of the pharmacologic aspects of cancer therapeutics has become more apparent in the past several years with the arrival of a cascade of target-based agents and the difficult challenge of bringing individualized precision medicine to oncology. Interpatient variability in drug action, singularly in novel agents, is in part caused by pharmacogenomic (PG), pharmacokinetic, and pharmacodynamic (PD) factors, and drug selection and dosing should take this into consideration to optimize the benefit for our patients in terms of antitumor activity and treatment tolerance. In this regard, somatic genetic evaluation of tumors is useful in not only predicting response to initial targeted therapies but also in anticipating and guiding therapy after the development of acquired resistance; therapeutic drug monitoring of novel small molecules and monoclonal antibodies must be incorporated in our day-to-day practice to minimize the negative effect on clinical outcome of interindividual variability on pharmacokinetic processes of these drugs for all patients, but especially for fragile patient populations and those with organ dysfunction or comorbidities. For these populations, incorporating frailty assessment tools into trials of newer agents and validating frailty-based dose adjustment should be an important part of further drug development.
Tailoring Chemotherapy in Early-Stage Breast Cancer: Based on Tumor Biology or Tumor Burden?
Authors: Ribnikar Domen , Cardoso Fatima
Published: October 2018

The question of whether to offer adjuvant chemotherapy to patients with early-stage breast cancer has always been challenging to answer. It is well known that a substantial proportion of patients with early-stage breast cancer are over treated, especially when staging and hormonal and HER2 receptors are solely taken into consideration. The advances in our knowledge of breast cancer biology and its clinical implications were the basis for the discovery of additional reliable prognostic markers to aid decision making for adjuvant treatment. Gene expression profiling is a molecular tool that more precisely defines the intrinsic characteristics of each individual tumor. The application of this technology has led to the development of gene signatures/profiles with relevant prognostic—and some predictive—value that have become important tools in defining which patients with early-stage breast cancer can be safely spared from chemotherapy. However, the exact clinical utility of these tools will only be determined after the results of two large prospective randomized trials, MINDACT and TailorX, evaluating their role become available. Notwithstanding the existence of these genomic tools, tumor burden (defined as tumor size and nodal status) still has independent prognostic value and must be incorporated in decision making. In addition, these gene signatures have limited predictive value, and new biomarkers and new targets are needed. Therefore close collaboration between clinicians and scientists is crucial. Lastly, issues of cost-effectiveness, reimbursement, and availability are crucial and widely variable around the globe.
The Past, Present, and Future of Pancreatic Cancer Clinical Trials
Authors: Matrisian Lynn M. , Berlin Jordan D.
Published: October 2018

Upper gastrointestinal malignancies comprise half of the deadliest cancers as defined by those with a 5-year survival rate less than 50%. Using pancreatic adenocarcinoma (PAC) as an example, we retrospectively evaluated the success of phase III clinical trials, examined the current landscape of clinical trials, and identified emerging areas that foretell the future for this disease. Pancreatic and liver cancers are on the rise and will be the second and third leading causes of cancer deaths in 2030. A total of 35 different agents or combinations have been tested in randomized phase III clinical trials for patients with advanced PAC over the past 25 years, but only 11% have been incorporated into clinical practice. There has been a 37% increase in the number of PAC trials open in the United States between 2011 to 2012 and 2014 to 2015. Enrollment has also increased slightly, from 3.85% of the newly diagnosed cases in 2011 to 4.15% in 2014. However, the demand for patients far exceeds the number of patients available for these trials. On the horizon is the realization that stratification of patients with PAC using biomarkers that predict a high probability of a response could reallocate patients to faster, smaller trials with a greater chance of a survival benefit. The current landscape of PAC clinical trials and the launch of the Pancreatic Cancer Action Network’s Know Your Tumor initiative indicate this shift is starting to occur, with particular emphasis on targeted therapies, immunotherapies, and agents that disrupt the stroma.
The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics
Authors: Anders Carey K. , Abramson Vandana , Tan Tira , Dent Rebecca
Published: October 2018

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as “immune-activated,” consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.
Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors
Authors: Robinson Giles W. , Witt Hendrik , Resnick Adam
Published: October 2018

Over a relatively short period of time, owing to improvements in biotechnology, our ability to identify the molecular mechanisms within pediatric brain tumors has dramatically increased. These findings have reshaped the way that we describe these diseases and have provided insights into how to better treat these often devastating diseases. Although still far from reaching the full therapeutic potential these advancements hold, the impact of these findings is steadily taking hold of pediatric brain tumor management. In this article, we summarize the major discoveries within three common pediatric brain tumor categories; medulloblastoma, ependymoma, and low-grade glioma. We discuss the current impact of these findings on treatment and the direction these findings may take the field of pediatric neuro-oncology.
Emerging Therapeutic Options for HER2-Positive Breast Cancer
Authors: Martin Miguel , López-Tarruella Sara
Published: October 2018

The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2 directed therapy (trastuzumab). Trastuzumab has significantly increased survival of patients with HER2-positive metastatic breast cancer and, after the standardization of the use of this drug in the adjuvant setting in 2005, has also avoided many disease recurrences and, consequently, saved many lives. Later on, the introduction of lapatinib offered new choices for patients with advanced HER2-positive breast cancer, although the drug has failed to show a clear efficacy in the adjuvant setting. New promising drugs have been approved to broaden the horizon of HER2-positive breast cancer such as pertuzumab or T-DM1, but we need new options to further improve the management of these diseases. In this review, we cover new strategies that are currently under evaluation for the treatment of patients with HER2-positive breast cancer, including new tyrosine kinase inhibitors (neratinib, ONT-380), new antibody-drug conjugates targeting HER2 (MM-302), and new indications of already approved drugs (T-DM1), as well as the potential dual combinations of anti-HER2 therapy with phosphoinositide 3-kinase/mTOR or cell cycle inhibitors (palbociclib, abemaciclib). Last but not least, we briefly review a new paradigm of emerging approaches that involve the host immune response, HER2 breast cancer vaccines, and other immune strategies, including immune checkpoint inhibition.
Improving Response to Hormone Therapy in Breast Cancer: New Targets, New Therapeutic Options
Authors: Rugo Hope S. , Vidula Neelima , Ma Cynthia
Published: October 2018

The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of resistance mechanisms leading to estrogen-independent growth of hormone receptor–positive (HR+) breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired mutations in ER-alpha ( ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK) 4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer, including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia (treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel combinations are under active investigation.
Issues in Breast Cancer Survivorship: Optimal Care, Bone Health, and Lifestyle Modifications
Authors: Melisko Michelle E. , Gradishar William J. , Moy Beverly
Published: October 2018

There are an estimated 3.1 million survivors of breast cancer in the United States. The predominant reasons for this substantially large population are that breast cancer is the most common noncutaneous malignancy among women and that 5-year survival rates after breast cancer treatment are approximately 90%. These patients have many medical considerations, including the need to monitor for disease recurrence and to manage complications of their previous cancer treatments. Most patients remain at risk indefinitely for local and systemic recurrences of their breast cancers and have an increased risk of developing contralateral new primary breast cancers. Therefore, optimizing care for this patient population is critical to the overall health care landscape in the United States. Here, we summarize survivorship care delivery and its challenges, the optimization of bone health in breast cancer survivors, and opportunities for risk reduction through lifestyle modifications.
Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic
Authors: Beltran Himisha , Antonarakis Emmanuel S. , Morris Michael J. , Attard Gerhardt
Published: October 2018

Recent clinical and preclinical studies focused on understanding the molecular landscape of castration-resistant prostate cancer (CRPC) have provided insights into mechanisms of treatment resistance, disease heterogeneity, and potential therapeutic targets. This work has served as a framework for several ongoing clinical studies focused on bringing novel observations into the clinic in the form of tissue, liquid, and imaging biomarkers. Resistance in CRPC typically is driven through reactivation of androgen receptor (AR) signaling, which can occur through AR-activating point mutations, amplification, splice variants (such as AR-V7), or other bypass mechanisms. Detection of AR aberrations in the circulation negatively impacts response to subsequent AR-directed therapies such as abiraterone and enzalutamide. Other potentially clinically relevant alterations in CRPC include defects in DNA damage repair (at either the somatic or germline level) in up to 20% of patients (with implications for PARP1 inhibitor therapy), PI3K/PTEN/Akt pathway activation, WNT signaling pathway alterations, cell cycle gene alterations, and less common but potentially targetable alterations involving RAF and FGFR2. Imaging biomarkers that include those focused on incorporating overexpressed androgen-regulated genes/proteins, such as prostate-specific membrane antigen (PSMA) and dihydrotestosterone (DHT) in combination with CT, can noninvasively identify patterns of AR-driven distribution of CRPC tumor cells, monitor early metastatic lesions, and potentially capture heterogeneity of response to AR-directed therapies and other therapeutics. This article focuses on the current state of clinical biomarker development and future directions for how they might be implemented into the clinic in the near term to improve risk stratification and treatment selection for patients.
Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving Therapies, and Patient-Specific Disease Burden
Authors: Mesa Ruben A. , Passamonti Francesco
Published: October 2018

Individualized medicine is important for patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, which are heterogeneous in terms of genetic mutation profile, prognosis, disease burden, and symptoms. Status of MPN driver mutations in JAK2, CALR, and MPL (or lack of one of these mutations) and other myeloid mutations (ASXL1, SRSF2, CBL, and IDH1/2, among others) affects diagnosis and prognosis. Management begins with estimating the prognosis, disease burden including MPN symptoms, and prevention of vascular events. Allogeneic stem cell transplantation is the definitive therapy in a subset of patients with myelofibrosis, the majority of whom receive JAK inhibition with ruxolitinib to relieve splenomegaly and symptoms and to prolong survival. Ruxolitinib is now a second-line therapy in polycythemia vera, with pegylated interferon being evaluated as a potential front-line therapy compared with hydroxyurea. The therapeutic landscape is evolving to include new JAK inhibitors, which may affect cytopenias (pacritinib and momelotinib), combination therapies including ruxolitinib, and novel targets such as pentraxin and telomerase. Assessing the therapeutic efficacy (including symptom impact) and toxicity of these new approaches is necessary to determine longitudinal management of MPNs in clinical practice and is a key component of “individualizing” care for patients with MPNs.
Why the Quality Oncology Practice Initiative Matters: It’s Not Just About Cost
Authors: Chiang Anne C.
Published: October 2018

The nature and cost of cancer care is evolving, affecting more patients and often involving expensive treatment options. The upward cost trends also coincide with a national landscape of increasing regulatory mandates that may demand improved outcomes and value, but that often require significant up-front investment in infrastructure to achieve safety and quality. Oncology practices participating in the American Society of Clinical Oncology (ASCO) Institute for Quality’s Quality Oncology Practice Initiative (QOPI) and the QOPI Certification Program (QCP) continue to grow in number and reflect changing demographics of the provision of cancer care. QOPI and QCP benchmarking can be used to achieve quality improvement and to build collaborative quality communities. These programs may be useful tools for oncology practices to comply with new legislation such as the Medicare Access and CHIP Reauthorization Act (MACRA).
Primary Surgery or Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: The Debate Continues…
Authors: Cowan Renee , Chi Dennis , Kehoe Sean , Nankivell Matthew , Leary Alexandra
Published: October 2018

Primary debulking surgery (PDS) followed by platinum-based chemotherapy has been the cornerstone of treatment for advanced ovarian cancer for decades. Primary debulking surgery has been repeatedly identified as one of the key factors in improving survival in patients with advanced ovarian cancer, especially when minimal or no residual disease is left behind. Achieving these results sometimes requires extensive abdominal and pelvic surgical procedures and consultation with other surgical teams. Some clinicians who propose a primary chemotherapy approach reported an increased likelihood of leaving no macroscopic disease after surgery and improved patient-reported outcomes and quality-of-life (QOL) measures. Given the ongoing debate regarding the relative benefit of PDS versus neoadjuvant chemotherapy (NACT), tumor biology may aid in patient selection for each approach. Neoadjuvant chemotherapy offers the opportunity for in vivo chemosensitivity testing. Studies are needed to determine the best way to evaluate the impact of NACT in each individual patient with advanced ovarian cancer. Indeed, the biggest utility of NACT may be in research, where this approach provides the opportunity for the investigation of predictive markers, mechanisms of resistance, and a forum to test novel therapies.
Biliary Tract Cancer: Epidemiology, Radiotherapy, and Molecular Profiling
Authors: Bridgewater John A. , Goodman Karyn A. , Kalyan Aparna , Mulcahy Mary F.
Published: October 2018

Biliary tract cancer, or cholangiocarcinoma, arises from the biliary epithelium of the small ducts in the periphery of the liver (intrahepatic) and the main ducts of the hilum (extrahepatic), extending into the gallbladder. The incidence and epidemiology of biliary tract cancer are fluid and complex. It is shown that intrahepatic cholangiocarcinoma is on the rise in the Western world, and gallbladder cancer is on the decline. Radiation therapy has emerged as an important component of adjuvant therapy for resected disease and definitive therapy for locally advanced disease. The emerging sophisticated techniques of imaging tumors and conformal dose delivery are expanding the indications for radiotherapy in the management of bile duct tumors. As we understand more about the molecular pathways driving biliary tract cancers, targeted therapies are at the forefront of new therapeutic combinations. Understanding the gene expression profile and mutational burden in biliary tract cancer allows us to better discern the pathogenesis and identify promising new developmental therapeutic targets.
Bench-to-Bedside Approaches for Personalized Exercise Therapy in Cancer
Authors: Jones Lee W. , Eves Neil D. , Scott Jessica M.
Published: October 2018

The past 2 decades have witnessed a growing body of work investigating the feasibility and efficacy of exercise therapy on a broad array of outcomes in many different oncology scenarios. Despite this heterogeneity, the exercise therapy prescription approach and the dose tested has been largely similar. Thus, current exercise therapy prescriptions in the oncology setting adopt a one-size-fits-all approach. In this article, we provide an overview of personalization of exercise therapy in cancer using the principles of training as an overarching framework. Specifically, we first review the fundamentals of exercise prescription in chronic disease before focusing attention on application of these principles to optimize the safety and efficacy of exercise therapy on (1) cancer treatment–induced cardiovascular toxicity and (2) tumor progression and metastasis.
Social Media and Mobile Technology for Cancer Prevention and Treatment
Authors: Prochaska Judith J. , Coughlin Steven S. , Lyons Elizabeth J.
Published: October 2018

Given the number of lives affected by cancer and the great potential for optimizing well-being via lifestyle changes, patients, providers, health care systems, advocacy groups, and entrepreneurs are looking to digital solutions to enhance patient care and broaden prevention efforts. Thousands of health-oriented mobile websites and apps have been developed, with a majority focused upon lifestyle behaviors (e.g., exercise, diet, smoking). In this review, we consider the use and potential of social media and mHealth technologies for cancer prevention, cancer treatment, and survivorship. We identify key principles in research and practice, summarize prior reviews, and highlight notable case studies and patient resources. Further, with the potential for scaled delivery and broad reach, we consider application of social media and mHealth technologies in low-resource settings. With clear advantages for reach, social media and mHealth technologies offer the ability to scale and engage entire populations at low cost, develop supportive social networks, connect patients and providers, encourage adherence with cancer care, and collect vast quantities of data for advancing cancer research. Development efforts have been rapid and numerous, yet evaluation of intervention effects on behavior change and health outcomes are sorely needed, and regulation around data security issues is notably lacking. Attention to broader audiences is also needed, with targeted development for culturally diverse groups and non-English speakers. Further investment in research to build the evidence base and identify best practices will help delineate and actualize the potential of social media and mHealth technologies for cancer prevention and treatment.
Mastering Resilience in Oncology: Learn to Thrive in the Face of Burnout
Authors: Hlubocky Fay J. , Rose Miko , Epstein Ronald M.
Published: October 2018

Oncology clinician burnout has become a noteworthy issue in medical oncology directly affecting the quality of patient care, patient satisfaction, and overall organizational success. Due to the increasing demands on clinical time, productivity, and the evolving medical landscape, the oncology clinician is at significant risk for burnout. Long hours in direct care with seriously ill patients/families, limited control over daily responsibilities, and endless electronic documentation, place considerable professional and personal demands on the oncologist. As a result, the oncology clinician's wellness is adversely impacted. Physical/emotional exhaustion, cynicism, and feelings of ineffectiveness evolve as core signs of burnout. Unaddressed burnout may affect cancer clinician relationships with their patients, the quality of care delivered, and the overall physical and emotional health of the clinician. Oncology clinicians should be encouraged to build upon their strengths, thrive in the face of adversity and stress, and learn to positively adapt to the changing cancer care system. Fostering individual resilience is a key protective factor against the development of and managing burnout. Empowering clinicians at both the individual and organizational level with tailored resilience strategies is crucial to ensuring clinician wellness. Resilience interventions may include: burnout education, work-life balance, adjustment of one’s relationship to work, mindful practice, and acceptance of the clinical work environment. Health care organizations must act to provide institutional solutions through the implementation of: team-based oncology care, communication skills training, and effective resiliency training programs in order to mitigate the effects of stress and prevent burnout in oncology.
Precision Oncology: Who, How, What, When, and When Not?
Authors: Schwartzberg Lee , Kim Edward S. , Liu David , Schrag Deborah
Published: October 2018

Precision oncology, defined as molecular profiling of tumors to identify targetable alterations, is rapidly developing and has entered the mainstream of clinical practice. Genomic testing involves many stakeholders working in a coordinated fashion to deliver high-quality tissue samples to high-quality laboratories, where appropriate next-generation sequencing (NGS) molecular analysis leads to actionable results. Clinicians should be familiar with the types of genomic variants reported by the laboratory and the technology used to determine the results, including limitations of current testing methodologies and reports. Interpretation of genomic results is best undertaken with multidisciplinary input to reduce uncertainty in clinical recommendations relating to a documented variant. Non–small cell lung cancer has emerged as a prototype disease where genomic data from at least several well-documented alterations with approved targeted agents are essential for optimal treatment from diagnosis of advanced disease. Due to the development of resistance to targeted therapies, resampling and retesting of tumors, including using liquid biopsy technology after clinical progression, may be important in making treatment decisions. The value of molecular profiling depends on avoiding both underutilization for well-documented variant target-drug pairs and overutilization of variant-drug therapy without proven benefit. As techniques evolve and become more cost effective, the use of molecular testing may prove to add more specificity and improve outcomes for a larger number of patients.
Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma
Authors: Gill David M. , Agarwal Neeraj , Vaishampayan Ulka
Published: October 2018

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel–Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA’s approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.
How Should We Intervene on the Financial Toxicity of Cancer Care? One Shot, Four Perspectives
Authors: Zafar S. Yousuf , Newcomer Lee N. , McCarthy Justin , Fuld Nasso Shelley , Saltz Leonard B.
Published: October 2018

The median price of a month of chemotherapy has increased by an order of magnitude during the past 20 years, far exceeding inflation over the same period. Along with rising prices, increases in cost sharing have forced patients to directly shoulder a greater portion of those costs, resulting in undue financial burden and, in some cases, cost-related nonadherence to treatment. What can we do to intervene on treatment-related financial toxicity of patients? No one party can single-handedly solve the problem, and the solution must be multifaceted and creative. A productive discussion of the problem must avoid casting blame and, instead, must look inward for concrete starting points toward improvement in the affordability and value of cancer care. With these points in mind, the authors—representatives from the pharmaceutical industry, insurance providers, oncologists, and patient advocacy—have each been asked to respond with a practical answer to the provocative hypothetical question, “If you could propose one thing, and one thing only, in terms of an action or change by the constituency you represent in this discussion, what would that be?”
Pathology Issues in Thoracic Oncology: Histologic Characterization and Tissue/Plasma Genotyping May Resolve Diagnostic Dilemmas
Authors: Dagogo-Jack Ibiayi , Saltos Andreas , Shaw Alice T. , Gray Jhanelle E.
Published: October 2018

Lung cancer is a heterogeneous diagnosis that encompasses a spectrum of histologic and molecular subgroups. A paradigm shift favoring selection of treatment based on histologic and molecular makeup has positively affected prognosis for patients with metastatic lung cancer, with select patients experiencing durable responses to treatment. However, prognosis remains poor for the majority of patients. Furthermore, oncologists are increasingly faced with challenging dilemmas related to histopathologic and molecular characterization of tumors, both at diagnosis and during treatment. In this review, we focus on three particular challenges: (1) management of mixed histology tumors, a particularly aggressive group of lung cancers, (2) distinguishing multiple primary lung tumors from intrapulmonary metastases, and (3) incorporation of liquid biopsies into the diagnostic algorithm and subsequent follow-up of patients with advanced lung cancer. This review will summarize the existing literature and highlight the potential for molecular genotyping to help refine approaches to each of these challenges.
Best Practices and Practical Nuances in the Treatment of Gastric Cancer in High-Risk Global Areas
Authors: Sanchez Federico A.
Published: October 2018

Gastric cancer is an aggressive disease that is very frequent in Latin America. The reasons for this increased incidence is not clear. Associated with the lack of minimum health care opportunities, lack of accurate statistics and reporting data beyond epidemiologic data, and raw nonreliable data, there is little known of the actual clinical course and treatment of these patients. Understanding epidemiologic data may allow us to encourage the adequate use and distribution of the meager resources that exist.
The Promise of Immunotherapy in the Treatment of Hepatocellular Carcinoma
Authors: El-Khoueiry Anthony
Published: October 2018

Advanced hepatocellular carcinoma (HCC) has presented a therapeutic challenge. Despite its heterogeneity, which is partially related to its various etiologies, it frequently arises in a background of chronic inflammation, which makes it a potentially excellent candidate for immunotherapeutic approaches. There is evidence of antitumor immunity in HCC as manifested by the cell infiltrate and its association with prognosis, the presence of tumor-associated antigens, and the reports of immune-mediated spontaneous regressions. However, both the liver itself and the tumor environment possess a diverse armamentarium of mechanisms that suppress antitumor immunity. Here, we describe the rationale for immunotherapy in HCC and discuss the emerging clinical data from various immunotherapeutic approaches including checkpoint inhibition, cell therapy, oncolytic viral therapy, and various combinatorial approaches. We also highlight the potential for various modalities to be adapted across different stages of the disease.
Immunotherapy for Esophageal and Gastric Cancer
Authors: Kelly Ronan J.
Published: October 2018

PD-L1 upregulation occurs in approximately 40% of gastroesophageal cancers. However, unlike other solid tumors, there is minimal PD-L1 expressed on the cancer cells; rather, expression occurs predominantly on infiltrating myeloid cells. Preliminary clinical data involving single-agent PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancer have reported response rates of 22%–27% for patients with PD-L1+ tumors and 10%–17% for unselected patients. The phase III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival for nivolumab compared with placebo for patients with heavily pretreated gastric cancer. In the future, we will need better biomarkers to select those most likely to respond and/or identify patients who may need combination immunotherapeutics or alternate strategies. A number of subsets of gastric cancer with different immune signatures, most notably tumors positive for Epstein-Barr virus and microsatellite instability, have been identified, with approximately 50% and 94% PD-L1+ staining seen on tumor cells and immune cells in the EBV subtype and approximately 33% and 45% PD-L1+ staining seen on tumor cells and immune cells in MSI high tumors. Both subtypes demonstrate PD-L1+ immune cells with tumor-infiltrating patterns, unlike the more commonly seen PD-L1+ immune cells at the invasive margin. PD-L2 expression has been reported in 52% of esophageal adenocarcinomas but little is known about the expression of other immune checkpoints. Additional factors that suggest gastroesophageal cancers may respond to checkpoint inhibition include the high somatic mutation burden and the link with chronic inflammation. Here we provide a comprehensive review of the checkpoint inhibitor data published to date in advanced esophagogastric cancers and rationalize how the immune microenvironment in these diverse tumors can explain response or resistance to immunotherapeutics.
Thinking Differently in Global Health in Oncology Using a Diagonal Approach: Harnessing Similarities, Improving Education, and Empowering an Alternative Oncology Workforce
Authors: Rodriguez Natalia M. , Brant Jeannine M. , Pendharkar Dinesh , Arreola-Ornelas Hector , Bhadelia Afsan , de Lima Lopes Gilberto , Knaul Felicia M.
Published: October 2018

Cancer is a leading global cause of death, and diverse and minority populations suffer worse outcomes compared with white people from Western societies. Within the United States, African Americans and other blacks, Hispanics, Asians, and American Indians have lower cancer survival rates than whites. In the rest of the world, those from low- and middle-income countries have the greatest disparities, but even those from non-Western high-income countries such as Oman and the United Arab Emirates are diagnosed with cancer at later stages and suffer increased mortality. Although considerable differences exist among these populations, similarities and synergies are also apparent. Challenges can be very similar in reaching these populations effectively for cancer control to improve outcomes, and innovative strategies are needed to effectively make change. In this review, the authors discuss new approaches to the prevention and early detection of cancer as well as the implementation of programs in global oncology and put in evidence cultural similarities and challenges of different populations, highlighting strategies to improve cancer survival and quality care around the world through innovations in training and education, empowerment of an alternative workforce, and a diagonal approach to cancer care using case studies drawn from the authors’ work and experience.
Advances in the Treatment of Advanced Extracutaneous Melanomas and Nonmelanoma Skin Cancers
Authors: Komatsubara Kimberly M. , Jeter Joanne , Carvajal Richard D. , Margolin Kim , Schadendorf Dirk , Hauschild Axel
Published: October 2018

Cutaneous malignancies make up the greatest proportion of all human cancers and include melanomas as well as nonmelanoma skin cancers (NMSCs) such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), as well as less common Merkel cell carcinoma (MCC), cutaneous lymphomas, cutaneous adnexal tumors, Kaposi sarcomas, and other sarcomas. Each of these NMSCs differ significantly in biology, clinical behavior, and optimal treatment recommendations from each other and from cutaneous melanoma. Similarly, less common extracutaneous melanomas, such as mucosal (MMs) and uveal (UMs), are unique biologic and clinical entities that require distinct diagnostic and management considerations. In this review, we summarize recent advances in biology and treatment of extracutaneous melanomas and NMSCs, including MMs, UMs, cSCC, BCC, and MCC.
Lifestyle Interventions to Improve Cardiorespiratory Fitness and Reduce Breast Cancer Recurrence
Authors: Haykowsky Mark J. , Scott Jessica M. , Hudson Kathryn , Denduluri Neelima
Published: October 2018

As patients are living longer after a cancer diagnosis, survivorship is becoming increasingly important in cancer care. The sequelae of multimodality therapies include weight gain and decreased cardiorespiratory fitness, which increase cardiovascular risk. Evidence suggests that physical activity reduces the risk of breast cancer recurrence and death. Avoidance of weight gain after therapy also improves outcomes after a diagnosis of breast cancer. Prospective randomized trials must be performed to determine the benefits of specific physical activity and dietary habits for survivors of breast cancer. This review outlines the important physiologic changes that occur with antineoplastic therapy and the important role of exercise and diet.
Advances in the Treatment of Pediatric Bone Sarcomas
Authors: Grohar Patrick J. , Janeway Katherine A. , Mase Luke D. , Schiffman Joshua D.
Published: October 2018

Bone tumors make up a significant portion of noncentral nervous system solid tumor diagnoses in pediatric oncology patients. Ewing sarcoma and osteosarcoma, both with distinct clinical and pathologic features, are the two most commonly encountered bone cancers in pediatrics. Although mutations in the germline have classically been more associated with osteosarcoma, there is recent evidence germline alterations in patients with Ewing sarcoma also play a significant role in pathogenesis. Treatment advances in this patient population have lagged behind that of other pediatric malignancies, particularly targeted interventions directed at the biologic underpinnings of disease. Recent advances in biologic and genomic understanding of these two cancers has expanded the potential for therapeutic advancement and prevention. In Ewing sarcoma, directed focus on inhibition of EWSR1-FLI1 and its effectors has produced promising results. In osteosarcoma, instead of a concentrated focus on one particular change, largely due to tumor heterogeneity, a more diversified approach has been adopted including investigations of growth factors inhibitors, signaling pathway inhibitors, and immune modulation. Continuing recently made treatment advances relies on clinical trial design and enrollment. Clinical trials should include incorporation of biological findings; specifically, for Ewing sarcoma, assessment of alternative fusions and, for osteosarcoma, stratification utilizing biomarkers. Expanded cancer genomics knowledge, particularly with solid tumors, as it relates to heritability and incorporation of family history has led to early identification of patients with cancer predisposition. In these patients through application of cost-effective evidence-based screening techniques the ultimate goal of cancer prevention is becoming a realization.
Health Disparities and the Global Landscape of Lymphoma Care Today
Authors: Phillips Adrienne A. , Smith Dominic A.
Published: October 2018

Lymphoma encompass a wide variety of distinct disease entities, including, but not limited to, subtypes of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). In the last 3 decades, therapeutic advancements have resulted in substantial improvements in lymphoma outcome. In most high-income regions, HL is a largely curable disease and for patients with two frequent subtypes of NHL, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), survival has dramatically improved with the incorporation of rituximab as a standard treatment approach. Despite these advances, outcomes vary between and across populations. This review will provide updated information about health disparities in lymphoma in the United States and across the globe.
Current Approaches to Mantle Cell Lymphoma: Diagnosis, Prognosis, and Therapies
Authors: Cohen Jonathon B. , Zain Jasmine M. , Kahl Brad S.
Published: October 2018

Mantle cell lymphoma (MCL) is a unique lymphoma subtype, both biologically and clinically. Virtually all cases are characterized by a common genetic lesion, t(11;14), resulting in overexpression of cyclin D1. The clinical course is moderately aggressive, and the disease is considered incurable. Considerable biologic and clinical heterogeneity exists, with some patients experiencing a rapidly progressive course, while others have disease that is readily managed. New tools exist for risk stratification and may allow for a more personalized approach in the future. Landmark studies have been completed in recent years and outcomes appear to be improving. Randomized clinical trials have clarified the role of high-dose cytarabine (Ara-C) for younger patients and have demonstrated a role for maintenance rituximab therapy. Multiple areas of uncertainty remain, however, and are the focus of ongoing research. This review focuses on (1) strategies to differentiate between aggressive and less aggressive cases, (2) understanding who should receive hematopoietic stem cell transplantation, and (3) the role for maintenance therapy in MCL.
Diagnosis and Treatment of Prostate Cancer: What Americans Can Learn From International Oncologists
Authors: James Nicholas , Graham John , Maurer Tobias , Eiber Matthias , Gschwend Jürgen E.
Published: October 2018

The three main sections in this article illustrate a number of facets of European health care. The first section looks at the influence of NICE on treatment of metastatic castration-resistant prostate cancer. The second section explores the impact of molecular imaging on diagnosis and treatment, in particular the development and clinical implementation of 68Ga PET imaging in prostate cancer. The final section of the session looks at the STAMPEDE trial and how running a trial on this scale has impacted care of prostate cancer in the United Kingdom and also at the uptake of docetaxel chemotherapy in hormone-sensitive advanced disease.
Personalizing Therapy for Metastatic Prostate Cancer: The Role of Solid and Liquid Tumor Biopsies
Authors: Friedlander Terence W. , Pritchard Colin C. , Beltran Himisha
Published: October 2018

Although biopsies of metastatic prostate cancer are rarely undertaken in the clinical setting, there is increasing interest in developing personalized approaches to therapy by taking into account the genetic and phenotypic changes in an individual tumor. Indeed, analysis of metastatic prostate tumors can predict sensitivity to agents that inhibit DNA repair and resistance to novel hormonal agents, such as abiraterone and enzalutamide, and identify phenotypic changes, such as neuroendocrine differentiation, that have important clinical implications. Although obtaining metastatic tumor tissue is necessary for this genomic and molecular profiling, knowing when to biopsy, selecting the appropriate metastatic lesion, and interpreting the results are major challenges facing clinicians today. In this article, we discuss the rationale for obtaining metastatic tumor tissue, review the bioinformatic approach to analyzing these specimens, discuss the timing and approach to solid and liquid tumor biopsies, review the challenges associated with obtaining and acting on clinically relevant results, and discuss opportunities for the future.