bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing High-Quality Cancer Rehabilitation Programs: A Timely Need
Authors: Alfano Catherine M. , Cheville Andrea L. , Mustian Karen
Published: October 2018

The number of survivors of cancer in the United States, already 14.5 million, is growing with improved cancer treatment and aging of the population. Two-thirds of cancer survivors will be older than age 65 and are likely to enter cancer treatment already deconditioned and with multiple comorbidities. Survivors of cancer face numerous adverse consequences of cancer treatment that add to or exacerbate the effects of existing comorbidities and increase risk of functional decline. Many of these problems are amenable to rehabilitation interventions, but referral to cancer rehabilitation professionals is not a standard part of care. We present an expanded prospective model of surveillance, cancer rehabilitation assessment, and referral efforts using a multidisciplinary team approach. In this model, cancer rehabilitation begins at the time of cancer diagnosis and continues through and beyond cancer treatment. Physical impairments and psychosocial symptoms are assessed and treated, and lifestyle and exercise interventions are provided to optimize functioning, health, and quality of life. We present a stepped-care framework to guide decisions on when, how, and where to refer survivors to cancer rehabilitation specialists depending on safety requirements and needs. This model has the potential to result in early identification of symptoms and impairments, appropriate referral and timely treatment, and, in turn, will better address and minimize both acute and long-term cancer morbidity.
The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies
Authors: Unger Joseph M. , Cook Elise , Tai Eric , Bleyer Archie
Published: October 2018

Fewer than one in 20 adult patients with cancer enroll in cancer clinical trials. Although barriers to trial participation have been the subject of frequent study, the rate of trial participation has not changed substantially over time. Barriers to trial participation are structural, clinical, and attitudinal, and they differ according to demographic and socioeconomic factors. In this article, we characterize the nature of cancer clinical trial barriers, and we consider global and local strategies for reducing barriers. We also consider the specific case of adolescents with cancer and show that the low rate of trial enrollment in this age group strongly correlates with limited improvements in cancer population outcomes compared with other age groups. Our analysis suggests that a clinical trial system that enrolls patients at a higher rate produces treatment advances at a faster rate and corresponding improvements in cancer population outcomes. Viewed in this light, the issue of clinical trial enrollment is foundational, lying at the heart of the cancer clinical trial endeavor. Fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results. Moreover, increased accrual to trials is important for patients, because trials provide patients the opportunity to receive the newest treatments. In an era of increasing emphasis on a treatment decision-making process that incorporates the patient perspective, the opportunity for patients to choose trial participation for their care is vital.
Local Ablative Therapies to Metastatic Soft Tissue Sarcoma
Authors: Gronchi Alessandro , Guadagnolo B. Ashleigh , Erinjeri Joseph Patrick
Published: October 2018

The approach to metastatic soft tissue sarcoma is complex and depends upon several factors, such as the extent of the disease, the histologic subtype of the primary tumor, the disease-free interval, patient status and comorbidities, and previous treatments. The effect of systemic chemotherapy is suboptimal, therefore local ablative therapies are often considered when the disease is limited, especially if confined to a single site/organ. Historically, surgery has been considered the treatment of choice for isolated lung metastases. This approach also has been extended to metastases in the liver, although a formal demonstration of its benefit has never been provided. Radiation therapy instead has been mainly used to obtain pain control and to reduce the risk of bone fracture and cord compression. Advances in techniques, such as the development of more precise conformational modalities and the employment of particles, may change the role of this modality in the strategic approach to metastatic soft tissue sarcoma. Recently, the use of interventional radiology in this scenario has expanded. Ablative approaches, such as radiofrequency ablation and cryoablation, have shown durable eradication of tumors. Catheter-directed therapies, such as hepatic artery embolization, are potential techniques for treating the patient who has multiple unresectable liver metastases. Understanding the timing and role of these three different modalities in the multidisciplinary approach to metastatic soft tissue sarcoma is critical to provide better care and to personalize the approach to the single patient.
Locoregional Recurrent or Second Primary Head and Neck Cancer: Management Strategies and Challenges
Authors: Wong Stuart J. , Heron Dwight E. , Stenson Kerstin , Ling Diane C. , Vargo John A.
Published: October 2018

Treatment of patients with locoregional recurrent or second primary head and neck squamous cell cancer (HNSCC) has been guided by well-reasoned principles and informed by carefully tested chemotherapy and radiation regimens. However, clinical decision making for this population is complicated by many factors. Although surgery is generally considered the treatment of choice for patients with HNSCC with recurrent disease or new second primary disease in a previously irradiated field, operability of cases is not always straightforward. Postoperative treatment is frequently warranted but carries significant risk. In addition, the rapid rise in the incidence of HPV-associated HNSCC raises the question of whether established treatment paradigms should be re-examined in this population of patients with a much better prognosis than the non-HPV population. Furthermore, new radiation techniques and new systemic agents show early promising results in recent clinical studies, suggesting potential for practice-changing effects in the future management of this disease. This article examines each of the treatment modalities used in the care of patients with HNSCC with recurrent or new second primary disease and provides a perspective to aid clinicians in the management of this disease.
Integrating Frailty, Comorbidity, and Quality of Life in the Management of Myelodysplastic Syndromes
Authors: Abel Gregory A. , Buckstein Rena
Published: October 2018

Myelodysplastic syndromes (MDS) are a group of acquired hematopoietic stem cell disorders that manifest with progressive bone marrow failure and have a propensity to transform into leukemia. Although an increase in biologic understanding of MDS has led to improved patient risk stratification and prognostication, advances in treatment have lagged behind. While hematopoietic cell transplantation (HCT) is a potentially curative option for some, most affected patients continue to be treated with supportive care or with drugs that offer temporary palliation such as hematopoietic growth factors, DNA hypomethylating agents, or immunomodulatory therapy. For several groups, such as those with intermediate-risk disease as classified by the Revised International Prognostic Scoring System (IPSS-R) or those with higher-risk disease for whom hypomethylating agents have failed, optimal treatment remains uncertain. Inclusion of patient-related factors such as frailty and comorbid conditions into risk assessment can improve prognostication beyond the disease-associated variables included in systems such as the IPSS-R. This article focuses on approaches to assessing and integrating frailty, comorbidities, and quality of life into the treatment of patients with MDS.
Seeking New Approaches to Patients With Small Cell Lung Cancer
Authors: Pietanza Marie Catherine , Zimmerman Stefan , Peters Solange , Curran Walter J.
Published: October 2018

The fundamental approach to the treatment of small cell lung cancer (SCLC) has not changed in the last several decades, with most advances being restricted to improved radiation approaches. The standard first-line chemotherapy regimen in the United States and Europe remains cisplatin or carboplatin plus etoposide in the treatment of limited stage (LS-SCLC) and extensive stage (ES-SCLC) disease. Radiation therapy is administered to those patients with LS-SCLC, whose cancer is confined to the chest in a single tolerable radiation field. This article will summarize a number of exciting observations regarding the biology of SCLC and how a deeper understanding of newly integrated targets and target pathways may lead to new and better therapeutic approaches in the near future.
Immunotherapy: Beyond Anti–PD-1 and Anti–PD-L1 Therapies
Authors: Antonia Scott J. , Vansteenkiste Johan F. , Moon Edmund
Published: October 2018

Advanced-stage non–small cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a survival benefit, although it is small. We now know that anti–PD-1/PD-L1 has substantial clinical activity in both of these diseases, with an overall response rate (ORR) of 15%–20%. These responses are frequently rapid and durable, increase median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant results, many patients do not benefit from anti–PD-1/PD-L1. This is because of the potential for malignancies to co-opt myriad immunosuppressive mechanisms other than aberrant expression of PD-L1. Conceptually, these can be divided into three categories. First, for some patients there is likely a failure to generate sufficient functional tumor antigen-specific T cells. Second, for others, tumor antigen–specific T cells may be generated but fail to enter into the tumor parenchyma. Finally, there are a large number of immunosuppressive mechanisms that have the potential to be operational within the tumor microenvironment: surface membrane immune checkpoint proteins PD-1, CTLA-4, LAG3, TIM3, BTLA, and adenosine A2AR; soluble factors and metabolic alterations interleukin (IL)-10, transforming growth factor (TGF)-β, adenosine, IDO, and arginase; and inhibitory cells, cancer-associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages. In this article, we discuss three strategies to generate more tumor-reactive T cells for patients: anti–CTLA-4, therapeutic tumor vaccination, and adoptive cellular therapy, with T cells redirected to tumor antigens using T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene modification. We also review some of the various strategies in development to thwart tumor microenvironment immunosuppressive mechanisms. Strategies to drive more T cells into tumors remain a significant challenge.
Local Therapy for Limited Metastatic Non–Small Cell Lung Cancer: What Are the Options and Is There a Benefit?
Authors: Iyengar Puneeth , Lau Steven , Donington Jessica S. , Suh Robert D.
Published: October 2018

Distant metastasis is common in non–small cell lung cancer (NSCLC) and typically associated with poor prognosis. Aggressive local therapy including surgery and/or radiation for limited metastatic disease from colorectal cancer and sarcoma is associated with survival benefit and has become part of the standard of care. In this article, we review the literature and ongoing studies concerning surgery, radiation, and radiofrequency ablation for oligometastatic NSCLC.
The Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma
Authors: Hutson Thomas E. , Thoreson Gregory R. , Figlin Robert A. , Rini Brian I.
Published: October 2018

The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.
Update on Intraperitoneal Chemotherapy for the Treatment of Epithelial Ovarian Cancer
Authors: Gourley Charlie , Walker Joan L. , Mackay Helen J.
Published: October 2018

Surgical treatment and chemotherapy administration in women with epithelial ovarian cancer is more controversial today than at any point in the last 3 decades. The use of chemotherapy administered intraperitoneally has been particularly contentious. Three large randomized phase III studies, multiple meta-analyses, and now real-world data have demonstrated substantial outcome benefit for the use of chemotherapy administered intraperitoneally versus intravenously for first-line postoperative treatment of optimally debulked advanced ovarian cancer. Unfortunately, for each of these randomized studies, there was scope to either criticize the design or otherwise refute adoption of this route of administration. As a result, the uptake has been variable in North America, although in Europe it has been practically nonexistent. Reasons for this include unquestionable additional toxicity, more inconvenience, and extra cost. However, 10-year follow up of these studies demonstrates unprecedented survival in the intraperitoneal arm (median survival 110 months in patients with completely debulked stage III), raising the possibility that by combining maximal debulking surgery with postoperative intraperitoneal chemotherapy it may be possible to bring about a step change in the outcomes for these patients. In this review, we discuss the rationale for administering chemotherapy intraperitoneally, the merits of the main randomized clinical trials, the evidence regarding optimal regimes, issues of toxicity, port considerations, and reasons for lack of universal adoption. We also explore potential clinical and biologic factors that may be useful for patient selection in the future.
Arming the Immune System Through Vaccination to Prevent Cancer Recurrence
Authors: Hale Diane F. , Vreeland Timothy J. , Peoples George E.
Published: October 2018

Cancer vaccines have the potential to provide a nontoxic treatment for the prevention of cancer recurrence in the adjuvant setting. Many cancer vaccines have been tested in multiple phase III trials with minimal success. However, through these failed clinical trials, we have learned that the ideal setting for vaccine therapy is the adjuvant setting. Also, we have learned important lessons about patient selection to maximize the probability of success. This article will highlight some of the successes, our trial results in the adjuvant setting, and future directions.
Treatment of Muscle-Invasive Bladder Cancer in Older Patients
Authors: Skinner Eila C.
Published: October 2018

Treatment of muscle-invasive bladder cancer in older patients is challenging. Definitive therapy of localized disease requires either surgery or radiation therapy, ideally combined with systemic chemotherapy. However, current population data suggest that less than half of patients older than age 70 are offered such treatments. We will review tools available to assess the fitness of older patients for surgery, alternatives, and tips for perioperative patient treatment.
The Role of Nephrectomy for Kidney Cancer in the Era of Targeted and Immune Therapies
Authors: Vaishampayan Ulka N.
Published: October 2018

Editor's Note: The following article is based on the 2016 ASCO Annual Meeting Education Session “Cytoreductive Nephrectomy in Renal Cell Carcinoma: A Debate.” The author reviews the pros and cons of cytoreductive nephrectomy and whether recent advances in systemic therapy warrant physicians to proceed directly to systemic therapy as in other metastatic solid tumors, without the integral step of cytoreductive nephrectomy.
Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long, How Much, and in Which Combination?
Authors: Brown Jennifer R. , Hallek Michael J. , Pagel John M.
Published: October 2018

During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features—particularly mutated immunoglobulin heavy chain variable region ( IGHV) genes—derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.
Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT
Authors: Lynch Ryan C. , Advani Ranjana H.
Published: October 2018

Although patients with advanced-stage classic Hodgkin lymphoma have excellent outcomes with contemporary therapy, the outcomes of patients with refractory disease is suboptimal. Identification of these high-risk patients at diagnosis is challenging as the differences in outcomes using clinical criteria are less marked using current modern therapy. Data suggest that an interim PET-CT may be a powerful tool in risk-stratifying patients. Retrospective studies show that a negative interim PET-CT after two to four cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is predictive of favorable outcome independent of IPS score. Currently, there are several ongoing trials that aim to determine whether early-response assessment can be used to select patients who might benefit from modifications of subsequent therapy, either by intensifying or abbreviating regimens and/or omitting radiotherapy with promising early results. Longer follow-up is required to assess whether this strategy impacts overall survival (OS). Herein, we review the results of recent trials using interim PET-CT-based adaptive design in the treatment of advanced HL.
Less Is More: The Evolving Surgical Approach to Breast Cancer
Authors: Esserman Laura , Gallant Etienne , Alvarado Michael
Published: October 2018

Editor's Note: The following article is based on the 2016 ASCO Annual Meeting Education Session “Less Is More: A Multidisciplinary Conversation on Treatment Options.” The authors review the indications for reducing the treatment burden for women with breast cancer by capitalizing on the emerging opportunity to identify and recognize more indolent forms of the disease using advanced tools, therapies, and screening methods.
The Role of Imaging in the Treatment of Patients With Multiple Myeloma in 2016
Authors: Terpos Evangelos , Dimopoulos Meletios A. , Moulopoulos Lia A.
Published: October 2018

The novel criteria for the diagnosis of symptomatic multiple myeloma have revealed the value of modern imaging for the management of patients with myeloma. Whole-body low-dose CT (LDCT) has increased sensitivity over conventional radiography for the detection of osteolytic lesions, and several myeloma organizations and institutions have suggested that whole-body LDCT should replace conventional radiography for the work-up of patients with myeloma. MRI is the best imaging method for the depiction of marrow infiltration by myeloma cells. Whole-body MRI (or at least MRI of the spine and pelvis if whole-body MRI is not available) should be performed for all patients with smoldering multiple myeloma with no lytic lesions to look for occult disease, which may justify treatment. In addition, MRI accurately illustrates the presence of plasmacytomas, spinal cord, and/or nerve compression for surgical intervention or radiation therapy; it is also recommended for the work-up of solitary bone plasmacytoma, and it may distinguish malignant from benign fractures (which is very important in cases of patients in biochemical remission with no other signs of progression). Diffusion weighted imaging (DWI) seems to improve MRI diagnosis in patients with myeloma. PET/CT is a functional imaging technique, more sensitive than conventional radiography for the detection of lytic lesions, which probably allows better definition of complete response and minimal residual disease compared with all other imaging methods. PET/CT has shown the best results in the follow-up of patients with myeloma and has an independent prognostic value both at diagnosis and following treatment. PET/CT can also be used for the work-up of solitary bone plasmacytoma and nonsecretory myeloma.
A Value-Based Approach to Treatment of HER2-Positive Breast Cancer: Examining the Evidence
Authors: Nixon Nancy , Verma Sunil
Published: October 2018

Over the past decade, treatment of HER2-positive breast cancer has been revolutionized with the introduction of targeted therapies. Survival in both early and advanced HER2-positive breast cancer has improved significantly. With evidence for major clinical benefit, it is imperative that health systems evaluate new treatments to maximize the value of health expenditures. Physicians, funding agencies, and policy makers are tasked with analyzing available evidence to ensure that each individual patient receives the optimal treatment in a resource-challenged environment.
Neuroblastoma: A Tough Nut to Crack
Authors: Speleman Frank , Park Julie R. , Henderson Tara O.
Published: October 2018

Neuroblastoma, an embryonal tumor arising from neural crest–derived progenitor cells, is the most common solid tumor in childhood, with more than 700 cases diagnosed per year in the United States. In the past several decades, significant advances have been made in the treatment of neuroblastoma. Treatment advances reflect improved understanding of the biology of neuroblastoma. Although amplification of MYCN was discovered in the early 1980s, our understanding of neuroblastoma oncogenesis has advanced in the last decade as a result of high-throughput genomic analysis, exome and whole-genome sequencing, genome-wide association studies, and synthetic lethal drug screens. Our refined understanding of neuroblastoma biology and genetics is reflected in improved prognostic stratification and appropriate tailoring of therapy in recent clinical trials. Moreover, for high-risk neuroblastoma, a disease that was uniformly fatal 3 decades ago, recent clinical trials incorporating autologous hematopoietic transplant and immunotherapy utilizing anti-GD2 antibody plus cytokines have shown improved event-free and overall survival. These advances have resulted in a growing population of long-term survivors of neuroblastoma. Examination of the late effects and second malignant neoplasms (SMNs) in both older generations of survivors and more recently treated survivors will inform both design of future trials and surveillance guidelines for long-term follow-up. As a consequence of advances in understanding of the biology of neuroblastoma, successful clinical trials, and refined understanding of the late effects and SMNs of survivors, the promise of precision medicine is becoming a reality for patients with neuroblastoma.
Liver Metastases in Colorectal Cancer
Authors: Folprecht Gunnar
Published: October 2018

Resection of colorectal liver metastases is a treatment standard because patients experience long-term disease-free survival or are even cured after undergoing this procedure. Improved surgical techniques for liver resection in combination with downsizing liver metastases by chemotherapy, interventions to induce liver hypertrophy before resection, and the use of ablative techniques have allowed us to expand the indications for liver surgery and local treatment in situations with limited metastatic colorectal cancer. Resectability and identification of patients who might benefit from liver surgery and local ablative techniques are key factors for the treatment of patients with colorectal cancer. Despite the wide acceptance of liver surgery and ablative techniques, there are many open questions on the management of limited metastatic disease, such as which patients benefit from an aggressive surgical approach, what the indications for ablative and other local techniques are, and what the role of chemotherapy is for patients with resectable or resected disease. Unfortunately, results of randomized trials are only available for a limited number of these questions.
Considerations for Implementation of Cancer Molecular Diagnostics Into Clinical Care
Authors: Hayes Daniel F.
Published: October 2018

Physicians have provided personalized care with as much precision as possible for several centuries. However, increasingly sophisticated understanding of the human genome and of cancer biology has permitted identification of genetic and phenotypic distinctions that might permit development of new tumor biomarker tests for risk categorization, screening, differential diagnosis, prognosis, prediction, and monitoring. Both commercial and academic laboratories are offering tests for single analytes, panels of tests of single analytes, multiparameter assays coalesced into a signature, and total genomic, transcriptomic, or proteomic analyses. However, the absence of a consistent regulatory environment has led to marketing of assays without proven analytic validity or clinical utility. U.S. Food and Drug Administration (FDA) approval or clearance does not necessarily imply that use of the test will improve patient outcomes, and FDA discretion to permit laboratory-developed tests results in unknown benefit, or harm, of others. In this regard, a “bad tumor marker is as bad as a bad drug.” Caveat emptor is not a satisfactory approach to delivering high-quality care. Rather, adoption of tumor biomarker tests should be based on high levels of evidence generated in scientifically rigorous studies that demonstrate both analytical validity and clinical utility. Doing so will ensure that clinicians and patients are confident that a tumor biomarker test is likely to improve their outcomes.
Localized Pancreatic Cancer: Multidisciplinary Management
Authors: Coveler Andrew L. , Herman Joseph M. , Simeone Diane M. , Chiorean E. Gabriela
Published: October 2018

Pancreatic cancer is an aggressive cancer that continues to have single-digit 5-year mortality rates despite advancements in the field. Surgery remains the only curative treatment; however, most patients present with late-stage disease deemed unresectable, either due to extensive local vascular involvement or the presence of distant metastasis. Resection guidelines that include a borderline resectable group, as well as advancements in neoadjuvant chemotherapy and radiation that improve resectability of locally advanced disease, may improve outcomes for patients with more invasive disease. Multi-agent chemotherapy regimens fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel with gemcitabine improved response rates and survival in metastatic pancreatic cancer and are now being used in earlier stages for patients with localized potentially resectable and unresectable disease, with goals of downstaging tumors to allow margin-negative resection and reducing systemic recurrence. Chemoradiotherapy, although still controversial for both resectable and unresectable pancreatic cancer, is being used in the context of contemporary chemotherapy backbone regimens, and novel radiation techniques such as stereotactic body frame radiation therapy (SBRT) are studied on the premise of maintaining or improving efficacy and reducing treatment duration. Patient selection for optimal treatment designation is currently provided by multidisciplinary tumor boards, but biomarker discovery, in blood, tumors, or through novel imaging, is an area of intense research. Results to date suggest that some patients with unresectable disease at the outset have survival rates as good as those with initially resectable disease if able to undergo surgical resection. Long-term follow-up and improved clinical trials options are needed to determine optimal treatment modalities for patients with localized pancreatic cancer.
Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic Syndromes
Authors: Komrokji Rami S.
Published: October 2018

Hypomethylating agents (HMAs) are the mainstay treatment of patients with myelodysplastic syndromes. Hypomethylating agents remain the only treatment, other than allogeneic hematopoietic stem cell transplantation (AHSCT), that improves overall survival (OS) for patients with higher-risk myelodysplastic syndromes. It is crucial to maximize the benefit of HMAs by selecting the appropriate dosing and schedule and continuing therapy until clear evidence of lack of response or failure of therapy. Strategies to improve outcome with HMAs include identifying tools and biomarkers for better patient selection, namely the ability to identify those who achieve complete response (CR) or long duration of response, combination strategies with HMAs aim to improve response rate or its duration. The outcome of patients with myelodysplastic syndromes after HMA failure is poor for both patients with higher-risk and lower-risk disease and represents an unmet medical need. The best outcomes after HMA failure are reported with AHSCT or novel agents in clinical trials. This article discusses the maximizing benefit of HMAs, offers strategies to improve outcome with HMAs, and, finally, reviews selected novel agents in development after HMA failure.
Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?
Authors: DeAngelo Daniel J. , Stein Eytan M. , Ravandi Farhad
Published: October 2018

Acute myeloid leukemia (AML) is an acquired disease characterized by chromosomal translocations and somatic mutations that lead to leukemogenesis. Systemic combination chemotherapy with an anthracycline and cytarabine remains the standard induction regimen for “fit” adults. Patients who achieve complete remission generally receive postinduction therapy with cytarabine-based chemotherapy or an allogeneic bone marrow transplant. Those unfit for induction chemotherapy are treated with hypomethylating agents (HMAs), low-dose cytarabine, or they are offered supportive care alone with transfusions and prophylactic antimicrobials. The revolution in understanding the genetics of AML, facilitated by next-generation sequencing, has led to many new drugs against driver mutations. Better methods of identification of leukemic blasts have provided us with better means to detect the disease left behind after cytotoxic chemotherapy regimens. This measurable residual disease has been correlated with poorer relapse-free survival, demonstrating the need for novel strategies to eradicate it to improve the outcome of patients with acute leukemias. In this article, we discuss adapting and improving AML therapy by age and comorbidities, emerging targeted therapies in AML, and minimal residual disease (MRD) assessment in AML.
Manipulating the Immune System With Checkpoint Inhibitors for Patients With Metastatic Sarcoma
Authors: D’Angelo Sandra P.
Published: October 2018

Sarcomas are a rare group of malignant tumors of mesenchymal origin that comprise 1% of all adult cancers. Despite initial surgery, distant metastatic disease will develop in approximately 25% of patients, and standard chemotherapy has limited durable efficacy. There is a dire need for more effective and less toxic therapies for the treatment of metastatic sarcoma. The immune system plays a major role in cancer control and progression. There have been tremendous breakthroughs in other malignancies by manipulating the immune system with checkpoint inhibitors. These agents, either alone or in combination with other approaches such as radiation, chemotherapy, targeted agents, or immunotherapeutics, have generally led to improved efficacy in selected malignancies thus far. Although promising, these drugs can cause specific immune-related adverse events that require prompt recognition and treatment. In addition, characterizing response and progression radiographically has become somewhat more challenging. Identifying predictive biomarkers of benefit will be essential. There remains optimism and hope that the strides made in other cancers will be emulated in sarcoma.
Higher-Level Pathway Objectives of Epigenetic Therapy: A Solution to the p53 Problem in Cancer
Authors: Velcheti Vamsidhar , Radivoyevitch Tomas , Saunthararajah Yogen
Published: October 2018

Searches for effective yet nontoxic oncotherapies are searches for exploitable differences between cancer and normal cells. In its core of cell division, cancer resembles normal life, coordinated by the master transcription factor MYC. Outside of this core, apoptosis and differentiation programs, which dominantly antagonize MYC to terminate cell division, necessarily differ between cancer and normal cells, as apoptosis is suppressed by biallelic inactivation of the master regulator of apoptosis, p53, or its cofactor p16/CDKN2A in approximately 80% of cancers. These genetic alterations impact therapy: conventional oncotherapy applies stress upstream of p53 to upregulate it and causes apoptosis (cytotoxicity)—a toxic, futile intent when it is absent or nonfunctional. Differentiation, on the other hand, cannot be completely suppressed because it is a continuum along which all cells exist. Neoplastic evolution stalls advances along this continuum at its most proliferative points—in lineage-committed progenitors that have division times measured in hours compared with weeks for tissue stem cells. This differentiation arrest is by mutations/deletions in differentiation-driving transcription factors or their coactivators that shift balances of gene-regulating protein complexes toward corepressors that repress instead of activate hundreds of terminal differentiation genes. That is, malignant proliferation without differentiation, also referred to as cancer “stem” cell self-renewal, hinges on druggable corepressors. Inhibiting these corepressors (e.g., DNMT1) releases p53-independent terminal differentiation in cancer stem cells but preserves self-renewal of normal stem cells that express stem cell transcription factors. Thus, epigenetic-differentiation therapies exploit a fundamental distinction between cancer and normal stem cell self-renewal and have a pathway of action downstream of genetic defects in cancer, affording favorable therapeutic indices needed for clinical progress.
Bone Sarcoma Pathology: Diagnostic Approach for Optimal Therapy
Authors: Rosenberg Andrew E.
Published: October 2018

The pathologic interpretation of malignant bone tumors is one of the more challenging areas in surgical pathology. This is based on the reality that primary bone sarcomas are uncommon, demonstrate significant morphologic heterogeneity, and have a broad spectrum of biology. Accordingly, it is difficult for pathologists to acquire the necessary experience to confidently and accurately diagnose bone sarcomas. The task is further complicated by the fact that it requires the integration of clinical and radiologic information into the diagnostic process. Lastly, molecular aberrations in sarcomas are being newly discovered and their identification is often critical to make specific diagnoses. The pathologist’s role in guiding optimal treatment in biopsy specimens is to make an accurate diagnosis and provide the grade and molecular aberrations when appropriate. The pathology report of resected tumors must confirm this information and assess the surgical resection margins and the percentage of necrosis if the sarcoma has been treated with neoadjuvant systemic therapy.
The Current Landscape of Early Drug Development for Patients With Sarcoma
Authors: Wilky Breelyn A. , Jones Robin L. , Keedy Vicki L.
Published: October 2018

Until recently, advancements in the treatment of patients with adult soft tissue sarcomas have been relatively slow. This is, in part, due to their heterogeneity and rarity. A better understanding of the biology and differences among the various histologies has led to substantial growth in novel strategies. In addition to novel cytotoxic chemotherapies, agents targeting platelet-derived growth factor receptor-α (PDGFRα), mTOR, and angiogenesis are areas of active investigation. Additionally, with the success of checkpoint inhibitors in other malignancies and early encouraging results of checkpoint inhibitors in some sarcoma subtypes, this approach is being widely investigated in various sarcomas. As we increasingly recognize and treat each sarcoma histology as a separate disease, it is important to spread awareness of the exciting clinical trials available to our patients with these rare malignancies.
Whence High-Grade Serous Ovarian Cancer
Authors: Kohn Elise C. , Ivy S. Percy
Published: October 2018

Our understanding of epithelial ovarian cancer has blossomed, and we now recognize that it is a collection of varied histologic and molecularly different malignancies, many of which may not derive from a true ovarian anatomic precursor. High-grade serous ovarian cancer (HGSOC) is a unique type of epithelial cancer. It is characterized by nearly universal mutation in and dysfunction of p53, genomic instability rather than driver mutations, advanced stage at onset, and probable fallopian tube epithelium origin, with a serous tubal in situ carcinoma precursor. Germline deleterious mutations in BRCA1 and BRCA2, as well as other less prevalent genes involved in DNA repair, such as PALB2 and RAD51c, are associated with its carcinogenesis and may predict susceptibility to classes of treatment agents, including DNA-damaging agents and DNA repair inhibitors. Loss of function of these genes is associated with homologous recombination dysfunction (HRD). It is now recognized that there may be HGSOC with wild-type BRCA1 and BRCA2 with an identifiable HRD phenotype. Such HRD tumors also may be more susceptible to certain classes of treatments and may be phenotypically detectable with a composite molecular biomarker that has been shown to be predictive for response to PARP inhibitors. Use of this new knowledge of the anatomic and molecular background of HGSOC has led to the rational design of novel combinations of treatment classes to create an HRD-like cellular environment and thus drive treatment benefits.
Systemic Therapy Options for Patients With Unresectable Melanoma
Authors: Yushak Melinda , Chapman Paul , Robert Caroline , Kudchadkar Ragini
Published: October 2018

There has been a therapeutic revolution in the treatment of metastatic melanoma over the past decade. Patients presenting with inoperable disease have several therapeutic options, which can include both targeted and immune therapy. Immune checkpoint inhibitors have demonstrated an improvement in overall survival and led to some durable responses. However, toxicity, especially in combination regimens, can be severe. Adverse events should be anticipated, diagnosed as early as possible, monitored, and managed. Combination BRAF and MEK inhibition has also been shown to improve overall survival in patients with V600E-mutated melanoma. Responses to therapy are often rapid, and treatment is not associated with immune-related adverse events. Current trials are under way to determine which option is optimal as frontline therapy for patients with V600E melanoma. In patients with progressive disease despite standard therapies, clinical trials are recommended. There are several promising agents in development.
Beyond Alkylating Agents for Gliomas: Quo Vadimus?
Authors: Puduvalli Vinay K. , Chaudhary Rekha , McClugage Samuel G. , Markert James
Published: October 2018

Recent advances in therapies have yielded notable success in terms of improved survival in several cancers. However, such treatments have failed to improve outcome in patients with gliomas for whom surgery followed by radiation therapy and chemotherapy with alkylating agents remain the standard of care. Genetic and epigenetic studies have helped identify several alterations specific to gliomas. Attempts to target these altered pathways have been unsuccessful due to various factors, including tumor heterogeneity, adaptive resistance of tumor cells, and limitations of access across the blood-brain barrier. Novel therapies that circumvent such limitations have been the focus of intense study and include approaches such as immunotherapy, targeting of signaling hubs and metabolic pathways, and use of biologic agents. Immunotherapeutic approaches including tumor-targeted vaccines, immune checkpoint blockade, antibody-drug conjugates, and chimeric antigen receptor–expressing cell therapies are in various stages of clinical trials. Similarly, identification of key metabolic pathways or converging hubs of signaling pathways that are tumor specific have yielded novel targets for therapy of gliomas. In addition, the failure of conventional therapies against gliomas has led to a growing interest among patients in the use of alternative therapies, which in turn has necessitated developing evidence-based approaches to the application of such therapies in clinical studies. The development of these novel approaches bears potential for providing breakthroughs in treatment of more meaningful and improved outcomes for patients with gliomas.
New Classification for Central Nervous System Tumors: Implications for Diagnosis and Therapy
Authors: Fuller Christine E. , Jones David T. W. , Kieran Mark W.
Published: October 2018

The 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) represents a noteworthy divergence from prior classification schemas. This new classification introduced the concept of “integrated diagnoses” based on a marriage of both phenotypic (microscopic) and genotypic parameters, with the intended goals of improving diagnostic accuracy and patient management. The result is a major restructuring in many of the brain tumor categories, with the codification of multiple new tumor entities and subgroups. It is therefore imperative that pathologists, clinicians, and neuro-oncology researchers alike rapidly become familiar with this new classification schema. Many of the diagnostic updates set forth in the WHO 2016 have impacted brain tumor types that commonly arise in the pediatric age group, particularly within the diffuse glioma, ependymoma, and embryonal tumor categories. This review gives a brief overview of (1) the WHO 2016 as it relates to pediatric central nervous system (CNS) tumors, with an emphasis on molecular diagnostic tools used in the clinical arena, (2) ongoing and developing approaches to the molecular and genomic classification of pediatric CNS tumors, and (3) the impact of this new classification schema on clinical trials in pediatric neuro-oncology.
Integration of Genomics Into Treatment: Are We There Yet?
Authors: Morgan Gareth J. , Jones John R.
Published: October 2018

Using advances in genetic analysis to segment and direct treatment of multiple myeloma (MM) represents a way of maintaining therapeutic progress. Recent genetic analyses have opened the possibility of enhancing risk stratification approaches and of using different risk and biologic strata as part of clinical trials. The Myeloma Genome Project is a collaborative project that has compiled the largest set of cases with sequencing and have outcome data that are available for stratification purposes. Mutation-targeted treatment of the Ras pathway has been shown to be active in MM, but is compromised by the presence of the subclonal genetic variation typical of myeloma. Going forward, risk and biologically stratified therapy for MM looks to be a promising way of maintaining therapeutic progress, as does precision immunotherapy directed by the cellular context of the bone marrow.
Myeloma in Elderly Patients: When Less Is More and More Is More
Authors: Rosko Ashley , Giralt Sergio , Mateos Maria-Victoria , Dispenzieri Angela
Published: October 2018

Multiple myeloma is a plasma cell malignancy that occurs among older adults and accounts for 15% of all hematologic malignancies in the United States. Thirty-five percent of patients are diagnosed at age 75 or older. Novel therapeutics and routine use of autologous stem cell transplantation (ASCT) have led to substantial improvements in patient survival, although improvements have been more impressive among patients younger than age 65. Finding the balance between under- and overtreating elderly patients is one of the biggest challenges specific to them as a subgroup of patients with MM. Decision making about which therapies and their dose intensity and duration should be influenced by a patient’s functional status, personal preferences, disease characteristics, and ability to tolerate therapy. ASCT should be considered for all patients younger than age 80, assuming that they are not frail. The attainment of a stringent complete response and minimal residual disease negativity is associated with improved progression-free and overall survival. Again, consideration of quality of life for these patients is paramount. Although there is a growing list of tools to sort through these issues, a fully integrated approach has not yet been finely tuned, leaving additional work to be done for the treatment of elderly patients with MM.
Established and Novel Prognostic Biomarkers in Multiple Myeloma
Authors: Bustoros Mark , Mouhieddine Tarek H. , Detappe Alexandre , Ghobrial Irene M.
Published: October 2018

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by notable interpatient heterogeneity. There have been important advances in therapy and overall survival, but some patients with high-risk features still have poor survival rates. Therefore, accurate identification of this subset of patients has been integral to improvement of patient outcome. During the last few years, cytogenetics, gene expression profiling, MRI and PET/CT, as well as serum free light chain assays have been used as accurate biomarkers to better characterize the diverse course and outcome of the disease. With the recent advances of massive parallel sequencing techniques, the development of new models that better stratify high-risk groups are beginning to be developed. The use of multiparameter flow cytometry and next-generation sequencing have paved the way for assessment of minimal residual disease and better prognostication of post-therapeutic outcomes. Circulating tumor cells and circulating tumor DNA are promising potential biomarkers that demonstrate the spatial and temporal heterogeneity of MM. Finally, more prognostic markers are being developed that are specific to immunotherapeutic agents. In this review, we discuss these traditional and novel biomarkers that have been developed for MM and also those that can predict disease progression from precursor stages. Together, these biomarkers will help improve our understanding of the intrapatient and interpatient variabilities and help develop precision medicine for patients with high-risk MM.