Editorial Board, iii
Contributors, v
Preface: New Therapeutic Developments in Cancer, xix
Leonidas C. Platanias
SECTION I: RADIATION ONCOLOGY
Opportunities and Advances in the use of Proton Radiotherapy for Management of Central Nervous System and Base of Skull Tumors, 1
Bansi Savla, Gregory Alexander, Ariel E. Pollock, Justin Cohen, and Mark V. Mishra
Advances in managing central nervous system (CNS) malignancies have led to improved survival outcomes and therefore an increased need to reduce the risk of treatment-related toxicities. Precise dose delivery through advanced radiation techniques can spare radiation dose to critical structures while maintaining adequate target coverage. This review discusses potential clinical applications of proton beam therapy for treatment of tumors of the central nervous system and reviews the emerging clinical data supporting use of proton beam therapy and ongoing clinical trial efforts.
Introduction, 1
Low-grade gliomas, 2
High-grade gliomas, 2
Meningiomas, 4
Medulloblastoma, 5
Chordoma, 5
Vestibular schwannomas, 6
Pituitary adenomas, 6
Discussion, 7
Summary, 8
Clinics care points, 8
Disclosure, 9
Breast Cancer-Related Lymphedema: Causes, Detection, Prevention, and Treatment, 13
Jonathan B. Strauss, Sumanas W. Jordan, George E. Naoum, Megan E. Fracol, Jennifer Bai, and Ann Marie Flores
Lymphatic fluid is composed of water, protein, and other debris emited from capillary beds into the intersitium. Under normal conditions lymphatic fluid is absorbed by lymphatic capillaries and pumped towards the thoracic duct, ultimately re-entering the venous circulation. Damage to lympahtic structures leads to accumuation of protein-rich lymphatic fluid in the interstitium leading to edema, inflamation, and ultimately the irreversible changes of fibrosis and adipose deposition. The major risk factors for the development of breast cancer-related lymphedema are: extent of axillary surgery, increasing BMI, and receipt of regional nodal irradiation. Exclusion of the dissected axilla from the radiotherapy field during regional nodal irradiaiton appears to be associated with a lower risk of lymphedema.
Introduction, 13
Pathophysiology, 14
Risk factors for the development of breast cancer-related lymphedema, 14
Breast cancer-related lymphedema screening, diagnosis, and staging, 16
Nonsurgical treatment of breast cancer-related lymphedema, 18
Surgical management of breast cancer-related lymphedema, 19
Treatment of lymphedema, 19
Surgical prophylaxis, 21
Summary, 21
Clinics care points, 22
Updates in Adjuvant Therapy for High-Risk and Locally Advanced Endometrial Cancer, 25
Anjali L. Saripalli, Anna C. Griffin, Dylan Ross, John C. Roeske, William Small Jr., and Matthew M. Harkenrider
Paradigms of adjuvant therapy for endometrial cancer continue to evolve, and there is no standard of care adjuvant therapy for locally advanced endometrial cancer patients. Several recently published clinical trials attempted to provide clarity on adjuvant therapy recommendations. The role of adjuvant radiation therapy may need to be re-evaluated as treatment delivery techniques have improved and evolved. The role of adjuvant therapy has and will continue to evolve as molecular-based treatment recommendations continue to be investigated. The aim of this manuscript is to review the evolution of recently published data to inform patient-centered decision making in the adjuvant treatment of high-risk and locally-advanced endometrial cancer.
Introduction, 25
Trials of adjuvant therapy for early-stage disease, 25
Trials of adjuvant therapy for locally advanced disease, 26
Advent of intensity-modulated radiation therapy, 26
Recent trials of adjuvant therapy for high-risk and locally advanced disease, 27
GOG 249, 27
PORTEC 3, 29
GOG 258, 29
Discussion , 30
Adjuvant therapy: early-stage IâII, high-intermediate risk, 30
Adjuvant therapy: early-stage IâII, high risk, 30
Adjuvant therapy: stage IâII, high-risk histologies (serous/clear cell), 30
Adjuvant therapy: stage IIIâIVA (all histologies), 30
The use of molecular profiling/precision oncology in guiding adjuvant therapy, 31
Summary, 31
Clinics care points, 31
SECTION II: SURGICAL ONCOLOGY
Updates on Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Adenocarcinoma, 35
Gregory C. Wilson, Sameer H. Patel, and Syed A. Ahmad
Mortality after the diagnosis of pancreatic ductal adenocarcinoma remains high for all patients. The role of multimodal therapy, including surgical resection and systemic chemotherapy, has been well established. Neoadjuvant treatment strategies continue to be used in resectable and borderline resectable PDAC. Results from ongoing or recently completed trials will continue to provide valuable insight into the management of patients with resectable and borderline resectable PDAC. Advances in the outcomes for this difficult disease and therefore the focus of futures studies should include a better understanding of tumor biology and markers, novel treatment agents, and combination treatment strategies.
Introduction, 35
Rationale for neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma, 35
The current state of multimodal therapy in pancreatic adenocarcinoma: lessons learned from adjuvant studies, 35
Rationale for neoadjuvant therapy, 37
Neoadjuvant therapy, 38
Neoadjuvant therapy for resectable pancreatic adenocarcinoma, 38
Neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma, 40
Updates in preoperative therapy for resectable and borderline resectable pancreatic adenocarcinoma, 40
PREOPANC study, 40
Southwestern oncology group S1505 study, 41
Jang and colleagues study, 41
Murphy and colleagues total preoperative therapy, 42
Alliance for clinical oncology A021501 study, 42
Summary, 42
Clinics care points, 43
Neoadjuvant Chemotherapy for Nonmetastatic Breast Cancer: How Response Impacts Locoregional and Adjuvant Systemic Therapy Decision Making, 47
Giacomo Montagna, Emanuela Ferraro, and Melissa L. Pilewskie
Neoadjuvant chemotherapy is now considered standard of care for most of the patients with clinically node-positive disease, and for a large proportion of triple-negative breast cancer and HER2-positive tumors. Here we reviewed the benefit of neoadjuvant chemotherapy on surgical de-escalation, the prognostic role of pathologic complete response, new therapeutic strategies across subtypes, and ongoing studies assessing locoregional treatment de-escalation according to treatment response. Thanks to the integration of new biomarkers, new ways to detect minimal residual disease after neoadjuvant chemotherapy, and new targeted therapies, the landscape of neoadjuvant therapy is evolving rapidly, and our ability to personalize breast cancer treatment is improving.
Introduction, 47
Surgical downstaging, 48
Breast surgery, 48
Axillary surgery, 49
Questioning the role of surgery in exceptional responders, 50
Trials to tailor locoregional therapy after neoadjuvant chemotherapy, 50
Assessing in vivo sensitivity: moving toward a refined approach for both escalation and de-escalation of systemic therapy, 53
Subtype specific considerations, 53
Hormone receptor-positive tumors, 55
Summary, 56
Funding source, 56
Clinics care points, 56
Contemporary Multimodal Management of Primary Retroperitoneal Sarcomas, 63
Rachel Hae-Soo Joung and Jeffrey D. Wayne
Retroperitoneal sarcoma is composed of a heterogeneous group of mesenchymal neoplasms that has poor prognosis. Although surgery remains the mainstay of treatment, achieving complete surgical resection with adequate margins is challenging, given anatomic constraints. Evidence on the use of adjunctive treatment modalities for retroperitoneal sarcoma is sparse, with the treatment rationale often based on data extrapolated from other soft tissue sarcomas. Recent studies demonstrate some benefits of neoadjuvant radiotherapy for histologic subtypes with high locoregional recurrence rates. Ongoing studies are evaluating various novel adjunctive treatment modalities.
Introduction, 63
General content, 64
Adjuvant Radiotherapy, 64
Intraoperative Radiotherapy, 64
Neoadjuvant Radiotherapy, 65
Adjuvant Chemotherapy, 65
Neoadjuvant Chemotherapy, 66
Targeted Therapy and Immunotherapy, 66
Ongoing Clinical Trials, 67
Summary, 67
Clinics care points, 67
Disclosure, 68
SECTION III: MEDICAL ONCOLOGY
NTRK Inhibitors in Adult Patients with Solid Tumors, 71
Meghan DioGuardi, Rachel Evans, and Christos Fountzilas
TRK receptors are primarily involved in neuronal growth and survival. NTRK gene fusions involving the receptor and a 5′ partner are oncogenic drivers in multiple cancer types. They are most often found as recurrent low-frequency events, although they can be the primary mutation in select cancer types. Larotrectinib and entrectinib are first-generation NTRK inhibitors and demonstrate potent antitumor efficacy across fusion gene type and cancer type. Development of second-generation inhibitors to assess on-target resistance mechanisms is ongoing. Off-target resistance causing alterations downstream from NTRK receptors will likely require a combinatorial approach.
Introduction, 71
Physiology of TRK receptors, 72
Oncogenic properties of NTRK fusions, downstream pathways, and detection, 73
First-generation NTRK inhibitors, 75
Resistance mechanisms and second-generation inhibitors, 75
Future directions, 77
Clinics care points, 77
Disclosure, 77
Geriatric Assessments: Tools for Every Oncologist to Stage the Aging When Caring for Older Adults with Cancer, 81
Vidit Kapoor and Sukeshi Patel Arora
The incidence of cancer among the elderly is increasing worldwide. Older adults with cancer are at an increased risk of adverse events and disease- or treatment-related complications. Incorporation of geriatric assessments as part of the routine care of such patients can help predict and minimize these adverse events and lead to improved outcomes. A comprehensive geriatric assessment includes an evaluation of a patient's functional status, comorbidities, medications, cognitive and psychological status, nutritional status and social support systems. With consistent implementation of geriatric assessments into practice and incorporation of principles of geriatrics into oncology, every oncologist can optimize the care for older adults with cancer.
Introduction, 81
The Burden, 81
Challenges, 81
Discussion , 82
Comprehensive Geriatric Assessment, 82
Barriers in Implementing Geriatric Assessment Tools in Clinical Practice, 88
Geriatric Screening Tools, 89
Chemotherapy Toxicity Prediction Tools, 91
Case Example of How to Use Chemotherapy Toxicity Tools, 91
Summary, 94
Disclosure, 94
SECTION IV: GYNECOLOGIC ONCOLOGY
The Landscape of Personalized Medicine in Gynecologic Cancer, 99
McKenzie Foxall and Rebecca Arend
Gynecologic malignancies are a heterogenous group of tumors driven by a wide variety of molecular alterations. Molecular profiling has become increasingly useful in the development of novel biomarkers, screening tools, and targeted therapeutic agents. The purpose of this article is to provide an overview of the current usage of personalized medicine in the field of gynecologic oncology.
Introduction, 99
Discussion, 99
Methods of molecular profiling, 99
Targeting homologous recombination deficiency, 100
Targeting the RAS/MAPK pathway, 101
Molecular targets in endometrial cancer, 101
Targeting HER2/neu, 101
Molecular targets in cervical cancer, 102
Developing indications and clinical trials, 102
Antibody drug conjugates, 102
Summary, 103
Clinics care points, 103
Sentinel Lymph Node Sampling in Endometrial Cancers, 107
Emma C. Rossi
The surgical staging of endometrial cancer has changed in recent years to include sentinel lymph node (SLN) biopsy as a tool to replace regional lymphadenectomy. This has afforded surgeons the ability to preserve surgical staging information, valuable for adjuvant therapy prescription, while minimizing associated morbidities, such as lymphedema. Although SLN biopsy has been established as being highly accurate in detecting metastatic disease, including in patients with high-grade cancers, future studies should focus on establishing the value of this technique with respect to patient survival and its role in concert with molecular markers to individualize and optimize treatment outcomes.
Technique development and optimization, 108
Key points:, 108
The accuracy of sentinel lymph node biopsy for endometrial cancer, 110
Key points:, 110
Future challenges and questions, 112
Key points:, 112
Summary, 115
Clinics care points, 115
Disclosure, 116
Health Care Disparities in Gynecologic Oncology, 119
Allison Grubbs, Emma L. Barber, and Dario R. Roque
Disparities in the treatment, incidence and outcomes of women with gynecologic malignancies are multifactorial. A significant amount of the literature on health disparities in gynecologic cancer care has focused on descriptively identifying disparities with a particular focus on the dichotomous care received by black and white patients. Although there are actionable improvements that can be made to improve research within this field as it is currently conceived, it is critical to broaden the academic approach to these difficult issues in order to develop frameworks in which both the medical factors and social and environmental factors are treated as an integrated system.
Introduction, 119
Endometrial cancer, 120
Ovarian cancer, 121
Cervical cancer, 123
Clinical trial participation and enrollment, 124
Addressing health disparities in gynecologic cancer care, 125
SECTION V: NEURO-ONCOLOGY
Circulating Tumor Cells and Cell-free Tumor DNA in Evaluation and Management of Gliomas: Current Evidence and Potential Future Clinical Use, 129
Kathryn Nevel
Liquid biopsy (LB) is the real-time sampling of tumor cells or tumor nucleotides from biofluids such as serum and cerebrospinal fluid (CSF). In systemic malignancies, LB is established as a useful clinical tool, but its role in central nervous system (CNS) tumors is less clear. Gliomas are primary brain tumors that are generally incurable; the most common malignant brain tumor in adults is glioblastoma which carries a dismal prognosis. LB holds promise in the clinical care of gliomas, particularly as it could enable tumor assessment without requiring invasive tissue biopsy or reliance on imaging which is subject to misleading results. Circulating tumor cells (CTCs) are released from the primary tumor site into the circulation and cell-free tumor DNA (ctDNA) are fragments of tumor DNA released from the breakdown of tumor cells into the biofluids. Both have been explored as diagnostic, prognostic, and predictive tools in gliomas. This review explores the potential future clinical applications of LB in glioma and the limitations to the current research.
Introduction, 129
Circulating Tumor Cells, 130
Serum, 131
Cerebrospinal fluid, 133
Cell-free tumor DNA, 133
Serum and plasma, 133
Cerebrospinal fluid, 135
Summary, 136
Clinics care points, 136
Disclosure, 137
Clinical Trials of Oncolytic Viruses in Glioblastoma, 139
Madison L. Shoaf and Katherine B. Peters
Virotherapy has shown promise as a novel therapeutic approach for treating glioblastoma and attempts to circumvent the challenges associated with conventional treatments. Oncolytic viruses create an antitumor effect via 2 mechanisms: direct oncolysis and stimulation of an immune response within the tumor microenvironment. Multiple oncolytic viruses have been investigated in completed and ongoing clinical trials. However, challenges remain, and clinical outcomes have been variable. It is anticipated that combinatory treatment regimens with other modalities, such as chemotherapy, radiation, or immunomodulatory agents, may provide a synergistic therapeutic benefit and warrant further investigation.
Introduction, 139
Background, 139
Mechanism of action of oncolytic viruses, 140
Clinical experience using oncolytic viruses in glioblastoma, 140
Herpes simplex virus-1, 140
Adenovirus, 151
Reovirus, 152
Poliovirus, 153
Retrovirus/murine leukemia virus, 153
Measles, 154
Newcastle disease virus, 154
Parvovirus, 154
Vaccinia, 154
Discussion, 154
Disclosure, 155
SECTION VI: HEMATOLOGICAL-ONCOLOGY
Moving Toward a Cure in Multiple Myeloma: Eradication of Measurable Residual Disease, 159
Benjamin A. Derman and Andrzej J. Jakubowiak
Controversy swirls around the concept of cure in multiple myeloma (MM) – how to define it, how to identify it, and whether it can be achieved at all. Measurable residual disease (MRD) negativity can be used to define the absence of disease, but it is sustained MRD-negativity over time that is key to establishing the definition of a cure in MM. There is a substantial minority of patients who are exceptional responders to contemporary therapies who may have a mortality rate similar to a normal age-matched population. Interventions that drive an increase in MRD-negativity may improve the cure fraction in MM.
Introduction, 159
Defining the absence of disease, 160
Exceptional responders as candidates for functional care, 162
Impact of maintenance on MRD-negativity, 164
MRD adaptive designs to identify functional cures, 165
The myth of the plateau, 166
Future directions to increase the cure fraction in multiple myeloma, 167
Clinics care points, 168
Conflicts of interest, 168
Optimizing Hematopoietic Cellular Transplantation in Older Adults with Hematologic Malignancies, 171
Samuel J. Yates and Mariam T. Nawas
Older adults undergoing hematopoietic cellular transplantation (HCT) with steadily increasing frequency, and carefully selected older patients experience favorable outcomes with this therapy. However, HCT remains heavily underutilized in patients over age 60. The evaluation of older adults for HCT is evolving beyond a simple assessment of chronological age, performance status and comorbidities. The Geriatric Assessment (GA) is a comprehensive battery of health testing that confers prognostic value when applied to older HCT candidates and guides impactful interventions. Work remains to address barriers to widespread adoption of the GA, and to reduce excess transplantation-associated toxicity in older adults.
Introduction, 171
Age and posthematopoietic cellular transplantation outcomes, 171
Optimizing older adults for transplant, 172
Geriatric assessment, 172
Optimizing the transplant for older adults, 174
Future directions and conclusions, 176
Clinics care points, 176
Disclosures, 176
Advances in Janus-Associated Kinase Inhibitor-Based Therapies for Philadelphia Chromosome–Negative Myeloproliferative Neoplasms, 179
Lisa Chu and Kristen Pettit
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by dysregulated myeloid cell production and proliferation, increased proinflammatory cytokine production, and propensity to transform to acute myeloid leukemia. Although the clinical spectrum of disease behavior across MPN subtypes is broad, they share a common pathogenic driver: excess activation of Janus kinase 2 (JAK2) signaling. JAK inhibitors have emerged as the cornerstone of treatment for MPNs given their ability to improve symptoms and splenomegaly in a subset of patients; however, their potential to modify the natural history of the disease is modest.
Introduction, 179
Ruxolitinib, 180
Ruxolitinib for myelofibrosis, 180
Ruxolitinib for essential thrombocytosis and polycythemia vera, 182
Fedratinib, 183
Limitations of current Janus-associated kinase inhibitors, 184
Investigational Janus-associated kinase inhibitors, 184
Pacritinib, 184
Momelotinib, 185
Alternative Janus-associated kinase inhibitors, 185
Janus-associated kinase inhibitor-based combination strategies, 185
Combination with epigenetic agents, 185
Combination with antiapoptotic inhibitors, 188
Combination with parallel signaling pathway inhibitors, 188
Combination with immune modulators, 189
Other combinations, 189
Combinations to improve cytopenias, 189
Discussion, 189
Summary, 190
Clinics care points, 190
SECTION VII: URO-ONCOLOGY
Deoxyribonucleic Acid Damage Response Defects: Clinical Implications and the Role of Poly-ADP Ribose Polymerase Inhibitors in Genitourinary Cancers and Beyond, 195
Ming Yin, Lauren Pomerantz, Ryan Vaca, Petros Grivas, and Monika Joshi
The intact deoxyribonucleic acid (DNA) damage response (DDR) is critical to guard against DNA damage and maintain genomic integrity/stability. DDR defects have been involved in cancer initiation, progression, and have been associated with anticancer treatment response and outcomes. A better understanding of the role of DDR alterations in cancer development has led to the utilization of DDR defects as relevant therapeutic targets and putative biomarkers, which is the focus of our review, focusing on genitourinary (GU) cancers. Poly-ADP ribose polymerase inhibitors (PARPi) have become a crucial tool for targeting this pathway in the treatment of certain cancers, including prostate cancer. Unfortunately, resistance to PARPi is common and this primarily drives the investigation of multiple combination strategies with other agents. Novel agents targeting the DDR pathway, in addition to PARPi constitute a promising therapeutic approach, while translational research aiming to refine patient selection and prove the clinical utility of putative biomarkers across various cancer types remains crucial.
Introduction, 195
The role of deoxyribonucleic acid damage response-directed therapy, 197
Poly-ADP ribose polymerase and poly-ADP ribose polymerase inhibitors, 197
Patient selection is crucial for efficacy, 198
Poly-ADP ribose polymerase inhibitors resistance, 198
Combination therapies using poly-ADP ribose polymerase inhibitors, 202
Poly-ADP ribose polymerase inhibitors and cytotoxic chemotherapy, 202
Poly-ADP ribose polymerase inhibitors and immunotherapy, 202
Poly-ADP ribose polymerase inhibitors and other deoxyribonucleic acid damage response-directed therapies, 203
Poly-ADP ribose polymerase inhibitors and other agents, 203
The role of poly-ADP ribose polymerase inhibitors in the management of genitourinary cancers, 204
Prostate cancer, 204
Urothelial cancer, 205
Other genitourinary cancers, 206
Role of deoxyribonucleic acid damage response defect as a biomarker, 206
Future directions, 207
Summary, 207
Clinics care points, 207
Conflict of interest, 208
Clinical Trial Considerations for Bladder Preservation in Muscle-Invasive Bladder Cancer, 213
Benjamin Miron, Jessica E. Hawley, Daniel M. Geynisman, Kent W. Mouw, John P. Sfakianos, Emily S. Weg, Fady Ghali, Jonathan Wright, Petros Grivas, and Ali Raza Khaki
Although the most common curative-intent approach for muscle-invasive bladder cancer is radical cystectomy, bladder preservation approaches have become desired by many patients, given the morbidity and quality-of-life implications of this procedure. In this review, the authors define the contemporary methods of bladder preservation including trimodality therapy (with or without [neo]adjuvant systemic therapy) and approaches of biomarker-based treatment allocation. They review examples of ongoing clinical trials and discuss relevant trial design considerations, including patient selection/eligibility, stratification, optimal endpoints, use of randomization with appropriate control arms, and relevant putative biomarkers.
Introduction, 213
Defining bladder sparing/preservation, 215
Defining the Population and Patient Selection, 215
Surrogate Endpoints, 219
Randomization and control arms, 220
Biomarkers and Risk Stratification in the Absence of Cystectomy, 220
Discussion, 222
Wish list for best practices, 223
Disclosures, 223
SECTION VIII: GASTROINTESTINAL ONCOLOGY
Total Neoadjuvant Strategies for Locally Advanced Rectal Cancer, 227
Dustin A. Deming
Locally advanced rectal cancer (LARC) is a common clinical problem, which is growing in incidence in younger populations. This disease often requires multi-modality treatment including chemotherapy, radiation, and surgery. The treatment options for patients with LARC are evolving rapidly with multiple studies now indicating significant benefit from a total neoadjuvant approach, instead of the recently more common sequencing whereby only chemoradiation was given neoadjuvantly. Additionally, there are now alternative options that can be used in different sequences as part of a total neoadjuvant approach, including chemotherapy and radiation options. There is also a growing interest in a nonoperative approach for patients who have achieved a clinical complete response to their neoadjuvant therapy. Here we review these differing approaches and outline the evolving treatment options for patients with LARC. Through multidisciplinary management of these patients, we can enhance treatment outcomes, while also aligning patient-care goals and minimizing treatment-related toxicities.
Introduction, 227
General content, 228
FOLFOX versus CAPEOX versus FOLFOXIRI chemotherapy, 228
Clinical care points, 230
Long-course versus short-course radiation, 230
Clinical care points , 231
Operative management versus watch and wait, 231
Clinical care points, 232
Chemotherapy or radiotherapy first, 232
Clinical care points, 232
Future directions, 232
Patient-derived cancer organoids, 234
Summary, 234
Disclosure, 234
The Changing Demographics of Colorectal Cancer: Rising Incidence in Younger Individuals, 237
Justin H. Lo and Kristen K. Ciombor
The incidence of early-onset colorectal cancer (EOCRC) has been rising in the United States in recent decades, with disparities based on race/ethnicity, sex, and geography. Risk factors associated with EOCRC include inflammatory bowel disease, obesity, smoking, heavy alcohol intake, and poor diet. EOCRC cases differ from late-onset cases on a clinical, histologic, and molecular level. They are more likely to present at advanced stages, affect the distal colon or rectum, exhibit adverse histologic features, and arise due to germline mutations. Recent changes to CRC screening guidelines may help address the rising trend in EOCRC, and studies are starting to shed light on the optimal management of EOCRC.
Introduction, 237
Epidemiology of early-onset colorectal cancer, 237
Characteristics of early-onset colorectal cancer, 240
Molecular profiles of early-onset colorectal cancer, 241
Risk factors for early-onset colorectal cancer, 243
Screening, management, and outcomes of early-onset colorectal cancer, 244
Summary, 245
Clinics care points, 246
Disclosures, 246
