Risk management seeks to reduce hazards to patients through a process of identification, evaluation, and analysis of potential or actual adverse events. Hospitalists should strive to comply with applicable laws and regulations, avoid conflicts of interest, and conduct the practice of medicine with integrity and ethics. Hospitalists should also take a collaborative and proactive role in risk management to improve safety and satisfaction in the hospital setting. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to:

• Explain the legal definition of negligence and the concept of standard of care. 

• Describe the components of informed consent.

• Describe Health Insurance Portability and Accountability Act (HIPAA) regulations related to patient confidentiality.

• Explain requirements for billing compliance.  

• Describe laws and regulations relevant to the practice of hospital medicine, including the Emergency Medical Treatment and Active Labor Act (EMTALA), the Patient Safety and Quality Improvement Act, and credentialing and licensing. 

• Explain how ethical principles can be applied to risk management.

Hospitalists should be able to:

• Ensure patient confidentiality and comply with HIPAA regulations in day-to-day practice.

• Conduct medical practice and complete chart documentation to meet patient care needs and billing compliance.

• Reduce risks through effective communication with all involved parties on the healthcare team. 

• Elicit and appropriately document informed consent from patients or surrogates for treatment plans and procedures when indicated.

• Provide adequate supervision of members of the patient care team, which may include physician assistants, fellows, residents, or medical students.

• Apply guidelines of clinical ethics to patient care and risk management.

• Compare and minimize hazards of diagnostic and treatment management strategies for the individual patient.

• Use appropriate systems to identify and report potential areas of risk to patients, families, or healthcare providers. 

Hospitalists should be able to:

• Apply ethical principles, which may include autonomy, beneficence, nonmaleficence, and justice, to promote patient-centered care.   

• Recognize the importance of prompt, honest, and open discussions with patients and families regarding medical errors or harm.

• Respect patient wishes for treatment decisions and plans, including those that may not resonate with personal beliefs.

• Respect patient confidentiality.

• Collaborate with risk management specialists to review and/or address adverse events.

Risk management seeks to reduce hazards to patients through a process of identification, evaluation, and analysis of potential or actual adverse events. Hospitalists should strive to comply with applicable laws and regulations, avoid conflicts of interest, and conduct the practice of medicine with integrity and ethics. Hospitalists should also take a collaborative and proactive role in risk management to improve safety and satisfaction in the hospital setting. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to:

• Explain the legal definition of negligence and the concept of standard of care. 

• Describe the components of informed consent.

• Describe Health Insurance Portability and Accountability Act (HIPAA) regulations related to patient confidentiality.

• Explain requirements for billing compliance.  

• Describe laws and regulations relevant to the practice of hospital medicine, including the Emergency Medical Treatment and Active Labor Act (EMTALA), the Patient Safety and Quality Improvement Act, and credentialing and licensing. 

• Explain how ethical principles can be applied to risk management.

Hospitalists should be able to:

• Ensure patient confidentiality and comply with HIPAA regulations in day-to-day practice.

• Conduct medical practice and complete chart documentation to meet patient care needs and billing compliance.

• Reduce risks through effective communication with all involved parties on the healthcare team. 

• Elicit and appropriately document informed consent from patients or surrogates for treatment plans and procedures when indicated.

• Provide adequate supervision of members of the patient care team, which may include physician assistants, fellows, residents, or medical students.

• Apply guidelines of clinical ethics to patient care and risk management.

• Compare and minimize hazards of diagnostic and treatment management strategies for the individual patient.

• Use appropriate systems to identify and report potential areas of risk to patients, families, or healthcare providers. 

Hospitalists should be able to:

• Apply ethical principles, which may include autonomy, beneficence, nonmaleficence, and justice, to promote patient-centered care.   

• Recognize the importance of prompt, honest, and open discussions with patients and families regarding medical errors or harm.

• Respect patient wishes for treatment decisions and plans, including those that may not resonate with personal beliefs.

• Respect patient confidentiality.

• Collaborate with risk management specialists to review and/or address adverse events.

Risk management seeks to reduce hazards to patients through a process of identification, evaluation, and analysis of potential or actual adverse events. Hospitalists should strive to comply with applicable laws and regulations, avoid conflicts of interest, and conduct the practice of medicine with integrity and ethics. Hospitalists should also take a collaborative and proactive role in risk management to improve safety and satisfaction in the hospital setting. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to:

• Explain the legal definition of negligence and the concept of standard of care. 

• Describe the components of informed consent.

• Describe Health Insurance Portability and Accountability Act (HIPAA) regulations related to patient confidentiality.

• Explain requirements for billing compliance.  

• Describe laws and regulations relevant to the practice of hospital medicine, including the Emergency Medical Treatment and Active Labor Act (EMTALA), the Patient Safety and Quality Improvement Act, and credentialing and licensing. 

• Explain how ethical principles can be applied to risk management.

Hospitalists should be able to:

• Ensure patient confidentiality and comply with HIPAA regulations in day-to-day practice.

• Conduct medical practice and complete chart documentation to meet patient care needs and billing compliance.

• Reduce risks through effective communication with all involved parties on the healthcare team. 

• Elicit and appropriately document informed consent from patients or surrogates for treatment plans and procedures when indicated.

• Provide adequate supervision of members of the patient care team, which may include physician assistants, fellows, residents, or medical students.

• Apply guidelines of clinical ethics to patient care and risk management.

• Compare and minimize hazards of diagnostic and treatment management strategies for the individual patient.

• Use appropriate systems to identify and report potential areas of risk to patients, families, or healthcare providers. 

Hospitalists should be able to:

• Apply ethical principles, which may include autonomy, beneficence, nonmaleficence, and justice, to promote patient-centered care.   

• Recognize the importance of prompt, honest, and open discussions with patients and families regarding medical errors or harm.

• Respect patient wishes for treatment decisions and plans, including those that may not resonate with personal beliefs.

• Respect patient confidentiality.

• Collaborate with risk management specialists to review and/or address adverse events.

Multidisciplinary care refers to active collaboration among various members of the healthcare team to develop and deliver optimal care plans for hospitalized patients. In an era of healthcare delivery reform, team-based care delivery is an integral strategy for enhancing care quality, improving patient safety, decreasing length of stay, lowering costs, and improving health outcomes.^1,2 It is well documented that communication and teamwork failures are the root cause of many preventable adverse events.^3-5 In addition, patients’ rating of nurse-physician coordination correlates with their perception of the quality of care they have received.^6,7 Hospitalists often lead multidisciplinary teams to coordinate complex inpatient medical care to address these and other issues and to improve care processes. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to:

• Describe the important elements of teamwork including mutual respect, effective communication techniques, establishing common goals and plans, and individual and team accountability.
• List behaviors and skills that contribute to effective and ineffective interactions, which may also influence team performance.
• Describe factors within an institution, including its local organizational culture, that may influence the structure and function of multidisciplinary teams.
• Recognize the complexity of healthcare systems and the myriad factors involved in patient care.

Hospitalists should be able to:

• Determine an effective team composition and work collaboratively to designate individual responsibilities within the group. 
• Demonstrate skills necessary to lead a team, including effective communication, negotiation, conflict resolution, delegation, and time management. 
• Assess individual team member abilities to identify areas of strength and improvement such that each member is incorporated effectively and productively into the team. 
• Assess and reassess group dynamics as needed and make necessary changes to optimize team function. 
• Use active listening techniques during interactions with team members and engage team participation. 
• Communicate effectively with all members of the multidisciplinary team. 
• Conduct effective multidisciplinary team rounds, which may include patients and their families. 
• Appropriately integrate and balance the assessments and recommendations from all contributing team members into a cohesive care plan.
• Assess performance of all team members, including self-assessment, and identify opportunities for improvement.
• Provide meaningful, behavior-based feedback to improve individual performance. 

Hospitalists should be able to:

• Emphasize the importance of mutual respect among team members. 
• Role model in professional conflict resolution and discussion of disagreements. 
• Within appropriate scopes of practice, share decision-making responsibilities with care team members. 
• Create an environment of shared responsibility with patients and caregivers and provide opportunities for patients and/or caregivers to participate in medical decision-making. 
• Encourage interactive education among team members. 
• Encourage team members to educate patients and families using effective techniques. 

Multidisciplinary care refers to active collaboration among various members of the healthcare team to develop and deliver optimal care plans for hospitalized patients. In an era of healthcare delivery reform, team-based care delivery is an integral strategy for enhancing care quality, improving patient safety, decreasing length of stay, lowering costs, and improving health outcomes.^1,2 It is well documented that communication and teamwork failures are the root cause of many preventable adverse events.^3-5 In addition, patients’ rating of nurse-physician coordination correlates with their perception of the quality of care they have received.^6,7 Hospitalists often lead multidisciplinary teams to coordinate complex inpatient medical care to address these and other issues and to improve care processes. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to:

• Describe the important elements of teamwork including mutual respect, effective communication techniques, establishing common goals and plans, and individual and team accountability.
• List behaviors and skills that contribute to effective and ineffective interactions, which may also influence team performance.
• Describe factors within an institution, including its local organizational culture, that may influence the structure and function of multidisciplinary teams.
• Recognize the complexity of healthcare systems and the myriad factors involved in patient care.

Hospitalists should be able to:

• Determine an effective team composition and work collaboratively to designate individual responsibilities within the group. 
• Demonstrate skills necessary to lead a team, including effective communication, negotiation, conflict resolution, delegation, and time management. 
• Assess individual team member abilities to identify areas of strength and improvement such that each member is incorporated effectively and productively into the team. 
• Assess and reassess group dynamics as needed and make necessary changes to optimize team function. 
• Use active listening techniques during interactions with team members and engage team participation. 
• Communicate effectively with all members of the multidisciplinary team. 
• Conduct effective multidisciplinary team rounds, which may include patients and their families. 
• Appropriately integrate and balance the assessments and recommendations from all contributing team members into a cohesive care plan.
• Assess performance of all team members, including self-assessment, and identify opportunities for improvement.
• Provide meaningful, behavior-based feedback to improve individual performance. 

Hospitalists should be able to:

• Emphasize the importance of mutual respect among team members. 
• Role model in professional conflict resolution and discussion of disagreements. 
• Within appropriate scopes of practice, share decision-making responsibilities with care team members. 
• Create an environment of shared responsibility with patients and caregivers and provide opportunities for patients and/or caregivers to participate in medical decision-making. 
• Encourage interactive education among team members. 
• Encourage team members to educate patients and families using effective techniques. 

Multidisciplinary care refers to active collaboration among various members of the healthcare team to develop and deliver optimal care plans for hospitalized patients. In an era of healthcare delivery reform, team-based care delivery is an integral strategy for enhancing care quality, improving patient safety, decreasing length of stay, lowering costs, and improving health outcomes.^1,2 It is well documented that communication and teamwork failures are the root cause of many preventable adverse events.^3-5 In addition, patients’ rating of nurse-physician coordination correlates with their perception of the quality of care they have received.^6,7 Hospitalists often lead multidisciplinary teams to coordinate complex inpatient medical care to address these and other issues and to improve care processes. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to:

• Describe the important elements of teamwork including mutual respect, effective communication techniques, establishing common goals and plans, and individual and team accountability.
• List behaviors and skills that contribute to effective and ineffective interactions, which may also influence team performance.
• Describe factors within an institution, including its local organizational culture, that may influence the structure and function of multidisciplinary teams.
• Recognize the complexity of healthcare systems and the myriad factors involved in patient care.

Hospitalists should be able to:

• Determine an effective team composition and work collaboratively to designate individual responsibilities within the group. 
• Demonstrate skills necessary to lead a team, including effective communication, negotiation, conflict resolution, delegation, and time management. 
• Assess individual team member abilities to identify areas of strength and improvement such that each member is incorporated effectively and productively into the team. 
• Assess and reassess group dynamics as needed and make necessary changes to optimize team function. 
• Use active listening techniques during interactions with team members and engage team participation. 
• Communicate effectively with all members of the multidisciplinary team. 
• Conduct effective multidisciplinary team rounds, which may include patients and their families. 
• Appropriately integrate and balance the assessments and recommendations from all contributing team members into a cohesive care plan.
• Assess performance of all team members, including self-assessment, and identify opportunities for improvement.
• Provide meaningful, behavior-based feedback to improve individual performance. 

Hospitalists should be able to:

• Emphasize the importance of mutual respect among team members. 
• Role model in professional conflict resolution and discussion of disagreements. 
• Within appropriate scopes of practice, share decision-making responsibilities with care team members. 
• Create an environment of shared responsibility with patients and caregivers and provide opportunities for patients and/or caregivers to participate in medical decision-making. 
• Encourage interactive education among team members. 
• Encourage team members to educate patients and families using effective techniques. 

The term “transitions of care” refers to specific interactions, communication, and planning required for patients to safely move from one care setting to another. These transitions apply not only to transfers of care between the inpatient and outpatient settings but also to handoffs that occur within facilities (eg, service to service) and communities (eg, inpatient to subacute rehabilitation). Ineffective transitions of care are associated with adverse events, and nearly 20% of patients experience adverse events (many of which are preventable) within 3 weeks of hospital discharge.^1,2 Hospitalists should promote efficient, safe transitions of care to ensure patient safety, reduce loss of information, and maintain the continuum of high-quality care. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to: 

• Describe the relevant parts of the medical record that should be retrieved and communicated during each care transition to ensure patient safety and maintain the continuum of care.  
• Describe the importance and limitations of patient transition processes. 
• Describe ancillary services that are available to facilitate patient transitions.
• Compare postacute care options for patients.
• Explain the strengths and limitations of different communication modalities and their role in patient transitions. 
• Explain elements of a high-quality patient handoff. 
• Recognize the value of real-time interactive dialogue among clinicians during care transitions. 
• Describe the characteristics of a high-quality discharge summary document.
• Recognize the impact of care transitions on patient outcomes and satisfaction.

Hospitalists should be able to:

• Use the most efficient, effective, reliable, and expeditious communication modalities appropriate for a patient’s care transition.
• Communicate and synthesize relevant medical information to and from referring healthcare providers into a cohesive care plan.
• Develop a care plan early during hospitalization that anticipates care needs beyond the inpatient care setting.  
• Prepare patients and families early in the hospitalization for anticipated care transitions. 
• Access available ancillary services that can facilitate patient transitions. 
• Expeditiously inform the primary care provider about significant changes in patient clinical status. 
• Inform receiving healthcare providers of pending tests and determine responsibility for the follow-up of pending results.
• Select an appropriate level of postacute care that is best suited to the patient’s needs.
• Incorporate patient preferences and use shared decision-making in the selection of postacute care. 
• Anticipate and address language and/or literacy barriers to patient education. 
• Communicate with patients and families to explain the patient’s condition, ongoing medical regimens and therapies, follow-up care, and available support services.
• Communicate with patients and families to explain clinical symptomatology that may require medical attention before scheduled follow-up.  
• Coordinate multidisciplinary teams early during hospitalization to facilitate patient education, optimize patient function, and improve discharge planning.
• Lead, coordinate, and/or participate in initiatives to develop and implement new protocols to improve or optimize transitions of care. 
• Lead, coordinate, and/or participate in the evaluation of new strategies or information systems designed to improve care transitions. 

Hospitalists should be able to:

• Engage in a multidisciplinary approach to care transitions, including nursing, rehabilitation, nutrition, pharmaceutical, and social services. 
• Engage stakeholders in hospital initiatives to continuously assess the quality of care transitions. 
• Maintain availability to discharged patients for questions during discharge and between discharge and the follow-up visit with the receiving physician. 

The term “transitions of care” refers to specific interactions, communication, and planning required for patients to safely move from one care setting to another. These transitions apply not only to transfers of care between the inpatient and outpatient settings but also to handoffs that occur within facilities (eg, service to service) and communities (eg, inpatient to subacute rehabilitation). Ineffective transitions of care are associated with adverse events, and nearly 20% of patients experience adverse events (many of which are preventable) within 3 weeks of hospital discharge.^1,2 Hospitalists should promote efficient, safe transitions of care to ensure patient safety, reduce loss of information, and maintain the continuum of high-quality care. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to: 

• Describe the relevant parts of the medical record that should be retrieved and communicated during each care transition to ensure patient safety and maintain the continuum of care.  
• Describe the importance and limitations of patient transition processes. 
• Describe ancillary services that are available to facilitate patient transitions.
• Compare postacute care options for patients.
• Explain the strengths and limitations of different communication modalities and their role in patient transitions. 
• Explain elements of a high-quality patient handoff. 
• Recognize the value of real-time interactive dialogue among clinicians during care transitions. 
• Describe the characteristics of a high-quality discharge summary document.
• Recognize the impact of care transitions on patient outcomes and satisfaction.

Hospitalists should be able to:

• Use the most efficient, effective, reliable, and expeditious communication modalities appropriate for a patient’s care transition.
• Communicate and synthesize relevant medical information to and from referring healthcare providers into a cohesive care plan.
• Develop a care plan early during hospitalization that anticipates care needs beyond the inpatient care setting.  
• Prepare patients and families early in the hospitalization for anticipated care transitions. 
• Access available ancillary services that can facilitate patient transitions. 
• Expeditiously inform the primary care provider about significant changes in patient clinical status. 
• Inform receiving healthcare providers of pending tests and determine responsibility for the follow-up of pending results.
• Select an appropriate level of postacute care that is best suited to the patient’s needs.
• Incorporate patient preferences and use shared decision-making in the selection of postacute care. 
• Anticipate and address language and/or literacy barriers to patient education. 
• Communicate with patients and families to explain the patient’s condition, ongoing medical regimens and therapies, follow-up care, and available support services.
• Communicate with patients and families to explain clinical symptomatology that may require medical attention before scheduled follow-up.  
• Coordinate multidisciplinary teams early during hospitalization to facilitate patient education, optimize patient function, and improve discharge planning.
• Lead, coordinate, and/or participate in initiatives to develop and implement new protocols to improve or optimize transitions of care. 
• Lead, coordinate, and/or participate in the evaluation of new strategies or information systems designed to improve care transitions. 

Hospitalists should be able to:

• Engage in a multidisciplinary approach to care transitions, including nursing, rehabilitation, nutrition, pharmaceutical, and social services. 
• Engage stakeholders in hospital initiatives to continuously assess the quality of care transitions. 
• Maintain availability to discharged patients for questions during discharge and between discharge and the follow-up visit with the receiving physician. 

The term “transitions of care” refers to specific interactions, communication, and planning required for patients to safely move from one care setting to another. These transitions apply not only to transfers of care between the inpatient and outpatient settings but also to handoffs that occur within facilities (eg, service to service) and communities (eg, inpatient to subacute rehabilitation). Ineffective transitions of care are associated with adverse events, and nearly 20% of patients experience adverse events (many of which are preventable) within 3 weeks of hospital discharge.^1,2 Hospitalists should promote efficient, safe transitions of care to ensure patient safety, reduce loss of information, and maintain the continuum of high-quality care. 

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to: 

• Describe the relevant parts of the medical record that should be retrieved and communicated during each care transition to ensure patient safety and maintain the continuum of care.  
• Describe the importance and limitations of patient transition processes. 
• Describe ancillary services that are available to facilitate patient transitions.
• Compare postacute care options for patients.
• Explain the strengths and limitations of different communication modalities and their role in patient transitions. 
• Explain elements of a high-quality patient handoff. 
• Recognize the value of real-time interactive dialogue among clinicians during care transitions. 
• Describe the characteristics of a high-quality discharge summary document.
• Recognize the impact of care transitions on patient outcomes and satisfaction.

Hospitalists should be able to:

• Use the most efficient, effective, reliable, and expeditious communication modalities appropriate for a patient’s care transition.
• Communicate and synthesize relevant medical information to and from referring healthcare providers into a cohesive care plan.
• Develop a care plan early during hospitalization that anticipates care needs beyond the inpatient care setting.  
• Prepare patients and families early in the hospitalization for anticipated care transitions. 
• Access available ancillary services that can facilitate patient transitions. 
• Expeditiously inform the primary care provider about significant changes in patient clinical status. 
• Inform receiving healthcare providers of pending tests and determine responsibility for the follow-up of pending results.
• Select an appropriate level of postacute care that is best suited to the patient’s needs.
• Incorporate patient preferences and use shared decision-making in the selection of postacute care. 
• Anticipate and address language and/or literacy barriers to patient education. 
• Communicate with patients and families to explain the patient’s condition, ongoing medical regimens and therapies, follow-up care, and available support services.
• Communicate with patients and families to explain clinical symptomatology that may require medical attention before scheduled follow-up.  
• Coordinate multidisciplinary teams early during hospitalization to facilitate patient education, optimize patient function, and improve discharge planning.
• Lead, coordinate, and/or participate in initiatives to develop and implement new protocols to improve or optimize transitions of care. 
• Lead, coordinate, and/or participate in the evaluation of new strategies or information systems designed to improve care transitions. 

Hospitalists should be able to:

• Engage in a multidisciplinary approach to care transitions, including nursing, rehabilitation, nutrition, pharmaceutical, and social services. 
• Engage stakeholders in hospital initiatives to continuously assess the quality of care transitions. 
• Maintain availability to discharged patients for questions during discharge and between discharge and the follow-up visit with the receiving physician. 

Acute coronary syndrome (ACS) encompasses a spectrum of ischemic heart disease that may include unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). Coronary artery disease (CAD) is the leading cause of mortality in the United States and accounts for 1 in 6 deaths annually. Each year, approximately 635,000 Americans have ACS and 300,000 have a recurrent event.¹ Of persons who experience a coronary event or myocardial infarction, approximately 34% and 15%, respectively, will die.¹ More than 45% of patients with symptoms of acute myocardial infarction arrive at the hospital 4 or more hours after symptom onset, and the mortality rate increases for every 30 minutes that elapse before a patient with ACS is diagnosed and treated.^2,3 A shorter time to intervention leads to improved outcomes.^4,5 If the acute stage of a myocardial infarction is survived, patients have a risk of illness and mortality that is 1.5 to 15 times higher than that of the general population.^1,6 Annually in the United States, the number of hospital discharges with a primary or secondary diagnosis of ACS approaches 1.2 million.¹ Hospitalists diagnose, risk stratify, and initiate early management of patients with ACS. Hospitalists provide leadership for multidisciplinary teams that optimize the quality of inpatient care, maximize opportunities for patient education, and efficiently use resources. In addition, hospitalists initiate secondary preventive measures and facilitate adherence to outpatient medical regimens.  

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to: 

• Define and differentiate UA, NSTEMI, and STEMI.
• Describe the pathophysiologic processes and variable clinical presentations of patients with ACS.  
• Distinguish ACS from other cardiac and noncardiac conditions that may mimic this disease process.
• Describe the use of cardiac biomarkers in the diagnosis of ACS, including timing of testing and the effects of renal disease and other conditions (such as pulmonary embolism or sepsis) on cardiac biomarker levels.  
• Describe the role of noninvasive cardiac tests in the diagnosis and management of ACS.
• Explain indications for and risks associated with cardiac catheterization. 
• Recognize indications for early specialty consultation, which may include cardiology and cardiothoracic surgery. 
• List the major and minor risk factors predisposing patients to CAD.
• Explain the value and use of validated risk stratification tools.  
• Explain indications for hospitalization of patients with chest pain.
• Explain indications and contraindications for fibrinolytic therapy. 
• Explain indications, contraindications, and mechanisms of action of pharmacologic agents that are used both upstream and downstream to treat ACS.   
• Describe factors that indicate the need for early invasive interventions, including angiography, percutaneous coronary intervention, and/or coronary artery bypass grafting. 
• Describe the optimal timeframe for coronary reperfusion when indicated.
• Identify clinical, laboratory, and imaging studies that indicate severity of disease.
• Recognize appropriate timing and thresholds for hospital discharge, including specific measures of clinical stability for safe transition of care.

Hospitalists should be able to: 

• Elicit a thorough and relevant medical history with emphasis on presenting symptoms and patient risk factors for CAD.  
• Perform a physical examination with emphasis on the cardiovascular and pulmonary systems and recognize clinical signs of ACS and disease severity.   
• Diagnose ACS through interpretation of expedited testing, including history, physical examination, electrocardiogram, chest radiograph, and biomarkers.
• Perform early risk stratification using validated risk stratification tools. 
• Synthesize results of history, physical examination, electrocardiography, laboratory and imaging studies, and risk stratification tools to determine therapeutic options, formulate an evidence-based treatment plan, and determine level of care required.
• Identify patients who may benefit from fibrinolytic therapy and/or early revascularization in a timely manner, and activate appropriate teams accordingly.
• Treat patients’ symptoms of chest pain, anxiety, and other discomfort associated with ACS.
• Initiate immediate indicated therapies when patients display symptoms and signs of decompensation.
• Anticipate and address factors that may complicate ACS or its management, which may include inadequate response to therapies, hemodynamic and cardiopulmonary compromise, life-threatening cardiac arrhythmias, or bleeding.
• Assess patients with suspected ACS in a timely manner, identify the level of care required, and manage or comanage the patient with the primary requesting service.
• Communicate with patients and families to explain the history and prognosis of their cardiac disease. 
• Communicate with patients and families to explain tests and procedures and their indications and to obtain informed consent. 
• Communicate with patients and families to explain the use and potential adverse effects of pharmacologic agents. 
• Facilitate discharge planning early during hospitalization. 
• Communicate with patients and families to explain the goals of care, discharge instructions, and management after hospital discharge to ensure safe follow-up and transition of care. 
• Initiate secondary preventive measures before discharge, which may include smoking cessation, dietary modification, and evidence-based medical therapies. 
• Communicate to outpatient providers the notable events of the hospitalization and postdischarge needs including outpatient cardiac rehabilitation. 
• Provide and coordinate resources to ensure safe transition from the hospital to arranged follow-up care. 

Hospitalists should be able to: 

• Employ a multidisciplinary approach, which may include nursing, nutrition, rehabilitation, and social services, in the care of patients with ACS that begins at admission and continues through all care transitions. 
• Follow evidence-based recommendations, protocols, and risk-stratification tools for the treatment of ACS. 

To improve efficiency and quality within their organizations, hospitalists should:

• Lead, coordinate, and/or participate in efforts to develop protocols to rapidly identify patients with ACS and minimize time to intervention.
• Lead, coordinate, and/or participate in efforts among institutions to develop protocols for the rapid identification and transfer of patients with ACS to appropriate facilities.
• Implement systems to ensure hospital-wide adherence to national standards and document those measures as specified by recognized organizations (eg, The Joint Commission, American Heart Association, American College of Cardiology, Agency for Healthcare Research and Quality).  
• Lead, coordinate, and/or participate in multidisciplinary initiatives to promote patient safety and optimize resource use, which may include order sets for ACS and chest pain.
• Lead, coordinate, and/or participate in efforts to educate staff on the importance of smoking cessation counseling and other preventive measures.
• Integrate outcomes research, institution-specific laboratory policies, and hospital formulary to create indicated and cost-effective diagnostic and management strategies for patients with ACS.  

Acute coronary syndrome (ACS) encompasses a spectrum of ischemic heart disease that may include unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). Coronary artery disease (CAD) is the leading cause of mortality in the United States and accounts for 1 in 6 deaths annually. Each year, approximately 635,000 Americans have ACS and 300,000 have a recurrent event.¹ Of persons who experience a coronary event or myocardial infarction, approximately 34% and 15%, respectively, will die.¹ More than 45% of patients with symptoms of acute myocardial infarction arrive at the hospital 4 or more hours after symptom onset, and the mortality rate increases for every 30 minutes that elapse before a patient with ACS is diagnosed and treated.^2,3 A shorter time to intervention leads to improved outcomes.^4,5 If the acute stage of a myocardial infarction is survived, patients have a risk of illness and mortality that is 1.5 to 15 times higher than that of the general population.^1,6 Annually in the United States, the number of hospital discharges with a primary or secondary diagnosis of ACS approaches 1.2 million.¹ Hospitalists diagnose, risk stratify, and initiate early management of patients with ACS. Hospitalists provide leadership for multidisciplinary teams that optimize the quality of inpatient care, maximize opportunities for patient education, and efficiently use resources. In addition, hospitalists initiate secondary preventive measures and facilitate adherence to outpatient medical regimens.  

Want all 52 JHM Core Competency articles in an easy-to-read compendium? Order your copy now from Amazon.com.

Hospitalists should be able to: 

• Define and differentiate UA, NSTEMI, and STEMI.
• Describe the pathophysiologic processes and variable clinical presentations of patients with ACS.  
• Distinguish ACS from other cardiac and noncardiac conditions that may mimic this disease process.
• Describe the use of cardiac biomarkers in the diagnosis of ACS, including timing of testing and the effects of renal disease and other conditions (such as pulmonary embolism or sepsis) on cardiac biomarker levels.  
• Describe the role of noninvasive cardiac tests in the diagnosis and management of ACS.
• Explain indications for and risks associated with cardiac catheterization. 
• Recognize indications for early specialty consultation, which may include cardiology and cardiothoracic surgery. 
• List the major and minor risk factors predisposing patients to CAD.
• Explain the value and use of validated risk stratification tools.  
• Explain indications for hospitalization of patients with chest pain.
• Explain indications and contraindications for fibrinolytic therapy. 
• Explain indications, contraindications, and mechanisms of action of pharmacologic agents that are used both upstream and downstream to treat ACS.   
• Describe factors that indicate the need for early invasive interventions, including angiography, percutaneous coronary intervention, and/or coronary artery bypass grafting. 
• Describe the optimal timeframe for coronary reperfusion when indicated.
• Identify clinical, laboratory, and imaging studies that indicate severity of disease.
• Recognize appropriate timing and thresholds for hospital discharge, including specific measures of clinical stability for safe transition of care.

Hospitalists should be able to: 

• Elicit a thorough and relevant medical history with emphasis on presenting symptoms and patient risk factors for CAD.  
• Perform a physical examination with emphasis on the cardiovascular and pulmonary systems and recognize clinical signs of ACS and disease severity.   
• Diagnose ACS through interpretation of expedited testing, including history, physical examination, electrocardiogram, chest radiograph, and biomarkers.
• Perform early risk stratification using validated risk stratification tools. 
• Synthesize results of history, physical examination, electrocardiography, laboratory and imaging studies, and risk stratification tools to determine therapeutic options, formulate an evidence-based treatment plan, and determine level of care required.
• Identify patients who may benefit from fibrinolytic therapy and/or early revascularization in a timely manner, and activate appropriate teams accordingly.
• Treat patients’ symptoms of chest pain, anxiety, and other discomfort associated with ACS.
• Initiate immediate indicated therapies when patients display symptoms and signs of decompensation.
• Anticipate and address factors that may complicate ACS or its management, which may include inadequate response to therapies, hemodynamic and cardiopulmonary compromise, life-threatening cardiac arrhythmias, or bleeding.
• Assess patients with suspected ACS in a timely manner, identify the level of care required, and manage or comanage the patient with the primary requesting service.
• Communicate with patients and families to explain the history and prognosis of their cardiac disease. 
• Communicate with patients and families to explain tests and procedures and their indications and to obtain informed consent. 
• Communicate with patients and families to explain the use and potential adverse effects of pharmacologic agents. 
• Facilitate discharge planning early during hospitalization. 
• Communicate with patients and families to explain the goals of care, discharge instructions, and management after hospital discharge to ensure safe follow-up and transition of care. 
• Initiate secondary preventive measures before discharge, which may include smoking cessation, dietary modification, and evidence-based medical therapies. 
• Communicate to outpatient providers the notable events of the hospitalization and postdischarge needs including outpatient cardiac rehabilitation. 
• Provide and coordinate resources to ensure safe transition from the hospital to arranged follow-up care. 

Hospitalists should be able to: 

• Employ a multidisciplinary approach, which may include nursing, nutrition, rehabilitation, and social services, in the care of patients with ACS that begins at admission and continues through all care transitions. 
• Follow evidence-based recommendations, protocols, and risk-stratification tools for the treatment of ACS. 

To improve efficiency and quality within their organizations, hospitalists should:

• Lead, coordinate, and/or participate in efforts to develop protocols to rapidly identify patients with ACS and minimize time to intervention.
• Lead, coordinate, and/or participate in efforts among institutions to develop protocols for the rapid identification and transfer of patients with ACS to appropriate facilities.
• Implement systems to ensure hospital-wide adherence to national standards and document those measures as specified by recognized organizations (eg, The Joint Commission, American Heart Association, American College of Cardiology, Agency for Healthcare Research and Quality).  
• Lead, coordinate, and/or participate in multidisciplinary initiatives to promote patient safety and optimize resource use, which may include order sets for ACS and chest pain.
• Lead, coordinate, and/or participate in efforts to educate staff on the importance of smoking cessation counseling and other preventive measures.
• Integrate outcomes research, institution-specific laboratory policies, and hospital formulary to create indicated and cost-effective diagnostic and management strategies for patients with ACS.  

Acute coronary syndrome (ACS) encompasses a spectrum of ischemic heart disease that may include unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). Coronary artery disease (CAD) is the leading cause of mortality in the United States and accounts for 1 in 6 deaths annually. Each year, approximately 635,000 Americans have ACS and 300,000 have a recurrent event.¹ Of persons who experience a coronary event or myocardial infarction, approximately 34% and 15%, respectively, will die.¹ More than 45% of patients with symptoms of acute myocardial infarction arrive at the hospital 4 or more hours after symptom onset, and the mortality rate increases for every 30 minutes that elapse before a patient with ACS is diagnosed and treated.^2,3 A shorter time to intervention leads to improved outcomes.^4,5 If the acute stage of a myocardial infarction is survived, patients have a risk of illness and mortality that is 1.5 to 15 times higher than that of the general population.^1,6 Annually in the United States, the number of hospital discharges with a primary or secondary diagnosis of ACS approaches 1.2 million.¹ Hospitalists diagnose, risk stratify, and initiate early management of patients with ACS. Hospitalists provide leadership for multidisciplinary teams that optimize the quality of inpatient care, maximize opportunities for patient education, and efficiently use resources. In addition, hospitalists initiate secondary preventive measures and facilitate adherence to outpatient medical regimens.  

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Hospitalists should be able to: 

• Define and differentiate UA, NSTEMI, and STEMI.
• Describe the pathophysiologic processes and variable clinical presentations of patients with ACS.  
• Distinguish ACS from other cardiac and noncardiac conditions that may mimic this disease process.
• Describe the use of cardiac biomarkers in the diagnosis of ACS, including timing of testing and the effects of renal disease and other conditions (such as pulmonary embolism or sepsis) on cardiac biomarker levels.  
• Describe the role of noninvasive cardiac tests in the diagnosis and management of ACS.
• Explain indications for and risks associated with cardiac catheterization. 
• Recognize indications for early specialty consultation, which may include cardiology and cardiothoracic surgery. 
• List the major and minor risk factors predisposing patients to CAD.
• Explain the value and use of validated risk stratification tools.  
• Explain indications for hospitalization of patients with chest pain.
• Explain indications and contraindications for fibrinolytic therapy. 
• Explain indications, contraindications, and mechanisms of action of pharmacologic agents that are used both upstream and downstream to treat ACS.   
• Describe factors that indicate the need for early invasive interventions, including angiography, percutaneous coronary intervention, and/or coronary artery bypass grafting. 
• Describe the optimal timeframe for coronary reperfusion when indicated.
• Identify clinical, laboratory, and imaging studies that indicate severity of disease.
• Recognize appropriate timing and thresholds for hospital discharge, including specific measures of clinical stability for safe transition of care.

Hospitalists should be able to: 

• Elicit a thorough and relevant medical history with emphasis on presenting symptoms and patient risk factors for CAD.  
• Perform a physical examination with emphasis on the cardiovascular and pulmonary systems and recognize clinical signs of ACS and disease severity.   
• Diagnose ACS through interpretation of expedited testing, including history, physical examination, electrocardiogram, chest radiograph, and biomarkers.
• Perform early risk stratification using validated risk stratification tools. 
• Synthesize results of history, physical examination, electrocardiography, laboratory and imaging studies, and risk stratification tools to determine therapeutic options, formulate an evidence-based treatment plan, and determine level of care required.
• Identify patients who may benefit from fibrinolytic therapy and/or early revascularization in a timely manner, and activate appropriate teams accordingly.
• Treat patients’ symptoms of chest pain, anxiety, and other discomfort associated with ACS.
• Initiate immediate indicated therapies when patients display symptoms and signs of decompensation.
• Anticipate and address factors that may complicate ACS or its management, which may include inadequate response to therapies, hemodynamic and cardiopulmonary compromise, life-threatening cardiac arrhythmias, or bleeding.
• Assess patients with suspected ACS in a timely manner, identify the level of care required, and manage or comanage the patient with the primary requesting service.
• Communicate with patients and families to explain the history and prognosis of their cardiac disease. 
• Communicate with patients and families to explain tests and procedures and their indications and to obtain informed consent. 
• Communicate with patients and families to explain the use and potential adverse effects of pharmacologic agents. 
• Facilitate discharge planning early during hospitalization. 
• Communicate with patients and families to explain the goals of care, discharge instructions, and management after hospital discharge to ensure safe follow-up and transition of care. 
• Initiate secondary preventive measures before discharge, which may include smoking cessation, dietary modification, and evidence-based medical therapies. 
• Communicate to outpatient providers the notable events of the hospitalization and postdischarge needs including outpatient cardiac rehabilitation. 
• Provide and coordinate resources to ensure safe transition from the hospital to arranged follow-up care. 

Hospitalists should be able to: 

• Employ a multidisciplinary approach, which may include nursing, nutrition, rehabilitation, and social services, in the care of patients with ACS that begins at admission and continues through all care transitions. 
• Follow evidence-based recommendations, protocols, and risk-stratification tools for the treatment of ACS. 

To improve efficiency and quality within their organizations, hospitalists should:

• Lead, coordinate, and/or participate in efforts to develop protocols to rapidly identify patients with ACS and minimize time to intervention.
• Lead, coordinate, and/or participate in efforts among institutions to develop protocols for the rapid identification and transfer of patients with ACS to appropriate facilities.
• Implement systems to ensure hospital-wide adherence to national standards and document those measures as specified by recognized organizations (eg, The Joint Commission, American Heart Association, American College of Cardiology, Agency for Healthcare Research and Quality).  
• Lead, coordinate, and/or participate in multidisciplinary initiatives to promote patient safety and optimize resource use, which may include order sets for ACS and chest pain.
• Lead, coordinate, and/or participate in efforts to educate staff on the importance of smoking cessation counseling and other preventive measures.
• Integrate outcomes research, institution-specific laboratory policies, and hospital formulary to create indicated and cost-effective diagnostic and management strategies for patients with ACS.  

Nearly half (46%) of children in the US report having experienced at > 1 traumatic event, according to a SAMHSA report, Helping Children and Youth Who Have Traumatic Experiences. The cited traumas include abuse, neglect, incarceration of a parent or caregiver, being a victim or witness of violence, being subjected to racial/ethnic prejudice, living with family members who have mental or substance use disorders, or the death of a parent or caregiver.

The numbers support data from SAMHSA’s Children’s Mental Health Initiative (CMHI), which found 82% of children, youth, and young adults in systems of care have experienced at > 1 traumatic event before entering services.

The effects of the trauma can be catastrophic: 41% of children and young adults with a history of trauma have had suicidal thoughts, and 23% have attempted suicide, compared with 24% and 13%, restpectively, of those without trauma history.

However, treatment through systems of care, such as CMHI, leads to significant improvement in behavioral and emotional health. Evaluation data after 1 year of treatment show that treatment reduces suicidal thoughts by 68% and suicide attempts by 78%. CMHI data also show that 1 year after intake in a system of care, 48% of children and youth had fewer school absences, 41% had improved school performance, and 15% improved competence in school and classroom tasks.

The full report is available at https://www.samhsa.gov/children/awareness-day/2018.

Nearly half (46%) of children in the US report having experienced at > 1 traumatic event, according to a SAMHSA report, Helping Children and Youth Who Have Traumatic Experiences. The cited traumas include abuse, neglect, incarceration of a parent or caregiver, being a victim or witness of violence, being subjected to racial/ethnic prejudice, living with family members who have mental or substance use disorders, or the death of a parent or caregiver.

The numbers support data from SAMHSA’s Children’s Mental Health Initiative (CMHI), which found 82% of children, youth, and young adults in systems of care have experienced at > 1 traumatic event before entering services.

The effects of the trauma can be catastrophic: 41% of children and young adults with a history of trauma have had suicidal thoughts, and 23% have attempted suicide, compared with 24% and 13%, restpectively, of those without trauma history.

However, treatment through systems of care, such as CMHI, leads to significant improvement in behavioral and emotional health. Evaluation data after 1 year of treatment show that treatment reduces suicidal thoughts by 68% and suicide attempts by 78%. CMHI data also show that 1 year after intake in a system of care, 48% of children and youth had fewer school absences, 41% had improved school performance, and 15% improved competence in school and classroom tasks.

The full report is available at https://www.samhsa.gov/children/awareness-day/2018.

Nearly half (46%) of children in the US report having experienced at > 1 traumatic event, according to a SAMHSA report, Helping Children and Youth Who Have Traumatic Experiences. The cited traumas include abuse, neglect, incarceration of a parent or caregiver, being a victim or witness of violence, being subjected to racial/ethnic prejudice, living with family members who have mental or substance use disorders, or the death of a parent or caregiver.

The numbers support data from SAMHSA’s Children’s Mental Health Initiative (CMHI), which found 82% of children, youth, and young adults in systems of care have experienced at > 1 traumatic event before entering services.

The effects of the trauma can be catastrophic: 41% of children and young adults with a history of trauma have had suicidal thoughts, and 23% have attempted suicide, compared with 24% and 13%, restpectively, of those without trauma history.

However, treatment through systems of care, such as CMHI, leads to significant improvement in behavioral and emotional health. Evaluation data after 1 year of treatment show that treatment reduces suicidal thoughts by 68% and suicide attempts by 78%. CMHI data also show that 1 year after intake in a system of care, 48% of children and youth had fewer school absences, 41% had improved school performance, and 15% improved competence in school and classroom tasks.

The full report is available at https://www.samhsa.gov/children/awareness-day/2018.

Introduction

Pancreatic ductal adenocarcinoma is a challenging disease with a poor prognosis, with 5-year survival rates in the single digits (~8%).¹ Survival rates in pancreatic cancer are low in part because most patients have advanced disease at the time of diagnosis and early development of systemic metastatic disease is common, with approximately 52% of patients with newly diagnosed pancreatic cancer having metastatic disease at diagnosis.¹ Surgical resection with negative margins is the cornerstone of potentially curative therapy for localized disease, but only 15% to 20% of patients are eligible for resection at the time of initial diagnosis. Patients with unresectable and metastatic disease are offered palliative chemotherapy. Unfortunately, early recurrence is common in patients with resectable tumors who achieve a complete resection and are treated with adjuvant therapy (5-year recurrence rate ~80%).^2,3 This article reviews the management of patients with unresectable and/or metastatic pancreatic cancer. A previous article reviewed the diagnosis and staging of pancreatic cancer and the approach to neoadjuvant and adjuvant therapy in patients with resectable and borderline-resectable disease.⁴

First-Line Systemic Treatment

Case Presentation

A 72-year-old man who underwent treatment for pancreatic adenocarcinoma 18 months ago presents to the emergency department after developing poor appetite, weight loss, and abdominal discomfort and fullness without diarrhea, which has been constant for the past 2 weeks even though he has been taking analgesics and pancreatic enzymes.

The patient was diagnosed with pancreatic cancer 18 months ago after presenting with yellowish skin and sclera color; abdominal and pelvis computed tomography (CT) with intravenous contrast showed a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein. Endoscopic ultrasound confirmed an irregular mass at the head of the pancreas and sonographic evidence suggested invasion into the portal vein. Examination of a tissue sample obtained during the procedure showed that the mass was consistent with pancreatic adenocarcinoma. Magnetic resonance imaging (MRI) performed to define venous vasculature involvement revealed a pancreatic head mass measuring 3.0 × 2.7 cm without arterial or venous vasculature invasion. The mass was abutting the portal vein and superior mesenteric veins, and a nonspecific 8-mm aortocaval lymph node was noted. The tumor was deemed to be borderline resectable, and the patient received neoadjuvant therapy with gemcitabine and nab-paclitaxel. After 4 cycles, his carbohydrate antigen (CA) 19-9 level decreased, and MRI revealed a smaller head mass (1.3 × 1.4 cm) with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remained stable. He was treated with gemcitabine chemoradiotherapy prior to undergoing an uncomplicated partial pancreaticoduodenectomy. Analysis of a surgical pathology specimen revealed T3N0 disease with a closest margin of 0.1 cm. Postsurgery, the patient completed 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine.

At his current presentation, MRI of the abdomen and pelvis reveals a new liver mass and peritoneal thickness. Serology testing reveals a CA 19-9 level of 240 U/mL, and other liver function tests are within normal limits. Biopsy of the mass confirms recurrence.

• What systemic chemotherapy would you recommend for this patient with metastatic pancreatic adenocarcinoma?

Most cases of pancreatic cancer are unresectable and/or metastatic at the time of diagnosis. Identifying treatment endpoints and the patient’s goals of care is a critical step in management. Systemic chemotherapy can provide significant survival benefit in first-line and second-line treatment compared to best supportive care. Palliative interventions also include systemic therapy, which often improves pain control and other cancer related–symptoms and hence quality of life. Participation in clinical trials should be offered to all patients. Therapy selection depends on the patient’s performance status, comorbidities, and liver profile and the results of biomarker testing and mutation analysis.

Several single-agents, including fluoropyrimidines, gemcitabine, irinotecan, platinum compounds, and taxanes, have minor objective response rates (< 10%) and a minimal survival benefit (~2 weeks) in metastatic pancreatic adenocarcinoma. Conversely, multi-agent therapies provide higher response rates and can extend overall survival (OS). Two combinations, nab-paclitaxel plus gemcitabine and FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and flourouracil), have significantly prolonged survival compared to best single-agent gemcitabine, as demonstrated in the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) and PRODIGE 4/ACCORD 11 trials.^5,6 Because both multi-agent regimens are also associated with a more toxic adverse effect profile, gemcitabine monotherapy continues to be a front-line therapy for patients with multiple comorbidities, elderly frail patients (> 80 years of age), or patients who cannot tolerate other combinations.⁷

Gemcitabine-Based Therapy

Gemcitabine became a standard of care treatment for pancreatic cancer in the mid-1990s, and was tested as a second-line therapy in a multicenter phase 2 clinical trial that accrued 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil therapy. In this trial, 27% of patients treated with gemcitabine achieved a clinical benefit response and the median OS was 3.85 months.⁸ The agent was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. Subsequently, a randomized clinical trial compared gemcitabine to fluorouracil in the front-line setting in 126 patients with newly diagnosed advanced pancreatic cancer.⁹ Patients were randomly assigned to receive single-agent intravenous fluorouracil administered without leucovorin as a short-term infusion (600 mg/m² once weekly) or gemcitabine (1000 mg/m² weekly for up to 7 weeks followed by 1 week of rest, and then weekly for 3 out of every 4 weeks thereafter). A higher proportion of patients treated with gemcitabine had a clinical benefit response (23.8% versus 4.8%), with an improvement in a composite measure of pain (pain intensity and analgesic consumption) and performance status. Clinical responses assessed by a secondary measure, weight gain, were below 10% in both arms, but the median OS was significantly longer for the gemcitabine arm (5.65 months versus 4.4 months, P = 0.0025) and the 1-year OS rate also favored the gemcitabine arm (18% versus 2%). Grade 3/4 neutropenia was reported more frequently in the gemcitabine arm (23% versus 5%). There is no evidence that increasing the dose intensity of the fixed-dose rate of gemcitabine (1000 mg/m² per week administered as a 30-minute infusion) leads to improved antitumor activity.

Following publication of the trial conducted by Burris and colleagues,⁹ a plethora of clinical trials have tried to outperform gemcitabine monotherapy, with all trials studying gemcitabine monotherapy compared with gemcitabine plus another agent (fluorouracil, cisplatin, oxaliplatin, irinotecan, pemetrexed, novel biologics including cetuximab, bevacizumab, axitinib, sorafenib, aflibercept). These combinations have failed to significantly extend OS compared to single-agent gemcitabine, although some showed a marginal clinical benefit:

• Capecitabine¹⁰ (hazard ratio [HR] 0.86 [95% confidence interval {CI} 0.75 to 0.98])
• Erlotinib¹¹ (HR 0.81 [95% CI 0.69 to 0.99])
• Cisplatin, epirubicin, fluorouracil, gemcitabine¹² (HR 0.65 [95% CI 0.43 to 0.99])

The best outcomes were obtained with gemcitabine plus nab-paclitaxel compared to gemcitabine monotherapy. The gemcitabine/nab-paclitaxel combination has not been compared to FOLFIRINOX in the front-line setting, as the ACCORD 11 and MPACT trials were ongoing simultaneously. However, a large retrospective trial that compared use of the regimens in the US Oncology Network in the United States demonstrated similar efficacy, although more patients treated with FOLFIRINOX needed white blood cell growth factor administration.¹³

Gemcitabine/nab-paclitaxel was studied in a phase 1/2 clinical trial with 67 untreated metastatic pancreatic cancer patients.¹⁴ Patients received nab-paclitaxel at doses of 100, 125, or 150 mg/m² followed by gemcitabine 1000 mg/m² on days 1, 8, and 15 every 28 days. The maximum tolerated dose (MTD) was 1000 mg/m² of gemcitabine plus 125 mg/m² of nab-paclitaxel once a week for 3 weeks every 28 days. Dose-limiting toxicities were sepsis and neutropenia. Patients who received the MTD had a response rate of 48%, median OS of 12.2 months, and a 1-year survival rate of 48%.

The landmark phase 3 MPACT trial confirmed that adding nab-paclitaxel to gemcitabine prolongs survival compared with gemcitabine monotherapy.⁵ This multinational randomized study included 861 treatment-naive patients with a Karnofsky performance score of 70 or higher. The median OS in the nab-paclitaxel/gemcitabine group was 8.5 months, as compared to 6.7 months in the gemcitabine monotherapy group (HR for death 0.72 [95% CI 0.62 to 0.83], P < 0.001). The survival rate was 35% in the nab-paclitaxel/gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. Median progression-free survival (PFS) was 5.5 months in the nab-paclitaxel/gemcitabine group, compared to 3.7 months in the gemcitabine group (HR for disease progression or death 0.69 [95% CI 0.58 to 0.82], P < 0.001). The overall response rate according to independent review was 23% compared with 7% in the 2 groups, respectively (P < 0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel/gemcitabine group versus 27% in the gemcitabine group), fatigue (17% versus 7%), and neuropathy (17% versus 1%). Febrile neutropenia occurred in 3% of the combination group versus 1% of the montherapy group. In the nab-paclitaxel/gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower a median of 29 days after discontinuation of nab-paclitaxel. In 2013, nab-paclitaxel in combination with gemcitabine received U.S. Food and Drug Administration (FDA) approval as first-line therapy for metastatic pancreatic cancer.

A pilot phase 1b/2 trial that added cisplatin to nab-paclitaxel and gemcitabine in treating 24 treatment-naive metastatic pancreatic adenocarcinoma patients showed impressive tumor response (complete response 8.3%, partial response 62.5%, stable disease 16.7%, progressive disease 12.5%) and extended median OS to 16.5 months.¹⁵ A phase 1b trial conducted in Europe added capecitabine to the cisplatin, nab-paclitaxel, and gemcitabine regimen, albeit with a different schedule and doses, in 24 patients with locally advanced and metastatic disease.¹⁶ This trial demonstrated an impressive overall response rate of 67%, with 43% of patients achieving a complete metabolic response on positron emission tomography scan and the CA 19-9 level decreasing by ≥ 49% in all 19 patients who had an elevated basal value. Moreover, PFS at 6 months was 96%. After chemotherapy 17 patients remained unresectable and 7 patients were taken to surgery; of the latter group, only 1 was determined to be unresectable at the time of surgery. This regimen is being explored in a larger study in patients with stage III and IV disease.

FOLFIRINOX

A randomized phase 2 clinical trial comparing FOLFIRINOX to gemcitabine monotherapy in 88 patients with treatment-naive metastatic pancreatic cancer revealed a high response rate for FOLFIRINOX (39% versus 11%, respectively) with a tolerable toxicity profile.¹⁷ FOLFIRINOX became the front-line standard of care therapy in pancreatic adenocarcinoma after the results of the subsequent phase 3 ACCORD 11 study preplanned interim analysis showed an unprecedented significantly improved OS benefit.⁶ The ACCORD 11 trial randomly assigned 342 patients with an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and a serum bilirubin level less than 1.5 times the upper limit of normal to receive FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 400 mg/m² given as a bolus followed by 2400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. The median OS in the FOLFIRINOX group was 11.1 months as compared with 6.8 months in the gemcitabine group (HR 0.57 [95% CI 0.45 to 0.73], P < 0.001). The FOLFIRINOX group also had a longer median PFS (6.4 months versus 3.3 months, HR 0.47 [95% CI 0.37 to 0.59], P < 0.001) and higher objective response rate (31.6% versus 9.4%, P < 0.001). More adverse events were noted in the FOLFIRINOX group, including grade 3 or 4 neutropenia (46% versus 21%), febrile neutropenia (5.4% versus 1.2%), thrombocytopenia (9.1% versus 3.6%), sensory neuropathy (9% versus 0%), vomiting (15% versus 8%), fatigue (23% versus 18%), and diarrhea (13% versus 2%). Despite the greater toxicity, only 31% of the FOLFIRINOX group had a definitive degradation of quality of life, as compared to 66% in the gemcitabine group (HR 0.47 [95% CI 0.30 to 0.70], P < 0.001), thus indicating an improvement in quality of life.

Of note, combinations containing irinotecan require adequate biliary function for excretion of its active glucuronide metabolite, SN-38. Approximately 10% of patients in the United States are homozygous for the UGT1A1*28 allele polymorphism, which causes increased SN-38 bioavailability and hence a potential for severe toxicities (eg, life threatening-refractory diarrhea).¹⁸ Therefore, it is recommended that physicians start with a lower dose of irinotecan or choose a different regimen altogether in such patients.

Current Approach and Future Directions

Based on results of the ACCORD 11 and MPACT trials, both front-line regimens (nab-paclitaxel/gemcitabine and FOLFIRINOX) can be considered appropriate treatment options for treatment-naive patients with good performance status who have locally advanced unresectable or metastatic pancreatic adenocarcinoma. FOLFIRINOX has a higher objective response rate than nab-paclitaxel-gemcitabine (32% versus 23%, respectively), but the adverse effect profile favors the nab-paclitaxel/gemcitabine combination, acknowledging this conclusion is limited due to lack of a comparative trial. Modifications to both regimens have been presented at American Society of Clinical Oncology symposiums, with preliminary data showing an extended median OS and a more tolerable toxicity profile.^19,20 In a recent retrospective observational cohort comparative analysis of nab-paclitaxel/gemcitabine versus FOLFIRINOX, results showed no statistical difference in median OS. The real-world data showed that gemcitabine-based therapy is being offered commonly to elderly patients and patients with poor performance status.¹³ There is no current research proposal for conducting a direct head-to-head comparison between these 2 regimens. Based on extrapolated data from the prior mentioned trials and retrospective analysis reviews, current guidelines recommend offering younger (< 65 years old), healthier (no comorbidity contraindication) patients with excellent performance status (ECOG 0) first-line FOLFIRINOX or gemcitabine/nab-paclitaxel. Elderly patients with stable comorbidities and good performance status (ECOG 1 or 2, Karnofsky performance status ≥ 70) could be preferably considered for treatment with nab-paclitaxel/gemcitabine as first-line or modified FOLFIRINOX if performance status is excellent. Patients with poor performance status (ECOG ≥ 2), advanced age, and significant comorbidities could still be considered candidates for gemcitabine monotherapy. However, there are promising indications that the combination of gemcitabine, nab-paclitaxel, and cisplatin could be a frontline therapy in advanced pancreaticobilliary malignancies in the future.

Second-Line Systemic Treatment

Case Continued

The patient and oncologist opt to begin treatment with modified FOLFIRINOX therapy, and after the patient completes 10 cycles CT scan shows progression of disease. His oncologist decides to refer the patient to a comprehensive cancer center for evaluation for participation in clinical trials, as his performance status remains very good (ECOG 1) and he would like to seek a novel therapy. His liver mass biopsy and blood liquid biopsy are sent for tumor mutational profile evaluation; results show a high tumor mutational burden and microsatellite instability.

• What are second-line treatment options for metastatic pancreatic cancer?

Second-line regimen recommendations for metastatic pancreatic cancer depend on which agents were used in first-line therapy and the patient’s performance status and comorbidities. Patients who progressed on first-line FOLFIRINOX and continue to have a good performance status (ECOG 0 or 1) may be considered for gemcitabine/nab-paclitaxel therapy; otherwise, they may be candidates for gemcitabine plus capecitabine or gemcitabine monotherapy based on performance status and goals of care. Patients who progressed on front-line gemcitabine/nab-paclitaxel may opt for FOLFIRINOX (or an oxaliplatin-based regimen [FOLFOX] or irinotecan-based regimen [FOLFIRI] if FOLFIRINOX is not tolerable), nanoliposomal irinotecan/fluorouracil/leucovorin, or a short-term infusional fluorouracil and leucovorin regimen. The preferences for second-line treatment are not well established, and patients should be encouraged to participate in clinical trials. Chemotherapy should be offered only to those patients who maintain good performance status after progression on first-line therapy. For patients with poor performance status (ECOG 3 or 4) or multiple comorbidities, a discussion about goals of care and palliative therapy is warranted.

Gemcitabine-Based Therapy

An AGEO prospective multicenter cohort assigned 57 patients with metastatic pancreatic adenocarcinoma who had disease progression on FOLFIRINOX therapy to receive gemcitabine/nab-paclitaxel (dose as per MPACT trial).²¹ The median OS was 8.8 months and median PFS was 5.1 months after FOLFIRINOX. There were reported manageable grade 3/4 toxicities in 40% of patients, which included neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%), and thrombocytopenia (6.5%). A phase 2 clinical trial that evaluated gemcitabine monotherapy in 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil showed a 3.85-month survival benefit.²²

Irinotecan-Based Regimens

The NAPOLI-1 (NAnoliPOsomaL Irinotecan) trial evaluated nanoliposomal irinotecan (MM-398, nal-IRI) and fluorouracil/leucovorin in patients with metastatic pancreatic cancer refractory to gemcitabine-based therapy.²³ This global, open-label phase 3 trial initially randomly assigned and stratified 417 patients in a 1:1 fashion to receive either nanoliposomal irinotecan monotherapy (120 mg/m² every 3 weeks, equivalent to 100 mg/m² of irinotecan base) or fluorouracil/leucovorin combination. A third treatment arm consisting of nanoliposomal irinotecan (80 mg/m², equivalent to 70 mg/m² of irinotecan base) with fluorouracil and leucovorin every 2 weeks was added later in a 1:1:1 fashion. Patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin had a significantly improved OS of 6.1 months compared to 4.2 months with fluorouracil/leucovorin (HR 0.67 [95% CI 0.49 to 0.92], P = 0.012). The results of an intention-to-treat analysis favored the nanoliposomal irinotecan regimen, with a median OS of 8.9 months compared with 5.1 months (HR 0.57, P = 0.011). In addition, median PFS was improved in the nanoliposomal irinotecan arm (3.1 months versus 1.5 months; HR 0.56, P < 0.001), and median OS did not differ between patients treated with nanoliposomal irinotecan monotherapy and those treated with fluorouracil/leucovorin (4.9 months versus 4.2 months; HR 0.99 [95% CI 0.77 to 1.28], P = 0.94). The grade 3/4 adverse events that occurred most frequently in the 117 patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). Nanoliposomal irinotecan combination provides another second-line treatment option for patients with metastatic pancreatic adenocarcinoma who have progressed on gemcitabine-based therapy but are not candidates for FOLFIRINOX.

Oxaliplatin-Based Regimens

Regimens that combine oxaliplatin with fluorouracil and leucovorin or capecitabine have shown superiority to fluorouracil/leucovorin or best supportive care (BSC). The CONKO study group compared oxaliplatin plus fluorouracil/leucovorin to BSC as second-line therapy in patients with advanced pancreatic cancer who progressed while on gemcitabine therapy (CONKO-003).²⁴ In this phase 3 trial, patients were randomly assigned (1:1) and stratified based on duration of first-line therapy, performance status, and tumor stage to receive BSC alone or the OFF regimen, which consisted of oxaliplatin (85 mg/m² on days 8 and 22) plus short-term infusional fluorouracil (2000 mg/m² over 24 hours) and leucovorin (200 mg/m² over 30 minutes), both given on days 1, 8, 15, and 22 of a 6-week cycle. This trial was terminated early according to predefined protocol regulations because of insufficient accrual (lack of acceptance of BSC by patients and physicians). Median second-line survival was 4.82 months for patients who received OFF treatment and 2.30 months for those who received BSC (HR 0.45 [95% CI 0.24 to 0.83], P = 0.008).  Neurotoxicity (grade 1/2) and nausea, emesis, and diarrhea (grade 2/3) were worse in the chemotherapy arm; otherwise, the regimen was well tolerated.

A later modification of the CONKO-003 trial changed the comparison arm from BSC to fluorouracil/leucovorin.²⁵ The median OS in the OFF group was 5.9 months versus 3.3 months in the fluorouracil/leucovorin group (HR 0.66 [95% CI 0.48 to 0.91], log-rank P = 0.010). Time to progression was significantly extended with OFF (2.9 months) as compared with fluorouracil/leucovorin (2.0 months; HR 0.68 [95% CI 0.50 to 0.94], log-rank P = 0.019). Rates of adverse events were similar between the treatment arms, with the exception of grades 1/2 neurotoxicity, which were reported in 38.2% and 7.1% of patients in the OFF and fluorouracil/leucovorin groups, respectively (P < 0.001).

The phase 3 PANCREOX trial failed to show superiority of modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) over fluorouracil/leucovorin.²⁶ A phase 2 trial of oxaliplatin plus capecitabine for second-line therapy in gemcitabine-treated advanced pancreatic cancer patients with dose adjustments for performance status (ECOG 2) and age (> 65 years) showed a median OS of 5.7 months without a comparison.²⁷ A modified oxaliplatin regimen may be a reasonable second-line therapy option for gemcitabine-treated patients who are not candidates for an irinotecan-based regimen (eg, elevated bilirubin) and continue to have an acceptable performance status.

Targeted Therapies

A variety of targeted therapies have failed to demonstrate major activity in metastatic pancreatic cancer, including bevacizumab targeting vascular endothelial growth factor, cetuximab targeting epidermal growth factor receptor, ruxolitinib targeting JAK pathway signaling, saridegib targeting the hedgehog pathway, and MK-0646 targeting insulin-like growth factor 1 receptor (IGFR). Other novel agents against targetable pathways that had promising early-phase results are currently being studied in ongoing clinical trials; these include JAK-2, PI3K, MEK, and BRAF inhibitors and immunotherapy.

Recent research efforts have focused on targeted testing of advanced pancreatic cancers for mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) and for the germline and somatic BRCA1/2 or PALB2 mutations to determine potential eligibility for immunotherapy. Patients with these tumor characteristics and/or mutations might also be more sensitive to platinum-based chemotherapy agents or poly (ADP-ribose) polymerase (PARP) inhibitors. Germline mutations in BRCA 1/2 are present in 5% to 8% of patients with pancreatic cancer (up to 10%–15% in Ashkenazi Jewish population).²⁸ A superior median OS was retrospectively observed for patients with advanced stage BRCA 1/2-associated pancreatic adenocarcinoma who were treated with platinum-based chemotherapy agents versus those treated with non-platinum-based agents (22 versus 9 months; P = 0.039).²² PARP inhibitors have shown activity in germline BRCA1/2-associated breast (off label) and ovarian cancers (approved by the FDA). The efficacy and safety of PARP inhibitors were evaluated in a phase 2 study of a spectrum of BRCA1/2-associated cancers, including pancreatic cancer. The results revealed a tumor response rate of 21.7% (5 of 23 patients with pancreatic cancer [95% CI 7.5 to 43.7]), and 35% of patients had stable disease for a duration of 8 weeks or more (95% CI 16.4 to 57.3) with good tolerability.²⁹ Three novel PARP inhibitors are currently under clinical trial investigation in patients with germline BRCA 1/2- and PALB2-mutated metastatic pancreatic cancer: maintenance olaparib (NCT02184195) and rucaparib (NCT03140670) are both being studied as monotherapy in patients whose disease has not progressed on first-line platinum-based chemotherapy, and veliparib is being evaluated in a 3-arm study that includes gemcitabine and cisplatin with or without veliparib and single-agent maintenance veliparib (NCT01585805).

In 2017, the FDA granted accelerated approval to pembrolizumab for treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors whose disease progressed on prior treatments, making it the first oncology drug to be approved based on the genetic features of the tumor rather than its location in the body. This first tissue/site-agnostic approval was based on results from 5 single-arm trials involving 149 patients, including 5 patients with pancreatic cancer.³⁰ The objective response rate with pembrolizumab was 39.6% (95% CI 31.7 to 47.9), including a 7.4% complete response rate and a 32.2% partial response rate. The median duration of response was not reached at the time of publication (range, 1.6+ months to 22.7+ months).

Palliative and Supportive Care

Case Continued

The patient opts to participate in a novel immunotherapy clinical trial and is currently on his second cycle. He continues to have right upper quadrant pain despite opioid analgesia, has not gained any weight, and noticed new right lower extremity swelling after a recent holiday vacation to Florida.

• What supportive measures should be in place for patients with metastatic adenocarcinoma?

Most patients with advanced pancreatic adenocarcinoma will require a palliative intervention. All new unresectable pancreatic cancer patients should have an early psychosocial evaluation; identification of symptoms and implementation of preventive interventions that would improve quality of life and reduce suffering are paramount. A multidisciplinary team including physician/nursing staff, nutritionist/dietitian, palliative service, a social worker, and a case manager should be involved in patient care. More than two-thirds of patients can develop symptomatic biliary obstruction.³¹ Bile duct obstruction due to locally advanced pancreatic adenocarcinoma causes hyperbilirubinemia, which requires endoscopic placement of a metallic or plastic stent; plastic stents have a higher rate of re-occlusion.³² Appropriate bile flow allows treatment with irinotecan-based regimens. Percutaneous biliary drainage may be necessary if endoscopic intervention is not feasible.

Approximately one quarter of patients may present with gastric outlet obstruction due to duodenal obstruction.³¹ Endoscopic placement of an enteral expandable metal stent is preferred. Alternatively, percutaneous endoscopic gastrostomy tube placement may give symptomatic relief. Palliative surgical interventions are reserved for patients with greater life expectancy and in whom all other interventions have failed or are not feasible.

Almost all patients with pancreatic adenocarcinoma will experience cancer-associated pain. Intractable pain should be treated with a celiac plexus block. Radiation therapy may be considered as an adjunct therapy for pain, bleeding, and/or local obstruction. The National Comprehensive Cancer Network guidelines recommend that patients who undergo a laparotomy for potentially resectable disease but are found to have unresectable disease at the time of surgery should undergo stenting, open biliary-enteric bypass with or without gastrojejunostomy, and/or celiac plexus neurolysis.³³

Pancreatic exocrine enzyme insufficiency due to tumor extension, duct blockage, or surgical removal may cause malabsoprtive steatorrhea, contributing to cancer cachexia syndrome. Nutritional evaluation and daily oral pancreatic enzyme supplementation are recommended.³⁴

Patients diagnosed with pancreatic adenocarcinoma have a venous thromboembolism (VTE) incidence of 20 per 100 person-years (5%–60% of patients) and are considered at very high risk for VTE based on the Khorana score.³⁵ The preferred VTE treatment is low-molecular-weight heparin rather than warfarin based on the results of the CLOT study.³⁶ There is no current evidence for routine prophylactic therapy or the use of direct oral anticoagulants.

Finally, a cancer diagnosis, particularly pancreatic cancer, causes a significant amount of psychosocial stress and requires active support and counseling from a professional.

Conclusion

Pancreatic adenocarcinoma is the most lethal of all the gastrointestinal malignancies. FOLFIRINOX and gemcitabine/nab-paclitaxel are superior to gemcitabine monotherapy for patients with advanced unresectable and/or metastatic pancreatic cancer who are candidates for more aggressive therapy and are considered first-line therapies. Early data on the gemcitabine, nab-paclitaxel, and cisplatin combination appears to show superior efficacy. Second-line therapies are selected based on the patient’s performance status, first-line regimen, and residual toxicities from the prior regimen; options include gemcitabine/nab-paclitaxel, FOLFIRINOX (± oxaliplatin or irinotecan), single-agent gemcitabine (elderly frail patients), fluorouracil and liposomal-irinotecan, or referral for a clinical trial. The main challenge with pancreatic cancer is the development of stroma around the tumor, which abrogates drug delivery, allows for tumor growth in a hypoxic microenvironment, alters the metabolomics, and causes an immunosuppressive microenvironment. Drugs that target the microenvironments, such as hedgehog pathway inhibitors, have failed to show any clinical benefit, and we hope to see more efficacious microenvironment-targeted novel drugs in the future. In addition, immunotherapy has not shown any significant efficacy in clinical trials and many trials are still ongoing.

Introduction

Pancreatic ductal adenocarcinoma is a challenging disease with a poor prognosis, with 5-year survival rates in the single digits (~8%).¹ Survival rates in pancreatic cancer are low in part because most patients have advanced disease at the time of diagnosis and early development of systemic metastatic disease is common, with approximately 52% of patients with newly diagnosed pancreatic cancer having metastatic disease at diagnosis.¹ Surgical resection with negative margins is the cornerstone of potentially curative therapy for localized disease, but only 15% to 20% of patients are eligible for resection at the time of initial diagnosis. Patients with unresectable and metastatic disease are offered palliative chemotherapy. Unfortunately, early recurrence is common in patients with resectable tumors who achieve a complete resection and are treated with adjuvant therapy (5-year recurrence rate ~80%).^2,3 This article reviews the management of patients with unresectable and/or metastatic pancreatic cancer. A previous article reviewed the diagnosis and staging of pancreatic cancer and the approach to neoadjuvant and adjuvant therapy in patients with resectable and borderline-resectable disease.⁴

First-Line Systemic Treatment

Case Presentation

A 72-year-old man who underwent treatment for pancreatic adenocarcinoma 18 months ago presents to the emergency department after developing poor appetite, weight loss, and abdominal discomfort and fullness without diarrhea, which has been constant for the past 2 weeks even though he has been taking analgesics and pancreatic enzymes.

The patient was diagnosed with pancreatic cancer 18 months ago after presenting with yellowish skin and sclera color; abdominal and pelvis computed tomography (CT) with intravenous contrast showed a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein. Endoscopic ultrasound confirmed an irregular mass at the head of the pancreas and sonographic evidence suggested invasion into the portal vein. Examination of a tissue sample obtained during the procedure showed that the mass was consistent with pancreatic adenocarcinoma. Magnetic resonance imaging (MRI) performed to define venous vasculature involvement revealed a pancreatic head mass measuring 3.0 × 2.7 cm without arterial or venous vasculature invasion. The mass was abutting the portal vein and superior mesenteric veins, and a nonspecific 8-mm aortocaval lymph node was noted. The tumor was deemed to be borderline resectable, and the patient received neoadjuvant therapy with gemcitabine and nab-paclitaxel. After 4 cycles, his carbohydrate antigen (CA) 19-9 level decreased, and MRI revealed a smaller head mass (1.3 × 1.4 cm) with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remained stable. He was treated with gemcitabine chemoradiotherapy prior to undergoing an uncomplicated partial pancreaticoduodenectomy. Analysis of a surgical pathology specimen revealed T3N0 disease with a closest margin of 0.1 cm. Postsurgery, the patient completed 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine.

At his current presentation, MRI of the abdomen and pelvis reveals a new liver mass and peritoneal thickness. Serology testing reveals a CA 19-9 level of 240 U/mL, and other liver function tests are within normal limits. Biopsy of the mass confirms recurrence.

• What systemic chemotherapy would you recommend for this patient with metastatic pancreatic adenocarcinoma?

Most cases of pancreatic cancer are unresectable and/or metastatic at the time of diagnosis. Identifying treatment endpoints and the patient’s goals of care is a critical step in management. Systemic chemotherapy can provide significant survival benefit in first-line and second-line treatment compared to best supportive care. Palliative interventions also include systemic therapy, which often improves pain control and other cancer related–symptoms and hence quality of life. Participation in clinical trials should be offered to all patients. Therapy selection depends on the patient’s performance status, comorbidities, and liver profile and the results of biomarker testing and mutation analysis.

Several single-agents, including fluoropyrimidines, gemcitabine, irinotecan, platinum compounds, and taxanes, have minor objective response rates (< 10%) and a minimal survival benefit (~2 weeks) in metastatic pancreatic adenocarcinoma. Conversely, multi-agent therapies provide higher response rates and can extend overall survival (OS). Two combinations, nab-paclitaxel plus gemcitabine and FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and flourouracil), have significantly prolonged survival compared to best single-agent gemcitabine, as demonstrated in the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) and PRODIGE 4/ACCORD 11 trials.^5,6 Because both multi-agent regimens are also associated with a more toxic adverse effect profile, gemcitabine monotherapy continues to be a front-line therapy for patients with multiple comorbidities, elderly frail patients (> 80 years of age), or patients who cannot tolerate other combinations.⁷

Gemcitabine-Based Therapy

Gemcitabine became a standard of care treatment for pancreatic cancer in the mid-1990s, and was tested as a second-line therapy in a multicenter phase 2 clinical trial that accrued 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil therapy. In this trial, 27% of patients treated with gemcitabine achieved a clinical benefit response and the median OS was 3.85 months.⁸ The agent was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. Subsequently, a randomized clinical trial compared gemcitabine to fluorouracil in the front-line setting in 126 patients with newly diagnosed advanced pancreatic cancer.⁹ Patients were randomly assigned to receive single-agent intravenous fluorouracil administered without leucovorin as a short-term infusion (600 mg/m² once weekly) or gemcitabine (1000 mg/m² weekly for up to 7 weeks followed by 1 week of rest, and then weekly for 3 out of every 4 weeks thereafter). A higher proportion of patients treated with gemcitabine had a clinical benefit response (23.8% versus 4.8%), with an improvement in a composite measure of pain (pain intensity and analgesic consumption) and performance status. Clinical responses assessed by a secondary measure, weight gain, were below 10% in both arms, but the median OS was significantly longer for the gemcitabine arm (5.65 months versus 4.4 months, P = 0.0025) and the 1-year OS rate also favored the gemcitabine arm (18% versus 2%). Grade 3/4 neutropenia was reported more frequently in the gemcitabine arm (23% versus 5%). There is no evidence that increasing the dose intensity of the fixed-dose rate of gemcitabine (1000 mg/m² per week administered as a 30-minute infusion) leads to improved antitumor activity.

Following publication of the trial conducted by Burris and colleagues,⁹ a plethora of clinical trials have tried to outperform gemcitabine monotherapy, with all trials studying gemcitabine monotherapy compared with gemcitabine plus another agent (fluorouracil, cisplatin, oxaliplatin, irinotecan, pemetrexed, novel biologics including cetuximab, bevacizumab, axitinib, sorafenib, aflibercept). These combinations have failed to significantly extend OS compared to single-agent gemcitabine, although some showed a marginal clinical benefit:

• Capecitabine¹⁰ (hazard ratio [HR] 0.86 [95% confidence interval {CI} 0.75 to 0.98])
• Erlotinib¹¹ (HR 0.81 [95% CI 0.69 to 0.99])
• Cisplatin, epirubicin, fluorouracil, gemcitabine¹² (HR 0.65 [95% CI 0.43 to 0.99])

The best outcomes were obtained with gemcitabine plus nab-paclitaxel compared to gemcitabine monotherapy. The gemcitabine/nab-paclitaxel combination has not been compared to FOLFIRINOX in the front-line setting, as the ACCORD 11 and MPACT trials were ongoing simultaneously. However, a large retrospective trial that compared use of the regimens in the US Oncology Network in the United States demonstrated similar efficacy, although more patients treated with FOLFIRINOX needed white blood cell growth factor administration.¹³

Gemcitabine/nab-paclitaxel was studied in a phase 1/2 clinical trial with 67 untreated metastatic pancreatic cancer patients.¹⁴ Patients received nab-paclitaxel at doses of 100, 125, or 150 mg/m² followed by gemcitabine 1000 mg/m² on days 1, 8, and 15 every 28 days. The maximum tolerated dose (MTD) was 1000 mg/m² of gemcitabine plus 125 mg/m² of nab-paclitaxel once a week for 3 weeks every 28 days. Dose-limiting toxicities were sepsis and neutropenia. Patients who received the MTD had a response rate of 48%, median OS of 12.2 months, and a 1-year survival rate of 48%.

The landmark phase 3 MPACT trial confirmed that adding nab-paclitaxel to gemcitabine prolongs survival compared with gemcitabine monotherapy.⁵ This multinational randomized study included 861 treatment-naive patients with a Karnofsky performance score of 70 or higher. The median OS in the nab-paclitaxel/gemcitabine group was 8.5 months, as compared to 6.7 months in the gemcitabine monotherapy group (HR for death 0.72 [95% CI 0.62 to 0.83], P < 0.001). The survival rate was 35% in the nab-paclitaxel/gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. Median progression-free survival (PFS) was 5.5 months in the nab-paclitaxel/gemcitabine group, compared to 3.7 months in the gemcitabine group (HR for disease progression or death 0.69 [95% CI 0.58 to 0.82], P < 0.001). The overall response rate according to independent review was 23% compared with 7% in the 2 groups, respectively (P < 0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel/gemcitabine group versus 27% in the gemcitabine group), fatigue (17% versus 7%), and neuropathy (17% versus 1%). Febrile neutropenia occurred in 3% of the combination group versus 1% of the montherapy group. In the nab-paclitaxel/gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower a median of 29 days after discontinuation of nab-paclitaxel. In 2013, nab-paclitaxel in combination with gemcitabine received U.S. Food and Drug Administration (FDA) approval as first-line therapy for metastatic pancreatic cancer.

A pilot phase 1b/2 trial that added cisplatin to nab-paclitaxel and gemcitabine in treating 24 treatment-naive metastatic pancreatic adenocarcinoma patients showed impressive tumor response (complete response 8.3%, partial response 62.5%, stable disease 16.7%, progressive disease 12.5%) and extended median OS to 16.5 months.¹⁵ A phase 1b trial conducted in Europe added capecitabine to the cisplatin, nab-paclitaxel, and gemcitabine regimen, albeit with a different schedule and doses, in 24 patients with locally advanced and metastatic disease.¹⁶ This trial demonstrated an impressive overall response rate of 67%, with 43% of patients achieving a complete metabolic response on positron emission tomography scan and the CA 19-9 level decreasing by ≥ 49% in all 19 patients who had an elevated basal value. Moreover, PFS at 6 months was 96%. After chemotherapy 17 patients remained unresectable and 7 patients were taken to surgery; of the latter group, only 1 was determined to be unresectable at the time of surgery. This regimen is being explored in a larger study in patients with stage III and IV disease.

FOLFIRINOX

A randomized phase 2 clinical trial comparing FOLFIRINOX to gemcitabine monotherapy in 88 patients with treatment-naive metastatic pancreatic cancer revealed a high response rate for FOLFIRINOX (39% versus 11%, respectively) with a tolerable toxicity profile.¹⁷ FOLFIRINOX became the front-line standard of care therapy in pancreatic adenocarcinoma after the results of the subsequent phase 3 ACCORD 11 study preplanned interim analysis showed an unprecedented significantly improved OS benefit.⁶ The ACCORD 11 trial randomly assigned 342 patients with an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and a serum bilirubin level less than 1.5 times the upper limit of normal to receive FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 400 mg/m² given as a bolus followed by 2400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. The median OS in the FOLFIRINOX group was 11.1 months as compared with 6.8 months in the gemcitabine group (HR 0.57 [95% CI 0.45 to 0.73], P < 0.001). The FOLFIRINOX group also had a longer median PFS (6.4 months versus 3.3 months, HR 0.47 [95% CI 0.37 to 0.59], P < 0.001) and higher objective response rate (31.6% versus 9.4%, P < 0.001). More adverse events were noted in the FOLFIRINOX group, including grade 3 or 4 neutropenia (46% versus 21%), febrile neutropenia (5.4% versus 1.2%), thrombocytopenia (9.1% versus 3.6%), sensory neuropathy (9% versus 0%), vomiting (15% versus 8%), fatigue (23% versus 18%), and diarrhea (13% versus 2%). Despite the greater toxicity, only 31% of the FOLFIRINOX group had a definitive degradation of quality of life, as compared to 66% in the gemcitabine group (HR 0.47 [95% CI 0.30 to 0.70], P < 0.001), thus indicating an improvement in quality of life.

Of note, combinations containing irinotecan require adequate biliary function for excretion of its active glucuronide metabolite, SN-38. Approximately 10% of patients in the United States are homozygous for the UGT1A1*28 allele polymorphism, which causes increased SN-38 bioavailability and hence a potential for severe toxicities (eg, life threatening-refractory diarrhea).¹⁸ Therefore, it is recommended that physicians start with a lower dose of irinotecan or choose a different regimen altogether in such patients.

Current Approach and Future Directions

Based on results of the ACCORD 11 and MPACT trials, both front-line regimens (nab-paclitaxel/gemcitabine and FOLFIRINOX) can be considered appropriate treatment options for treatment-naive patients with good performance status who have locally advanced unresectable or metastatic pancreatic adenocarcinoma. FOLFIRINOX has a higher objective response rate than nab-paclitaxel-gemcitabine (32% versus 23%, respectively), but the adverse effect profile favors the nab-paclitaxel/gemcitabine combination, acknowledging this conclusion is limited due to lack of a comparative trial. Modifications to both regimens have been presented at American Society of Clinical Oncology symposiums, with preliminary data showing an extended median OS and a more tolerable toxicity profile.^19,20 In a recent retrospective observational cohort comparative analysis of nab-paclitaxel/gemcitabine versus FOLFIRINOX, results showed no statistical difference in median OS. The real-world data showed that gemcitabine-based therapy is being offered commonly to elderly patients and patients with poor performance status.¹³ There is no current research proposal for conducting a direct head-to-head comparison between these 2 regimens. Based on extrapolated data from the prior mentioned trials and retrospective analysis reviews, current guidelines recommend offering younger (< 65 years old), healthier (no comorbidity contraindication) patients with excellent performance status (ECOG 0) first-line FOLFIRINOX or gemcitabine/nab-paclitaxel. Elderly patients with stable comorbidities and good performance status (ECOG 1 or 2, Karnofsky performance status ≥ 70) could be preferably considered for treatment with nab-paclitaxel/gemcitabine as first-line or modified FOLFIRINOX if performance status is excellent. Patients with poor performance status (ECOG ≥ 2), advanced age, and significant comorbidities could still be considered candidates for gemcitabine monotherapy. However, there are promising indications that the combination of gemcitabine, nab-paclitaxel, and cisplatin could be a frontline therapy in advanced pancreaticobilliary malignancies in the future.

Second-Line Systemic Treatment

Case Continued

The patient and oncologist opt to begin treatment with modified FOLFIRINOX therapy, and after the patient completes 10 cycles CT scan shows progression of disease. His oncologist decides to refer the patient to a comprehensive cancer center for evaluation for participation in clinical trials, as his performance status remains very good (ECOG 1) and he would like to seek a novel therapy. His liver mass biopsy and blood liquid biopsy are sent for tumor mutational profile evaluation; results show a high tumor mutational burden and microsatellite instability.

• What are second-line treatment options for metastatic pancreatic cancer?

Second-line regimen recommendations for metastatic pancreatic cancer depend on which agents were used in first-line therapy and the patient’s performance status and comorbidities. Patients who progressed on first-line FOLFIRINOX and continue to have a good performance status (ECOG 0 or 1) may be considered for gemcitabine/nab-paclitaxel therapy; otherwise, they may be candidates for gemcitabine plus capecitabine or gemcitabine monotherapy based on performance status and goals of care. Patients who progressed on front-line gemcitabine/nab-paclitaxel may opt for FOLFIRINOX (or an oxaliplatin-based regimen [FOLFOX] or irinotecan-based regimen [FOLFIRI] if FOLFIRINOX is not tolerable), nanoliposomal irinotecan/fluorouracil/leucovorin, or a short-term infusional fluorouracil and leucovorin regimen. The preferences for second-line treatment are not well established, and patients should be encouraged to participate in clinical trials. Chemotherapy should be offered only to those patients who maintain good performance status after progression on first-line therapy. For patients with poor performance status (ECOG 3 or 4) or multiple comorbidities, a discussion about goals of care and palliative therapy is warranted.

Gemcitabine-Based Therapy

An AGEO prospective multicenter cohort assigned 57 patients with metastatic pancreatic adenocarcinoma who had disease progression on FOLFIRINOX therapy to receive gemcitabine/nab-paclitaxel (dose as per MPACT trial).²¹ The median OS was 8.8 months and median PFS was 5.1 months after FOLFIRINOX. There were reported manageable grade 3/4 toxicities in 40% of patients, which included neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%), and thrombocytopenia (6.5%). A phase 2 clinical trial that evaluated gemcitabine monotherapy in 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil showed a 3.85-month survival benefit.²²

Irinotecan-Based Regimens

The NAPOLI-1 (NAnoliPOsomaL Irinotecan) trial evaluated nanoliposomal irinotecan (MM-398, nal-IRI) and fluorouracil/leucovorin in patients with metastatic pancreatic cancer refractory to gemcitabine-based therapy.²³ This global, open-label phase 3 trial initially randomly assigned and stratified 417 patients in a 1:1 fashion to receive either nanoliposomal irinotecan monotherapy (120 mg/m² every 3 weeks, equivalent to 100 mg/m² of irinotecan base) or fluorouracil/leucovorin combination. A third treatment arm consisting of nanoliposomal irinotecan (80 mg/m², equivalent to 70 mg/m² of irinotecan base) with fluorouracil and leucovorin every 2 weeks was added later in a 1:1:1 fashion. Patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin had a significantly improved OS of 6.1 months compared to 4.2 months with fluorouracil/leucovorin (HR 0.67 [95% CI 0.49 to 0.92], P = 0.012). The results of an intention-to-treat analysis favored the nanoliposomal irinotecan regimen, with a median OS of 8.9 months compared with 5.1 months (HR 0.57, P = 0.011). In addition, median PFS was improved in the nanoliposomal irinotecan arm (3.1 months versus 1.5 months; HR 0.56, P < 0.001), and median OS did not differ between patients treated with nanoliposomal irinotecan monotherapy and those treated with fluorouracil/leucovorin (4.9 months versus 4.2 months; HR 0.99 [95% CI 0.77 to 1.28], P = 0.94). The grade 3/4 adverse events that occurred most frequently in the 117 patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). Nanoliposomal irinotecan combination provides another second-line treatment option for patients with metastatic pancreatic adenocarcinoma who have progressed on gemcitabine-based therapy but are not candidates for FOLFIRINOX.

Oxaliplatin-Based Regimens

Regimens that combine oxaliplatin with fluorouracil and leucovorin or capecitabine have shown superiority to fluorouracil/leucovorin or best supportive care (BSC). The CONKO study group compared oxaliplatin plus fluorouracil/leucovorin to BSC as second-line therapy in patients with advanced pancreatic cancer who progressed while on gemcitabine therapy (CONKO-003).²⁴ In this phase 3 trial, patients were randomly assigned (1:1) and stratified based on duration of first-line therapy, performance status, and tumor stage to receive BSC alone or the OFF regimen, which consisted of oxaliplatin (85 mg/m² on days 8 and 22) plus short-term infusional fluorouracil (2000 mg/m² over 24 hours) and leucovorin (200 mg/m² over 30 minutes), both given on days 1, 8, 15, and 22 of a 6-week cycle. This trial was terminated early according to predefined protocol regulations because of insufficient accrual (lack of acceptance of BSC by patients and physicians). Median second-line survival was 4.82 months for patients who received OFF treatment and 2.30 months for those who received BSC (HR 0.45 [95% CI 0.24 to 0.83], P = 0.008).  Neurotoxicity (grade 1/2) and nausea, emesis, and diarrhea (grade 2/3) were worse in the chemotherapy arm; otherwise, the regimen was well tolerated.

A later modification of the CONKO-003 trial changed the comparison arm from BSC to fluorouracil/leucovorin.²⁵ The median OS in the OFF group was 5.9 months versus 3.3 months in the fluorouracil/leucovorin group (HR 0.66 [95% CI 0.48 to 0.91], log-rank P = 0.010). Time to progression was significantly extended with OFF (2.9 months) as compared with fluorouracil/leucovorin (2.0 months; HR 0.68 [95% CI 0.50 to 0.94], log-rank P = 0.019). Rates of adverse events were similar between the treatment arms, with the exception of grades 1/2 neurotoxicity, which were reported in 38.2% and 7.1% of patients in the OFF and fluorouracil/leucovorin groups, respectively (P < 0.001).

The phase 3 PANCREOX trial failed to show superiority of modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) over fluorouracil/leucovorin.²⁶ A phase 2 trial of oxaliplatin plus capecitabine for second-line therapy in gemcitabine-treated advanced pancreatic cancer patients with dose adjustments for performance status (ECOG 2) and age (> 65 years) showed a median OS of 5.7 months without a comparison.²⁷ A modified oxaliplatin regimen may be a reasonable second-line therapy option for gemcitabine-treated patients who are not candidates for an irinotecan-based regimen (eg, elevated bilirubin) and continue to have an acceptable performance status.

Targeted Therapies

A variety of targeted therapies have failed to demonstrate major activity in metastatic pancreatic cancer, including bevacizumab targeting vascular endothelial growth factor, cetuximab targeting epidermal growth factor receptor, ruxolitinib targeting JAK pathway signaling, saridegib targeting the hedgehog pathway, and MK-0646 targeting insulin-like growth factor 1 receptor (IGFR). Other novel agents against targetable pathways that had promising early-phase results are currently being studied in ongoing clinical trials; these include JAK-2, PI3K, MEK, and BRAF inhibitors and immunotherapy.

Recent research efforts have focused on targeted testing of advanced pancreatic cancers for mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) and for the germline and somatic BRCA1/2 or PALB2 mutations to determine potential eligibility for immunotherapy. Patients with these tumor characteristics and/or mutations might also be more sensitive to platinum-based chemotherapy agents or poly (ADP-ribose) polymerase (PARP) inhibitors. Germline mutations in BRCA 1/2 are present in 5% to 8% of patients with pancreatic cancer (up to 10%–15% in Ashkenazi Jewish population).²⁸ A superior median OS was retrospectively observed for patients with advanced stage BRCA 1/2-associated pancreatic adenocarcinoma who were treated with platinum-based chemotherapy agents versus those treated with non-platinum-based agents (22 versus 9 months; P = 0.039).²² PARP inhibitors have shown activity in germline BRCA1/2-associated breast (off label) and ovarian cancers (approved by the FDA). The efficacy and safety of PARP inhibitors were evaluated in a phase 2 study of a spectrum of BRCA1/2-associated cancers, including pancreatic cancer. The results revealed a tumor response rate of 21.7% (5 of 23 patients with pancreatic cancer [95% CI 7.5 to 43.7]), and 35% of patients had stable disease for a duration of 8 weeks or more (95% CI 16.4 to 57.3) with good tolerability.²⁹ Three novel PARP inhibitors are currently under clinical trial investigation in patients with germline BRCA 1/2- and PALB2-mutated metastatic pancreatic cancer: maintenance olaparib (NCT02184195) and rucaparib (NCT03140670) are both being studied as monotherapy in patients whose disease has not progressed on first-line platinum-based chemotherapy, and veliparib is being evaluated in a 3-arm study that includes gemcitabine and cisplatin with or without veliparib and single-agent maintenance veliparib (NCT01585805).

In 2017, the FDA granted accelerated approval to pembrolizumab for treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors whose disease progressed on prior treatments, making it the first oncology drug to be approved based on the genetic features of the tumor rather than its location in the body. This first tissue/site-agnostic approval was based on results from 5 single-arm trials involving 149 patients, including 5 patients with pancreatic cancer.³⁰ The objective response rate with pembrolizumab was 39.6% (95% CI 31.7 to 47.9), including a 7.4% complete response rate and a 32.2% partial response rate. The median duration of response was not reached at the time of publication (range, 1.6+ months to 22.7+ months).

Palliative and Supportive Care

Case Continued

The patient opts to participate in a novel immunotherapy clinical trial and is currently on his second cycle. He continues to have right upper quadrant pain despite opioid analgesia, has not gained any weight, and noticed new right lower extremity swelling after a recent holiday vacation to Florida.

• What supportive measures should be in place for patients with metastatic adenocarcinoma?

Most patients with advanced pancreatic adenocarcinoma will require a palliative intervention. All new unresectable pancreatic cancer patients should have an early psychosocial evaluation; identification of symptoms and implementation of preventive interventions that would improve quality of life and reduce suffering are paramount. A multidisciplinary team including physician/nursing staff, nutritionist/dietitian, palliative service, a social worker, and a case manager should be involved in patient care. More than two-thirds of patients can develop symptomatic biliary obstruction.³¹ Bile duct obstruction due to locally advanced pancreatic adenocarcinoma causes hyperbilirubinemia, which requires endoscopic placement of a metallic or plastic stent; plastic stents have a higher rate of re-occlusion.³² Appropriate bile flow allows treatment with irinotecan-based regimens. Percutaneous biliary drainage may be necessary if endoscopic intervention is not feasible.

Approximately one quarter of patients may present with gastric outlet obstruction due to duodenal obstruction.³¹ Endoscopic placement of an enteral expandable metal stent is preferred. Alternatively, percutaneous endoscopic gastrostomy tube placement may give symptomatic relief. Palliative surgical interventions are reserved for patients with greater life expectancy and in whom all other interventions have failed or are not feasible.

Almost all patients with pancreatic adenocarcinoma will experience cancer-associated pain. Intractable pain should be treated with a celiac plexus block. Radiation therapy may be considered as an adjunct therapy for pain, bleeding, and/or local obstruction. The National Comprehensive Cancer Network guidelines recommend that patients who undergo a laparotomy for potentially resectable disease but are found to have unresectable disease at the time of surgery should undergo stenting, open biliary-enteric bypass with or without gastrojejunostomy, and/or celiac plexus neurolysis.³³

Pancreatic exocrine enzyme insufficiency due to tumor extension, duct blockage, or surgical removal may cause malabsoprtive steatorrhea, contributing to cancer cachexia syndrome. Nutritional evaluation and daily oral pancreatic enzyme supplementation are recommended.³⁴

Patients diagnosed with pancreatic adenocarcinoma have a venous thromboembolism (VTE) incidence of 20 per 100 person-years (5%–60% of patients) and are considered at very high risk for VTE based on the Khorana score.³⁵ The preferred VTE treatment is low-molecular-weight heparin rather than warfarin based on the results of the CLOT study.³⁶ There is no current evidence for routine prophylactic therapy or the use of direct oral anticoagulants.

Finally, a cancer diagnosis, particularly pancreatic cancer, causes a significant amount of psychosocial stress and requires active support and counseling from a professional.

Conclusion

Pancreatic adenocarcinoma is the most lethal of all the gastrointestinal malignancies. FOLFIRINOX and gemcitabine/nab-paclitaxel are superior to gemcitabine monotherapy for patients with advanced unresectable and/or metastatic pancreatic cancer who are candidates for more aggressive therapy and are considered first-line therapies. Early data on the gemcitabine, nab-paclitaxel, and cisplatin combination appears to show superior efficacy. Second-line therapies are selected based on the patient’s performance status, first-line regimen, and residual toxicities from the prior regimen; options include gemcitabine/nab-paclitaxel, FOLFIRINOX (± oxaliplatin or irinotecan), single-agent gemcitabine (elderly frail patients), fluorouracil and liposomal-irinotecan, or referral for a clinical trial. The main challenge with pancreatic cancer is the development of stroma around the tumor, which abrogates drug delivery, allows for tumor growth in a hypoxic microenvironment, alters the metabolomics, and causes an immunosuppressive microenvironment. Drugs that target the microenvironments, such as hedgehog pathway inhibitors, have failed to show any clinical benefit, and we hope to see more efficacious microenvironment-targeted novel drugs in the future. In addition, immunotherapy has not shown any significant efficacy in clinical trials and many trials are still ongoing.

Introduction

Pancreatic ductal adenocarcinoma is a challenging disease with a poor prognosis, with 5-year survival rates in the single digits (~8%).¹ Survival rates in pancreatic cancer are low in part because most patients have advanced disease at the time of diagnosis and early development of systemic metastatic disease is common, with approximately 52% of patients with newly diagnosed pancreatic cancer having metastatic disease at diagnosis.¹ Surgical resection with negative margins is the cornerstone of potentially curative therapy for localized disease, but only 15% to 20% of patients are eligible for resection at the time of initial diagnosis. Patients with unresectable and metastatic disease are offered palliative chemotherapy. Unfortunately, early recurrence is common in patients with resectable tumors who achieve a complete resection and are treated with adjuvant therapy (5-year recurrence rate ~80%).^2,3 This article reviews the management of patients with unresectable and/or metastatic pancreatic cancer. A previous article reviewed the diagnosis and staging of pancreatic cancer and the approach to neoadjuvant and adjuvant therapy in patients with resectable and borderline-resectable disease.⁴

First-Line Systemic Treatment

Case Presentation

A 72-year-old man who underwent treatment for pancreatic adenocarcinoma 18 months ago presents to the emergency department after developing poor appetite, weight loss, and abdominal discomfort and fullness without diarrhea, which has been constant for the past 2 weeks even though he has been taking analgesics and pancreatic enzymes.

The patient was diagnosed with pancreatic cancer 18 months ago after presenting with yellowish skin and sclera color; abdominal and pelvis computed tomography (CT) with intravenous contrast showed a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein. Endoscopic ultrasound confirmed an irregular mass at the head of the pancreas and sonographic evidence suggested invasion into the portal vein. Examination of a tissue sample obtained during the procedure showed that the mass was consistent with pancreatic adenocarcinoma. Magnetic resonance imaging (MRI) performed to define venous vasculature involvement revealed a pancreatic head mass measuring 3.0 × 2.7 cm without arterial or venous vasculature invasion. The mass was abutting the portal vein and superior mesenteric veins, and a nonspecific 8-mm aortocaval lymph node was noted. The tumor was deemed to be borderline resectable, and the patient received neoadjuvant therapy with gemcitabine and nab-paclitaxel. After 4 cycles, his carbohydrate antigen (CA) 19-9 level decreased, and MRI revealed a smaller head mass (1.3 × 1.4 cm) with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remained stable. He was treated with gemcitabine chemoradiotherapy prior to undergoing an uncomplicated partial pancreaticoduodenectomy. Analysis of a surgical pathology specimen revealed T3N0 disease with a closest margin of 0.1 cm. Postsurgery, the patient completed 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine.

At his current presentation, MRI of the abdomen and pelvis reveals a new liver mass and peritoneal thickness. Serology testing reveals a CA 19-9 level of 240 U/mL, and other liver function tests are within normal limits. Biopsy of the mass confirms recurrence.

• What systemic chemotherapy would you recommend for this patient with metastatic pancreatic adenocarcinoma?

Most cases of pancreatic cancer are unresectable and/or metastatic at the time of diagnosis. Identifying treatment endpoints and the patient’s goals of care is a critical step in management. Systemic chemotherapy can provide significant survival benefit in first-line and second-line treatment compared to best supportive care. Palliative interventions also include systemic therapy, which often improves pain control and other cancer related–symptoms and hence quality of life. Participation in clinical trials should be offered to all patients. Therapy selection depends on the patient’s performance status, comorbidities, and liver profile and the results of biomarker testing and mutation analysis.

Several single-agents, including fluoropyrimidines, gemcitabine, irinotecan, platinum compounds, and taxanes, have minor objective response rates (< 10%) and a minimal survival benefit (~2 weeks) in metastatic pancreatic adenocarcinoma. Conversely, multi-agent therapies provide higher response rates and can extend overall survival (OS). Two combinations, nab-paclitaxel plus gemcitabine and FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and flourouracil), have significantly prolonged survival compared to best single-agent gemcitabine, as demonstrated in the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) and PRODIGE 4/ACCORD 11 trials.^5,6 Because both multi-agent regimens are also associated with a more toxic adverse effect profile, gemcitabine monotherapy continues to be a front-line therapy for patients with multiple comorbidities, elderly frail patients (> 80 years of age), or patients who cannot tolerate other combinations.⁷

Gemcitabine-Based Therapy

Gemcitabine became a standard of care treatment for pancreatic cancer in the mid-1990s, and was tested as a second-line therapy in a multicenter phase 2 clinical trial that accrued 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil therapy. In this trial, 27% of patients treated with gemcitabine achieved a clinical benefit response and the median OS was 3.85 months.⁸ The agent was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. Subsequently, a randomized clinical trial compared gemcitabine to fluorouracil in the front-line setting in 126 patients with newly diagnosed advanced pancreatic cancer.⁹ Patients were randomly assigned to receive single-agent intravenous fluorouracil administered without leucovorin as a short-term infusion (600 mg/m² once weekly) or gemcitabine (1000 mg/m² weekly for up to 7 weeks followed by 1 week of rest, and then weekly for 3 out of every 4 weeks thereafter). A higher proportion of patients treated with gemcitabine had a clinical benefit response (23.8% versus 4.8%), with an improvement in a composite measure of pain (pain intensity and analgesic consumption) and performance status. Clinical responses assessed by a secondary measure, weight gain, were below 10% in both arms, but the median OS was significantly longer for the gemcitabine arm (5.65 months versus 4.4 months, P = 0.0025) and the 1-year OS rate also favored the gemcitabine arm (18% versus 2%). Grade 3/4 neutropenia was reported more frequently in the gemcitabine arm (23% versus 5%). There is no evidence that increasing the dose intensity of the fixed-dose rate of gemcitabine (1000 mg/m² per week administered as a 30-minute infusion) leads to improved antitumor activity.

Following publication of the trial conducted by Burris and colleagues,⁹ a plethora of clinical trials have tried to outperform gemcitabine monotherapy, with all trials studying gemcitabine monotherapy compared with gemcitabine plus another agent (fluorouracil, cisplatin, oxaliplatin, irinotecan, pemetrexed, novel biologics including cetuximab, bevacizumab, axitinib, sorafenib, aflibercept). These combinations have failed to significantly extend OS compared to single-agent gemcitabine, although some showed a marginal clinical benefit:

• Capecitabine¹⁰ (hazard ratio [HR] 0.86 [95% confidence interval {CI} 0.75 to 0.98])
• Erlotinib¹¹ (HR 0.81 [95% CI 0.69 to 0.99])
• Cisplatin, epirubicin, fluorouracil, gemcitabine¹² (HR 0.65 [95% CI 0.43 to 0.99])

The best outcomes were obtained with gemcitabine plus nab-paclitaxel compared to gemcitabine monotherapy. The gemcitabine/nab-paclitaxel combination has not been compared to FOLFIRINOX in the front-line setting, as the ACCORD 11 and MPACT trials were ongoing simultaneously. However, a large retrospective trial that compared use of the regimens in the US Oncology Network in the United States demonstrated similar efficacy, although more patients treated with FOLFIRINOX needed white blood cell growth factor administration.¹³

Gemcitabine/nab-paclitaxel was studied in a phase 1/2 clinical trial with 67 untreated metastatic pancreatic cancer patients.¹⁴ Patients received nab-paclitaxel at doses of 100, 125, or 150 mg/m² followed by gemcitabine 1000 mg/m² on days 1, 8, and 15 every 28 days. The maximum tolerated dose (MTD) was 1000 mg/m² of gemcitabine plus 125 mg/m² of nab-paclitaxel once a week for 3 weeks every 28 days. Dose-limiting toxicities were sepsis and neutropenia. Patients who received the MTD had a response rate of 48%, median OS of 12.2 months, and a 1-year survival rate of 48%.

The landmark phase 3 MPACT trial confirmed that adding nab-paclitaxel to gemcitabine prolongs survival compared with gemcitabine monotherapy.⁵ This multinational randomized study included 861 treatment-naive patients with a Karnofsky performance score of 70 or higher. The median OS in the nab-paclitaxel/gemcitabine group was 8.5 months, as compared to 6.7 months in the gemcitabine monotherapy group (HR for death 0.72 [95% CI 0.62 to 0.83], P < 0.001). The survival rate was 35% in the nab-paclitaxel/gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. Median progression-free survival (PFS) was 5.5 months in the nab-paclitaxel/gemcitabine group, compared to 3.7 months in the gemcitabine group (HR for disease progression or death 0.69 [95% CI 0.58 to 0.82], P < 0.001). The overall response rate according to independent review was 23% compared with 7% in the 2 groups, respectively (P < 0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel/gemcitabine group versus 27% in the gemcitabine group), fatigue (17% versus 7%), and neuropathy (17% versus 1%). Febrile neutropenia occurred in 3% of the combination group versus 1% of the montherapy group. In the nab-paclitaxel/gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower a median of 29 days after discontinuation of nab-paclitaxel. In 2013, nab-paclitaxel in combination with gemcitabine received U.S. Food and Drug Administration (FDA) approval as first-line therapy for metastatic pancreatic cancer.

A pilot phase 1b/2 trial that added cisplatin to nab-paclitaxel and gemcitabine in treating 24 treatment-naive metastatic pancreatic adenocarcinoma patients showed impressive tumor response (complete response 8.3%, partial response 62.5%, stable disease 16.7%, progressive disease 12.5%) and extended median OS to 16.5 months.¹⁵ A phase 1b trial conducted in Europe added capecitabine to the cisplatin, nab-paclitaxel, and gemcitabine regimen, albeit with a different schedule and doses, in 24 patients with locally advanced and metastatic disease.¹⁶ This trial demonstrated an impressive overall response rate of 67%, with 43% of patients achieving a complete metabolic response on positron emission tomography scan and the CA 19-9 level decreasing by ≥ 49% in all 19 patients who had an elevated basal value. Moreover, PFS at 6 months was 96%. After chemotherapy 17 patients remained unresectable and 7 patients were taken to surgery; of the latter group, only 1 was determined to be unresectable at the time of surgery. This regimen is being explored in a larger study in patients with stage III and IV disease.

FOLFIRINOX

A randomized phase 2 clinical trial comparing FOLFIRINOX to gemcitabine monotherapy in 88 patients with treatment-naive metastatic pancreatic cancer revealed a high response rate for FOLFIRINOX (39% versus 11%, respectively) with a tolerable toxicity profile.¹⁷ FOLFIRINOX became the front-line standard of care therapy in pancreatic adenocarcinoma after the results of the subsequent phase 3 ACCORD 11 study preplanned interim analysis showed an unprecedented significantly improved OS benefit.⁶ The ACCORD 11 trial randomly assigned 342 patients with an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and a serum bilirubin level less than 1.5 times the upper limit of normal to receive FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 400 mg/m² given as a bolus followed by 2400 mg/m² given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg/m² weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. The median OS in the FOLFIRINOX group was 11.1 months as compared with 6.8 months in the gemcitabine group (HR 0.57 [95% CI 0.45 to 0.73], P < 0.001). The FOLFIRINOX group also had a longer median PFS (6.4 months versus 3.3 months, HR 0.47 [95% CI 0.37 to 0.59], P < 0.001) and higher objective response rate (31.6% versus 9.4%, P < 0.001). More adverse events were noted in the FOLFIRINOX group, including grade 3 or 4 neutropenia (46% versus 21%), febrile neutropenia (5.4% versus 1.2%), thrombocytopenia (9.1% versus 3.6%), sensory neuropathy (9% versus 0%), vomiting (15% versus 8%), fatigue (23% versus 18%), and diarrhea (13% versus 2%). Despite the greater toxicity, only 31% of the FOLFIRINOX group had a definitive degradation of quality of life, as compared to 66% in the gemcitabine group (HR 0.47 [95% CI 0.30 to 0.70], P < 0.001), thus indicating an improvement in quality of life.

Of note, combinations containing irinotecan require adequate biliary function for excretion of its active glucuronide metabolite, SN-38. Approximately 10% of patients in the United States are homozygous for the UGT1A1*28 allele polymorphism, which causes increased SN-38 bioavailability and hence a potential for severe toxicities (eg, life threatening-refractory diarrhea).¹⁸ Therefore, it is recommended that physicians start with a lower dose of irinotecan or choose a different regimen altogether in such patients.

Current Approach and Future Directions

Based on results of the ACCORD 11 and MPACT trials, both front-line regimens (nab-paclitaxel/gemcitabine and FOLFIRINOX) can be considered appropriate treatment options for treatment-naive patients with good performance status who have locally advanced unresectable or metastatic pancreatic adenocarcinoma. FOLFIRINOX has a higher objective response rate than nab-paclitaxel-gemcitabine (32% versus 23%, respectively), but the adverse effect profile favors the nab-paclitaxel/gemcitabine combination, acknowledging this conclusion is limited due to lack of a comparative trial. Modifications to both regimens have been presented at American Society of Clinical Oncology symposiums, with preliminary data showing an extended median OS and a more tolerable toxicity profile.^19,20 In a recent retrospective observational cohort comparative analysis of nab-paclitaxel/gemcitabine versus FOLFIRINOX, results showed no statistical difference in median OS. The real-world data showed that gemcitabine-based therapy is being offered commonly to elderly patients and patients with poor performance status.¹³ There is no current research proposal for conducting a direct head-to-head comparison between these 2 regimens. Based on extrapolated data from the prior mentioned trials and retrospective analysis reviews, current guidelines recommend offering younger (< 65 years old), healthier (no comorbidity contraindication) patients with excellent performance status (ECOG 0) first-line FOLFIRINOX or gemcitabine/nab-paclitaxel. Elderly patients with stable comorbidities and good performance status (ECOG 1 or 2, Karnofsky performance status ≥ 70) could be preferably considered for treatment with nab-paclitaxel/gemcitabine as first-line or modified FOLFIRINOX if performance status is excellent. Patients with poor performance status (ECOG ≥ 2), advanced age, and significant comorbidities could still be considered candidates for gemcitabine monotherapy. However, there are promising indications that the combination of gemcitabine, nab-paclitaxel, and cisplatin could be a frontline therapy in advanced pancreaticobilliary malignancies in the future.

Second-Line Systemic Treatment

Case Continued

The patient and oncologist opt to begin treatment with modified FOLFIRINOX therapy, and after the patient completes 10 cycles CT scan shows progression of disease. His oncologist decides to refer the patient to a comprehensive cancer center for evaluation for participation in clinical trials, as his performance status remains very good (ECOG 1) and he would like to seek a novel therapy. His liver mass biopsy and blood liquid biopsy are sent for tumor mutational profile evaluation; results show a high tumor mutational burden and microsatellite instability.

• What are second-line treatment options for metastatic pancreatic cancer?

Second-line regimen recommendations for metastatic pancreatic cancer depend on which agents were used in first-line therapy and the patient’s performance status and comorbidities. Patients who progressed on first-line FOLFIRINOX and continue to have a good performance status (ECOG 0 or 1) may be considered for gemcitabine/nab-paclitaxel therapy; otherwise, they may be candidates for gemcitabine plus capecitabine or gemcitabine monotherapy based on performance status and goals of care. Patients who progressed on front-line gemcitabine/nab-paclitaxel may opt for FOLFIRINOX (or an oxaliplatin-based regimen [FOLFOX] or irinotecan-based regimen [FOLFIRI] if FOLFIRINOX is not tolerable), nanoliposomal irinotecan/fluorouracil/leucovorin, or a short-term infusional fluorouracil and leucovorin regimen. The preferences for second-line treatment are not well established, and patients should be encouraged to participate in clinical trials. Chemotherapy should be offered only to those patients who maintain good performance status after progression on first-line therapy. For patients with poor performance status (ECOG 3 or 4) or multiple comorbidities, a discussion about goals of care and palliative therapy is warranted.

Gemcitabine-Based Therapy

An AGEO prospective multicenter cohort assigned 57 patients with metastatic pancreatic adenocarcinoma who had disease progression on FOLFIRINOX therapy to receive gemcitabine/nab-paclitaxel (dose as per MPACT trial).²¹ The median OS was 8.8 months and median PFS was 5.1 months after FOLFIRINOX. There were reported manageable grade 3/4 toxicities in 40% of patients, which included neutropenia (12.5%), neurotoxicity (12.5%), asthenia (9%), and thrombocytopenia (6.5%). A phase 2 clinical trial that evaluated gemcitabine monotherapy in 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil showed a 3.85-month survival benefit.²²

Irinotecan-Based Regimens

The NAPOLI-1 (NAnoliPOsomaL Irinotecan) trial evaluated nanoliposomal irinotecan (MM-398, nal-IRI) and fluorouracil/leucovorin in patients with metastatic pancreatic cancer refractory to gemcitabine-based therapy.²³ This global, open-label phase 3 trial initially randomly assigned and stratified 417 patients in a 1:1 fashion to receive either nanoliposomal irinotecan monotherapy (120 mg/m² every 3 weeks, equivalent to 100 mg/m² of irinotecan base) or fluorouracil/leucovorin combination. A third treatment arm consisting of nanoliposomal irinotecan (80 mg/m², equivalent to 70 mg/m² of irinotecan base) with fluorouracil and leucovorin every 2 weeks was added later in a 1:1:1 fashion. Patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin had a significantly improved OS of 6.1 months compared to 4.2 months with fluorouracil/leucovorin (HR 0.67 [95% CI 0.49 to 0.92], P = 0.012). The results of an intention-to-treat analysis favored the nanoliposomal irinotecan regimen, with a median OS of 8.9 months compared with 5.1 months (HR 0.57, P = 0.011). In addition, median PFS was improved in the nanoliposomal irinotecan arm (3.1 months versus 1.5 months; HR 0.56, P < 0.001), and median OS did not differ between patients treated with nanoliposomal irinotecan monotherapy and those treated with fluorouracil/leucovorin (4.9 months versus 4.2 months; HR 0.99 [95% CI 0.77 to 1.28], P = 0.94). The grade 3/4 adverse events that occurred most frequently in the 117 patients assigned to nanoliposomal irinotecan plus fluorouracil/leucovorin were neutropenia (27%), diarrhea (13%), vomiting (11%), and fatigue (14%). Nanoliposomal irinotecan combination provides another second-line treatment option for patients with metastatic pancreatic adenocarcinoma who have progressed on gemcitabine-based therapy but are not candidates for FOLFIRINOX.

Oxaliplatin-Based Regimens

Regimens that combine oxaliplatin with fluorouracil and leucovorin or capecitabine have shown superiority to fluorouracil/leucovorin or best supportive care (BSC). The CONKO study group compared oxaliplatin plus fluorouracil/leucovorin to BSC as second-line therapy in patients with advanced pancreatic cancer who progressed while on gemcitabine therapy (CONKO-003).²⁴ In this phase 3 trial, patients were randomly assigned (1:1) and stratified based on duration of first-line therapy, performance status, and tumor stage to receive BSC alone or the OFF regimen, which consisted of oxaliplatin (85 mg/m² on days 8 and 22) plus short-term infusional fluorouracil (2000 mg/m² over 24 hours) and leucovorin (200 mg/m² over 30 minutes), both given on days 1, 8, 15, and 22 of a 6-week cycle. This trial was terminated early according to predefined protocol regulations because of insufficient accrual (lack of acceptance of BSC by patients and physicians). Median second-line survival was 4.82 months for patients who received OFF treatment and 2.30 months for those who received BSC (HR 0.45 [95% CI 0.24 to 0.83], P = 0.008).  Neurotoxicity (grade 1/2) and nausea, emesis, and diarrhea (grade 2/3) were worse in the chemotherapy arm; otherwise, the regimen was well tolerated.

A later modification of the CONKO-003 trial changed the comparison arm from BSC to fluorouracil/leucovorin.²⁵ The median OS in the OFF group was 5.9 months versus 3.3 months in the fluorouracil/leucovorin group (HR 0.66 [95% CI 0.48 to 0.91], log-rank P = 0.010). Time to progression was significantly extended with OFF (2.9 months) as compared with fluorouracil/leucovorin (2.0 months; HR 0.68 [95% CI 0.50 to 0.94], log-rank P = 0.019). Rates of adverse events were similar between the treatment arms, with the exception of grades 1/2 neurotoxicity, which were reported in 38.2% and 7.1% of patients in the OFF and fluorouracil/leucovorin groups, respectively (P < 0.001).

The phase 3 PANCREOX trial failed to show superiority of modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) over fluorouracil/leucovorin.²⁶ A phase 2 trial of oxaliplatin plus capecitabine for second-line therapy in gemcitabine-treated advanced pancreatic cancer patients with dose adjustments for performance status (ECOG 2) and age (> 65 years) showed a median OS of 5.7 months without a comparison.²⁷ A modified oxaliplatin regimen may be a reasonable second-line therapy option for gemcitabine-treated patients who are not candidates for an irinotecan-based regimen (eg, elevated bilirubin) and continue to have an acceptable performance status.

Targeted Therapies

A variety of targeted therapies have failed to demonstrate major activity in metastatic pancreatic cancer, including bevacizumab targeting vascular endothelial growth factor, cetuximab targeting epidermal growth factor receptor, ruxolitinib targeting JAK pathway signaling, saridegib targeting the hedgehog pathway, and MK-0646 targeting insulin-like growth factor 1 receptor (IGFR). Other novel agents against targetable pathways that had promising early-phase results are currently being studied in ongoing clinical trials; these include JAK-2, PI3K, MEK, and BRAF inhibitors and immunotherapy.

Recent research efforts have focused on targeted testing of advanced pancreatic cancers for mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) and for the germline and somatic BRCA1/2 or PALB2 mutations to determine potential eligibility for immunotherapy. Patients with these tumor characteristics and/or mutations might also be more sensitive to platinum-based chemotherapy agents or poly (ADP-ribose) polymerase (PARP) inhibitors. Germline mutations in BRCA 1/2 are present in 5% to 8% of patients with pancreatic cancer (up to 10%–15% in Ashkenazi Jewish population).²⁸ A superior median OS was retrospectively observed for patients with advanced stage BRCA 1/2-associated pancreatic adenocarcinoma who were treated with platinum-based chemotherapy agents versus those treated with non-platinum-based agents (22 versus 9 months; P = 0.039).²² PARP inhibitors have shown activity in germline BRCA1/2-associated breast (off label) and ovarian cancers (approved by the FDA). The efficacy and safety of PARP inhibitors were evaluated in a phase 2 study of a spectrum of BRCA1/2-associated cancers, including pancreatic cancer. The results revealed a tumor response rate of 21.7% (5 of 23 patients with pancreatic cancer [95% CI 7.5 to 43.7]), and 35% of patients had stable disease for a duration of 8 weeks or more (95% CI 16.4 to 57.3) with good tolerability.²⁹ Three novel PARP inhibitors are currently under clinical trial investigation in patients with germline BRCA 1/2- and PALB2-mutated metastatic pancreatic cancer: maintenance olaparib (NCT02184195) and rucaparib (NCT03140670) are both being studied as monotherapy in patients whose disease has not progressed on first-line platinum-based chemotherapy, and veliparib is being evaluated in a 3-arm study that includes gemcitabine and cisplatin with or without veliparib and single-agent maintenance veliparib (NCT01585805).

In 2017, the FDA granted accelerated approval to pembrolizumab for treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors whose disease progressed on prior treatments, making it the first oncology drug to be approved based on the genetic features of the tumor rather than its location in the body. This first tissue/site-agnostic approval was based on results from 5 single-arm trials involving 149 patients, including 5 patients with pancreatic cancer.³⁰ The objective response rate with pembrolizumab was 39.6% (95% CI 31.7 to 47.9), including a 7.4% complete response rate and a 32.2% partial response rate. The median duration of response was not reached at the time of publication (range, 1.6+ months to 22.7+ months).

Palliative and Supportive Care

Case Continued

The patient opts to participate in a novel immunotherapy clinical trial and is currently on his second cycle. He continues to have right upper quadrant pain despite opioid analgesia, has not gained any weight, and noticed new right lower extremity swelling after a recent holiday vacation to Florida.

• What supportive measures should be in place for patients with metastatic adenocarcinoma?

Most patients with advanced pancreatic adenocarcinoma will require a palliative intervention. All new unresectable pancreatic cancer patients should have an early psychosocial evaluation; identification of symptoms and implementation of preventive interventions that would improve quality of life and reduce suffering are paramount. A multidisciplinary team including physician/nursing staff, nutritionist/dietitian, palliative service, a social worker, and a case manager should be involved in patient care. More than two-thirds of patients can develop symptomatic biliary obstruction.³¹ Bile duct obstruction due to locally advanced pancreatic adenocarcinoma causes hyperbilirubinemia, which requires endoscopic placement of a metallic or plastic stent; plastic stents have a higher rate of re-occlusion.³² Appropriate bile flow allows treatment with irinotecan-based regimens. Percutaneous biliary drainage may be necessary if endoscopic intervention is not feasible.

Approximately one quarter of patients may present with gastric outlet obstruction due to duodenal obstruction.³¹ Endoscopic placement of an enteral expandable metal stent is preferred. Alternatively, percutaneous endoscopic gastrostomy tube placement may give symptomatic relief. Palliative surgical interventions are reserved for patients with greater life expectancy and in whom all other interventions have failed or are not feasible.

Almost all patients with pancreatic adenocarcinoma will experience cancer-associated pain. Intractable pain should be treated with a celiac plexus block. Radiation therapy may be considered as an adjunct therapy for pain, bleeding, and/or local obstruction. The National Comprehensive Cancer Network guidelines recommend that patients who undergo a laparotomy for potentially resectable disease but are found to have unresectable disease at the time of surgery should undergo stenting, open biliary-enteric bypass with or without gastrojejunostomy, and/or celiac plexus neurolysis.³³

Pancreatic exocrine enzyme insufficiency due to tumor extension, duct blockage, or surgical removal may cause malabsoprtive steatorrhea, contributing to cancer cachexia syndrome. Nutritional evaluation and daily oral pancreatic enzyme supplementation are recommended.³⁴

Patients diagnosed with pancreatic adenocarcinoma have a venous thromboembolism (VTE) incidence of 20 per 100 person-years (5%–60% of patients) and are considered at very high risk for VTE based on the Khorana score.³⁵ The preferred VTE treatment is low-molecular-weight heparin rather than warfarin based on the results of the CLOT study.³⁶ There is no current evidence for routine prophylactic therapy or the use of direct oral anticoagulants.

Finally, a cancer diagnosis, particularly pancreatic cancer, causes a significant amount of psychosocial stress and requires active support and counseling from a professional.

Conclusion

Pancreatic adenocarcinoma is the most lethal of all the gastrointestinal malignancies. FOLFIRINOX and gemcitabine/nab-paclitaxel are superior to gemcitabine monotherapy for patients with advanced unresectable and/or metastatic pancreatic cancer who are candidates for more aggressive therapy and are considered first-line therapies. Early data on the gemcitabine, nab-paclitaxel, and cisplatin combination appears to show superior efficacy. Second-line therapies are selected based on the patient’s performance status, first-line regimen, and residual toxicities from the prior regimen; options include gemcitabine/nab-paclitaxel, FOLFIRINOX (± oxaliplatin or irinotecan), single-agent gemcitabine (elderly frail patients), fluorouracil and liposomal-irinotecan, or referral for a clinical trial. The main challenge with pancreatic cancer is the development of stroma around the tumor, which abrogates drug delivery, allows for tumor growth in a hypoxic microenvironment, alters the metabolomics, and causes an immunosuppressive microenvironment. Drugs that target the microenvironments, such as hedgehog pathway inhibitors, have failed to show any clinical benefit, and we hope to see more efficacious microenvironment-targeted novel drugs in the future. In addition, immunotherapy has not shown any significant efficacy in clinical trials and many trials are still ongoing.

Introduction

Non-Hodgkin lymphoma (NHL) comprises a wide variety of malignant hematologic disorders with varying clinical and biological features. The more than 60 separate NHL subtypes can be classified according to cell of origin (B cell versus T cell), anatomical location (eg, orbital, testicular, bone, central nervous system), clinical behavior (indolent versus aggressive), histological features, or cytogenetic abnormalities. Although various NHL classification schemes have been used over the years, the World Health Organization (WHO) classification is now widely accepted as the definitive pathologic classification system for lymphoproliferative disorders, incorporating morphologic, immunohistochemical, flow cytometric, cytogenetic, and molecular features.¹ While the pathologic and molecular subclassification of NHL has become increasingly refined in recent years, from a management standpoint, classification based on clinical behavior remains very useful. This approach separates NHL subtypes into indolent versus aggressive categories. Whereas indolent NHLs may remain clinically insignificant for months to years, aggressive B-cell NHLs generally become life-threatening within weeks to months without treatment.

Epidemiology

Data from cancer registries show a steady, unexplainable increase in the incidence of NHL during the second half of the 20th century; the incidence has subsequently plateaued. There was a significant increase in NHL incidence between 1970 and 1995, which has been attributed in part to the HIV epidemic. More than 72,000 new cases of NHL were diagnosed in the United States in 2017, compared to just over 8000 cases of Hodgkin lymphoma, making NHL the sixth most common cancer in adult men and the fifth most common in adult women.² NHL appears to occur more frequently in Western countries than in Asian populations.

Various factors associated with increased risk for B-cell NHL have been identified over the years, including occupational and environmental exposure to certain pesticides and herbicides,³ immunosuppression associated with HIV infection,⁴ autoimmune disorders,⁵ iatrogenically induced immune suppression in the post-transplant and other settings,⁶ family history of NHL,⁷ and a personal history of a prior cancer, including Hodgkin lymphoma and prior NHL.⁸ In terms of infectious agents associated with aggressive B-cell NHLs, Epstein-Barr virus (EBV) has a clear pathogenic role in Burkitt lymphoma, in many cases of post-transplant lymphoproliferative disorders, and in some cases of HIV-related aggressive B-cell lymphoma.⁹ Human herpesvirus-8 viral genomes have been found in virtually all cases of primary effusion lymphomas.¹⁰ Epidemiological studies also have linked hepatitis B and C to increased incidences of certain NHL subtypes,^11–13 including primary hepatic diffuse large B-cell lymphoma (DLBCL). Similarly, Helicobacter pylori has been associated with gastric DLBCL.

Staging and Work-Up

A tissue biopsy is essential in the diagnosis and management of NHL. The most significant disadvantage of fine-needle aspiration cytology is the lack of histologic architecture. The optimal specimen is an excisional biopsy; when this cannot be performed, a core needle biopsy, ideally using a 16-gauge or larger caliber needle, is the next best choice.

The baseline tests appropriate for most cases of newly diagnosed aggressive B-cell NHL are listed in Table 1. Both hepatitis B and C have been associated with increased risk of NHL. In addition, there is a risk of hepatitis B reactivation following certain NHL therapies. A contrast-enhanced computed tomography (CT) scan in addition to positron emission tomography (PET) is useful to define the extent of disease in situations needing greater definition (eg, lymphadenopathy close to the bowel, cervical and supraclavicular nodal involvement, and lymphadenopathy causing thrombosis or compression of nearby structures).¹⁴ In cases where it is apparent that the patient has advanced stage disease (Ann Arbor stage III/IV) based on imaging, bone marrow biopsy is unlikely to alter the treatment plan. For such patients, if the complete blood count is unremarkable, deferral of bone marrow biopsy may be reasonable. For new cases of DLBCL, assessment for MYC translocation by fluorescence in situ hybridization (FISH) is recommended. If a MYC translocation is identified, then testing for BCL2 and BCL6 translocations by FISH should be performed.

Prior to the initiation of treatment, patients should always undergo a thorough cardiac and pulmonary evaluation, especially if the patient will be treated with an anthracycline or mediastinal irradiation. Central nervous system (CNS) evaluation with magnetic resonance imaging (MRI) and lumbar puncture is essential if there are neurological signs or symptoms. In addition, certain anatomical sites including the testicles, paranasal sinuses, kidney, adrenal glands, and epidural space have been associated with increased involvement of the CNS and may warrant MRI evaluation and lumbar puncture. Certain NHL subtypes like Burkitt lymphoma, high-grade NHL with translocations of MYC and BCL-2 or BCL-6 (double-hit lymphoma), blastoid mantle cell lymphoma, and lymphoblastic lymphoma have a high risk of CNS involvement, and patients with these subtypes need CNS evaluation.

The Lugano classification is used to stage patients with NHL.¹⁴ This classification is based on the Ann Arbor staging system and uses the distribution and number of tumor sites to stage disease. In general, this staging system in isolation is of limited value in predicting survival after treatment. However, the Ann Arbor stage does have prognostic impact when incorporated into risk scoring systems such as the International Prognostic Index (IPI). In clinical practice, the Ann Arbor stage is useful primarily to determine eligibility for localized therapy approaches. The absence or presence of systemic symptoms such as fevers, drenching night sweats, or weight loss (> 10% of baseline over 6 months or less) is designated by A or B, respectively.

Diffuse Large B-Cell Lymphoma

DLBCL is the most common lymphoid neoplasm in adults, accounting for about 25% of all NHL cases.² It is increasingly clear that the diagnostic category of DLBCL is quite heterogeneous in terms of morphology, genetics, and biologic behavior. A number of clinicopathologic subtypes of DLBCL exist, such as T cell/histiocyte–rich large B-cell lymphoma, primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, and EBV-positive large B-cell lymphoma, among others. Gene expression profiling (GEP) can distinguish 2 cell of origin DLBCL subtypes: the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes.¹⁵

DLBCL may be primary (de novo) or may arise through the transformation of many different types of low-grade B-cell lymphomas. This latter scenario is referred to as histologic transformation or transformed lymphoma. In some cases, patients may have a previously diagnosed low-grade B-cell NHL; in other cases, both low-grade and aggressive B-cell NHL may be diagnosed concurrently. The presence of elements of both low-grade and aggressive B-cell NHL in the same biopsy specimen is sometimes referred to as a composite lymphoma.

In the United States, incidence varies by ethnicity, with DLBCL being more common in Caucasians than other races.¹⁶ There is a slight male predominance (55%), median age at diagnosis is 65 years,^16,17 and the incidence increases with age.

Presentation, Pathology, and Prognostic Factors

The most common presentation of patients with DLBCL is rapidly enlarging lymphadenopathy, usually in the neck or abdomen. Extranodal/extramedullary presentation is seen in approximately 40% of cases, with the gastrointestinal (GI) tract being the most common site. However, extranodal DLBCL can arise in virtually any tissue.¹⁸ Nodal DLBCL presents with symptoms related to the sites of involvement (eg, shortness of breath or chest pain with mediastinal lymphadenopathy), while extranodal DLBCL typically presents with symptoms secondary to dysfunction at the site of origin. Up to one third of patients present with constitutional symptoms (B symptoms) and more than 50% have elevated serum lactate dehydrogenase (LDH) at diagnosis.¹⁹

Approximately 40% of patients present with stage I/II disease. Of these, only a subset present with stage I, or truly localized disease (defined as that which can be contained within 1 irradiation field). About 60% of patients present with advanced (stage III–IV) disease.²⁰ The bone marrow is involved in about 15% to 30% of cases. DLBCL involvement of the bone marrow is associated with a less favorable prognosis. Patients with DLBCL elsewhere may have low-grade NHL involvement of the bone marrow. Referred to as discordant bone marrow involvement,²¹ this feature does not carry the same poor prognosis associated with transformed disease²² or DLBCL involvement of the bone marrow.²³

DLBCL is defined as a neoplasm of large B-lymphoid cells with a diffuse growth pattern. The proliferative fraction of cells, as determined by Ki-67 staining, is usually greater than 40%, and may even exceed 90%. Lymph nodes usually demonstrate complete effacement of the normal architecture by sheets of atypical lymphoid cells. Tumor cells in DLBCL generally express pan B-cell antigens (CD19, CD20, CD22, CD79a, Pax-5) as well as CD45 and surface immunoglobulin. Between 20% and 37% of DLBCL cases express the BCL-2 protein,²⁴ and about 70% express the BCL-6 protein.²⁵ C-MYC protein expression is seen in a higher percentage (~ 30%–50%) of cases of DLBCL.²⁶

Many factors are associated with outcome in DLBCL. The IPI score was developed in the pre-rituximab era and is a robust prognostic tool. This simple tool uses 5 easily obtained clinical factors (age > 60 years, impaired performance status, elevated LDH, > 1 extranodal site of disease, and stage III/IV disease). By summing these factors, 4 groups with distinct 5-year overall survival (OS) rates ranging from 26% to 73% were identified (Table 2). Subsequently, modifications were made to adjust for age and stage, with the latest iteration being the NCCN (National Comprehensive Cancer Network) IPI.²⁷ This tool uses age, performance status, LDH ratio (relative to the upper limit of normal), a more precise definition for presence of extranodal sites of disease (defined as lymphomatous involvement in the bone marrow, CNS, liver/GI tract, or lung), and Ann Arbor stage to stratify patients into 4 risk groups with significantly different 5-year OS, ranging from 38% to 96% based on the subgroup. Importantly, the NCCN-IPI was derived in a cohort of patients treated with rituximab-based therapy.

Cytogenetic and molecular factors also predict outcome in DLBCL. The ABC subtype distinguished by GEP has consistently been shown to have inferior outcomes with first-line therapy. As GEP is not routinely available in clinical practice, immunohistochemical (IHC) approaches (eg, the Hans algorithm) have been developed that can approximate the GEP subtypes. These IHC approaches have approximately 80% concordance with GEP.²⁸ The 3 most common chromosomal translocations in DLBCL involve BCL-2, BCL-6 and MYC. MYC-rearranged DLBCLs have a less favorable prognosis.^29,30 Cases in which a MYC translocation occurs in combination with a BCL-2 or BCL-6 translocation are commonly referred to as double-hit lymphoma (DHL); cases with all 3 translocations are referred to as triple-hit lymphoma (THL). Both DHL and THL have a worse prognosis with standard DLBCL therapy compared to non-DHL/THL cases. In the 2016 revised WHO classification, DHL and THL are an entity technically distinct from DLBCL, referred to as high-grade B-cell lymphoma.¹ In some cases, MYC and BCL-2 protein overexpression occurs in the absence of chromosomal translocations. Cases in which MYC and BCL-2 are overexpressed (by IHC) are referred to as double expressor lymphoma (DEL), and also have inferior outcome compared with non-DEL DLBCL.^31,32 Interestingly, MYC protein expression alone does not confer inferior outcomes, unlike isolated MYC translocation, which is associated with inferior outcomes.

Treatment

First-Line Therapy

DLBCL is an aggressive disease and, in most cases, survival without treatment can be measured in weeks to months. The advent of combination chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] or CHOP-like regimens) led to disease-free survival (DFS) rates of 35% to 40% at 3 to 5 years.³³ The addition of rituximab to CHOP (R-CHOP) has improved both progression-free surivial (PFS) and OS.^34,35

Treatment options vary for patients with localized (stage I/II) and advanced (stage III/IV) disease. Options for limited-stage DLBCL include an abbreviated course of R-CHOP (3 or 4 cycles) with involved-field radiation therapy (IFRT) versus a full course (6–8 cycles) of R-CHOP without radiation therapy (RT). Most studies comparing combined modality therapy (chemotherapy plus RT) versus chemotherapy alone were conducted in the pre-rituximab era. With the introduction of rituximab, Persky and colleagues³⁶ studied the use of 3 cycles of R-CHOP followed by RT, demonstrating a slightly improved OS of 92% at 4 years as compared to 88% in a historical cohort. The French LYSA/GOELAMS group performed the only direct comparison in the rituximab era (4 cycles of R-CHOP followed by RT versus 4 cycles of R-CHOP followed by 2 additional cycles of R-CHOP) and reported similar outcomes between both arms,³⁷ with OS of 92% in the R-CHOP alone arm and 96% in the R-CHOP + RT arm (nonsignificant difference statistically). IFRT alone is not recommended other than for palliation in patients who cannot tolerate chemotherapy or combined modality therapy. Stage I and II patients with bulky disease (> 10 cm) have a prognosis similar to patients with advanced DLBCL and should be treated aggressively with 6 to 8 cycles of R-CHOP with or without RT.³⁶

For patients with advanced stage disease, a full course of R-CHOP-21 (6–8 cycles given on a 21-day cycle) is the standard of care. This approach results in OS rates of 70% and 60% at 2 and 5 years, respectively. For older adults unable to tolerate full-dose R-CHOP, attenuated versions of R-CHOP with decreased dose density or decreased dose intensity have been developed.³⁸ Numerous randomized trials have attempted to improve upon the results of R-CHOP-21 using strategies such as infusional chemotherapy (DA-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab]);³⁹ dose-dense therapy (R-CHOP-14);replacement of rituximab with obinutuzuimab;⁴⁰ addition of novel agents such as bortezomib,⁴¹ lenalidomide,⁴² or ibrutinib^43,44 to R-CHOP; and various maintenance strategies such as rituximab, lenalidomide,⁴⁵ enzastaurin,⁴⁶ and everolimus.⁴⁷ Unfortunately, none of these strategies has been shown to improve OS in DLBCL. In part this appears to be due to the fact that inclusion/exclusion criteria for DLBCL trials have been too strict, such that the most severely ill DLBCL patients are typically not included. As a result, the results in the control arms have ended up better than what was expected based on historical data. Efforts are underway to include all patients in future first-line DLBCL studies.

Currently, autologous hematopoietic cell transplantation (auto-HCT) is not routinely used in the initial treatment of DLBCL. In the pre-rituximab era, numerous trials were conducted in DLBCL patients with high and/or high-intermediate risk disease based on the IPI score to determine if outcomes could be improved with high-dose therapy and auto-HCT as consolidation after patients achieved complete remission with first-line therapy. The results of these trials were conflicting. A 2003 meta-analysis of 11 such trials concluded that the results were very heterogeneous and showed no OS benefit.⁴⁸ More recently, the Southwestern Oncology Group published the results of a prospective trial testing the impact of auto-HCT for consolidation of aggressive NHL patients with an IPI score of 3 to 5 who achieved complete remission with first-line therapy with CHOP or R-CHOP. In this study, 75% of the patients had DLBCL and, of the B-cell NHL patients, 47% received R-CHOP. A survival benefit was seen only in the subgroup that had an IPI score of 4 or 5; a subgroup analysis restricted to those receiving R-CHOP as induction was not performed, however.⁴⁹ As a result, this area remains controversial, with most institutions not routinely performing auto-HCT for any DLBCL patients in first complete remission and some institutions considering auto-HCT in first complete remission for patients with an IPI score of 4 or 5. These studies all used the IPI score to identify high-risk patients. It is possible that the use of newer biomarkers or minimal-residual disease analysis will lead to a more robust algorithm for identifying high-risk patients and selecting patients who might benefit from consolidation of first complete remission with auto-HCT.

For patients with DHL or THL, long-term PFS with standard R-CHOP therapy is poor (20% to 40%).^50,51 Treatment with more intensive first-line regimens such as DA-EPOCH-R, R-hyperCVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), or CODOX-M/IVAC±R (cyclophosphamide, vincristine, doxorubicin, high‐dose methotrexate/ifosfamide, etoposide, high‐dose cytarabine ± rituximab), along with CNS prophylaxis, however, has been shown to produce superior outcomes,⁵² with 3-year relapse-free survival rates of 88% compared to 56% for R-CHOP. For patients who achieve a complete response by PET/CT scan after intensive induction, consolidation with auto-HCT has not been shown to improve outcomes based on retrospective analysis. However for DHL/THL patients who achieve complete response after R-CHOP, PFS was improved if auto-HCT was given as consolidation of first remission.⁵³

Patients with DLBCL have an approximately 5% risk of subsequently developing CNS involvement. Historically (in the pre-rituximab era), patients who presented with multiple sites of extranodal disease and/or extensive bone marrow involvement and/or an elevated LDH had an increased risk (up to 20%–30%) of developing CNS involvement. In addition, patients with involvement of certain anatomical sites (testicular, paranasal sinuses, epidural space) had an increased risk of CNS disease. Several algorithms have been proposed to identify patients who should receive prophylactic CNS therapy. One of the most robust tools for this purpose is the CNS-IPI, which is a 6-point score consisting of the 5 IPI elements, plus 1 additional point if the adrenal glands or kidneys are involved. Importantly, the CNS-IPI was developed and validated in patients treated with R-CHOP-like therapy. Subsequent risk of CNS relapse was 0.6%, 3.4%, and 10.2% for those with low-, intermediate- and high-risk CNS-IPI scores, respectively.⁵⁴ A reasonable strategy, therefore, is to perform CNS prophylaxis in those with a CNS-IPI score of 4 to 6. When CNS prophylaxis is used, intrathecal methotrexate or high-dose systemic methotrexate is most frequently given, with high-dose systemic methotrexate favored over intrathecal chemotherapy given that high-dose methotrexate penetrates the brain and spinal cord parenchyma, in addition to treating the cerebrospinal fluid (CSF).⁵⁵ In contrast, intrathecal therapy only treats the CSF and requires repeated lumbar punctures or placement of an Ommaya reservoir. For DLBCL patients who present with active CSF involvement (known as lymphomatous meningitis), intrathecal chemotherapy treatments are typically given 2 or 3 times weekly until the CSF clears, followed by weekly intrathecal treatment for 4 weeks, and then monthly intrathecal treatment for 4 months.⁵⁶ For those with concurrent systemic and brain parenchymal DLBCL, a strategy of alternating R-CHOP with mid-cycle high-dose methotrexate can be successful. In addition, consolidation with high-dose therapy and auto-HCT improved survival in such patients in 1 retrospective series.⁵⁷

Relapsed/Refractory Disease

Between 30% and 40% of patients with advanced stage DLBCL will either fail to attain a remission with primary therapy (referred to as primary induction failure) or will relapse. In general, for those with progressive or relapsed disease, an updated tissue biopsy is recommended. This is especially true for patients who have had prior complete remission and have new lymph node enlargement, or those who have emergence of new sites of disease at the completion of first-line therapy.

Patients with relapsed disease are treated with systemic second-line platinum-based chemoimmunotherapy, with the usual goal of ultimately proceeding to auto-HCT. A number of platinum-based regimens have been used in this setting such as R-ICE, R-DHAP, R-GDP, R-Gem-Ox, and R-ESHAP. None of these regimens has been shown to be superior in terms of efficacy, and the choice of regimen is typically made based on the anticipated tolerance of the patient in light of comorbidities, laboratory studies, and physician preference. In the CORAL study, R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin) seemed to show superior PFS in patients with the GCB subtype.⁵⁸ However, this was an unplanned subgroup analysis and R-DHAP was associated with higher renal toxicity.

Several studies have demonstrated that long-term PFS can be observed for relapsed/refractory DLBCL patients who respond to second-line therapy and then undergo high-dose therapy with auto-HCT. The Parma trial remains the only published prospective randomized trial performed in relapsed DLBCL comparing a transplant strategy to a non-transplant strategy. This study, performed in the pre-rituximab era, clearly showed a benefit in terms of DFS and OS in favor of auto-HCT versus salvage therapy alone.⁵⁹ The benefit of auto-HCT in patients treated in the rituximab era, even in patients who experience early failure (within 1 year of diagnosis), was confirmed in a retrospective analysis by the Center for International Blood and Marrow Transplant Research. In this study, a 44% 3-year PFS was seen in the early failure cohort versus 52% in the late failure cohort.⁶⁰

Some DLBCL patients are very unlikely to benefit from auto-HCT. The REFINE study focused on patients with primary induction failure or early relapse within 6 months of completing first-line therapy. Among such patients, primary progressive disease (defined as progression while still receiving first-line therapy), a high NCCN-IPI score at relapse, and MYC rearrangement were risk factors for poor PFS following auto-HCT.⁶¹ Patients with 2 or 3 high-risk features had a 2-year OS of 10.7% compared to 74.3% for those without any high-risk features.

Allogeneic HCT (allo-HCT) is a treatment option for relapsed/refractory DLBCL. This option is more commonly considered for patients in whom an autotransplant has failed to achieve durable remission. For properly selected patients in this setting, a long-term PFS in the 30% to 40% range can be attained.⁶² However, in practice, only about 20% of patients who fail auto-HCT end up undergoing allo-HCT due to rapid progression of disease, age, poor performance status, or lack of suitable donor. It has been proposed that in the coming years, allo-HCT will be utilized less commonly in this setting due to the advent of chimeric antigen receptor T-cell (CAR T) therapy.

CAR T-cell therapy genetically modifies the patient’s own T lymphocytes with a gene that encodes an antigen receptor to direct the T cells against lymphoma cells. Typically, the T cells are genetically modified and expanded in a production facility and then infused back into the patient. Axicabtagene ciloleucel is directed against the CD-19 receptor and has been approved by the US Food and Drug Administration (FDA) for treatment of patients with DLBCL who have failed 2 or more lines of systemic therapy. Use of CAR-T therapy in such patients was examined in a multicenter trial (ZUMA-1), which reported a 54% complete response rate and 52% OS rate at 18 months.⁶³ CAR-T therapy is associated with serious side effects such as cytokine release syndrome, neurological toxicities, and prolonged cytopenias. While there are now some patients with ongoing remission 2 or more years after undergoing CAR-T therapy, it remains uncertain what proportion of patients have been truly cured with this modality. Nevertheless, this new treatment option remains a source of optimism for relapsed and refractory DLBCL patients.

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma (PMBCL) is a form of DLBCL arising in the mediastinum from the thymic B cell. It is an uncommon entity and has clinical and pathologic features distinct from systemic DLBCL.⁶⁴ PMBCL accounts for 2% of all NHLs and about 7% of all DLBCL.²⁰ It typically affects women in the third to fourth decade of life.

Presentation and Prognostic Features

PMBCL usually presents as a locally invasive anterior mediastinal mass, often with a superior vena cava syndrome which may or may not be clinically obvious.⁶⁴ Other presentations include pericardial tamponade, thrombosis of neck veins, and acute airway obstruction. About 80% of patients present with bulky (> 10 cm) stage I or II disease,⁶⁵ with distant spread uncommon on presentation. Morphologically and on GEP, PMBL has a profile more similar to classical Hodgkin lymphoma (cHL) than non-mediastinal DLBCL.⁶⁶ PMBL is distinguished from cHL by immunophenotyping: unlike cHL, PMBCL has pan B cell markers, rarely expresses CD15, and has weak CD30.

Poor prognostic features in PMBCL are Eastern Cooperative Oncology Group (ECOG) performance status greater than 2, pericardial effusion, bulky disease, and elevated serum LDH. The diagnosis of PMBCL can be difficult because the tumor is often encased with extensive fibrosis and necrosis. As a result, a needle biopsy may not yield sufficient tissue, thus making a surgical biopsy often the only viable way to obtain sufficient tissue.

Treatment

Early series suggested that PMBCL is unusually aggressive, with a poor prognosis.⁶⁷ This led to studies using more aggressive chemotherapy regimens (often in combination with mediastinal radiation) as well as upfront auto-HCT.^68–70 The addition of rituximab to treatment regimens significantly improved outcomes in PMBCL. For example, a subgroup analysis of the PMBCL patients in the MinT trial revealed a 3-year event-free survival (EFS) of 78%⁷¹ when rituximab was combined with CHOP. Because of previous reports demonstrating radiosensitivity of PMBL, radiation was traditionally sequenced into treatment regimens for PMBL. However, this is associated with higher long-term toxicities, often a concern in PMBCL patients given that the disease frequently affects younger females, and given that breast tissue will be in the radiation field. For patients with a strong personal or family history of breast cancer or cardiovascular disease, these concerns are even more significant. More recently, the DA-EPOCH-R regimen has been shown to produce very high rates (80%–90%) of long-term DFS, without the need for mediastinal radiation in most cases.^72,73 For patients receiving R-CHOP, consolidation with mediastinal radiation is still commonly given. This approach also leads to high rates of long-term remission and, although utilizing mediastinal radiation, allows for less intensive chemotherapy. Determining which approach is most appropriate for an individual patient requires an assessment of the risks of each treatment option for that patient. A randomized trial by the International Extranodal Lymphoma Study Group (IELSG37) is evaluating whether RT may be safely omitted in PMBCL patients who achieve a complete metabolic response after R-CHOP.

Most relapses of PMBCL occur within the first 1 to 2 years and often present with extranodal disease in various organs. For those with relapsed or refractory disease, high-dose chemotherapy followed by auto-HCT provides 5-year survival rates of 50% to 80%.^74–76 In a phase 1b trial evaluating the role of pembrolizumab in relapsed/refractory patients (KEYNOTE-13), 7 of 17 PMBCL patients achieved responses, with an additional 6 demonstrating stable disease.⁷⁷ This provides an additional option for patients who might be too weak to undergo auto-HCT or for those who relapse following auto-HCT.

Mantle Cell Lymphoma

The name mantle cell lymphoma (MCL) is based on the presumed normal cell counterpart to MCL, which is believed to be found in the mantle zone surrounding germinal center follicles. It represents approximately 6% of all NHL cases in the United States and Europe.⁷⁸ MCL occurs at a median age of 63 to 68 years and has a male predominance.

Presentation and Prognostic Features

Patients can present with a broad spectrum of clinical features, and most patients (70%) present with advanced disease.⁷⁹ Up to one third of patients have B symptoms, with most demonstrating lymphadenopathy and bone marrow involvement. Approximately 25% present with extranodal disease as the primary presentation (eg, GI tract, pleura, breast, or orbits). MCL can involve any part of the GI tract and often presents as polypoid lesions.

Histologically, the pattern of MCL may be diffuse, nodular, mantle zone, or a combination of the these; morphologically, MCL can range from small, more irregular lymphocytes to lymphoblast-like cells. Blastoid and pleomorphic variants of MCL have a higher proliferation index and a more aggressive clinical course than other variants. MCL is characterized by the expression of pan B cell antigens (CD19+, CD20+) with coexpression of the T-cell antigen CD5, lack of CD23 expression, and nuclear expression of cyclin D1. Nuclear staining for cyclin D1 is present in more than 98% of cases.⁸⁰ In rare cases, CD5 or cyclin D1 may be negative.⁸⁰ Most MCL cases have a unique translocation that fuses the immunoglobulin heavy chain gene promoter (14q32) to the promoter of the BCL-1 gene (11q13), which encodes the cyclin D1 protein. This translocation is not unique to MCL and can be present in multiple myeloma as well. Interestingly, cyclin D1 is overproduced in cases lacking t(11:14), likely from other point mutations resulting in its overexpression.⁸¹ Cyclin D1–negative tumors overexpress cyclin D2 or D3, with no apparent difference in clinical behavior or outcome.⁸² In cyclin D1–negative cases, SOX11 expression may help with diagnosis.⁸³ A proliferation rate greater than 30% (as measured by Ki-67 staining), low SOX11 expression, and presence of p53 mutations have all been associated with adverse outcome.

In a minority of cases, MCL follows an indolent clinical course. For the remainder, however, MCL is an aggressive disease that generally requires treatment soon after diagnosis. When initially described in the 1980s and 1990s, treatment of MCL was characterized by low complete response rates, short durations of remission, repeated recurrences, and a median survival in the 2- to 5-year range.⁸⁴ In recent years, intensive regimens incorporating rituximab and high-dose cytarabine with or without auto-HCT have been developed and are associated with high complete response rates and median duration of first remission in the 6- to 9-year range.^85–87 Several prognostic indices have been applied to patients with MCL, including the IPI, the Follicular Lymphoma International Prognostic Index , and the Mantle Cell Lymphoma International Prognostic Index (MIPI). The MIPI was originally described based on a cohort from the period 1996 to 2004,⁸⁸ and subsequently confirmed in a separate cohort of 958 patients with MCL treated on prospective trials between 2004 and 2010.⁸⁹ The MIPI score can identify 3 risk groups with significant survival differences (83%, 63%, and 34% survival at 5 years). A refined version of the MIPI score, the combined MIPI or MIPI-c, incorporates proliferation rate and is better able to stratify patients.⁹⁰ The blastoid variant of MCL follows a more aggressive clinical course and is associated with a high proliferation rate, shorter remissions, and a higher rate of CNS involvement.⁹¹

In most patients, MCL is an aggressive disease with a short OS without treatment. A subset of patients may have a more indolent course,⁹² but unfortunately reliable factors that identify this group at the time of diagnosis are not available. Pretreatment evaluation is as with other lymphomas, with lumbar puncture and MRI of the brain also recommended for patients with the blastoid variant. For those presenting with GI symptoms, endoscopy is recommended as part of the initial evaluation as well.

Treatment

First-line Therapy

For patients under age 65 to 70 years with a good performance status and few comorbidities, an intensive induction regimen (such as R-CHOP/R-DHAP, Maxi-R-CHOP/R-araC, or R-DHAP) followed by consolidation with auto-HCT is commonly given, with a goal of achieving a durable (6–9 year) first remission.^87,93,94 Auto-HCT is now routinely followed by 3 years of maintenance rituximab based on the survival benefit seen in the recent LYSA trial.⁹³ At many centers, auto-HCT in first remission is a standard of care, with the greatest benefit seen in patients who have achieved a complete remission with no more than 2 lines of chemotherapy.⁹⁵ However, there remains some controversy about whether all patients truly benefit from auto-HCT in first remission, and current research efforts are focused on identifying patients most likely to benefit from auto-HCT and incorporation of new agents into first-line regimens. For patients who are not candidates for auto-HCT, bendamustine plus rituximab (BR) or R-CHOP alone or followed by maintenance rituximab is a reasonable approach.⁹⁶ Based on the StiL and BRIGHT trials, BR seems to have less toxicity and higher rates of response with no difference in OS when compared to R-CHOP.^97,98

In summary, dose-intense induction chemotherapy with consolidative auto-HCT results in high rates of long-term remission and can be considered in MCL patients who lack significant comorbidities and who understand the risks and benefits of this approach. For other patients, the less aggressive frontline approaches are more appropriate.

Relapsed/Refractory Disease

Despite initial high response rates, most patients with MCL will eventually relapse. For example, most patients given CHOP or R-CHOP alone as first-line therapy will relapse within 2 years.⁹⁹ In recent years, a number of therapies have emerged for relapsed/refractory MCL; however, the optimal sequencing of these is unclear. FDA-approved options for relapsed/refractory MCL include the proteasome inhibitor bortezomib,^100,101 the BTK inhibitors ibrutinib^102,103 and acalabrutinib,¹⁰⁴ and the immunomodulatory agent lenalidomide.¹⁰⁵

Auto-HCT can be considered for patients who did not undergo auto-HCT as part of first-line therapy and who had a reasonably long first remission.⁹⁵ Allo-HCT has curative potential in MCL with good evidence of a graft-versus-lymphoma effect. With a matched related or matched unrelated donor, the chance for treatment-related mortality is 15% to 25% at 1 to 2 years, with a 50% to 60% chance for long-term PFS. However, given the risk of treatment-related mortality and graft-versus-host disease, this option is typically reserved for patients with early relapse after auto-HCT, multiple relapses, or relatively chemotherapy-unresponsive disease.^95,106 A number of clinical trials for relapsed/refractory MCL are ongoing, and participation in these is encouraged whenever possible.

Burkitt Lymphoma

Burkitt lymphoma is a rare, aggressive and highly curable subtype of NHL. It can occur at any age, although peak incidence is in the first decade of life. There are 3 distinct clinical forms of Burkitt lymphoma.¹⁰⁷ The endemic form is common in African children and commonly involves the jaw and kidneys. The sporadic (nonendemic) form accounts for 1% to 2% of all lymphomas in the United States and Western Europe and usually has an abdominal presentation. The immunodeficiency-associated form is commonly seen in HIV patients with a relatively preserved CD4 cell count.

Patients typically present with rapidly growing masses and tumor lysis syndrome. CNS and bone marrow involvement are common. Burkitt lymphoma cells are high-grade, rapidly proliferating medium-sized cells with a monomorphic appearance. Biopsies show a classic histological appearance known as a “starry sky pattern” due to benign macrophages engulfing debris resulting from apoptosis. It is derived from a germinal center B cell and has distinct oncogenic pathways. Translocations such as t(8;14), t(2;8) or t(8;22) juxtapose the MYC locus with immunoglobulin heavy or light chain loci and result in MYC overexpression. Burkitt lymphoma is typically CD10-positive and BCL-2-negative, with a MYC translocation and a proliferation rate greater than 95%.

With conventional NHL regimens, Burkitt lymphoma had a poor prognosis, with complete remission in the 30% to 70% range and low rates of long-term remission. With the introduction of short-term, dose-intensive, multiagent chemotherapy regimens (adapted from pediatric acute lymphoblastic leukemia [ALL] regimens), the complete remission rate improved to 60% to 90%.¹⁰⁷ Early stage disease (localized or completely resected intra-abdominal disease) can have complete remission rates of 100%, with 2- to 5-year freedom-from-progression rates of 95%. CNS prophylaxis, including high-dose methotrexate, high-dose cytarabine, and intrathecal chemotherapy, is a standard component of Burkitt lymphoma regimens (CNS relapse rates can reach 50% without prophylactic therapy). Crucially, relapse after 1 to 2 years is very rare following complete response to induction therapy. Classically, several intensive regimens have been used for Burkitt lymphoma. In recent years, the most commonly used regimens have been the modified Magrath regimen of R-CODOX-M/IVAC and R-hyperCVAD. DA-EPOCH-R has also been used, typically for older, more frail, or HIV-positive patients. However, at the American Society of Hematology 2017 annual meeting, results from the NCI 9177 trial were presented which validated, in a prospective multi-center fashion, the use of DA-EPOCH-R in all Burkitt lymphoma patients.¹⁰⁸ In NCI 9177, low-risk patients (defined as normal LDH, ECOG performance score 0 or 1, ≤ stage II, and no tumor lesion > 7 cm) received 2 cycles of DA-EPOCH-R without intrathecal therapy followed by PET. If interim PET was negative, low-risk patients then received 1 more cycle of DA-EPOCH-R. High-risk patients with negative brain MRI and CSF cytology/flow cytometry received 2 cycles of DA-EPOCH-R with intrathecal therapy (2 doses per cycle) followed by PET. Unless interim PET showed progression, high-risk patients received 4 additional cycles of DA-EPOCH-R including methotrexate 12 mg intrathecally on days 1 and 5 (8 total doses). With a median follow-up of 36 months, this regimen resulted in an EFS of 85.7%. As expected, patients with CNS, marrow, or peripheral blood involvement fared worse. For those without CNS, marrow, or peripheral blood involvement, the results were excellent, with an EFS of 94.6% compared to 62.8% for those with CNS, bone marrow, or blood involvement at diagnosis.

Although no standard of care has been defined, patients with relapsed/refractory Burkitt lymphoma are often given standard second-line aggressive NHL regimens (eg, R-ICE); for those with chemosensitive disease, auto- or allo-HCT is often pursued, with long-term remissions possible following HCT.¹⁰⁹

Lymphoblastic Lymphoma

Lymphoblastic lymphoma (LBL) is a rare disease postulated to arise from precursor B or T lymphoblasts at varying stages of differentiation. Accounting for approximately 2% of all NHLs, 85% to 90% of all cases have a T-cell phenotype, while B-cell LBL comprises approximately 10% to 15% of cases. LBL and ALL are thought to represent the same disease entity, but LBL has been arbitrarily defined as cases with lymph node or mediastinal disease. Those with significant (> 25%) bone marrow or peripheral blood involvement are classified as ALL.

Precursor T-cell LBL patients are usually adolescent and young males who commonly present with a mediastinal mass and peripheral lymphadenopathy. Precursor B-cell LBL patients are usually older (median age 39 years) with peripheral lymphadenopathy and extranodal involvement. Mediastinal involvement with B-cell LBL is uncommon, and there is no male predominance. LBL has a propensity for dissemination to the bone marrow and CNS.

Morphologically, the tumor cells are medium sized, with a scant cytoplasm and finely dispersed chromatin. Mitotic features and apoptotic bodies are present since it is a high-grade malignancy. The lymphoblasts are typically positive for CD7 and either surface or cytoplasmic CD3. Terminal deoxynucleotidyl transferase expression is a defining feature. Other markers such as CD19, CD22, CD20, CD79a, CD45, and CD10 are variably expressed. Poor prognostic factors in T-cell LBL are female gender, age greater than 35 years, complex cytogenetics, and lack of a matched sibling donor.

Regimens for LBL are based on dose-dense, multi-agent protocols used in ALL. Most of these regimens are characterized by intensive remission-induction chemotherapy, CNS prophylaxis, a phase of consolidation therapy, and a prolonged maintenance phase, often lasting for 12 to 18 months with long-term DFS rates of 40% to 70%.^110,111 High-dose therapy with auto-HCT or allo-HCT in first complete response has been evaluated in an attempt to reduce the incidence of relapse.¹¹² However, the intensity of primary chemotherapy appears to be a stronger determinant of long-term survival than the use of HCT as consolidation. As a result, HCT is not routinely applied to patients in first complete remission following modern induction regimens. After relapse, prognosis is poor, with median survival rates of 6 to 9 months with conventional chemotherapy, although long-term survival rates of 30% and 20%, respectively, are reported after HCT in relapsed and primary refractory disease.¹¹³

Treatment options in relapsed disease are limited. Nelarabine can produce responses in up to 40% of relapsed/refractory LBL/ALL patients.¹¹⁴ For the minority of LBL patients with a B-cell phenotype, emerging options for relapsed/refractory LBL/ALL such as inotuzumab, blinatumomab, or anti-CD19 CAR T-cell therapy should be considered. These are not options for the majority who have a T-cell phenotype, and treatment options for these patients are limited to conventional relapsed/refractory ALL and aggressive NHL regimens.

Summary

Aggressive NHLs are characterized by rapid clinical progression without therapy. However, a significant proportion of patients are cured with appropriate combination chemotherapy or combined modality (chemotherapy + RT) regimens. In contrast, the indolent lymphomas have a relatively good prognosis (median survival of 10 years or longer) but usually are not curable in advanced clinical stages. Overall 5-year survival for aggressive NHLs with current treatment is approximately 50% to 60%, with relapses typically occurring within the first 5 years. Treatment strategies for relapsed patients offer some potential for cure; however, clinical trial participation should be encouraged whenever possible to investigate new approaches for improving outcomes in this patient population.

Introduction

Non-Hodgkin lymphoma (NHL) comprises a wide variety of malignant hematologic disorders with varying clinical and biological features. The more than 60 separate NHL subtypes can be classified according to cell of origin (B cell versus T cell), anatomical location (eg, orbital, testicular, bone, central nervous system), clinical behavior (indolent versus aggressive), histological features, or cytogenetic abnormalities. Although various NHL classification schemes have been used over the years, the World Health Organization (WHO) classification is now widely accepted as the definitive pathologic classification system for lymphoproliferative disorders, incorporating morphologic, immunohistochemical, flow cytometric, cytogenetic, and molecular features.¹ While the pathologic and molecular subclassification of NHL has become increasingly refined in recent years, from a management standpoint, classification based on clinical behavior remains very useful. This approach separates NHL subtypes into indolent versus aggressive categories. Whereas indolent NHLs may remain clinically insignificant for months to years, aggressive B-cell NHLs generally become life-threatening within weeks to months without treatment.

Epidemiology

Data from cancer registries show a steady, unexplainable increase in the incidence of NHL during the second half of the 20th century; the incidence has subsequently plateaued. There was a significant increase in NHL incidence between 1970 and 1995, which has been attributed in part to the HIV epidemic. More than 72,000 new cases of NHL were diagnosed in the United States in 2017, compared to just over 8000 cases of Hodgkin lymphoma, making NHL the sixth most common cancer in adult men and the fifth most common in adult women.² NHL appears to occur more frequently in Western countries than in Asian populations.

Various factors associated with increased risk for B-cell NHL have been identified over the years, including occupational and environmental exposure to certain pesticides and herbicides,³ immunosuppression associated with HIV infection,⁴ autoimmune disorders,⁵ iatrogenically induced immune suppression in the post-transplant and other settings,⁶ family history of NHL,⁷ and a personal history of a prior cancer, including Hodgkin lymphoma and prior NHL.⁸ In terms of infectious agents associated with aggressive B-cell NHLs, Epstein-Barr virus (EBV) has a clear pathogenic role in Burkitt lymphoma, in many cases of post-transplant lymphoproliferative disorders, and in some cases of HIV-related aggressive B-cell lymphoma.⁹ Human herpesvirus-8 viral genomes have been found in virtually all cases of primary effusion lymphomas.¹⁰ Epidemiological studies also have linked hepatitis B and C to increased incidences of certain NHL subtypes,^11–13 including primary hepatic diffuse large B-cell lymphoma (DLBCL). Similarly, Helicobacter pylori has been associated with gastric DLBCL.

Staging and Work-Up

A tissue biopsy is essential in the diagnosis and management of NHL. The most significant disadvantage of fine-needle aspiration cytology is the lack of histologic architecture. The optimal specimen is an excisional biopsy; when this cannot be performed, a core needle biopsy, ideally using a 16-gauge or larger caliber needle, is the next best choice.

The baseline tests appropriate for most cases of newly diagnosed aggressive B-cell NHL are listed in Table 1. Both hepatitis B and C have been associated with increased risk of NHL. In addition, there is a risk of hepatitis B reactivation following certain NHL therapies. A contrast-enhanced computed tomography (CT) scan in addition to positron emission tomography (PET) is useful to define the extent of disease in situations needing greater definition (eg, lymphadenopathy close to the bowel, cervical and supraclavicular nodal involvement, and lymphadenopathy causing thrombosis or compression of nearby structures).¹⁴ In cases where it is apparent that the patient has advanced stage disease (Ann Arbor stage III/IV) based on imaging, bone marrow biopsy is unlikely to alter the treatment plan. For such patients, if the complete blood count is unremarkable, deferral of bone marrow biopsy may be reasonable. For new cases of DLBCL, assessment for MYC translocation by fluorescence in situ hybridization (FISH) is recommended. If a MYC translocation is identified, then testing for BCL2 and BCL6 translocations by FISH should be performed.

Prior to the initiation of treatment, patients should always undergo a thorough cardiac and pulmonary evaluation, especially if the patient will be treated with an anthracycline or mediastinal irradiation. Central nervous system (CNS) evaluation with magnetic resonance imaging (MRI) and lumbar puncture is essential if there are neurological signs or symptoms. In addition, certain anatomical sites including the testicles, paranasal sinuses, kidney, adrenal glands, and epidural space have been associated with increased involvement of the CNS and may warrant MRI evaluation and lumbar puncture. Certain NHL subtypes like Burkitt lymphoma, high-grade NHL with translocations of MYC and BCL-2 or BCL-6 (double-hit lymphoma), blastoid mantle cell lymphoma, and lymphoblastic lymphoma have a high risk of CNS involvement, and patients with these subtypes need CNS evaluation.

The Lugano classification is used to stage patients with NHL.¹⁴ This classification is based on the Ann Arbor staging system and uses the distribution and number of tumor sites to stage disease. In general, this staging system in isolation is of limited value in predicting survival after treatment. However, the Ann Arbor stage does have prognostic impact when incorporated into risk scoring systems such as the International Prognostic Index (IPI). In clinical practice, the Ann Arbor stage is useful primarily to determine eligibility for localized therapy approaches. The absence or presence of systemic symptoms such as fevers, drenching night sweats, or weight loss (> 10% of baseline over 6 months or less) is designated by A or B, respectively.

Diffuse Large B-Cell Lymphoma

DLBCL is the most common lymphoid neoplasm in adults, accounting for about 25% of all NHL cases.² It is increasingly clear that the diagnostic category of DLBCL is quite heterogeneous in terms of morphology, genetics, and biologic behavior. A number of clinicopathologic subtypes of DLBCL exist, such as T cell/histiocyte–rich large B-cell lymphoma, primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, and EBV-positive large B-cell lymphoma, among others. Gene expression profiling (GEP) can distinguish 2 cell of origin DLBCL subtypes: the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes.¹⁵

DLBCL may be primary (de novo) or may arise through the transformation of many different types of low-grade B-cell lymphomas. This latter scenario is referred to as histologic transformation or transformed lymphoma. In some cases, patients may have a previously diagnosed low-grade B-cell NHL; in other cases, both low-grade and aggressive B-cell NHL may be diagnosed concurrently. The presence of elements of both low-grade and aggressive B-cell NHL in the same biopsy specimen is sometimes referred to as a composite lymphoma.

In the United States, incidence varies by ethnicity, with DLBCL being more common in Caucasians than other races.¹⁶ There is a slight male predominance (55%), median age at diagnosis is 65 years,^16,17 and the incidence increases with age.

Presentation, Pathology, and Prognostic Factors

The most common presentation of patients with DLBCL is rapidly enlarging lymphadenopathy, usually in the neck or abdomen. Extranodal/extramedullary presentation is seen in approximately 40% of cases, with the gastrointestinal (GI) tract being the most common site. However, extranodal DLBCL can arise in virtually any tissue.¹⁸ Nodal DLBCL presents with symptoms related to the sites of involvement (eg, shortness of breath or chest pain with mediastinal lymphadenopathy), while extranodal DLBCL typically presents with symptoms secondary to dysfunction at the site of origin. Up to one third of patients present with constitutional symptoms (B symptoms) and more than 50% have elevated serum lactate dehydrogenase (LDH) at diagnosis.¹⁹

Approximately 40% of patients present with stage I/II disease. Of these, only a subset present with stage I, or truly localized disease (defined as that which can be contained within 1 irradiation field). About 60% of patients present with advanced (stage III–IV) disease.²⁰ The bone marrow is involved in about 15% to 30% of cases. DLBCL involvement of the bone marrow is associated with a less favorable prognosis. Patients with DLBCL elsewhere may have low-grade NHL involvement of the bone marrow. Referred to as discordant bone marrow involvement,²¹ this feature does not carry the same poor prognosis associated with transformed disease²² or DLBCL involvement of the bone marrow.²³

DLBCL is defined as a neoplasm of large B-lymphoid cells with a diffuse growth pattern. The proliferative fraction of cells, as determined by Ki-67 staining, is usually greater than 40%, and may even exceed 90%. Lymph nodes usually demonstrate complete effacement of the normal architecture by sheets of atypical lymphoid cells. Tumor cells in DLBCL generally express pan B-cell antigens (CD19, CD20, CD22, CD79a, Pax-5) as well as CD45 and surface immunoglobulin. Between 20% and 37% of DLBCL cases express the BCL-2 protein,²⁴ and about 70% express the BCL-6 protein.²⁵ C-MYC protein expression is seen in a higher percentage (~ 30%–50%) of cases of DLBCL.²⁶

Many factors are associated with outcome in DLBCL. The IPI score was developed in the pre-rituximab era and is a robust prognostic tool. This simple tool uses 5 easily obtained clinical factors (age > 60 years, impaired performance status, elevated LDH, > 1 extranodal site of disease, and stage III/IV disease). By summing these factors, 4 groups with distinct 5-year overall survival (OS) rates ranging from 26% to 73% were identified (Table 2). Subsequently, modifications were made to adjust for age and stage, with the latest iteration being the NCCN (National Comprehensive Cancer Network) IPI.²⁷ This tool uses age, performance status, LDH ratio (relative to the upper limit of normal), a more precise definition for presence of extranodal sites of disease (defined as lymphomatous involvement in the bone marrow, CNS, liver/GI tract, or lung), and Ann Arbor stage to stratify patients into 4 risk groups with significantly different 5-year OS, ranging from 38% to 96% based on the subgroup. Importantly, the NCCN-IPI was derived in a cohort of patients treated with rituximab-based therapy.

Cytogenetic and molecular factors also predict outcome in DLBCL. The ABC subtype distinguished by GEP has consistently been shown to have inferior outcomes with first-line therapy. As GEP is not routinely available in clinical practice, immunohistochemical (IHC) approaches (eg, the Hans algorithm) have been developed that can approximate the GEP subtypes. These IHC approaches have approximately 80% concordance with GEP.²⁸ The 3 most common chromosomal translocations in DLBCL involve BCL-2, BCL-6 and MYC. MYC-rearranged DLBCLs have a less favorable prognosis.^29,30 Cases in which a MYC translocation occurs in combination with a BCL-2 or BCL-6 translocation are commonly referred to as double-hit lymphoma (DHL); cases with all 3 translocations are referred to as triple-hit lymphoma (THL). Both DHL and THL have a worse prognosis with standard DLBCL therapy compared to non-DHL/THL cases. In the 2016 revised WHO classification, DHL and THL are an entity technically distinct from DLBCL, referred to as high-grade B-cell lymphoma.¹ In some cases, MYC and BCL-2 protein overexpression occurs in the absence of chromosomal translocations. Cases in which MYC and BCL-2 are overexpressed (by IHC) are referred to as double expressor lymphoma (DEL), and also have inferior outcome compared with non-DEL DLBCL.^31,32 Interestingly, MYC protein expression alone does not confer inferior outcomes, unlike isolated MYC translocation, which is associated with inferior outcomes.

Treatment

First-Line Therapy

DLBCL is an aggressive disease and, in most cases, survival without treatment can be measured in weeks to months. The advent of combination chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] or CHOP-like regimens) led to disease-free survival (DFS) rates of 35% to 40% at 3 to 5 years.³³ The addition of rituximab to CHOP (R-CHOP) has improved both progression-free surivial (PFS) and OS.^34,35

Treatment options vary for patients with localized (stage I/II) and advanced (stage III/IV) disease. Options for limited-stage DLBCL include an abbreviated course of R-CHOP (3 or 4 cycles) with involved-field radiation therapy (IFRT) versus a full course (6–8 cycles) of R-CHOP without radiation therapy (RT). Most studies comparing combined modality therapy (chemotherapy plus RT) versus chemotherapy alone were conducted in the pre-rituximab era. With the introduction of rituximab, Persky and colleagues³⁶ studied the use of 3 cycles of R-CHOP followed by RT, demonstrating a slightly improved OS of 92% at 4 years as compared to 88% in a historical cohort. The French LYSA/GOELAMS group performed the only direct comparison in the rituximab era (4 cycles of R-CHOP followed by RT versus 4 cycles of R-CHOP followed by 2 additional cycles of R-CHOP) and reported similar outcomes between both arms,³⁷ with OS of 92% in the R-CHOP alone arm and 96% in the R-CHOP + RT arm (nonsignificant difference statistically). IFRT alone is not recommended other than for palliation in patients who cannot tolerate chemotherapy or combined modality therapy. Stage I and II patients with bulky disease (> 10 cm) have a prognosis similar to patients with advanced DLBCL and should be treated aggressively with 6 to 8 cycles of R-CHOP with or without RT.³⁶

For patients with advanced stage disease, a full course of R-CHOP-21 (6–8 cycles given on a 21-day cycle) is the standard of care. This approach results in OS rates of 70% and 60% at 2 and 5 years, respectively. For older adults unable to tolerate full-dose R-CHOP, attenuated versions of R-CHOP with decreased dose density or decreased dose intensity have been developed.³⁸ Numerous randomized trials have attempted to improve upon the results of R-CHOP-21 using strategies such as infusional chemotherapy (DA-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab]);³⁹ dose-dense therapy (R-CHOP-14);replacement of rituximab with obinutuzuimab;⁴⁰ addition of novel agents such as bortezomib,⁴¹ lenalidomide,⁴² or ibrutinib^43,44 to R-CHOP; and various maintenance strategies such as rituximab, lenalidomide,⁴⁵ enzastaurin,⁴⁶ and everolimus.⁴⁷ Unfortunately, none of these strategies has been shown to improve OS in DLBCL. In part this appears to be due to the fact that inclusion/exclusion criteria for DLBCL trials have been too strict, such that the most severely ill DLBCL patients are typically not included. As a result, the results in the control arms have ended up better than what was expected based on historical data. Efforts are underway to include all patients in future first-line DLBCL studies.

Currently, autologous hematopoietic cell transplantation (auto-HCT) is not routinely used in the initial treatment of DLBCL. In the pre-rituximab era, numerous trials were conducted in DLBCL patients with high and/or high-intermediate risk disease based on the IPI score to determine if outcomes could be improved with high-dose therapy and auto-HCT as consolidation after patients achieved complete remission with first-line therapy. The results of these trials were conflicting. A 2003 meta-analysis of 11 such trials concluded that the results were very heterogeneous and showed no OS benefit.⁴⁸ More recently, the Southwestern Oncology Group published the results of a prospective trial testing the impact of auto-HCT for consolidation of aggressive NHL patients with an IPI score of 3 to 5 who achieved complete remission with first-line therapy with CHOP or R-CHOP. In this study, 75% of the patients had DLBCL and, of the B-cell NHL patients, 47% received R-CHOP. A survival benefit was seen only in the subgroup that had an IPI score of 4 or 5; a subgroup analysis restricted to those receiving R-CHOP as induction was not performed, however.⁴⁹ As a result, this area remains controversial, with most institutions not routinely performing auto-HCT for any DLBCL patients in first complete remission and some institutions considering auto-HCT in first complete remission for patients with an IPI score of 4 or 5. These studies all used the IPI score to identify high-risk patients. It is possible that the use of newer biomarkers or minimal-residual disease analysis will lead to a more robust algorithm for identifying high-risk patients and selecting patients who might benefit from consolidation of first complete remission with auto-HCT.

For patients with DHL or THL, long-term PFS with standard R-CHOP therapy is poor (20% to 40%).^50,51 Treatment with more intensive first-line regimens such as DA-EPOCH-R, R-hyperCVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), or CODOX-M/IVAC±R (cyclophosphamide, vincristine, doxorubicin, high‐dose methotrexate/ifosfamide, etoposide, high‐dose cytarabine ± rituximab), along with CNS prophylaxis, however, has been shown to produce superior outcomes,⁵² with 3-year relapse-free survival rates of 88% compared to 56% for R-CHOP. For patients who achieve a complete response by PET/CT scan after intensive induction, consolidation with auto-HCT has not been shown to improve outcomes based on retrospective analysis. However for DHL/THL patients who achieve complete response after R-CHOP, PFS was improved if auto-HCT was given as consolidation of first remission.⁵³

Patients with DLBCL have an approximately 5% risk of subsequently developing CNS involvement. Historically (in the pre-rituximab era), patients who presented with multiple sites of extranodal disease and/or extensive bone marrow involvement and/or an elevated LDH had an increased risk (up to 20%–30%) of developing CNS involvement. In addition, patients with involvement of certain anatomical sites (testicular, paranasal sinuses, epidural space) had an increased risk of CNS disease. Several algorithms have been proposed to identify patients who should receive prophylactic CNS therapy. One of the most robust tools for this purpose is the CNS-IPI, which is a 6-point score consisting of the 5 IPI elements, plus 1 additional point if the adrenal glands or kidneys are involved. Importantly, the CNS-IPI was developed and validated in patients treated with R-CHOP-like therapy. Subsequent risk of CNS relapse was 0.6%, 3.4%, and 10.2% for those with low-, intermediate- and high-risk CNS-IPI scores, respectively.⁵⁴ A reasonable strategy, therefore, is to perform CNS prophylaxis in those with a CNS-IPI score of 4 to 6. When CNS prophylaxis is used, intrathecal methotrexate or high-dose systemic methotrexate is most frequently given, with high-dose systemic methotrexate favored over intrathecal chemotherapy given that high-dose methotrexate penetrates the brain and spinal cord parenchyma, in addition to treating the cerebrospinal fluid (CSF).⁵⁵ In contrast, intrathecal therapy only treats the CSF and requires repeated lumbar punctures or placement of an Ommaya reservoir. For DLBCL patients who present with active CSF involvement (known as lymphomatous meningitis), intrathecal chemotherapy treatments are typically given 2 or 3 times weekly until the CSF clears, followed by weekly intrathecal treatment for 4 weeks, and then monthly intrathecal treatment for 4 months.⁵⁶ For those with concurrent systemic and brain parenchymal DLBCL, a strategy of alternating R-CHOP with mid-cycle high-dose methotrexate can be successful. In addition, consolidation with high-dose therapy and auto-HCT improved survival in such patients in 1 retrospective series.⁵⁷

Relapsed/Refractory Disease

Between 30% and 40% of patients with advanced stage DLBCL will either fail to attain a remission with primary therapy (referred to as primary induction failure) or will relapse. In general, for those with progressive or relapsed disease, an updated tissue biopsy is recommended. This is especially true for patients who have had prior complete remission and have new lymph node enlargement, or those who have emergence of new sites of disease at the completion of first-line therapy.

Patients with relapsed disease are treated with systemic second-line platinum-based chemoimmunotherapy, with the usual goal of ultimately proceeding to auto-HCT. A number of platinum-based regimens have been used in this setting such as R-ICE, R-DHAP, R-GDP, R-Gem-Ox, and R-ESHAP. None of these regimens has been shown to be superior in terms of efficacy, and the choice of regimen is typically made based on the anticipated tolerance of the patient in light of comorbidities, laboratory studies, and physician preference. In the CORAL study, R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin) seemed to show superior PFS in patients with the GCB subtype.⁵⁸ However, this was an unplanned subgroup analysis and R-DHAP was associated with higher renal toxicity.

Several studies have demonstrated that long-term PFS can be observed for relapsed/refractory DLBCL patients who respond to second-line therapy and then undergo high-dose therapy with auto-HCT. The Parma trial remains the only published prospective randomized trial performed in relapsed DLBCL comparing a transplant strategy to a non-transplant strategy. This study, performed in the pre-rituximab era, clearly showed a benefit in terms of DFS and OS in favor of auto-HCT versus salvage therapy alone.⁵⁹ The benefit of auto-HCT in patients treated in the rituximab era, even in patients who experience early failure (within 1 year of diagnosis), was confirmed in a retrospective analysis by the Center for International Blood and Marrow Transplant Research. In this study, a 44% 3-year PFS was seen in the early failure cohort versus 52% in the late failure cohort.⁶⁰

Some DLBCL patients are very unlikely to benefit from auto-HCT. The REFINE study focused on patients with primary induction failure or early relapse within 6 months of completing first-line therapy. Among such patients, primary progressive disease (defined as progression while still receiving first-line therapy), a high NCCN-IPI score at relapse, and MYC rearrangement were risk factors for poor PFS following auto-HCT.⁶¹ Patients with 2 or 3 high-risk features had a 2-year OS of 10.7% compared to 74.3% for those without any high-risk features.

Allogeneic HCT (allo-HCT) is a treatment option for relapsed/refractory DLBCL. This option is more commonly considered for patients in whom an autotransplant has failed to achieve durable remission. For properly selected patients in this setting, a long-term PFS in the 30% to 40% range can be attained.⁶² However, in practice, only about 20% of patients who fail auto-HCT end up undergoing allo-HCT due to rapid progression of disease, age, poor performance status, or lack of suitable donor. It has been proposed that in the coming years, allo-HCT will be utilized less commonly in this setting due to the advent of chimeric antigen receptor T-cell (CAR T) therapy.

CAR T-cell therapy genetically modifies the patient’s own T lymphocytes with a gene that encodes an antigen receptor to direct the T cells against lymphoma cells. Typically, the T cells are genetically modified and expanded in a production facility and then infused back into the patient. Axicabtagene ciloleucel is directed against the CD-19 receptor and has been approved by the US Food and Drug Administration (FDA) for treatment of patients with DLBCL who have failed 2 or more lines of systemic therapy. Use of CAR-T therapy in such patients was examined in a multicenter trial (ZUMA-1), which reported a 54% complete response rate and 52% OS rate at 18 months.⁶³ CAR-T therapy is associated with serious side effects such as cytokine release syndrome, neurological toxicities, and prolonged cytopenias. While there are now some patients with ongoing remission 2 or more years after undergoing CAR-T therapy, it remains uncertain what proportion of patients have been truly cured with this modality. Nevertheless, this new treatment option remains a source of optimism for relapsed and refractory DLBCL patients.

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma (PMBCL) is a form of DLBCL arising in the mediastinum from the thymic B cell. It is an uncommon entity and has clinical and pathologic features distinct from systemic DLBCL.⁶⁴ PMBCL accounts for 2% of all NHLs and about 7% of all DLBCL.²⁰ It typically affects women in the third to fourth decade of life.

Presentation and Prognostic Features

PMBCL usually presents as a locally invasive anterior mediastinal mass, often with a superior vena cava syndrome which may or may not be clinically obvious.⁶⁴ Other presentations include pericardial tamponade, thrombosis of neck veins, and acute airway obstruction. About 80% of patients present with bulky (> 10 cm) stage I or II disease,⁶⁵ with distant spread uncommon on presentation. Morphologically and on GEP, PMBL has a profile more similar to classical Hodgkin lymphoma (cHL) than non-mediastinal DLBCL.⁶⁶ PMBL is distinguished from cHL by immunophenotyping: unlike cHL, PMBCL has pan B cell markers, rarely expresses CD15, and has weak CD30.

Poor prognostic features in PMBCL are Eastern Cooperative Oncology Group (ECOG) performance status greater than 2, pericardial effusion, bulky disease, and elevated serum LDH. The diagnosis of PMBCL can be difficult because the tumor is often encased with extensive fibrosis and necrosis. As a result, a needle biopsy may not yield sufficient tissue, thus making a surgical biopsy often the only viable way to obtain sufficient tissue.

Treatment

Early series suggested that PMBCL is unusually aggressive, with a poor prognosis.⁶⁷ This led to studies using more aggressive chemotherapy regimens (often in combination with mediastinal radiation) as well as upfront auto-HCT.^68–70 The addition of rituximab to treatment regimens significantly improved outcomes in PMBCL. For example, a subgroup analysis of the PMBCL patients in the MinT trial revealed a 3-year event-free survival (EFS) of 78%⁷¹ when rituximab was combined with CHOP. Because of previous reports demonstrating radiosensitivity of PMBL, radiation was traditionally sequenced into treatment regimens for PMBL. However, this is associated with higher long-term toxicities, often a concern in PMBCL patients given that the disease frequently affects younger females, and given that breast tissue will be in the radiation field. For patients with a strong personal or family history of breast cancer or cardiovascular disease, these concerns are even more significant. More recently, the DA-EPOCH-R regimen has been shown to produce very high rates (80%–90%) of long-term DFS, without the need for mediastinal radiation in most cases.^72,73 For patients receiving R-CHOP, consolidation with mediastinal radiation is still commonly given. This approach also leads to high rates of long-term remission and, although utilizing mediastinal radiation, allows for less intensive chemotherapy. Determining which approach is most appropriate for an individual patient requires an assessment of the risks of each treatment option for that patient. A randomized trial by the International Extranodal Lymphoma Study Group (IELSG37) is evaluating whether RT may be safely omitted in PMBCL patients who achieve a complete metabolic response after R-CHOP.

Most relapses of PMBCL occur within the first 1 to 2 years and often present with extranodal disease in various organs. For those with relapsed or refractory disease, high-dose chemotherapy followed by auto-HCT provides 5-year survival rates of 50% to 80%.^74–76 In a phase 1b trial evaluating the role of pembrolizumab in relapsed/refractory patients (KEYNOTE-13), 7 of 17 PMBCL patients achieved responses, with an additional 6 demonstrating stable disease.⁷⁷ This provides an additional option for patients who might be too weak to undergo auto-HCT or for those who relapse following auto-HCT.

Mantle Cell Lymphoma

The name mantle cell lymphoma (MCL) is based on the presumed normal cell counterpart to MCL, which is believed to be found in the mantle zone surrounding germinal center follicles. It represents approximately 6% of all NHL cases in the United States and Europe.⁷⁸ MCL occurs at a median age of 63 to 68 years and has a male predominance.

Presentation and Prognostic Features

Patients can present with a broad spectrum of clinical features, and most patients (70%) present with advanced disease.⁷⁹ Up to one third of patients have B symptoms, with most demonstrating lymphadenopathy and bone marrow involvement. Approximately 25% present with extranodal disease as the primary presentation (eg, GI tract, pleura, breast, or orbits). MCL can involve any part of the GI tract and often presents as polypoid lesions.

Histologically, the pattern of MCL may be diffuse, nodular, mantle zone, or a combination of the these; morphologically, MCL can range from small, more irregular lymphocytes to lymphoblast-like cells. Blastoid and pleomorphic variants of MCL have a higher proliferation index and a more aggressive clinical course than other variants. MCL is characterized by the expression of pan B cell antigens (CD19+, CD20+) with coexpression of the T-cell antigen CD5, lack of CD23 expression, and nuclear expression of cyclin D1. Nuclear staining for cyclin D1 is present in more than 98% of cases.⁸⁰ In rare cases, CD5 or cyclin D1 may be negative.⁸⁰ Most MCL cases have a unique translocation that fuses the immunoglobulin heavy chain gene promoter (14q32) to the promoter of the BCL-1 gene (11q13), which encodes the cyclin D1 protein. This translocation is not unique to MCL and can be present in multiple myeloma as well. Interestingly, cyclin D1 is overproduced in cases lacking t(11:14), likely from other point mutations resulting in its overexpression.⁸¹ Cyclin D1–negative tumors overexpress cyclin D2 or D3, with no apparent difference in clinical behavior or outcome.⁸² In cyclin D1–negative cases, SOX11 expression may help with diagnosis.⁸³ A proliferation rate greater than 30% (as measured by Ki-67 staining), low SOX11 expression, and presence of p53 mutations have all been associated with adverse outcome.

In a minority of cases, MCL follows an indolent clinical course. For the remainder, however, MCL is an aggressive disease that generally requires treatment soon after diagnosis. When initially described in the 1980s and 1990s, treatment of MCL was characterized by low complete response rates, short durations of remission, repeated recurrences, and a median survival in the 2- to 5-year range.⁸⁴ In recent years, intensive regimens incorporating rituximab and high-dose cytarabine with or without auto-HCT have been developed and are associated with high complete response rates and median duration of first remission in the 6- to 9-year range.^85–87 Several prognostic indices have been applied to patients with MCL, including the IPI, the Follicular Lymphoma International Prognostic Index , and the Mantle Cell Lymphoma International Prognostic Index (MIPI). The MIPI was originally described based on a cohort from the period 1996 to 2004,⁸⁸ and subsequently confirmed in a separate cohort of 958 patients with MCL treated on prospective trials between 2004 and 2010.⁸⁹ The MIPI score can identify 3 risk groups with significant survival differences (83%, 63%, and 34% survival at 5 years). A refined version of the MIPI score, the combined MIPI or MIPI-c, incorporates proliferation rate and is better able to stratify patients.⁹⁰ The blastoid variant of MCL follows a more aggressive clinical course and is associated with a high proliferation rate, shorter remissions, and a higher rate of CNS involvement.⁹¹

In most patients, MCL is an aggressive disease with a short OS without treatment. A subset of patients may have a more indolent course,⁹² but unfortunately reliable factors that identify this group at the time of diagnosis are not available. Pretreatment evaluation is as with other lymphomas, with lumbar puncture and MRI of the brain also recommended for patients with the blastoid variant. For those presenting with GI symptoms, endoscopy is recommended as part of the initial evaluation as well.

Treatment

First-line Therapy

For patients under age 65 to 70 years with a good performance status and few comorbidities, an intensive induction regimen (such as R-CHOP/R-DHAP, Maxi-R-CHOP/R-araC, or R-DHAP) followed by consolidation with auto-HCT is commonly given, with a goal of achieving a durable (6–9 year) first remission.^87,93,94 Auto-HCT is now routinely followed by 3 years of maintenance rituximab based on the survival benefit seen in the recent LYSA trial.⁹³ At many centers, auto-HCT in first remission is a standard of care, with the greatest benefit seen in patients who have achieved a complete remission with no more than 2 lines of chemotherapy.⁹⁵ However, there remains some controversy about whether all patients truly benefit from auto-HCT in first remission, and current research efforts are focused on identifying patients most likely to benefit from auto-HCT and incorporation of new agents into first-line regimens. For patients who are not candidates for auto-HCT, bendamustine plus rituximab (BR) or R-CHOP alone or followed by maintenance rituximab is a reasonable approach.⁹⁶ Based on the StiL and BRIGHT trials, BR seems to have less toxicity and higher rates of response with no difference in OS when compared to R-CHOP.^97,98

In summary, dose-intense induction chemotherapy with consolidative auto-HCT results in high rates of long-term remission and can be considered in MCL patients who lack significant comorbidities and who understand the risks and benefits of this approach. For other patients, the less aggressive frontline approaches are more appropriate.

Relapsed/Refractory Disease

Despite initial high response rates, most patients with MCL will eventually relapse. For example, most patients given CHOP or R-CHOP alone as first-line therapy will relapse within 2 years.⁹⁹ In recent years, a number of therapies have emerged for relapsed/refractory MCL; however, the optimal sequencing of these is unclear. FDA-approved options for relapsed/refractory MCL include the proteasome inhibitor bortezomib,^100,101 the BTK inhibitors ibrutinib^102,103 and acalabrutinib,¹⁰⁴ and the immunomodulatory agent lenalidomide.¹⁰⁵

Auto-HCT can be considered for patients who did not undergo auto-HCT as part of first-line therapy and who had a reasonably long first remission.⁹⁵ Allo-HCT has curative potential in MCL with good evidence of a graft-versus-lymphoma effect. With a matched related or matched unrelated donor, the chance for treatment-related mortality is 15% to 25% at 1 to 2 years, with a 50% to 60% chance for long-term PFS. However, given the risk of treatment-related mortality and graft-versus-host disease, this option is typically reserved for patients with early relapse after auto-HCT, multiple relapses, or relatively chemotherapy-unresponsive disease.^95,106 A number of clinical trials for relapsed/refractory MCL are ongoing, and participation in these is encouraged whenever possible.

Burkitt Lymphoma

Burkitt lymphoma is a rare, aggressive and highly curable subtype of NHL. It can occur at any age, although peak incidence is in the first decade of life. There are 3 distinct clinical forms of Burkitt lymphoma.¹⁰⁷ The endemic form is common in African children and commonly involves the jaw and kidneys. The sporadic (nonendemic) form accounts for 1% to 2% of all lymphomas in the United States and Western Europe and usually has an abdominal presentation. The immunodeficiency-associated form is commonly seen in HIV patients with a relatively preserved CD4 cell count.

Patients typically present with rapidly growing masses and tumor lysis syndrome. CNS and bone marrow involvement are common. Burkitt lymphoma cells are high-grade, rapidly proliferating medium-sized cells with a monomorphic appearance. Biopsies show a classic histological appearance known as a “starry sky pattern” due to benign macrophages engulfing debris resulting from apoptosis. It is derived from a germinal center B cell and has distinct oncogenic pathways. Translocations such as t(8;14), t(2;8) or t(8;22) juxtapose the MYC locus with immunoglobulin heavy or light chain loci and result in MYC overexpression. Burkitt lymphoma is typically CD10-positive and BCL-2-negative, with a MYC translocation and a proliferation rate greater than 95%.

With conventional NHL regimens, Burkitt lymphoma had a poor prognosis, with complete remission in the 30% to 70% range and low rates of long-term remission. With the introduction of short-term, dose-intensive, multiagent chemotherapy regimens (adapted from pediatric acute lymphoblastic leukemia [ALL] regimens), the complete remission rate improved to 60% to 90%.¹⁰⁷ Early stage disease (localized or completely resected intra-abdominal disease) can have complete remission rates of 100%, with 2- to 5-year freedom-from-progression rates of 95%. CNS prophylaxis, including high-dose methotrexate, high-dose cytarabine, and intrathecal chemotherapy, is a standard component of Burkitt lymphoma regimens (CNS relapse rates can reach 50% without prophylactic therapy). Crucially, relapse after 1 to 2 years is very rare following complete response to induction therapy. Classically, several intensive regimens have been used for Burkitt lymphoma. In recent years, the most commonly used regimens have been the modified Magrath regimen of R-CODOX-M/IVAC and R-hyperCVAD. DA-EPOCH-R has also been used, typically for older, more frail, or HIV-positive patients. However, at the American Society of Hematology 2017 annual meeting, results from the NCI 9177 trial were presented which validated, in a prospective multi-center fashion, the use of DA-EPOCH-R in all Burkitt lymphoma patients.¹⁰⁸ In NCI 9177, low-risk patients (defined as normal LDH, ECOG performance score 0 or 1, ≤ stage II, and no tumor lesion > 7 cm) received 2 cycles of DA-EPOCH-R without intrathecal therapy followed by PET. If interim PET was negative, low-risk patients then received 1 more cycle of DA-EPOCH-R. High-risk patients with negative brain MRI and CSF cytology/flow cytometry received 2 cycles of DA-EPOCH-R with intrathecal therapy (2 doses per cycle) followed by PET. Unless interim PET showed progression, high-risk patients received 4 additional cycles of DA-EPOCH-R including methotrexate 12 mg intrathecally on days 1 and 5 (8 total doses). With a median follow-up of 36 months, this regimen resulted in an EFS of 85.7%. As expected, patients with CNS, marrow, or peripheral blood involvement fared worse. For those without CNS, marrow, or peripheral blood involvement, the results were excellent, with an EFS of 94.6% compared to 62.8% for those with CNS, bone marrow, or blood involvement at diagnosis.

Although no standard of care has been defined, patients with relapsed/refractory Burkitt lymphoma are often given standard second-line aggressive NHL regimens (eg, R-ICE); for those with chemosensitive disease, auto- or allo-HCT is often pursued, with long-term remissions possible following HCT.¹⁰⁹

Lymphoblastic Lymphoma

Lymphoblastic lymphoma (LBL) is a rare disease postulated to arise from precursor B or T lymphoblasts at varying stages of differentiation. Accounting for approximately 2% of all NHLs, 85% to 90% of all cases have a T-cell phenotype, while B-cell LBL comprises approximately 10% to 15% of cases. LBL and ALL are thought to represent the same disease entity, but LBL has been arbitrarily defined as cases with lymph node or mediastinal disease. Those with significant (> 25%) bone marrow or peripheral blood involvement are classified as ALL.

Precursor T-cell LBL patients are usually adolescent and young males who commonly present with a mediastinal mass and peripheral lymphadenopathy. Precursor B-cell LBL patients are usually older (median age 39 years) with peripheral lymphadenopathy and extranodal involvement. Mediastinal involvement with B-cell LBL is uncommon, and there is no male predominance. LBL has a propensity for dissemination to the bone marrow and CNS.

Morphologically, the tumor cells are medium sized, with a scant cytoplasm and finely dispersed chromatin. Mitotic features and apoptotic bodies are present since it is a high-grade malignancy. The lymphoblasts are typically positive for CD7 and either surface or cytoplasmic CD3. Terminal deoxynucleotidyl transferase expression is a defining feature. Other markers such as CD19, CD22, CD20, CD79a, CD45, and CD10 are variably expressed. Poor prognostic factors in T-cell LBL are female gender, age greater than 35 years, complex cytogenetics, and lack of a matched sibling donor.

Regimens for LBL are based on dose-dense, multi-agent protocols used in ALL. Most of these regimens are characterized by intensive remission-induction chemotherapy, CNS prophylaxis, a phase of consolidation therapy, and a prolonged maintenance phase, often lasting for 12 to 18 months with long-term DFS rates of 40% to 70%.^110,111 High-dose therapy with auto-HCT or allo-HCT in first complete response has been evaluated in an attempt to reduce the incidence of relapse.¹¹² However, the intensity of primary chemotherapy appears to be a stronger determinant of long-term survival than the use of HCT as consolidation. As a result, HCT is not routinely applied to patients in first complete remission following modern induction regimens. After relapse, prognosis is poor, with median survival rates of 6 to 9 months with conventional chemotherapy, although long-term survival rates of 30% and 20%, respectively, are reported after HCT in relapsed and primary refractory disease.¹¹³

Treatment options in relapsed disease are limited. Nelarabine can produce responses in up to 40% of relapsed/refractory LBL/ALL patients.¹¹⁴ For the minority of LBL patients with a B-cell phenotype, emerging options for relapsed/refractory LBL/ALL such as inotuzumab, blinatumomab, or anti-CD19 CAR T-cell therapy should be considered. These are not options for the majority who have a T-cell phenotype, and treatment options for these patients are limited to conventional relapsed/refractory ALL and aggressive NHL regimens.

Summary

Aggressive NHLs are characterized by rapid clinical progression without therapy. However, a significant proportion of patients are cured with appropriate combination chemotherapy or combined modality (chemotherapy + RT) regimens. In contrast, the indolent lymphomas have a relatively good prognosis (median survival of 10 years or longer) but usually are not curable in advanced clinical stages. Overall 5-year survival for aggressive NHLs with current treatment is approximately 50% to 60%, with relapses typically occurring within the first 5 years. Treatment strategies for relapsed patients offer some potential for cure; however, clinical trial participation should be encouraged whenever possible to investigate new approaches for improving outcomes in this patient population.

Introduction

Non-Hodgkin lymphoma (NHL) comprises a wide variety of malignant hematologic disorders with varying clinical and biological features. The more than 60 separate NHL subtypes can be classified according to cell of origin (B cell versus T cell), anatomical location (eg, orbital, testicular, bone, central nervous system), clinical behavior (indolent versus aggressive), histological features, or cytogenetic abnormalities. Although various NHL classification schemes have been used over the years, the World Health Organization (WHO) classification is now widely accepted as the definitive pathologic classification system for lymphoproliferative disorders, incorporating morphologic, immunohistochemical, flow cytometric, cytogenetic, and molecular features.¹ While the pathologic and molecular subclassification of NHL has become increasingly refined in recent years, from a management standpoint, classification based on clinical behavior remains very useful. This approach separates NHL subtypes into indolent versus aggressive categories. Whereas indolent NHLs may remain clinically insignificant for months to years, aggressive B-cell NHLs generally become life-threatening within weeks to months without treatment.

Epidemiology

Data from cancer registries show a steady, unexplainable increase in the incidence of NHL during the second half of the 20th century; the incidence has subsequently plateaued. There was a significant increase in NHL incidence between 1970 and 1995, which has been attributed in part to the HIV epidemic. More than 72,000 new cases of NHL were diagnosed in the United States in 2017, compared to just over 8000 cases of Hodgkin lymphoma, making NHL the sixth most common cancer in adult men and the fifth most common in adult women.² NHL appears to occur more frequently in Western countries than in Asian populations.

Various factors associated with increased risk for B-cell NHL have been identified over the years, including occupational and environmental exposure to certain pesticides and herbicides,³ immunosuppression associated with HIV infection,⁴ autoimmune disorders,⁵ iatrogenically induced immune suppression in the post-transplant and other settings,⁶ family history of NHL,⁷ and a personal history of a prior cancer, including Hodgkin lymphoma and prior NHL.⁸ In terms of infectious agents associated with aggressive B-cell NHLs, Epstein-Barr virus (EBV) has a clear pathogenic role in Burkitt lymphoma, in many cases of post-transplant lymphoproliferative disorders, and in some cases of HIV-related aggressive B-cell lymphoma.⁹ Human herpesvirus-8 viral genomes have been found in virtually all cases of primary effusion lymphomas.¹⁰ Epidemiological studies also have linked hepatitis B and C to increased incidences of certain NHL subtypes,^11–13 including primary hepatic diffuse large B-cell lymphoma (DLBCL). Similarly, Helicobacter pylori has been associated with gastric DLBCL.

Staging and Work-Up

A tissue biopsy is essential in the diagnosis and management of NHL. The most significant disadvantage of fine-needle aspiration cytology is the lack of histologic architecture. The optimal specimen is an excisional biopsy; when this cannot be performed, a core needle biopsy, ideally using a 16-gauge or larger caliber needle, is the next best choice.

The baseline tests appropriate for most cases of newly diagnosed aggressive B-cell NHL are listed in Table 1. Both hepatitis B and C have been associated with increased risk of NHL. In addition, there is a risk of hepatitis B reactivation following certain NHL therapies. A contrast-enhanced computed tomography (CT) scan in addition to positron emission tomography (PET) is useful to define the extent of disease in situations needing greater definition (eg, lymphadenopathy close to the bowel, cervical and supraclavicular nodal involvement, and lymphadenopathy causing thrombosis or compression of nearby structures).¹⁴ In cases where it is apparent that the patient has advanced stage disease (Ann Arbor stage III/IV) based on imaging, bone marrow biopsy is unlikely to alter the treatment plan. For such patients, if the complete blood count is unremarkable, deferral of bone marrow biopsy may be reasonable. For new cases of DLBCL, assessment for MYC translocation by fluorescence in situ hybridization (FISH) is recommended. If a MYC translocation is identified, then testing for BCL2 and BCL6 translocations by FISH should be performed.

Prior to the initiation of treatment, patients should always undergo a thorough cardiac and pulmonary evaluation, especially if the patient will be treated with an anthracycline or mediastinal irradiation. Central nervous system (CNS) evaluation with magnetic resonance imaging (MRI) and lumbar puncture is essential if there are neurological signs or symptoms. In addition, certain anatomical sites including the testicles, paranasal sinuses, kidney, adrenal glands, and epidural space have been associated with increased involvement of the CNS and may warrant MRI evaluation and lumbar puncture. Certain NHL subtypes like Burkitt lymphoma, high-grade NHL with translocations of MYC and BCL-2 or BCL-6 (double-hit lymphoma), blastoid mantle cell lymphoma, and lymphoblastic lymphoma have a high risk of CNS involvement, and patients with these subtypes need CNS evaluation.

The Lugano classification is used to stage patients with NHL.¹⁴ This classification is based on the Ann Arbor staging system and uses the distribution and number of tumor sites to stage disease. In general, this staging system in isolation is of limited value in predicting survival after treatment. However, the Ann Arbor stage does have prognostic impact when incorporated into risk scoring systems such as the International Prognostic Index (IPI). In clinical practice, the Ann Arbor stage is useful primarily to determine eligibility for localized therapy approaches. The absence or presence of systemic symptoms such as fevers, drenching night sweats, or weight loss (> 10% of baseline over 6 months or less) is designated by A or B, respectively.

Diffuse Large B-Cell Lymphoma

DLBCL is the most common lymphoid neoplasm in adults, accounting for about 25% of all NHL cases.² It is increasingly clear that the diagnostic category of DLBCL is quite heterogeneous in terms of morphology, genetics, and biologic behavior. A number of clinicopathologic subtypes of DLBCL exist, such as T cell/histiocyte–rich large B-cell lymphoma, primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, and EBV-positive large B-cell lymphoma, among others. Gene expression profiling (GEP) can distinguish 2 cell of origin DLBCL subtypes: the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes.¹⁵

DLBCL may be primary (de novo) or may arise through the transformation of many different types of low-grade B-cell lymphomas. This latter scenario is referred to as histologic transformation or transformed lymphoma. In some cases, patients may have a previously diagnosed low-grade B-cell NHL; in other cases, both low-grade and aggressive B-cell NHL may be diagnosed concurrently. The presence of elements of both low-grade and aggressive B-cell NHL in the same biopsy specimen is sometimes referred to as a composite lymphoma.

In the United States, incidence varies by ethnicity, with DLBCL being more common in Caucasians than other races.¹⁶ There is a slight male predominance (55%), median age at diagnosis is 65 years,^16,17 and the incidence increases with age.

Presentation, Pathology, and Prognostic Factors

The most common presentation of patients with DLBCL is rapidly enlarging lymphadenopathy, usually in the neck or abdomen. Extranodal/extramedullary presentation is seen in approximately 40% of cases, with the gastrointestinal (GI) tract being the most common site. However, extranodal DLBCL can arise in virtually any tissue.¹⁸ Nodal DLBCL presents with symptoms related to the sites of involvement (eg, shortness of breath or chest pain with mediastinal lymphadenopathy), while extranodal DLBCL typically presents with symptoms secondary to dysfunction at the site of origin. Up to one third of patients present with constitutional symptoms (B symptoms) and more than 50% have elevated serum lactate dehydrogenase (LDH) at diagnosis.¹⁹

Approximately 40% of patients present with stage I/II disease. Of these, only a subset present with stage I, or truly localized disease (defined as that which can be contained within 1 irradiation field). About 60% of patients present with advanced (stage III–IV) disease.²⁰ The bone marrow is involved in about 15% to 30% of cases. DLBCL involvement of the bone marrow is associated with a less favorable prognosis. Patients with DLBCL elsewhere may have low-grade NHL involvement of the bone marrow. Referred to as discordant bone marrow involvement,²¹ this feature does not carry the same poor prognosis associated with transformed disease²² or DLBCL involvement of the bone marrow.²³

DLBCL is defined as a neoplasm of large B-lymphoid cells with a diffuse growth pattern. The proliferative fraction of cells, as determined by Ki-67 staining, is usually greater than 40%, and may even exceed 90%. Lymph nodes usually demonstrate complete effacement of the normal architecture by sheets of atypical lymphoid cells. Tumor cells in DLBCL generally express pan B-cell antigens (CD19, CD20, CD22, CD79a, Pax-5) as well as CD45 and surface immunoglobulin. Between 20% and 37% of DLBCL cases express the BCL-2 protein,²⁴ and about 70% express the BCL-6 protein.²⁵ C-MYC protein expression is seen in a higher percentage (~ 30%–50%) of cases of DLBCL.²⁶

Many factors are associated with outcome in DLBCL. The IPI score was developed in the pre-rituximab era and is a robust prognostic tool. This simple tool uses 5 easily obtained clinical factors (age > 60 years, impaired performance status, elevated LDH, > 1 extranodal site of disease, and stage III/IV disease). By summing these factors, 4 groups with distinct 5-year overall survival (OS) rates ranging from 26% to 73% were identified (Table 2). Subsequently, modifications were made to adjust for age and stage, with the latest iteration being the NCCN (National Comprehensive Cancer Network) IPI.²⁷ This tool uses age, performance status, LDH ratio (relative to the upper limit of normal), a more precise definition for presence of extranodal sites of disease (defined as lymphomatous involvement in the bone marrow, CNS, liver/GI tract, or lung), and Ann Arbor stage to stratify patients into 4 risk groups with significantly different 5-year OS, ranging from 38% to 96% based on the subgroup. Importantly, the NCCN-IPI was derived in a cohort of patients treated with rituximab-based therapy.

Cytogenetic and molecular factors also predict outcome in DLBCL. The ABC subtype distinguished by GEP has consistently been shown to have inferior outcomes with first-line therapy. As GEP is not routinely available in clinical practice, immunohistochemical (IHC) approaches (eg, the Hans algorithm) have been developed that can approximate the GEP subtypes. These IHC approaches have approximately 80% concordance with GEP.²⁸ The 3 most common chromosomal translocations in DLBCL involve BCL-2, BCL-6 and MYC. MYC-rearranged DLBCLs have a less favorable prognosis.^29,30 Cases in which a MYC translocation occurs in combination with a BCL-2 or BCL-6 translocation are commonly referred to as double-hit lymphoma (DHL); cases with all 3 translocations are referred to as triple-hit lymphoma (THL). Both DHL and THL have a worse prognosis with standard DLBCL therapy compared to non-DHL/THL cases. In the 2016 revised WHO classification, DHL and THL are an entity technically distinct from DLBCL, referred to as high-grade B-cell lymphoma.¹ In some cases, MYC and BCL-2 protein overexpression occurs in the absence of chromosomal translocations. Cases in which MYC and BCL-2 are overexpressed (by IHC) are referred to as double expressor lymphoma (DEL), and also have inferior outcome compared with non-DEL DLBCL.^31,32 Interestingly, MYC protein expression alone does not confer inferior outcomes, unlike isolated MYC translocation, which is associated with inferior outcomes.

Treatment

First-Line Therapy

DLBCL is an aggressive disease and, in most cases, survival without treatment can be measured in weeks to months. The advent of combination chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] or CHOP-like regimens) led to disease-free survival (DFS) rates of 35% to 40% at 3 to 5 years.³³ The addition of rituximab to CHOP (R-CHOP) has improved both progression-free surivial (PFS) and OS.^34,35

Treatment options vary for patients with localized (stage I/II) and advanced (stage III/IV) disease. Options for limited-stage DLBCL include an abbreviated course of R-CHOP (3 or 4 cycles) with involved-field radiation therapy (IFRT) versus a full course (6–8 cycles) of R-CHOP without radiation therapy (RT). Most studies comparing combined modality therapy (chemotherapy plus RT) versus chemotherapy alone were conducted in the pre-rituximab era. With the introduction of rituximab, Persky and colleagues³⁶ studied the use of 3 cycles of R-CHOP followed by RT, demonstrating a slightly improved OS of 92% at 4 years as compared to 88% in a historical cohort. The French LYSA/GOELAMS group performed the only direct comparison in the rituximab era (4 cycles of R-CHOP followed by RT versus 4 cycles of R-CHOP followed by 2 additional cycles of R-CHOP) and reported similar outcomes between both arms,³⁷ with OS of 92% in the R-CHOP alone arm and 96% in the R-CHOP + RT arm (nonsignificant difference statistically). IFRT alone is not recommended other than for palliation in patients who cannot tolerate chemotherapy or combined modality therapy. Stage I and II patients with bulky disease (> 10 cm) have a prognosis similar to patients with advanced DLBCL and should be treated aggressively with 6 to 8 cycles of R-CHOP with or without RT.³⁶

For patients with advanced stage disease, a full course of R-CHOP-21 (6–8 cycles given on a 21-day cycle) is the standard of care. This approach results in OS rates of 70% and 60% at 2 and 5 years, respectively. For older adults unable to tolerate full-dose R-CHOP, attenuated versions of R-CHOP with decreased dose density or decreased dose intensity have been developed.³⁸ Numerous randomized trials have attempted to improve upon the results of R-CHOP-21 using strategies such as infusional chemotherapy (DA-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab]);³⁹ dose-dense therapy (R-CHOP-14);replacement of rituximab with obinutuzuimab;⁴⁰ addition of novel agents such as bortezomib,⁴¹ lenalidomide,⁴² or ibrutinib^43,44 to R-CHOP; and various maintenance strategies such as rituximab, lenalidomide,⁴⁵ enzastaurin,⁴⁶ and everolimus.⁴⁷ Unfortunately, none of these strategies has been shown to improve OS in DLBCL. In part this appears to be due to the fact that inclusion/exclusion criteria for DLBCL trials have been too strict, such that the most severely ill DLBCL patients are typically not included. As a result, the results in the control arms have ended up better than what was expected based on historical data. Efforts are underway to include all patients in future first-line DLBCL studies.

Currently, autologous hematopoietic cell transplantation (auto-HCT) is not routinely used in the initial treatment of DLBCL. In the pre-rituximab era, numerous trials were conducted in DLBCL patients with high and/or high-intermediate risk disease based on the IPI score to determine if outcomes could be improved with high-dose therapy and auto-HCT as consolidation after patients achieved complete remission with first-line therapy. The results of these trials were conflicting. A 2003 meta-analysis of 11 such trials concluded that the results were very heterogeneous and showed no OS benefit.⁴⁸ More recently, the Southwestern Oncology Group published the results of a prospective trial testing the impact of auto-HCT for consolidation of aggressive NHL patients with an IPI score of 3 to 5 who achieved complete remission with first-line therapy with CHOP or R-CHOP. In this study, 75% of the patients had DLBCL and, of the B-cell NHL patients, 47% received R-CHOP. A survival benefit was seen only in the subgroup that had an IPI score of 4 or 5; a subgroup analysis restricted to those receiving R-CHOP as induction was not performed, however.⁴⁹ As a result, this area remains controversial, with most institutions not routinely performing auto-HCT for any DLBCL patients in first complete remission and some institutions considering auto-HCT in first complete remission for patients with an IPI score of 4 or 5. These studies all used the IPI score to identify high-risk patients. It is possible that the use of newer biomarkers or minimal-residual disease analysis will lead to a more robust algorithm for identifying high-risk patients and selecting patients who might benefit from consolidation of first complete remission with auto-HCT.

For patients with DHL or THL, long-term PFS with standard R-CHOP therapy is poor (20% to 40%).^50,51 Treatment with more intensive first-line regimens such as DA-EPOCH-R, R-hyperCVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), or CODOX-M/IVAC±R (cyclophosphamide, vincristine, doxorubicin, high‐dose methotrexate/ifosfamide, etoposide, high‐dose cytarabine ± rituximab), along with CNS prophylaxis, however, has been shown to produce superior outcomes,⁵² with 3-year relapse-free survival rates of 88% compared to 56% for R-CHOP. For patients who achieve a complete response by PET/CT scan after intensive induction, consolidation with auto-HCT has not been shown to improve outcomes based on retrospective analysis. However for DHL/THL patients who achieve complete response after R-CHOP, PFS was improved if auto-HCT was given as consolidation of first remission.⁵³

Patients with DLBCL have an approximately 5% risk of subsequently developing CNS involvement. Historically (in the pre-rituximab era), patients who presented with multiple sites of extranodal disease and/or extensive bone marrow involvement and/or an elevated LDH had an increased risk (up to 20%–30%) of developing CNS involvement. In addition, patients with involvement of certain anatomical sites (testicular, paranasal sinuses, epidural space) had an increased risk of CNS disease. Several algorithms have been proposed to identify patients who should receive prophylactic CNS therapy. One of the most robust tools for this purpose is the CNS-IPI, which is a 6-point score consisting of the 5 IPI elements, plus 1 additional point if the adrenal glands or kidneys are involved. Importantly, the CNS-IPI was developed and validated in patients treated with R-CHOP-like therapy. Subsequent risk of CNS relapse was 0.6%, 3.4%, and 10.2% for those with low-, intermediate- and high-risk CNS-IPI scores, respectively.⁵⁴ A reasonable strategy, therefore, is to perform CNS prophylaxis in those with a CNS-IPI score of 4 to 6. When CNS prophylaxis is used, intrathecal methotrexate or high-dose systemic methotrexate is most frequently given, with high-dose systemic methotrexate favored over intrathecal chemotherapy given that high-dose methotrexate penetrates the brain and spinal cord parenchyma, in addition to treating the cerebrospinal fluid (CSF).⁵⁵ In contrast, intrathecal therapy only treats the CSF and requires repeated lumbar punctures or placement of an Ommaya reservoir. For DLBCL patients who present with active CSF involvement (known as lymphomatous meningitis), intrathecal chemotherapy treatments are typically given 2 or 3 times weekly until the CSF clears, followed by weekly intrathecal treatment for 4 weeks, and then monthly intrathecal treatment for 4 months.⁵⁶ For those with concurrent systemic and brain parenchymal DLBCL, a strategy of alternating R-CHOP with mid-cycle high-dose methotrexate can be successful. In addition, consolidation with high-dose therapy and auto-HCT improved survival in such patients in 1 retrospective series.⁵⁷

Relapsed/Refractory Disease

Between 30% and 40% of patients with advanced stage DLBCL will either fail to attain a remission with primary therapy (referred to as primary induction failure) or will relapse. In general, for those with progressive or relapsed disease, an updated tissue biopsy is recommended. This is especially true for patients who have had prior complete remission and have new lymph node enlargement, or those who have emergence of new sites of disease at the completion of first-line therapy.

Patients with relapsed disease are treated with systemic second-line platinum-based chemoimmunotherapy, with the usual goal of ultimately proceeding to auto-HCT. A number of platinum-based regimens have been used in this setting such as R-ICE, R-DHAP, R-GDP, R-Gem-Ox, and R-ESHAP. None of these regimens has been shown to be superior in terms of efficacy, and the choice of regimen is typically made based on the anticipated tolerance of the patient in light of comorbidities, laboratory studies, and physician preference. In the CORAL study, R-DHAP (rituximab, dexamethasone, high-dose cytarabine, cisplatin) seemed to show superior PFS in patients with the GCB subtype.⁵⁸ However, this was an unplanned subgroup analysis and R-DHAP was associated with higher renal toxicity.

Several studies have demonstrated that long-term PFS can be observed for relapsed/refractory DLBCL patients who respond to second-line therapy and then undergo high-dose therapy with auto-HCT. The Parma trial remains the only published prospective randomized trial performed in relapsed DLBCL comparing a transplant strategy to a non-transplant strategy. This study, performed in the pre-rituximab era, clearly showed a benefit in terms of DFS and OS in favor of auto-HCT versus salvage therapy alone.⁵⁹ The benefit of auto-HCT in patients treated in the rituximab era, even in patients who experience early failure (within 1 year of diagnosis), was confirmed in a retrospective analysis by the Center for International Blood and Marrow Transplant Research. In this study, a 44% 3-year PFS was seen in the early failure cohort versus 52% in the late failure cohort.⁶⁰

Some DLBCL patients are very unlikely to benefit from auto-HCT. The REFINE study focused on patients with primary induction failure or early relapse within 6 months of completing first-line therapy. Among such patients, primary progressive disease (defined as progression while still receiving first-line therapy), a high NCCN-IPI score at relapse, and MYC rearrangement were risk factors for poor PFS following auto-HCT.⁶¹ Patients with 2 or 3 high-risk features had a 2-year OS of 10.7% compared to 74.3% for those without any high-risk features.

Allogeneic HCT (allo-HCT) is a treatment option for relapsed/refractory DLBCL. This option is more commonly considered for patients in whom an autotransplant has failed to achieve durable remission. For properly selected patients in this setting, a long-term PFS in the 30% to 40% range can be attained.⁶² However, in practice, only about 20% of patients who fail auto-HCT end up undergoing allo-HCT due to rapid progression of disease, age, poor performance status, or lack of suitable donor. It has been proposed that in the coming years, allo-HCT will be utilized less commonly in this setting due to the advent of chimeric antigen receptor T-cell (CAR T) therapy.

CAR T-cell therapy genetically modifies the patient’s own T lymphocytes with a gene that encodes an antigen receptor to direct the T cells against lymphoma cells. Typically, the T cells are genetically modified and expanded in a production facility and then infused back into the patient. Axicabtagene ciloleucel is directed against the CD-19 receptor and has been approved by the US Food and Drug Administration (FDA) for treatment of patients with DLBCL who have failed 2 or more lines of systemic therapy. Use of CAR-T therapy in such patients was examined in a multicenter trial (ZUMA-1), which reported a 54% complete response rate and 52% OS rate at 18 months.⁶³ CAR-T therapy is associated with serious side effects such as cytokine release syndrome, neurological toxicities, and prolonged cytopenias. While there are now some patients with ongoing remission 2 or more years after undergoing CAR-T therapy, it remains uncertain what proportion of patients have been truly cured with this modality. Nevertheless, this new treatment option remains a source of optimism for relapsed and refractory DLBCL patients.

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma (PMBCL) is a form of DLBCL arising in the mediastinum from the thymic B cell. It is an uncommon entity and has clinical and pathologic features distinct from systemic DLBCL.⁶⁴ PMBCL accounts for 2% of all NHLs and about 7% of all DLBCL.²⁰ It typically affects women in the third to fourth decade of life.

Presentation and Prognostic Features

PMBCL usually presents as a locally invasive anterior mediastinal mass, often with a superior vena cava syndrome which may or may not be clinically obvious.⁶⁴ Other presentations include pericardial tamponade, thrombosis of neck veins, and acute airway obstruction. About 80% of patients present with bulky (> 10 cm) stage I or II disease,⁶⁵ with distant spread uncommon on presentation. Morphologically and on GEP, PMBL has a profile more similar to classical Hodgkin lymphoma (cHL) than non-mediastinal DLBCL.⁶⁶ PMBL is distinguished from cHL by immunophenotyping: unlike cHL, PMBCL has pan B cell markers, rarely expresses CD15, and has weak CD30.

Poor prognostic features in PMBCL are Eastern Cooperative Oncology Group (ECOG) performance status greater than 2, pericardial effusion, bulky disease, and elevated serum LDH. The diagnosis of PMBCL can be difficult because the tumor is often encased with extensive fibrosis and necrosis. As a result, a needle biopsy may not yield sufficient tissue, thus making a surgical biopsy often the only viable way to obtain sufficient tissue.

Treatment

Early series suggested that PMBCL is unusually aggressive, with a poor prognosis.⁶⁷ This led to studies using more aggressive chemotherapy regimens (often in combination with mediastinal radiation) as well as upfront auto-HCT.^68–70 The addition of rituximab to treatment regimens significantly improved outcomes in PMBCL. For example, a subgroup analysis of the PMBCL patients in the MinT trial revealed a 3-year event-free survival (EFS) of 78%⁷¹ when rituximab was combined with CHOP. Because of previous reports demonstrating radiosensitivity of PMBL, radiation was traditionally sequenced into treatment regimens for PMBL. However, this is associated with higher long-term toxicities, often a concern in PMBCL patients given that the disease frequently affects younger females, and given that breast tissue will be in the radiation field. For patients with a strong personal or family history of breast cancer or cardiovascular disease, these concerns are even more significant. More recently, the DA-EPOCH-R regimen has been shown to produce very high rates (80%–90%) of long-term DFS, without the need for mediastinal radiation in most cases.^72,73 For patients receiving R-CHOP, consolidation with mediastinal radiation is still commonly given. This approach also leads to high rates of long-term remission and, although utilizing mediastinal radiation, allows for less intensive chemotherapy. Determining which approach is most appropriate for an individual patient requires an assessment of the risks of each treatment option for that patient. A randomized trial by the International Extranodal Lymphoma Study Group (IELSG37) is evaluating whether RT may be safely omitted in PMBCL patients who achieve a complete metabolic response after R-CHOP.

Most relapses of PMBCL occur within the first 1 to 2 years and often present with extranodal disease in various organs. For those with relapsed or refractory disease, high-dose chemotherapy followed by auto-HCT provides 5-year survival rates of 50% to 80%.^74–76 In a phase 1b trial evaluating the role of pembrolizumab in relapsed/refractory patients (KEYNOTE-13), 7 of 17 PMBCL patients achieved responses, with an additional 6 demonstrating stable disease.⁷⁷ This provides an additional option for patients who might be too weak to undergo auto-HCT or for those who relapse following auto-HCT.

Mantle Cell Lymphoma

The name mantle cell lymphoma (MCL) is based on the presumed normal cell counterpart to MCL, which is believed to be found in the mantle zone surrounding germinal center follicles. It represents approximately 6% of all NHL cases in the United States and Europe.⁷⁸ MCL occurs at a median age of 63 to 68 years and has a male predominance.

Presentation and Prognostic Features

Patients can present with a broad spectrum of clinical features, and most patients (70%) present with advanced disease.⁷⁹ Up to one third of patients have B symptoms, with most demonstrating lymphadenopathy and bone marrow involvement. Approximately 25% present with extranodal disease as the primary presentation (eg, GI tract, pleura, breast, or orbits). MCL can involve any part of the GI tract and often presents as polypoid lesions.

Histologically, the pattern of MCL may be diffuse, nodular, mantle zone, or a combination of the these; morphologically, MCL can range from small, more irregular lymphocytes to lymphoblast-like cells. Blastoid and pleomorphic variants of MCL have a higher proliferation index and a more aggressive clinical course than other variants. MCL is characterized by the expression of pan B cell antigens (CD19+, CD20+) with coexpression of the T-cell antigen CD5, lack of CD23 expression, and nuclear expression of cyclin D1. Nuclear staining for cyclin D1 is present in more than 98% of cases.⁸⁰ In rare cases, CD5 or cyclin D1 may be negative.⁸⁰ Most MCL cases have a unique translocation that fuses the immunoglobulin heavy chain gene promoter (14q32) to the promoter of the BCL-1 gene (11q13), which encodes the cyclin D1 protein. This translocation is not unique to MCL and can be present in multiple myeloma as well. Interestingly, cyclin D1 is overproduced in cases lacking t(11:14), likely from other point mutations resulting in its overexpression.⁸¹ Cyclin D1–negative tumors overexpress cyclin D2 or D3, with no apparent difference in clinical behavior or outcome.⁸² In cyclin D1–negative cases, SOX11 expression may help with diagnosis.⁸³ A proliferation rate greater than 30% (as measured by Ki-67 staining), low SOX11 expression, and presence of p53 mutations have all been associated with adverse outcome.

In a minority of cases, MCL follows an indolent clinical course. For the remainder, however, MCL is an aggressive disease that generally requires treatment soon after diagnosis. When initially described in the 1980s and 1990s, treatment of MCL was characterized by low complete response rates, short durations of remission, repeated recurrences, and a median survival in the 2- to 5-year range.⁸⁴ In recent years, intensive regimens incorporating rituximab and high-dose cytarabine with or without auto-HCT have been developed and are associated with high complete response rates and median duration of first remission in the 6- to 9-year range.^85–87 Several prognostic indices have been applied to patients with MCL, including the IPI, the Follicular Lymphoma International Prognostic Index , and the Mantle Cell Lymphoma International Prognostic Index (MIPI). The MIPI was originally described based on a cohort from the period 1996 to 2004,⁸⁸ and subsequently confirmed in a separate cohort of 958 patients with MCL treated on prospective trials between 2004 and 2010.⁸⁹ The MIPI score can identify 3 risk groups with significant survival differences (83%, 63%, and 34% survival at 5 years). A refined version of the MIPI score, the combined MIPI or MIPI-c, incorporates proliferation rate and is better able to stratify patients.⁹⁰ The blastoid variant of MCL follows a more aggressive clinical course and is associated with a high proliferation rate, shorter remissions, and a higher rate of CNS involvement.⁹¹

In most patients, MCL is an aggressive disease with a short OS without treatment. A subset of patients may have a more indolent course,⁹² but unfortunately reliable factors that identify this group at the time of diagnosis are not available. Pretreatment evaluation is as with other lymphomas, with lumbar puncture and MRI of the brain also recommended for patients with the blastoid variant. For those presenting with GI symptoms, endoscopy is recommended as part of the initial evaluation as well.

Treatment

First-line Therapy

For patients under age 65 to 70 years with a good performance status and few comorbidities, an intensive induction regimen (such as R-CHOP/R-DHAP, Maxi-R-CHOP/R-araC, or R-DHAP) followed by consolidation with auto-HCT is commonly given, with a goal of achieving a durable (6–9 year) first remission.^87,93,94 Auto-HCT is now routinely followed by 3 years of maintenance rituximab based on the survival benefit seen in the recent LYSA trial.⁹³ At many centers, auto-HCT in first remission is a standard of care, with the greatest benefit seen in patients who have achieved a complete remission with no more than 2 lines of chemotherapy.⁹⁵ However, there remains some controversy about whether all patients truly benefit from auto-HCT in first remission, and current research efforts are focused on identifying patients most likely to benefit from auto-HCT and incorporation of new agents into first-line regimens. For patients who are not candidates for auto-HCT, bendamustine plus rituximab (BR) or R-CHOP alone or followed by maintenance rituximab is a reasonable approach.⁹⁶ Based on the StiL and BRIGHT trials, BR seems to have less toxicity and higher rates of response with no difference in OS when compared to R-CHOP.^97,98

In summary, dose-intense induction chemotherapy with consolidative auto-HCT results in high rates of long-term remission and can be considered in MCL patients who lack significant comorbidities and who understand the risks and benefits of this approach. For other patients, the less aggressive frontline approaches are more appropriate.

Relapsed/Refractory Disease

Despite initial high response rates, most patients with MCL will eventually relapse. For example, most patients given CHOP or R-CHOP alone as first-line therapy will relapse within 2 years.⁹⁹ In recent years, a number of therapies have emerged for relapsed/refractory MCL; however, the optimal sequencing of these is unclear. FDA-approved options for relapsed/refractory MCL include the proteasome inhibitor bortezomib,^100,101 the BTK inhibitors ibrutinib^102,103 and acalabrutinib,¹⁰⁴ and the immunomodulatory agent lenalidomide.¹⁰⁵

Auto-HCT can be considered for patients who did not undergo auto-HCT as part of first-line therapy and who had a reasonably long first remission.⁹⁵ Allo-HCT has curative potential in MCL with good evidence of a graft-versus-lymphoma effect. With a matched related or matched unrelated donor, the chance for treatment-related mortality is 15% to 25% at 1 to 2 years, with a 50% to 60% chance for long-term PFS. However, given the risk of treatment-related mortality and graft-versus-host disease, this option is typically reserved for patients with early relapse after auto-HCT, multiple relapses, or relatively chemotherapy-unresponsive disease.^95,106 A number of clinical trials for relapsed/refractory MCL are ongoing, and participation in these is encouraged whenever possible.

Burkitt Lymphoma

Burkitt lymphoma is a rare, aggressive and highly curable subtype of NHL. It can occur at any age, although peak incidence is in the first decade of life. There are 3 distinct clinical forms of Burkitt lymphoma.¹⁰⁷ The endemic form is common in African children and commonly involves the jaw and kidneys. The sporadic (nonendemic) form accounts for 1% to 2% of all lymphomas in the United States and Western Europe and usually has an abdominal presentation. The immunodeficiency-associated form is commonly seen in HIV patients with a relatively preserved CD4 cell count.

Patients typically present with rapidly growing masses and tumor lysis syndrome. CNS and bone marrow involvement are common. Burkitt lymphoma cells are high-grade, rapidly proliferating medium-sized cells with a monomorphic appearance. Biopsies show a classic histological appearance known as a “starry sky pattern” due to benign macrophages engulfing debris resulting from apoptosis. It is derived from a germinal center B cell and has distinct oncogenic pathways. Translocations such as t(8;14), t(2;8) or t(8;22) juxtapose the MYC locus with immunoglobulin heavy or light chain loci and result in MYC overexpression. Burkitt lymphoma is typically CD10-positive and BCL-2-negative, with a MYC translocation and a proliferation rate greater than 95%.

With conventional NHL regimens, Burkitt lymphoma had a poor prognosis, with complete remission in the 30% to 70% range and low rates of long-term remission. With the introduction of short-term, dose-intensive, multiagent chemotherapy regimens (adapted from pediatric acute lymphoblastic leukemia [ALL] regimens), the complete remission rate improved to 60% to 90%.¹⁰⁷ Early stage disease (localized or completely resected intra-abdominal disease) can have complete remission rates of 100%, with 2- to 5-year freedom-from-progression rates of 95%. CNS prophylaxis, including high-dose methotrexate, high-dose cytarabine, and intrathecal chemotherapy, is a standard component of Burkitt lymphoma regimens (CNS relapse rates can reach 50% without prophylactic therapy). Crucially, relapse after 1 to 2 years is very rare following complete response to induction therapy. Classically, several intensive regimens have been used for Burkitt lymphoma. In recent years, the most commonly used regimens have been the modified Magrath regimen of R-CODOX-M/IVAC and R-hyperCVAD. DA-EPOCH-R has also been used, typically for older, more frail, or HIV-positive patients. However, at the American Society of Hematology 2017 annual meeting, results from the NCI 9177 trial were presented which validated, in a prospective multi-center fashion, the use of DA-EPOCH-R in all Burkitt lymphoma patients.¹⁰⁸ In NCI 9177, low-risk patients (defined as normal LDH, ECOG performance score 0 or 1, ≤ stage II, and no tumor lesion > 7 cm) received 2 cycles of DA-EPOCH-R without intrathecal therapy followed by PET. If interim PET was negative, low-risk patients then received 1 more cycle of DA-EPOCH-R. High-risk patients with negative brain MRI and CSF cytology/flow cytometry received 2 cycles of DA-EPOCH-R with intrathecal therapy (2 doses per cycle) followed by PET. Unless interim PET showed progression, high-risk patients received 4 additional cycles of DA-EPOCH-R including methotrexate 12 mg intrathecally on days 1 and 5 (8 total doses). With a median follow-up of 36 months, this regimen resulted in an EFS of 85.7%. As expected, patients with CNS, marrow, or peripheral blood involvement fared worse. For those without CNS, marrow, or peripheral blood involvement, the results were excellent, with an EFS of 94.6% compared to 62.8% for those with CNS, bone marrow, or blood involvement at diagnosis.

Although no standard of care has been defined, patients with relapsed/refractory Burkitt lymphoma are often given standard second-line aggressive NHL regimens (eg, R-ICE); for those with chemosensitive disease, auto- or allo-HCT is often pursued, with long-term remissions possible following HCT.¹⁰⁹

Lymphoblastic Lymphoma

Lymphoblastic lymphoma (LBL) is a rare disease postulated to arise from precursor B or T lymphoblasts at varying stages of differentiation. Accounting for approximately 2% of all NHLs, 85% to 90% of all cases have a T-cell phenotype, while B-cell LBL comprises approximately 10% to 15% of cases. LBL and ALL are thought to represent the same disease entity, but LBL has been arbitrarily defined as cases with lymph node or mediastinal disease. Those with significant (> 25%) bone marrow or peripheral blood involvement are classified as ALL.

Precursor T-cell LBL patients are usually adolescent and young males who commonly present with a mediastinal mass and peripheral lymphadenopathy. Precursor B-cell LBL patients are usually older (median age 39 years) with peripheral lymphadenopathy and extranodal involvement. Mediastinal involvement with B-cell LBL is uncommon, and there is no male predominance. LBL has a propensity for dissemination to the bone marrow and CNS.

Morphologically, the tumor cells are medium sized, with a scant cytoplasm and finely dispersed chromatin. Mitotic features and apoptotic bodies are present since it is a high-grade malignancy. The lymphoblasts are typically positive for CD7 and either surface or cytoplasmic CD3. Terminal deoxynucleotidyl transferase expression is a defining feature. Other markers such as CD19, CD22, CD20, CD79a, CD45, and CD10 are variably expressed. Poor prognostic factors in T-cell LBL are female gender, age greater than 35 years, complex cytogenetics, and lack of a matched sibling donor.

Regimens for LBL are based on dose-dense, multi-agent protocols used in ALL. Most of these regimens are characterized by intensive remission-induction chemotherapy, CNS prophylaxis, a phase of consolidation therapy, and a prolonged maintenance phase, often lasting for 12 to 18 months with long-term DFS rates of 40% to 70%.^110,111 High-dose therapy with auto-HCT or allo-HCT in first complete response has been evaluated in an attempt to reduce the incidence of relapse.¹¹² However, the intensity of primary chemotherapy appears to be a stronger determinant of long-term survival than the use of HCT as consolidation. As a result, HCT is not routinely applied to patients in first complete remission following modern induction regimens. After relapse, prognosis is poor, with median survival rates of 6 to 9 months with conventional chemotherapy, although long-term survival rates of 30% and 20%, respectively, are reported after HCT in relapsed and primary refractory disease.¹¹³

Treatment options in relapsed disease are limited. Nelarabine can produce responses in up to 40% of relapsed/refractory LBL/ALL patients.¹¹⁴ For the minority of LBL patients with a B-cell phenotype, emerging options for relapsed/refractory LBL/ALL such as inotuzumab, blinatumomab, or anti-CD19 CAR T-cell therapy should be considered. These are not options for the majority who have a T-cell phenotype, and treatment options for these patients are limited to conventional relapsed/refractory ALL and aggressive NHL regimens.

Summary

Aggressive NHLs are characterized by rapid clinical progression without therapy. However, a significant proportion of patients are cured with appropriate combination chemotherapy or combined modality (chemotherapy + RT) regimens. In contrast, the indolent lymphomas have a relatively good prognosis (median survival of 10 years or longer) but usually are not curable in advanced clinical stages. Overall 5-year survival for aggressive NHLs with current treatment is approximately 50% to 60%, with relapses typically occurring within the first 5 years. Treatment strategies for relapsed patients offer some potential for cure; however, clinical trial participation should be encouraged whenever possible to investigate new approaches for improving outcomes in this patient population.

Introduction

Breast cancer is the second leading cause of cancer deaths among women in the United States, according to the SEER database. It is estimated that 1 in 8 women will be diagnosed with breast cancer at some point during their lifetime (12.4% lifetime risk).^1,2 Because breast tumors are clinically and histopathologically heterogeneous, different diagnostic and therapeutic approaches are required for each subtype. Among the subtypes, tumors that are positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of all newly diagnosed localized and metastatic invasive breast tumors.^3,4 Historically, this subset of tumors has been considered the most aggressive due to a higher propensity to relapse and metastasize, translating into poorer prognosis compared with other subtypes.^5–7 However, with the advent of HER2-targeted therapy in the late 1990s, prognosis has significantly improved for both early- and late-stage HER2-positive tumors.⁸

Pathogenesis

The HER2 proto-oncogene belongs to a family of human epidermal growth factor receptors that includes 4 transmembrane tyrosine kinase receptors: HER1 (also commonly known as epidermal growth factor receptor, EGFR), HER2, HER3, and HER4. Another commonly used nomenclature for this family of receptors is ERBB1 to ERBB4. Each of the receptors has a similar structure consisting of a growth factor–binding extracellular domain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. Activation of the extracellular domain leads to conformational changes that initiate a cascade of reactions resulting in protein kinase activation. ERBB tyrosine receptor kinases subsequently activate several intracellular pathways that are critical for cellular function and survival, including the PI3K-AKT, RAS-MAPK, and mTOR pathways. Hyperactivation or overexpression of these receptors leads to uncontrolled cell growth and proliferation, and eventually cancerogenesis.^9,10

HER2 gene amplification can cause activation of the receptor’s extramembranous domain by way of either dimerization of two HER2 receptors or heterodimerization with other ERBB family receptors, leading to ligand-independent activation of cell signaling (ie, activation in the absence of external growth factors). Besides breast cancer, HER2 protein is overexpressed in several other tumor types, including esophageal and gastric adenocarcinomas, colon and gynecological malignancies, and to a lesser extent in other malignancies.

Biomarker Testing

All patients with newly diagnosed breast cancer should have their tumor tissue submitted for biomarker testing for estrogen receptors (ER), progesterone receptors (PR), and HER2 overexpression, as the result this testing dictates therapy choices. The purpose of HER2 testing is to investigate whether the HER2 gene, located on chromosome 17, is overexpressed or amplified. HER2 status provides the basis for treatment selection, which impacts long-term outcome measures such as recurrence and survival. Routine testing of carcinoma in situ for HER2 expression/amplification is not recommended and has no implication on choice of therapy at this time.

In 2013, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) updated their clinical guideline recommendations for HER2 testing in breast cancer to improve its accuracy and its utility as a predictive marker.¹¹ There are currently 2 approved modalities for HER2 testing: detection of HER2 protein overexpression by immunohistochemical staining (IHC), and detection of HER2 gene amplification using in-situ hybridization. The results of each type of testing are reported as positive, equivocal, or negative (Table 1).¹¹  IHC uses antibodies against HER2 protein to assess the level of protein expression at the membrane of invasive tumor cells; overexpression of HER2 is established based upon the intensity of cell membrane staining and the number of stained cells. Results are reported as positive for HER2 expression (3+ staining), negative for HER2 expression (0 or 1+ staining), or equivocal for HER2 expression (2+ staining).

Fluorescence in-situ hybridization (FISH) testing assesses for HER2 amplification by determining the number of HER2 signals and chromosome 17 centromere (CEP17) signals, respectively, in a tissue sample. HER2 status is based on the ratio of average HER2 signals to CEP17 signals and the average HER2 signal count per cell. FISH testing is considered positive when there are ≥ 6 copies of HER2 signals per cell or when the HER2/CEP17 ratio is ≥ 2. FISH testing is reported as negative when there are fewer than 4 copies of HER2 per cell and the HER2/CEP17 ratio is < 2. 

Neoadjuvant and Adjuvant Therapy for Locoregional Disease

Case Patient 1

A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.

• What is the recommended management approach for this patient?

According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.^12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).

Case 1 Continued

The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.

• What agents are used for adjuvant therapy in HER2-postive breast cancer?

Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.⁸ A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.¹⁴ The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.

Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.¹⁵ Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.¹⁶

A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.¹⁷ This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.¹⁸ Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.

BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.^8,17–20

Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.²¹ In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.

One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.²² In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.²² OS benefit has not yet been established.²³

Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,²⁴ while a longer duration, 24 months, has been shown to provide no additional benefit.²⁵

Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.

Case 1 Conclusion

The patient can be offered 1 of 2 adjuvant treatment regimens, either TH or TCH (Table 2). Since the patient had lumpectomy, she is an appropriate candidate for adjuvant radiation, which would be started after completion of the chemotherapy backbone (taxane/platinum). Endocrine therapy for at least 5 years should be offered sequentially or concurrently with radiation. Her long-term prognosis is very favorable.

Case Patient 2

A 43-year-old woman presents with a 4-cm breast mass, a separate skin nodule, and palpable matted axillary lymphadenopathy. Biopsies of the breast mass and subcutaneous nodule reveal invasive ductal carcinoma that is ER-negative, PR-negative, and HER2-positive by IHC (3+ staining). Based on clinical findings, the patient is staged as T4b (separate tumor nodule), N2 (matted axillary lymph nodes). Systemic staging with CT scan of the chest, abdomen, and pelvis shows no evidence of distant metastases.

• What is the recommended approach to management for this patient?

Recommendations for neoadjuvant therapy, given before definitive surgery, follow the same path as with other subtypes of breast cancer. Patients with suspected anatomical stage III disease are strongly encouraged to undergo upfront (neoadjuvant) chemotherapy in combination with HER2-targeted agents. In addition, all HER2-positive patients with clinically node-positive disease can be offered neoadjuvant therapy using chemotherapy plus dual anti-HER2 therapy (trastuzumab and pertuzumab), with complete pathological response expected in more than 60% of patients.^26,27 Because this patient has locally advanced disease, especially skin involvement and matted axillary nodes, she should undergo neoadjuvant therapy. Preferred regimens contain both trastuzumab and pertuzumab in combination with cytotoxic chemotherapy. The latter may be given concurrently (nonanthracycline regimens, such as docetaxel plus carboplatin) or sequentially (anthracycline-based regimens), as outlined in Table 2. Administration of anthracyclines and trastuzumab simultaneously is contraindicated due to increased risk of cardiomyopathy.²⁸

Endocrine therapy is not indicated for this patient per the current standard of care because the tumor was ER- and PR-negative. Had the tumor been hormone receptor–positive, endocrine therapy for a minimum of 5 years would have been indicated. Likewise, in the case of hormone receptor–positive disease, 12 months of neratinib therapy after completion of trastuzumab may add further benefit, as shown in the ExteNET trial.^22,23 Neratinib seems to have a propensity to prevent or delay trastuzumab-induced overexpression of estrogen receptors. This is mainly due to hormone receptor/HER2 crosstalk, a potential mechanism of resistance to trastuzumab.^29,30

In addition to the medical therapy options discussed here, this patient would be expected to benefit from adjuvant radiation to the breast and regional lymph nodes, given the presence of T4 disease and bulky adenopathy in the axilla.³¹

Case 2 Conclusion

The patient undergoes neoadjuvant treatment (docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for a total of 6 cycles), followed by surgical resection (modified radical mastectomy) that reveals complete pathological response (no residual invasive carcinoma). Subsequently, she receives radiation therapy to the primary tumor site and regional lymph nodes while continuing trastuzumab and pertuzumab for 11 more cycles (17 total). Despite presenting with locally advanced disease, the patient has a favorable overall prognosis due to an excellent pathological response.

• What is the approach to follow-up after completion of primary therapy?

Patients may follow up every 3 to 6 months for clinical evaluation in the first 5 years after completing primary adjuvant therapy. An annual screening mammogram is recommended as well. Body imaging can be done if dictated by symptoms. However, routine CT, positron emission tomography, or bone scans are not recommended as part of follow-up in the absence of symptoms, mainly because of a lack of evidence that such surveillance improves survival.³²

Metastatic HER2-Positive Breast Cancer

Metastatic breast cancer most commonly presents as a distant recurrence of previously treated local disease. However, 6% to 18% of patients have no prior history of breast cancer and present with de novo metastatic disease.^33,34 The most commonly involved distant organs are the skeletal bones, liver, lung, distant lymph node stations, and brain. Compared to other subtypes, HER2-positive tumors have an increased tendency to involve the central nervous system.^35–38 Although metastatic HER2-positive breast cancer is not considered curable, significant improvement in survival has been achieved, and patients with metastatic disease have median survival approaching 5 years.³⁹

Case Presentation 3

A 69-year-old woman with a history of breast cancer 4 years ago presents with new-onset back pain and unintentional weight loss. On exam, she is found to have palpable axillary adenopathy on the same side as her previous cancer. Her initial disease was stage IIB ER-positive and HER2-positive and was treated with chemotherapy, mastectomy, and anastrozole, which the patient is still taking. She undergoes CT scan of the chest, abdomen, and pelvis and radionucleotide bone scan, which show multiple liver and bony lesions suspicious for metastatic disease. Axillary lymph node biopsy confirms recurrent invasive carcinoma that is ER-positive and HER2-positive by IHC (3+).

• What is the approach to management of a patient who presents with symptoms of recurrent HER2-positive disease?

This patient likely has metastatic breast cancer based on the imaging findings. In such cases, a biopsy of the recurrent disease should always be considered, if feasible, to confirm the diagnosis and rule out other etiologies such as different malignances and benign conditions. Hormone-receptor and HER2 testing should also be performed on recurrent disease, since a change in HER2 status can be seen in 15% to 33% of cases.^40–42

Based on data from the phase 3 CLEOPATRA trial, first-line systemic regimens for patients with metastatic breast cancer that is positive for HER2 should consist of a combination of docetaxel, trastuzumab, and pertuzumab.  Compared to placebo, adding pertuzumab yielded superior progression-free survival of 18.4 months (versus 12.4 months for placebo) and an unprecedented OS of 56.5 months (versus 40.8 for placebo).³⁹ Weekly paclitaxel can replace docetaxel with comparable efficacy (Table 3).⁴³

Patients can develop significant neuropathy as well as skin and nail changes after multiple cycles of taxane-based chemotherapy. Therefore, the taxane backbone may be dropped after 6 to 8 cycles, while patients continue the trastuzumab and pertuzumab combination until disease progression or unacceptable toxicity. Some patients may enjoy remarkable long-term survival on “maintenance” anti-HER2 therapy.⁴⁴ Despite lack of high-level evidence, such as from large randomized trials, some experts recommend the addition of a hormone blocker after discontinuation of the taxane in ER-positive tumors.⁴⁵

Premenopausal and perimenopausal women with hormone receptor–positive metastatic disease should be considered for simultaneous ovarian suppression. Ovarian suppression can be accomplished medically using a gonadotropin-releasing hormone agonist (goserelin) or surgically via salpingo-oophorectomy.^46–48

Case 3 Conclusion

The patient receives 6 cycles of docetaxel, trastuzumab, and pertuzumab, after which the docetaxel is discontinued due to neuropathy while she continues the other 2 agents. After 26 months of disease control, the patient is found to have new liver metastatic lesions, indicating progression of disease.

• What therapeutic options are available for this patient?

Patients whose disease progresses after receiving taxane- and trastuzumab-containing regimens are candidates to receive the novel antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Early progressors (ie, patients with early stage disease who have progression of disease while receiving adjuvant trastuzumab or within 6 months of completion of adjuvant trastuzumab) are also candidates for T-DM1. Treatment usually fits in the second line or beyond based on data from the EMILIA trial, which randomly assigned patients to receive either capecitabine plus lapatinib or T-DM1.^49,50 Progression-free survival in the T-DM1 group was 9.6 months versus 6.4 months for the comparator. Improvement of 4 months in OS persisted with longer follow-up despite a crossover rate of 27%. Furthermore, a significantly higher objective response rate and fewer adverse effects were reported in the T-DM1 patients. Most patients included in the EMILIA trial were pertuzumab-naive. However, the benefit of T-DM1 appears to persist, albeit to a lesser extent, for pertuzumab-pretreated patients.^51,52

Patients in whom treatment fails with 2 or more lines of therapy containing taxane-trastuzumab (with or without pertuzumab) and T-DM1 are candidates to receive a combination of capecitabine and lapatinib, a TKI, in the third line and beyond. Similarly, the combination of capecitabine with trastuzumab in the same settings appears to have equal efficacy.^53,54 Trastuzumab may be continued beyond progression while changing the single-agent chemotherapy drug for subsequent lines of therapy, per ASCO guidelines,⁵⁵ although improvement in OS has not been demonstrated beyond the third line in a large randomized trial (Table 3).

Approved HER2-Targeted Drugs

HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).

Trastuzumab

Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV).  Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.⁵⁶ Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.^57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.^60,61

An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.^{28,57,60–63}

Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2). 

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3). 

Lapatinib

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.^69,70 Lapatinib is not approved for use in adjuvant settings.

Neratinib

Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.^21,71 Neratinib is not FDA-approved in the metastatic settings.

Conclusion

HER2-positive tumors represent a distinct subset(s) of breast tumors with unique pathological and clinical characteristics. Treatment with a combination of cytotoxic chemotherapy and HER2-targeted agents has led to a dramatic improvement in survival for patients with locoregional and advanced disease. Trastuzumab is an integral part of adjuvant therapy for HER2-positive invasive disease. Pertuzumab should be added to trastuzumab in node-positive disease. Neratinib may be considered after completion of trastuzumab therapy in patients with hormone receptor–positive disease. For metastatic HER2-positive breast cancer, a regimen consisting of docetaxel plus trastuzumab and pertuzumab is the standard first-line therapy. Ado-trastuzumab is an ideal next line option for patients whose disease progresses on trastuzumab and taxanes.

Introduction

Breast cancer is the second leading cause of cancer deaths among women in the United States, according to the SEER database. It is estimated that 1 in 8 women will be diagnosed with breast cancer at some point during their lifetime (12.4% lifetime risk).^1,2 Because breast tumors are clinically and histopathologically heterogeneous, different diagnostic and therapeutic approaches are required for each subtype. Among the subtypes, tumors that are positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of all newly diagnosed localized and metastatic invasive breast tumors.^3,4 Historically, this subset of tumors has been considered the most aggressive due to a higher propensity to relapse and metastasize, translating into poorer prognosis compared with other subtypes.^5–7 However, with the advent of HER2-targeted therapy in the late 1990s, prognosis has significantly improved for both early- and late-stage HER2-positive tumors.⁸

Pathogenesis

The HER2 proto-oncogene belongs to a family of human epidermal growth factor receptors that includes 4 transmembrane tyrosine kinase receptors: HER1 (also commonly known as epidermal growth factor receptor, EGFR), HER2, HER3, and HER4. Another commonly used nomenclature for this family of receptors is ERBB1 to ERBB4. Each of the receptors has a similar structure consisting of a growth factor–binding extracellular domain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. Activation of the extracellular domain leads to conformational changes that initiate a cascade of reactions resulting in protein kinase activation. ERBB tyrosine receptor kinases subsequently activate several intracellular pathways that are critical for cellular function and survival, including the PI3K-AKT, RAS-MAPK, and mTOR pathways. Hyperactivation or overexpression of these receptors leads to uncontrolled cell growth and proliferation, and eventually cancerogenesis.^9,10

HER2 gene amplification can cause activation of the receptor’s extramembranous domain by way of either dimerization of two HER2 receptors or heterodimerization with other ERBB family receptors, leading to ligand-independent activation of cell signaling (ie, activation in the absence of external growth factors). Besides breast cancer, HER2 protein is overexpressed in several other tumor types, including esophageal and gastric adenocarcinomas, colon and gynecological malignancies, and to a lesser extent in other malignancies.

Biomarker Testing

All patients with newly diagnosed breast cancer should have their tumor tissue submitted for biomarker testing for estrogen receptors (ER), progesterone receptors (PR), and HER2 overexpression, as the result this testing dictates therapy choices. The purpose of HER2 testing is to investigate whether the HER2 gene, located on chromosome 17, is overexpressed or amplified. HER2 status provides the basis for treatment selection, which impacts long-term outcome measures such as recurrence and survival. Routine testing of carcinoma in situ for HER2 expression/amplification is not recommended and has no implication on choice of therapy at this time.

In 2013, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) updated their clinical guideline recommendations for HER2 testing in breast cancer to improve its accuracy and its utility as a predictive marker.¹¹ There are currently 2 approved modalities for HER2 testing: detection of HER2 protein overexpression by immunohistochemical staining (IHC), and detection of HER2 gene amplification using in-situ hybridization. The results of each type of testing are reported as positive, equivocal, or negative (Table 1).¹¹  IHC uses antibodies against HER2 protein to assess the level of protein expression at the membrane of invasive tumor cells; overexpression of HER2 is established based upon the intensity of cell membrane staining and the number of stained cells. Results are reported as positive for HER2 expression (3+ staining), negative for HER2 expression (0 or 1+ staining), or equivocal for HER2 expression (2+ staining).

Fluorescence in-situ hybridization (FISH) testing assesses for HER2 amplification by determining the number of HER2 signals and chromosome 17 centromere (CEP17) signals, respectively, in a tissue sample. HER2 status is based on the ratio of average HER2 signals to CEP17 signals and the average HER2 signal count per cell. FISH testing is considered positive when there are ≥ 6 copies of HER2 signals per cell or when the HER2/CEP17 ratio is ≥ 2. FISH testing is reported as negative when there are fewer than 4 copies of HER2 per cell and the HER2/CEP17 ratio is < 2. 

Neoadjuvant and Adjuvant Therapy for Locoregional Disease

Case Patient 1

A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.

• What is the recommended management approach for this patient?

According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.^12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).

Case 1 Continued

The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.

• What agents are used for adjuvant therapy in HER2-postive breast cancer?

Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.⁸ A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.¹⁴ The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.

Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.¹⁵ Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.¹⁶

A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.¹⁷ This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.¹⁸ Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.

BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.^8,17–20

Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.²¹ In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.

One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.²² In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.²² OS benefit has not yet been established.²³

Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,²⁴ while a longer duration, 24 months, has been shown to provide no additional benefit.²⁵

Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.

Case 1 Conclusion

The patient can be offered 1 of 2 adjuvant treatment regimens, either TH or TCH (Table 2). Since the patient had lumpectomy, she is an appropriate candidate for adjuvant radiation, which would be started after completion of the chemotherapy backbone (taxane/platinum). Endocrine therapy for at least 5 years should be offered sequentially or concurrently with radiation. Her long-term prognosis is very favorable.

Case Patient 2

A 43-year-old woman presents with a 4-cm breast mass, a separate skin nodule, and palpable matted axillary lymphadenopathy. Biopsies of the breast mass and subcutaneous nodule reveal invasive ductal carcinoma that is ER-negative, PR-negative, and HER2-positive by IHC (3+ staining). Based on clinical findings, the patient is staged as T4b (separate tumor nodule), N2 (matted axillary lymph nodes). Systemic staging with CT scan of the chest, abdomen, and pelvis shows no evidence of distant metastases.

• What is the recommended approach to management for this patient?

Recommendations for neoadjuvant therapy, given before definitive surgery, follow the same path as with other subtypes of breast cancer. Patients with suspected anatomical stage III disease are strongly encouraged to undergo upfront (neoadjuvant) chemotherapy in combination with HER2-targeted agents. In addition, all HER2-positive patients with clinically node-positive disease can be offered neoadjuvant therapy using chemotherapy plus dual anti-HER2 therapy (trastuzumab and pertuzumab), with complete pathological response expected in more than 60% of patients.^26,27 Because this patient has locally advanced disease, especially skin involvement and matted axillary nodes, she should undergo neoadjuvant therapy. Preferred regimens contain both trastuzumab and pertuzumab in combination with cytotoxic chemotherapy. The latter may be given concurrently (nonanthracycline regimens, such as docetaxel plus carboplatin) or sequentially (anthracycline-based regimens), as outlined in Table 2. Administration of anthracyclines and trastuzumab simultaneously is contraindicated due to increased risk of cardiomyopathy.²⁸

Endocrine therapy is not indicated for this patient per the current standard of care because the tumor was ER- and PR-negative. Had the tumor been hormone receptor–positive, endocrine therapy for a minimum of 5 years would have been indicated. Likewise, in the case of hormone receptor–positive disease, 12 months of neratinib therapy after completion of trastuzumab may add further benefit, as shown in the ExteNET trial.^22,23 Neratinib seems to have a propensity to prevent or delay trastuzumab-induced overexpression of estrogen receptors. This is mainly due to hormone receptor/HER2 crosstalk, a potential mechanism of resistance to trastuzumab.^29,30

In addition to the medical therapy options discussed here, this patient would be expected to benefit from adjuvant radiation to the breast and regional lymph nodes, given the presence of T4 disease and bulky adenopathy in the axilla.³¹

Case 2 Conclusion

The patient undergoes neoadjuvant treatment (docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for a total of 6 cycles), followed by surgical resection (modified radical mastectomy) that reveals complete pathological response (no residual invasive carcinoma). Subsequently, she receives radiation therapy to the primary tumor site and regional lymph nodes while continuing trastuzumab and pertuzumab for 11 more cycles (17 total). Despite presenting with locally advanced disease, the patient has a favorable overall prognosis due to an excellent pathological response.

• What is the approach to follow-up after completion of primary therapy?

Patients may follow up every 3 to 6 months for clinical evaluation in the first 5 years after completing primary adjuvant therapy. An annual screening mammogram is recommended as well. Body imaging can be done if dictated by symptoms. However, routine CT, positron emission tomography, or bone scans are not recommended as part of follow-up in the absence of symptoms, mainly because of a lack of evidence that such surveillance improves survival.³²

Metastatic HER2-Positive Breast Cancer

Metastatic breast cancer most commonly presents as a distant recurrence of previously treated local disease. However, 6% to 18% of patients have no prior history of breast cancer and present with de novo metastatic disease.^33,34 The most commonly involved distant organs are the skeletal bones, liver, lung, distant lymph node stations, and brain. Compared to other subtypes, HER2-positive tumors have an increased tendency to involve the central nervous system.^35–38 Although metastatic HER2-positive breast cancer is not considered curable, significant improvement in survival has been achieved, and patients with metastatic disease have median survival approaching 5 years.³⁹

Case Presentation 3

A 69-year-old woman with a history of breast cancer 4 years ago presents with new-onset back pain and unintentional weight loss. On exam, she is found to have palpable axillary adenopathy on the same side as her previous cancer. Her initial disease was stage IIB ER-positive and HER2-positive and was treated with chemotherapy, mastectomy, and anastrozole, which the patient is still taking. She undergoes CT scan of the chest, abdomen, and pelvis and radionucleotide bone scan, which show multiple liver and bony lesions suspicious for metastatic disease. Axillary lymph node biopsy confirms recurrent invasive carcinoma that is ER-positive and HER2-positive by IHC (3+).

• What is the approach to management of a patient who presents with symptoms of recurrent HER2-positive disease?

This patient likely has metastatic breast cancer based on the imaging findings. In such cases, a biopsy of the recurrent disease should always be considered, if feasible, to confirm the diagnosis and rule out other etiologies such as different malignances and benign conditions. Hormone-receptor and HER2 testing should also be performed on recurrent disease, since a change in HER2 status can be seen in 15% to 33% of cases.^40–42

Based on data from the phase 3 CLEOPATRA trial, first-line systemic regimens for patients with metastatic breast cancer that is positive for HER2 should consist of a combination of docetaxel, trastuzumab, and pertuzumab.  Compared to placebo, adding pertuzumab yielded superior progression-free survival of 18.4 months (versus 12.4 months for placebo) and an unprecedented OS of 56.5 months (versus 40.8 for placebo).³⁹ Weekly paclitaxel can replace docetaxel with comparable efficacy (Table 3).⁴³

Patients can develop significant neuropathy as well as skin and nail changes after multiple cycles of taxane-based chemotherapy. Therefore, the taxane backbone may be dropped after 6 to 8 cycles, while patients continue the trastuzumab and pertuzumab combination until disease progression or unacceptable toxicity. Some patients may enjoy remarkable long-term survival on “maintenance” anti-HER2 therapy.⁴⁴ Despite lack of high-level evidence, such as from large randomized trials, some experts recommend the addition of a hormone blocker after discontinuation of the taxane in ER-positive tumors.⁴⁵

Premenopausal and perimenopausal women with hormone receptor–positive metastatic disease should be considered for simultaneous ovarian suppression. Ovarian suppression can be accomplished medically using a gonadotropin-releasing hormone agonist (goserelin) or surgically via salpingo-oophorectomy.^46–48

Case 3 Conclusion

The patient receives 6 cycles of docetaxel, trastuzumab, and pertuzumab, after which the docetaxel is discontinued due to neuropathy while she continues the other 2 agents. After 26 months of disease control, the patient is found to have new liver metastatic lesions, indicating progression of disease.

• What therapeutic options are available for this patient?

Patients whose disease progresses after receiving taxane- and trastuzumab-containing regimens are candidates to receive the novel antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Early progressors (ie, patients with early stage disease who have progression of disease while receiving adjuvant trastuzumab or within 6 months of completion of adjuvant trastuzumab) are also candidates for T-DM1. Treatment usually fits in the second line or beyond based on data from the EMILIA trial, which randomly assigned patients to receive either capecitabine plus lapatinib or T-DM1.^49,50 Progression-free survival in the T-DM1 group was 9.6 months versus 6.4 months for the comparator. Improvement of 4 months in OS persisted with longer follow-up despite a crossover rate of 27%. Furthermore, a significantly higher objective response rate and fewer adverse effects were reported in the T-DM1 patients. Most patients included in the EMILIA trial were pertuzumab-naive. However, the benefit of T-DM1 appears to persist, albeit to a lesser extent, for pertuzumab-pretreated patients.^51,52

Patients in whom treatment fails with 2 or more lines of therapy containing taxane-trastuzumab (with or without pertuzumab) and T-DM1 are candidates to receive a combination of capecitabine and lapatinib, a TKI, in the third line and beyond. Similarly, the combination of capecitabine with trastuzumab in the same settings appears to have equal efficacy.^53,54 Trastuzumab may be continued beyond progression while changing the single-agent chemotherapy drug for subsequent lines of therapy, per ASCO guidelines,⁵⁵ although improvement in OS has not been demonstrated beyond the third line in a large randomized trial (Table 3).

Approved HER2-Targeted Drugs

HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).

Trastuzumab

Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV).  Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.⁵⁶ Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.^57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.^60,61

An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.^{28,57,60–63}

Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2). 

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3). 

Lapatinib

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.^69,70 Lapatinib is not approved for use in adjuvant settings.

Neratinib

Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.^21,71 Neratinib is not FDA-approved in the metastatic settings.

Conclusion

HER2-positive tumors represent a distinct subset(s) of breast tumors with unique pathological and clinical characteristics. Treatment with a combination of cytotoxic chemotherapy and HER2-targeted agents has led to a dramatic improvement in survival for patients with locoregional and advanced disease. Trastuzumab is an integral part of adjuvant therapy for HER2-positive invasive disease. Pertuzumab should be added to trastuzumab in node-positive disease. Neratinib may be considered after completion of trastuzumab therapy in patients with hormone receptor–positive disease. For metastatic HER2-positive breast cancer, a regimen consisting of docetaxel plus trastuzumab and pertuzumab is the standard first-line therapy. Ado-trastuzumab is an ideal next line option for patients whose disease progresses on trastuzumab and taxanes.

Introduction

Breast cancer is the second leading cause of cancer deaths among women in the United States, according to the SEER database. It is estimated that 1 in 8 women will be diagnosed with breast cancer at some point during their lifetime (12.4% lifetime risk).^1,2 Because breast tumors are clinically and histopathologically heterogeneous, different diagnostic and therapeutic approaches are required for each subtype. Among the subtypes, tumors that are positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of all newly diagnosed localized and metastatic invasive breast tumors.^3,4 Historically, this subset of tumors has been considered the most aggressive due to a higher propensity to relapse and metastasize, translating into poorer prognosis compared with other subtypes.^5–7 However, with the advent of HER2-targeted therapy in the late 1990s, prognosis has significantly improved for both early- and late-stage HER2-positive tumors.⁸

Pathogenesis

The HER2 proto-oncogene belongs to a family of human epidermal growth factor receptors that includes 4 transmembrane tyrosine kinase receptors: HER1 (also commonly known as epidermal growth factor receptor, EGFR), HER2, HER3, and HER4. Another commonly used nomenclature for this family of receptors is ERBB1 to ERBB4. Each of the receptors has a similar structure consisting of a growth factor–binding extracellular domain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. Activation of the extracellular domain leads to conformational changes that initiate a cascade of reactions resulting in protein kinase activation. ERBB tyrosine receptor kinases subsequently activate several intracellular pathways that are critical for cellular function and survival, including the PI3K-AKT, RAS-MAPK, and mTOR pathways. Hyperactivation or overexpression of these receptors leads to uncontrolled cell growth and proliferation, and eventually cancerogenesis.^9,10

HER2 gene amplification can cause activation of the receptor’s extramembranous domain by way of either dimerization of two HER2 receptors or heterodimerization with other ERBB family receptors, leading to ligand-independent activation of cell signaling (ie, activation in the absence of external growth factors). Besides breast cancer, HER2 protein is overexpressed in several other tumor types, including esophageal and gastric adenocarcinomas, colon and gynecological malignancies, and to a lesser extent in other malignancies.

Biomarker Testing

All patients with newly diagnosed breast cancer should have their tumor tissue submitted for biomarker testing for estrogen receptors (ER), progesterone receptors (PR), and HER2 overexpression, as the result this testing dictates therapy choices. The purpose of HER2 testing is to investigate whether the HER2 gene, located on chromosome 17, is overexpressed or amplified. HER2 status provides the basis for treatment selection, which impacts long-term outcome measures such as recurrence and survival. Routine testing of carcinoma in situ for HER2 expression/amplification is not recommended and has no implication on choice of therapy at this time.

In 2013, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) updated their clinical guideline recommendations for HER2 testing in breast cancer to improve its accuracy and its utility as a predictive marker.¹¹ There are currently 2 approved modalities for HER2 testing: detection of HER2 protein overexpression by immunohistochemical staining (IHC), and detection of HER2 gene amplification using in-situ hybridization. The results of each type of testing are reported as positive, equivocal, or negative (Table 1).¹¹  IHC uses antibodies against HER2 protein to assess the level of protein expression at the membrane of invasive tumor cells; overexpression of HER2 is established based upon the intensity of cell membrane staining and the number of stained cells. Results are reported as positive for HER2 expression (3+ staining), negative for HER2 expression (0 or 1+ staining), or equivocal for HER2 expression (2+ staining).

Fluorescence in-situ hybridization (FISH) testing assesses for HER2 amplification by determining the number of HER2 signals and chromosome 17 centromere (CEP17) signals, respectively, in a tissue sample. HER2 status is based on the ratio of average HER2 signals to CEP17 signals and the average HER2 signal count per cell. FISH testing is considered positive when there are ≥ 6 copies of HER2 signals per cell or when the HER2/CEP17 ratio is ≥ 2. FISH testing is reported as negative when there are fewer than 4 copies of HER2 per cell and the HER2/CEP17 ratio is < 2. 

Neoadjuvant and Adjuvant Therapy for Locoregional Disease

Case Patient 1

A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.

• What is the recommended management approach for this patient?

According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.^12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).

Case 1 Continued

The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.

• What agents are used for adjuvant therapy in HER2-postive breast cancer?

Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.⁸ A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.¹⁴ The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.

Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.¹⁵ Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.¹⁶

A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.¹⁷ This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.¹⁸ Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.

BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.^8,17–20

Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.²¹ In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.

One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.²² In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.²² OS benefit has not yet been established.²³

Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,²⁴ while a longer duration, 24 months, has been shown to provide no additional benefit.²⁵

Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.

Case 1 Conclusion

The patient can be offered 1 of 2 adjuvant treatment regimens, either TH or TCH (Table 2). Since the patient had lumpectomy, she is an appropriate candidate for adjuvant radiation, which would be started after completion of the chemotherapy backbone (taxane/platinum). Endocrine therapy for at least 5 years should be offered sequentially or concurrently with radiation. Her long-term prognosis is very favorable.

Case Patient 2

A 43-year-old woman presents with a 4-cm breast mass, a separate skin nodule, and palpable matted axillary lymphadenopathy. Biopsies of the breast mass and subcutaneous nodule reveal invasive ductal carcinoma that is ER-negative, PR-negative, and HER2-positive by IHC (3+ staining). Based on clinical findings, the patient is staged as T4b (separate tumor nodule), N2 (matted axillary lymph nodes). Systemic staging with CT scan of the chest, abdomen, and pelvis shows no evidence of distant metastases.

• What is the recommended approach to management for this patient?

Recommendations for neoadjuvant therapy, given before definitive surgery, follow the same path as with other subtypes of breast cancer. Patients with suspected anatomical stage III disease are strongly encouraged to undergo upfront (neoadjuvant) chemotherapy in combination with HER2-targeted agents. In addition, all HER2-positive patients with clinically node-positive disease can be offered neoadjuvant therapy using chemotherapy plus dual anti-HER2 therapy (trastuzumab and pertuzumab), with complete pathological response expected in more than 60% of patients.^26,27 Because this patient has locally advanced disease, especially skin involvement and matted axillary nodes, she should undergo neoadjuvant therapy. Preferred regimens contain both trastuzumab and pertuzumab in combination with cytotoxic chemotherapy. The latter may be given concurrently (nonanthracycline regimens, such as docetaxel plus carboplatin) or sequentially (anthracycline-based regimens), as outlined in Table 2. Administration of anthracyclines and trastuzumab simultaneously is contraindicated due to increased risk of cardiomyopathy.²⁸

Endocrine therapy is not indicated for this patient per the current standard of care because the tumor was ER- and PR-negative. Had the tumor been hormone receptor–positive, endocrine therapy for a minimum of 5 years would have been indicated. Likewise, in the case of hormone receptor–positive disease, 12 months of neratinib therapy after completion of trastuzumab may add further benefit, as shown in the ExteNET trial.^22,23 Neratinib seems to have a propensity to prevent or delay trastuzumab-induced overexpression of estrogen receptors. This is mainly due to hormone receptor/HER2 crosstalk, a potential mechanism of resistance to trastuzumab.^29,30

In addition to the medical therapy options discussed here, this patient would be expected to benefit from adjuvant radiation to the breast and regional lymph nodes, given the presence of T4 disease and bulky adenopathy in the axilla.³¹

Case 2 Conclusion

The patient undergoes neoadjuvant treatment (docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for a total of 6 cycles), followed by surgical resection (modified radical mastectomy) that reveals complete pathological response (no residual invasive carcinoma). Subsequently, she receives radiation therapy to the primary tumor site and regional lymph nodes while continuing trastuzumab and pertuzumab for 11 more cycles (17 total). Despite presenting with locally advanced disease, the patient has a favorable overall prognosis due to an excellent pathological response.

• What is the approach to follow-up after completion of primary therapy?

Patients may follow up every 3 to 6 months for clinical evaluation in the first 5 years after completing primary adjuvant therapy. An annual screening mammogram is recommended as well. Body imaging can be done if dictated by symptoms. However, routine CT, positron emission tomography, or bone scans are not recommended as part of follow-up in the absence of symptoms, mainly because of a lack of evidence that such surveillance improves survival.³²

Metastatic HER2-Positive Breast Cancer

Metastatic breast cancer most commonly presents as a distant recurrence of previously treated local disease. However, 6% to 18% of patients have no prior history of breast cancer and present with de novo metastatic disease.^33,34 The most commonly involved distant organs are the skeletal bones, liver, lung, distant lymph node stations, and brain. Compared to other subtypes, HER2-positive tumors have an increased tendency to involve the central nervous system.^35–38 Although metastatic HER2-positive breast cancer is not considered curable, significant improvement in survival has been achieved, and patients with metastatic disease have median survival approaching 5 years.³⁹

Case Presentation 3

A 69-year-old woman with a history of breast cancer 4 years ago presents with new-onset back pain and unintentional weight loss. On exam, she is found to have palpable axillary adenopathy on the same side as her previous cancer. Her initial disease was stage IIB ER-positive and HER2-positive and was treated with chemotherapy, mastectomy, and anastrozole, which the patient is still taking. She undergoes CT scan of the chest, abdomen, and pelvis and radionucleotide bone scan, which show multiple liver and bony lesions suspicious for metastatic disease. Axillary lymph node biopsy confirms recurrent invasive carcinoma that is ER-positive and HER2-positive by IHC (3+).

• What is the approach to management of a patient who presents with symptoms of recurrent HER2-positive disease?

This patient likely has metastatic breast cancer based on the imaging findings. In such cases, a biopsy of the recurrent disease should always be considered, if feasible, to confirm the diagnosis and rule out other etiologies such as different malignances and benign conditions. Hormone-receptor and HER2 testing should also be performed on recurrent disease, since a change in HER2 status can be seen in 15% to 33% of cases.^40–42

Based on data from the phase 3 CLEOPATRA trial, first-line systemic regimens for patients with metastatic breast cancer that is positive for HER2 should consist of a combination of docetaxel, trastuzumab, and pertuzumab.  Compared to placebo, adding pertuzumab yielded superior progression-free survival of 18.4 months (versus 12.4 months for placebo) and an unprecedented OS of 56.5 months (versus 40.8 for placebo).³⁹ Weekly paclitaxel can replace docetaxel with comparable efficacy (Table 3).⁴³

Patients can develop significant neuropathy as well as skin and nail changes after multiple cycles of taxane-based chemotherapy. Therefore, the taxane backbone may be dropped after 6 to 8 cycles, while patients continue the trastuzumab and pertuzumab combination until disease progression or unacceptable toxicity. Some patients may enjoy remarkable long-term survival on “maintenance” anti-HER2 therapy.⁴⁴ Despite lack of high-level evidence, such as from large randomized trials, some experts recommend the addition of a hormone blocker after discontinuation of the taxane in ER-positive tumors.⁴⁵

Premenopausal and perimenopausal women with hormone receptor–positive metastatic disease should be considered for simultaneous ovarian suppression. Ovarian suppression can be accomplished medically using a gonadotropin-releasing hormone agonist (goserelin) or surgically via salpingo-oophorectomy.^46–48

Case 3 Conclusion

The patient receives 6 cycles of docetaxel, trastuzumab, and pertuzumab, after which the docetaxel is discontinued due to neuropathy while she continues the other 2 agents. After 26 months of disease control, the patient is found to have new liver metastatic lesions, indicating progression of disease.

• What therapeutic options are available for this patient?

Patients whose disease progresses after receiving taxane- and trastuzumab-containing regimens are candidates to receive the novel antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Early progressors (ie, patients with early stage disease who have progression of disease while receiving adjuvant trastuzumab or within 6 months of completion of adjuvant trastuzumab) are also candidates for T-DM1. Treatment usually fits in the second line or beyond based on data from the EMILIA trial, which randomly assigned patients to receive either capecitabine plus lapatinib or T-DM1.^49,50 Progression-free survival in the T-DM1 group was 9.6 months versus 6.4 months for the comparator. Improvement of 4 months in OS persisted with longer follow-up despite a crossover rate of 27%. Furthermore, a significantly higher objective response rate and fewer adverse effects were reported in the T-DM1 patients. Most patients included in the EMILIA trial were pertuzumab-naive. However, the benefit of T-DM1 appears to persist, albeit to a lesser extent, for pertuzumab-pretreated patients.^51,52

Patients in whom treatment fails with 2 or more lines of therapy containing taxane-trastuzumab (with or without pertuzumab) and T-DM1 are candidates to receive a combination of capecitabine and lapatinib, a TKI, in the third line and beyond. Similarly, the combination of capecitabine with trastuzumab in the same settings appears to have equal efficacy.^53,54 Trastuzumab may be continued beyond progression while changing the single-agent chemotherapy drug for subsequent lines of therapy, per ASCO guidelines,⁵⁵ although improvement in OS has not been demonstrated beyond the third line in a large randomized trial (Table 3).

Approved HER2-Targeted Drugs

HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).

Trastuzumab

Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV).  Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.⁵⁶ Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.^57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.^60,61

An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.^{28,57,60–63}

Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2). 

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3). 

Lapatinib

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.^69,70 Lapatinib is not approved for use in adjuvant settings.

Neratinib

Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.^21,71 Neratinib is not FDA-approved in the metastatic settings.

Conclusion

HER2-positive tumors represent a distinct subset(s) of breast tumors with unique pathological and clinical characteristics. Treatment with a combination of cytotoxic chemotherapy and HER2-targeted agents has led to a dramatic improvement in survival for patients with locoregional and advanced disease. Trastuzumab is an integral part of adjuvant therapy for HER2-positive invasive disease. Pertuzumab should be added to trastuzumab in node-positive disease. Neratinib may be considered after completion of trastuzumab therapy in patients with hormone receptor–positive disease. For metastatic HER2-positive breast cancer, a regimen consisting of docetaxel plus trastuzumab and pertuzumab is the standard first-line therapy. Ado-trastuzumab is an ideal next line option for patients whose disease progresses on trastuzumab and taxanes.

Photo by Bill Branson

Currently, 1,120 new medicines and vaccines are being developed to treat cancer, according to a new report of the Pharmaceutical Research and Manufacturers of America (PhRMA).

And all of them, the organization states, are in clinical trials or awaiting review by the US Food and Drug Administration (FDA).

Leading the way are treatments for solid tumors, with 397 in development. Treatments for blood cancers are not far behind, with nearly 340 medicines in development: 137 for leukemias, 135 for lymphomas, and 62 for multiple myeloma.

Immuno-oncology and personalized medicine have a hand in this increase.

In the last year, according to PhRMA’s  "Medicines in Development for Cancer 2018 Report," 47 new immune-oncology treatments have been added to the development pipeline, including CAR-T therapies and checkpoint inhibitors.

This brings the total to 295 immuno-oncology medicines and vaccines in the development pipeline this year.

The report also states that about 85% of these medicines in the oncology pipeline are first-in-class.

And PhRMA attributes the approximately 73% of survival gains in cancer to the new medicines.

Despite the bright picture, PhRMA acknowledges the financial burden and medical care challenges patients encounter.

It addresses them in a new chart pack, "Cancer Medicines: Value in Context," which puts cancer costs in perspective and offers solutions for improving the current system in the United States.

The association reports the top medical financial concerns of patients to be diagnostic tests or scans (53%), prescription medicines (43%), physician office visits (39%), outpatient treatments-including radiation (37%), and surgery (36%).

Spending on cancer medicines represents about 1% of overall healthcare spending, according to the organization, with cancer medications accounting for $49.8 billion of the $3.49 trillion healthcare spending in the United States.

Cancer medicines represent about 20% of spending on cancer, PhrMA notes, and some insurance plans place treatments for certain high-cost conditions on the highest drug formulary cost-sharing tier.

And patients with the highest copay were 5 times more likely to abandon treatment than the lowest copay group, PhRMA points out.

“No patient should struggle to afford their needed treatments,” PhRMA stated in a release, “and it is important that we address patient access challenges.” 

Photo by Bill Branson

Currently, 1,120 new medicines and vaccines are being developed to treat cancer, according to a new report of the Pharmaceutical Research and Manufacturers of America (PhRMA).

And all of them, the organization states, are in clinical trials or awaiting review by the US Food and Drug Administration (FDA).

Leading the way are treatments for solid tumors, with 397 in development. Treatments for blood cancers are not far behind, with nearly 340 medicines in development: 137 for leukemias, 135 for lymphomas, and 62 for multiple myeloma.

Immuno-oncology and personalized medicine have a hand in this increase.

In the last year, according to PhRMA’s  "Medicines in Development for Cancer 2018 Report," 47 new immune-oncology treatments have been added to the development pipeline, including CAR-T therapies and checkpoint inhibitors.

This brings the total to 295 immuno-oncology medicines and vaccines in the development pipeline this year.

The report also states that about 85% of these medicines in the oncology pipeline are first-in-class.

And PhRMA attributes the approximately 73% of survival gains in cancer to the new medicines.

Despite the bright picture, PhRMA acknowledges the financial burden and medical care challenges patients encounter.

It addresses them in a new chart pack, "Cancer Medicines: Value in Context," which puts cancer costs in perspective and offers solutions for improving the current system in the United States.

The association reports the top medical financial concerns of patients to be diagnostic tests or scans (53%), prescription medicines (43%), physician office visits (39%), outpatient treatments-including radiation (37%), and surgery (36%).

Spending on cancer medicines represents about 1% of overall healthcare spending, according to the organization, with cancer medications accounting for $49.8 billion of the $3.49 trillion healthcare spending in the United States.

Cancer medicines represent about 20% of spending on cancer, PhrMA notes, and some insurance plans place treatments for certain high-cost conditions on the highest drug formulary cost-sharing tier.

And patients with the highest copay were 5 times more likely to abandon treatment than the lowest copay group, PhRMA points out.

“No patient should struggle to afford their needed treatments,” PhRMA stated in a release, “and it is important that we address patient access challenges.” 

Photo by Bill Branson

Currently, 1,120 new medicines and vaccines are being developed to treat cancer, according to a new report of the Pharmaceutical Research and Manufacturers of America (PhRMA).

And all of them, the organization states, are in clinical trials or awaiting review by the US Food and Drug Administration (FDA).

Leading the way are treatments for solid tumors, with 397 in development. Treatments for blood cancers are not far behind, with nearly 340 medicines in development: 137 for leukemias, 135 for lymphomas, and 62 for multiple myeloma.

Immuno-oncology and personalized medicine have a hand in this increase.

In the last year, according to PhRMA’s  "Medicines in Development for Cancer 2018 Report," 47 new immune-oncology treatments have been added to the development pipeline, including CAR-T therapies and checkpoint inhibitors.

This brings the total to 295 immuno-oncology medicines and vaccines in the development pipeline this year.

The report also states that about 85% of these medicines in the oncology pipeline are first-in-class.

And PhRMA attributes the approximately 73% of survival gains in cancer to the new medicines.

Despite the bright picture, PhRMA acknowledges the financial burden and medical care challenges patients encounter.

It addresses them in a new chart pack, "Cancer Medicines: Value in Context," which puts cancer costs in perspective and offers solutions for improving the current system in the United States.

The association reports the top medical financial concerns of patients to be diagnostic tests or scans (53%), prescription medicines (43%), physician office visits (39%), outpatient treatments-including radiation (37%), and surgery (36%).

Spending on cancer medicines represents about 1% of overall healthcare spending, according to the organization, with cancer medications accounting for $49.8 billion of the $3.49 trillion healthcare spending in the United States.

Cancer medicines represent about 20% of spending on cancer, PhrMA notes, and some insurance plans place treatments for certain high-cost conditions on the highest drug formulary cost-sharing tier.

And patients with the highest copay were 5 times more likely to abandon treatment than the lowest copay group, PhRMA points out.

“No patient should struggle to afford their needed treatments,” PhRMA stated in a release, “and it is important that we address patient access challenges.” 

Just over a year ago, I established a solo colorectal surgery clinic within a comprehensive academic medical center hospital system and have since seen a variety of cases: benign anorectal conditions, acute and chronic diseases, complex defecatory dysfunction, and colorectal surgery pre- and postop patients. I also manage a colorectal cancer survivorship clinic. As a PA in this field, I very much appreciated the November 2017 CE/CME, “Anorectal Evaluations: Diagnosing & Treating Benign Conditions” (Clinician Reviews. 2017;27[11]:28-37). The article offered useful highlights and clinical pearls for diagnosing common anorectal conditions. It supplied corresponding images for quick reference, discussed the need for a thorough history, and detailed the finesse of the often-dreaded-yet-so-important physical exam, reassuring providers that the majority of anorectal complaints are, indeed, benign and often treatable on first visit. However, the latter is contingent on one key factor: Are you willing to look?

Primary care is typically a patient’s first stop when experiencing anorectal symptoms. If you see a high volume of these cases and are comfortable and confident in your exam skills, the patient is likely well-served. But because it is not expected of general practitioners to have the experience or knowledge to recognize or discern the more minute features of anorectal atypia, I fully advocate the “when in doubt, refer it out” mentality without hesitation or judgement—and I quickly learned the importance of a quality referral network when I established my own clinic.

What concerns me, though, is how often a referral is made with no mention of an anorectal exam in the office note. I can certainly make a rare exception for the exam that mistakenly did not get recorded, but ultimately, if it wasn’t documented, it didn’t happen, right? And when questioned, most of these patients report that the referring provider didn’t look!

The greater issue therein occurs when a provider who doesn’t perform a physical exam recommends a course of treatment. For example—I see this on a weekly basis—a provider may prescribe a rectal preparation ointment for a patient complaining of “hemorrhoids.” Sometimes, that initial appointment is the only one before the patient is referred to my office; more often, the patient is subject to multiple office visits and excessive trials of prescription and/or homeopathic remedies before a referral is finally made. And all of this occurs without a proper exam!

The patient being treated for a presumed diagnosis of hemorrhoids may have a completely different problem altogether—if only the provider had looked. Optimistically, the patient may have an anal fissure, and the only downfall is a delay in appropriate treatment and symptom resolution. Unfortunately, grimmer outcomes can—and often do—result. I have diagnosed several cases of anal squamous cell cancer from referrals of this nature.

What’s more, recent studies have found that the incidence of anal cancer (all ages) and of colorectal cancer (adults ages 20-54) is on the rise.^1,2 And because both may manifest with mild or seemingly benign symptoms, such as rectal bleeding, anorectal pain, or a change in bowel habits, making an early and accurate diagnosis can be challenging.

These data reinforce my belief that referral to a trusted colorectal specialist with whom you can easily communicate is the best option if any doubt exists. As a provider, I would rather see a patient who is urgently referred for what turns out to be a benign condition than diagnose a serious problem, such as cancer, in a patient who has been lost in the shuffle.

Continue to: Of course, the key in all this is...

Of course, the key in all this is the relationship you establish with your patients. In my case, building relationships with my patients encourages them to more freely discuss anorectal concerns and allows me to regularly perform necessary exams. Since I’ve created my own clinic, I also have the “luxury” (I would call it the responsibility) of maintaining a flexible schedule. Many practice settings accommodate same-day or urgent appointments, but I can assure you that patients with anorectal complaints offer a unique expression of urgency when they call with colorful phrases to describe their pain. My referral coordinator, schedulers, and triage nurses can reach me anytime during the workday; I even see patients during non-clinic time if I’m available and it is appropriate. I know that not everyone can implement this practice the way I can, but putting patients first is part of providing quality care—and it often requires flexibility.

At the very least, I encourage you to read the CE/CME article that sparked this commentary. Incorporate the techniques into your patient care when someone presents with anorectal discomfort. In short, be willing to look. You never know when you might save a life!

Just over a year ago, I established a solo colorectal surgery clinic within a comprehensive academic medical center hospital system and have since seen a variety of cases: benign anorectal conditions, acute and chronic diseases, complex defecatory dysfunction, and colorectal surgery pre- and postop patients. I also manage a colorectal cancer survivorship clinic. As a PA in this field, I very much appreciated the November 2017 CE/CME, “Anorectal Evaluations: Diagnosing & Treating Benign Conditions” (Clinician Reviews. 2017;27[11]:28-37). The article offered useful highlights and clinical pearls for diagnosing common anorectal conditions. It supplied corresponding images for quick reference, discussed the need for a thorough history, and detailed the finesse of the often-dreaded-yet-so-important physical exam, reassuring providers that the majority of anorectal complaints are, indeed, benign and often treatable on first visit. However, the latter is contingent on one key factor: Are you willing to look?

Primary care is typically a patient’s first stop when experiencing anorectal symptoms. If you see a high volume of these cases and are comfortable and confident in your exam skills, the patient is likely well-served. But because it is not expected of general practitioners to have the experience or knowledge to recognize or discern the more minute features of anorectal atypia, I fully advocate the “when in doubt, refer it out” mentality without hesitation or judgement—and I quickly learned the importance of a quality referral network when I established my own clinic.

What concerns me, though, is how often a referral is made with no mention of an anorectal exam in the office note. I can certainly make a rare exception for the exam that mistakenly did not get recorded, but ultimately, if it wasn’t documented, it didn’t happen, right? And when questioned, most of these patients report that the referring provider didn’t look!

The greater issue therein occurs when a provider who doesn’t perform a physical exam recommends a course of treatment. For example—I see this on a weekly basis—a provider may prescribe a rectal preparation ointment for a patient complaining of “hemorrhoids.” Sometimes, that initial appointment is the only one before the patient is referred to my office; more often, the patient is subject to multiple office visits and excessive trials of prescription and/or homeopathic remedies before a referral is finally made. And all of this occurs without a proper exam!

The patient being treated for a presumed diagnosis of hemorrhoids may have a completely different problem altogether—if only the provider had looked. Optimistically, the patient may have an anal fissure, and the only downfall is a delay in appropriate treatment and symptom resolution. Unfortunately, grimmer outcomes can—and often do—result. I have diagnosed several cases of anal squamous cell cancer from referrals of this nature.

What’s more, recent studies have found that the incidence of anal cancer (all ages) and of colorectal cancer (adults ages 20-54) is on the rise.^1,2 And because both may manifest with mild or seemingly benign symptoms, such as rectal bleeding, anorectal pain, or a change in bowel habits, making an early and accurate diagnosis can be challenging.

These data reinforce my belief that referral to a trusted colorectal specialist with whom you can easily communicate is the best option if any doubt exists. As a provider, I would rather see a patient who is urgently referred for what turns out to be a benign condition than diagnose a serious problem, such as cancer, in a patient who has been lost in the shuffle.

Continue to: Of course, the key in all this is...

Of course, the key in all this is the relationship you establish with your patients. In my case, building relationships with my patients encourages them to more freely discuss anorectal concerns and allows me to regularly perform necessary exams. Since I’ve created my own clinic, I also have the “luxury” (I would call it the responsibility) of maintaining a flexible schedule. Many practice settings accommodate same-day or urgent appointments, but I can assure you that patients with anorectal complaints offer a unique expression of urgency when they call with colorful phrases to describe their pain. My referral coordinator, schedulers, and triage nurses can reach me anytime during the workday; I even see patients during non-clinic time if I’m available and it is appropriate. I know that not everyone can implement this practice the way I can, but putting patients first is part of providing quality care—and it often requires flexibility.

At the very least, I encourage you to read the CE/CME article that sparked this commentary. Incorporate the techniques into your patient care when someone presents with anorectal discomfort. In short, be willing to look. You never know when you might save a life!

Just over a year ago, I established a solo colorectal surgery clinic within a comprehensive academic medical center hospital system and have since seen a variety of cases: benign anorectal conditions, acute and chronic diseases, complex defecatory dysfunction, and colorectal surgery pre- and postop patients. I also manage a colorectal cancer survivorship clinic. As a PA in this field, I very much appreciated the November 2017 CE/CME, “Anorectal Evaluations: Diagnosing & Treating Benign Conditions” (Clinician Reviews. 2017;27[11]:28-37). The article offered useful highlights and clinical pearls for diagnosing common anorectal conditions. It supplied corresponding images for quick reference, discussed the need for a thorough history, and detailed the finesse of the often-dreaded-yet-so-important physical exam, reassuring providers that the majority of anorectal complaints are, indeed, benign and often treatable on first visit. However, the latter is contingent on one key factor: Are you willing to look?

Primary care is typically a patient’s first stop when experiencing anorectal symptoms. If you see a high volume of these cases and are comfortable and confident in your exam skills, the patient is likely well-served. But because it is not expected of general practitioners to have the experience or knowledge to recognize or discern the more minute features of anorectal atypia, I fully advocate the “when in doubt, refer it out” mentality without hesitation or judgement—and I quickly learned the importance of a quality referral network when I established my own clinic.

What concerns me, though, is how often a referral is made with no mention of an anorectal exam in the office note. I can certainly make a rare exception for the exam that mistakenly did not get recorded, but ultimately, if it wasn’t documented, it didn’t happen, right? And when questioned, most of these patients report that the referring provider didn’t look!

The greater issue therein occurs when a provider who doesn’t perform a physical exam recommends a course of treatment. For example—I see this on a weekly basis—a provider may prescribe a rectal preparation ointment for a patient complaining of “hemorrhoids.” Sometimes, that initial appointment is the only one before the patient is referred to my office; more often, the patient is subject to multiple office visits and excessive trials of prescription and/or homeopathic remedies before a referral is finally made. And all of this occurs without a proper exam!

The patient being treated for a presumed diagnosis of hemorrhoids may have a completely different problem altogether—if only the provider had looked. Optimistically, the patient may have an anal fissure, and the only downfall is a delay in appropriate treatment and symptom resolution. Unfortunately, grimmer outcomes can—and often do—result. I have diagnosed several cases of anal squamous cell cancer from referrals of this nature.

What’s more, recent studies have found that the incidence of anal cancer (all ages) and of colorectal cancer (adults ages 20-54) is on the rise.^1,2 And because both may manifest with mild or seemingly benign symptoms, such as rectal bleeding, anorectal pain, or a change in bowel habits, making an early and accurate diagnosis can be challenging.

These data reinforce my belief that referral to a trusted colorectal specialist with whom you can easily communicate is the best option if any doubt exists. As a provider, I would rather see a patient who is urgently referred for what turns out to be a benign condition than diagnose a serious problem, such as cancer, in a patient who has been lost in the shuffle.

Continue to: Of course, the key in all this is...

Of course, the key in all this is the relationship you establish with your patients. In my case, building relationships with my patients encourages them to more freely discuss anorectal concerns and allows me to regularly perform necessary exams. Since I’ve created my own clinic, I also have the “luxury” (I would call it the responsibility) of maintaining a flexible schedule. Many practice settings accommodate same-day or urgent appointments, but I can assure you that patients with anorectal complaints offer a unique expression of urgency when they call with colorful phrases to describe their pain. My referral coordinator, schedulers, and triage nurses can reach me anytime during the workday; I even see patients during non-clinic time if I’m available and it is appropriate. I know that not everyone can implement this practice the way I can, but putting patients first is part of providing quality care—and it often requires flexibility.

At the very least, I encourage you to read the CE/CME article that sparked this commentary. Incorporate the techniques into your patient care when someone presents with anorectal discomfort. In short, be willing to look. You never know when you might save a life!