Practice-based learning and improvement (PBLI) is a means of evaluating individual and system practice patterns and incorporating the best available evidence to improve patient care. PBLI is recognized as a critical skill for all clinicians by the Accreditation Council for Graduate Medical Education (ACGME), the American Board of Internal Medicine (ABIM), the American Board of Pediatrics (ABP), and the American Academy of Family Physicians (AAFP). As the practice of hospital medicine rapidly evolves, hospitalists apply the most up-to-date knowledge to their care of inpatients. Hospitalists use a PBLI approach to lead, coordinate, and participate in initiatives to improve hospital processes and clinical care. 

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Hospitalists should be able to:

• Describe systematic methods of analyzing practice experience.

• Explain key concepts of practice-based improvement methodology, which include the plan-do-study-act (PDSA) model.

• Define the role of multidisciplinary teams and team leaders in improving patient care.

• Describe how the critical appraisal and assimilation of scientific evidence applies to PBLI.

• Describe how information technology can be used to identify opportunities to improve patient care.

Hospitalists should be able to:

• Translate information about a general population into management of subpopulations or individual patients.

• Critically assess individual and system practice patterns and experience to identify areas for improvement and minimize heterogeneity of practice.

• Design practice interventions to improve quality, efficiency, and consistency of patient care using standard PBLI methodology and tools.

• Critically assess medical information to support self-directed learning.

• Critically appraise and apply the reports of new medical evidence.

• Identify and use high-quality, evidence-based information resources to inform clinical decisions.

• Use health information systems efficiently to manage and improve care at the individual and system levels. 

Hospitalists should be able to:

• Advocate for the use of PBLI in clinical practice and in system improvement projects.

• Create an environment conducive to self-evaluation and improvement and seek to incorporate formative feedback into daily practice.

• Advocate for investment in information technology that can harness up-to-date clinical resources.

• Facilitate and encourage self-directed learning among healthcare professionals and trainees.

• Promote self-improvement and care standardization using best evidence and practice.

Practice-based learning and improvement (PBLI) is a means of evaluating individual and system practice patterns and incorporating the best available evidence to improve patient care. PBLI is recognized as a critical skill for all clinicians by the Accreditation Council for Graduate Medical Education (ACGME), the American Board of Internal Medicine (ABIM), the American Board of Pediatrics (ABP), and the American Academy of Family Physicians (AAFP). As the practice of hospital medicine rapidly evolves, hospitalists apply the most up-to-date knowledge to their care of inpatients. Hospitalists use a PBLI approach to lead, coordinate, and participate in initiatives to improve hospital processes and clinical 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 systematic methods of analyzing practice experience.

• Explain key concepts of practice-based improvement methodology, which include the plan-do-study-act (PDSA) model.

• Define the role of multidisciplinary teams and team leaders in improving patient care.

• Describe how the critical appraisal and assimilation of scientific evidence applies to PBLI.

• Describe how information technology can be used to identify opportunities to improve patient care.

Hospitalists should be able to:

• Translate information about a general population into management of subpopulations or individual patients.

• Critically assess individual and system practice patterns and experience to identify areas for improvement and minimize heterogeneity of practice.

• Design practice interventions to improve quality, efficiency, and consistency of patient care using standard PBLI methodology and tools.

• Critically assess medical information to support self-directed learning.

• Critically appraise and apply the reports of new medical evidence.

• Identify and use high-quality, evidence-based information resources to inform clinical decisions.

• Use health information systems efficiently to manage and improve care at the individual and system levels. 

Hospitalists should be able to:

• Advocate for the use of PBLI in clinical practice and in system improvement projects.

• Create an environment conducive to self-evaluation and improvement and seek to incorporate formative feedback into daily practice.

• Advocate for investment in information technology that can harness up-to-date clinical resources.

• Facilitate and encourage self-directed learning among healthcare professionals and trainees.

• Promote self-improvement and care standardization using best evidence and practice.

Practice-based learning and improvement (PBLI) is a means of evaluating individual and system practice patterns and incorporating the best available evidence to improve patient care. PBLI is recognized as a critical skill for all clinicians by the Accreditation Council for Graduate Medical Education (ACGME), the American Board of Internal Medicine (ABIM), the American Board of Pediatrics (ABP), and the American Academy of Family Physicians (AAFP). As the practice of hospital medicine rapidly evolves, hospitalists apply the most up-to-date knowledge to their care of inpatients. Hospitalists use a PBLI approach to lead, coordinate, and participate in initiatives to improve hospital processes and clinical 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 systematic methods of analyzing practice experience.

• Explain key concepts of practice-based improvement methodology, which include the plan-do-study-act (PDSA) model.

• Define the role of multidisciplinary teams and team leaders in improving patient care.

• Describe how the critical appraisal and assimilation of scientific evidence applies to PBLI.

• Describe how information technology can be used to identify opportunities to improve patient care.

Hospitalists should be able to:

• Translate information about a general population into management of subpopulations or individual patients.

• Critically assess individual and system practice patterns and experience to identify areas for improvement and minimize heterogeneity of practice.

• Design practice interventions to improve quality, efficiency, and consistency of patient care using standard PBLI methodology and tools.

• Critically assess medical information to support self-directed learning.

• Critically appraise and apply the reports of new medical evidence.

• Identify and use high-quality, evidence-based information resources to inform clinical decisions.

• Use health information systems efficiently to manage and improve care at the individual and system levels. 

Hospitalists should be able to:

• Advocate for the use of PBLI in clinical practice and in system improvement projects.

• Create an environment conducive to self-evaluation and improvement and seek to incorporate formative feedback into daily practice.

• Advocate for investment in information technology that can harness up-to-date clinical resources.

• Facilitate and encourage self-directed learning among healthcare professionals and trainees.

• Promote self-improvement and care standardization using best evidence and practice.

Healthcare-associated infections (HAIs) impose a significant burden on the healthcare system in the Unites States, both economically and in terms of patient outcomes. On any given day, approximately 1 in 25 patients in US acute care hospitals has at least 1 HAI, and more than 700,000 HAIs occur annually in hospitalized patients.¹ More than half of HAIs occur outside the intensive care unit.1 HAIs are among the leading causes of preventable death. These infections often lead to increases in length of hospitalization and excess direct and indirect hospital costs. The overall annual direct medical cost of HAIs to US hospitals is $28 to $45 billon.² The central aim of infection control is to prevent HAIs and the emergence of resistant organisms. Hospitalists work in concert with other members of the healthcare organization to reduce HAIs, develop institutional initiatives for prevention, and promote and implement evidence-based infection control measures. 

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 acceptable methods of hand hygiene technique and timing in relationship to patient contact in various circumstances.

• Describe the prophylactic measures required for all types of isolation precautions, which include standard, contact, droplet, and airborne precautions, and list the indications for implementing each type of precaution.

• List common types of HAI and describe the risk factors associated with urinary tract infections, surgical site infections, hospital-acquired pneumonia, and blood stream infections.

• Identify major resources for infection control information, including hospital infection control staff, hospital infection control policies and procedures, local and state public health departments, and Centers for Disease Control guidelines.

• Describe the indicated prevention measures necessary to perform hospital-based procedures in a sterile fashion.

• Appreciate that specific infection control practices and engineering controls are required to protect very high-risk patient populations, which may include hematopoietic stem cell transplant and solid organ transplant recipients, from HAIs.

Hospitalists should be able to:

• Perform consistent and optimal hand hygiene techniques at all indicated points of care.

• Identify and implement indicated isolation precautions for patients with high-risk transmissible diseases or highly resistant infections.

• Identify and use local hospital resources, including antibiograms and infection control officers.

• Perform indicated infection control and prevention technique during all procedures.

• Implement precautions and infection control practices to protect patients from acquiring HAIs.

• Implement antibiotic de-escalation when possible on the basis of microbiologic culture results.

• Adopt the use of care bundles when shown to reduce the incidence of HAIs.

• Avoid devices that are more likely to cause HAIs if alternatives are safe, effective, and available.

• Encourage removal of invasive devices, especially central venous catheters and urinary catheters, early during the hospital stay and as soon as is clinically safe to do so.

• Communicate effectively the rationale and importance of infection control practices to patients, families, visitors, other healthcare providers, and hospital staff.

• Communicate appropriate patient information to infection control staff regarding potentially transmissible diseases.

• Lead, coordinate, and/or participate in efforts to educate other healthcare personnel and hospital staff about necessary infection control prevention measures.

• Lead, coordinate, and/or participate in multidisciplinary teams that organize, implement, and study infection control protocols, guidelines, or pathways using evidence-based systematic methods.

• Lead, coordinate, and/or participate in multidisciplinary efforts to develop antibiotic stewardship programs. 

Hospitalists should be able to:

• Serve as a role model in adherence to recommended hand hygiene and infection control practices.

• Engage collaboratively with multidisciplinary teams, which may include infection control, nursing service, and infectious disease consultants, to rapidly implement and maintain isolation precautions.

• Engage collaboratively with multidisciplinary teams, which may include infection control, nursing service, care coordination, long-term care facilities, home healthcare staff, and public health personnel, to plan for hospital discharge of patients with transmissible infectious diseases.

Healthcare-associated infections (HAIs) impose a significant burden on the healthcare system in the Unites States, both economically and in terms of patient outcomes. On any given day, approximately 1 in 25 patients in US acute care hospitals has at least 1 HAI, and more than 700,000 HAIs occur annually in hospitalized patients.¹ More than half of HAIs occur outside the intensive care unit.1 HAIs are among the leading causes of preventable death. These infections often lead to increases in length of hospitalization and excess direct and indirect hospital costs. The overall annual direct medical cost of HAIs to US hospitals is $28 to $45 billon.² The central aim of infection control is to prevent HAIs and the emergence of resistant organisms. Hospitalists work in concert with other members of the healthcare organization to reduce HAIs, develop institutional initiatives for prevention, and promote and implement evidence-based infection control measures. 

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 acceptable methods of hand hygiene technique and timing in relationship to patient contact in various circumstances.

• Describe the prophylactic measures required for all types of isolation precautions, which include standard, contact, droplet, and airborne precautions, and list the indications for implementing each type of precaution.

• List common types of HAI and describe the risk factors associated with urinary tract infections, surgical site infections, hospital-acquired pneumonia, and blood stream infections.

• Identify major resources for infection control information, including hospital infection control staff, hospital infection control policies and procedures, local and state public health departments, and Centers for Disease Control guidelines.

• Describe the indicated prevention measures necessary to perform hospital-based procedures in a sterile fashion.

• Appreciate that specific infection control practices and engineering controls are required to protect very high-risk patient populations, which may include hematopoietic stem cell transplant and solid organ transplant recipients, from HAIs.

Hospitalists should be able to:

• Perform consistent and optimal hand hygiene techniques at all indicated points of care.

• Identify and implement indicated isolation precautions for patients with high-risk transmissible diseases or highly resistant infections.

• Identify and use local hospital resources, including antibiograms and infection control officers.

• Perform indicated infection control and prevention technique during all procedures.

• Implement precautions and infection control practices to protect patients from acquiring HAIs.

• Implement antibiotic de-escalation when possible on the basis of microbiologic culture results.

• Adopt the use of care bundles when shown to reduce the incidence of HAIs.

• Avoid devices that are more likely to cause HAIs if alternatives are safe, effective, and available.

• Encourage removal of invasive devices, especially central venous catheters and urinary catheters, early during the hospital stay and as soon as is clinically safe to do so.

• Communicate effectively the rationale and importance of infection control practices to patients, families, visitors, other healthcare providers, and hospital staff.

• Communicate appropriate patient information to infection control staff regarding potentially transmissible diseases.

• Lead, coordinate, and/or participate in efforts to educate other healthcare personnel and hospital staff about necessary infection control prevention measures.

• Lead, coordinate, and/or participate in multidisciplinary teams that organize, implement, and study infection control protocols, guidelines, or pathways using evidence-based systematic methods.

• Lead, coordinate, and/or participate in multidisciplinary efforts to develop antibiotic stewardship programs. 

Hospitalists should be able to:

• Serve as a role model in adherence to recommended hand hygiene and infection control practices.

• Engage collaboratively with multidisciplinary teams, which may include infection control, nursing service, and infectious disease consultants, to rapidly implement and maintain isolation precautions.

• Engage collaboratively with multidisciplinary teams, which may include infection control, nursing service, care coordination, long-term care facilities, home healthcare staff, and public health personnel, to plan for hospital discharge of patients with transmissible infectious diseases.

Healthcare-associated infections (HAIs) impose a significant burden on the healthcare system in the Unites States, both economically and in terms of patient outcomes. On any given day, approximately 1 in 25 patients in US acute care hospitals has at least 1 HAI, and more than 700,000 HAIs occur annually in hospitalized patients.¹ More than half of HAIs occur outside the intensive care unit.1 HAIs are among the leading causes of preventable death. These infections often lead to increases in length of hospitalization and excess direct and indirect hospital costs. The overall annual direct medical cost of HAIs to US hospitals is $28 to $45 billon.² The central aim of infection control is to prevent HAIs and the emergence of resistant organisms. Hospitalists work in concert with other members of the healthcare organization to reduce HAIs, develop institutional initiatives for prevention, and promote and implement evidence-based infection control measures. 

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 acceptable methods of hand hygiene technique and timing in relationship to patient contact in various circumstances.

• Describe the prophylactic measures required for all types of isolation precautions, which include standard, contact, droplet, and airborne precautions, and list the indications for implementing each type of precaution.

• List common types of HAI and describe the risk factors associated with urinary tract infections, surgical site infections, hospital-acquired pneumonia, and blood stream infections.

• Identify major resources for infection control information, including hospital infection control staff, hospital infection control policies and procedures, local and state public health departments, and Centers for Disease Control guidelines.

• Describe the indicated prevention measures necessary to perform hospital-based procedures in a sterile fashion.

• Appreciate that specific infection control practices and engineering controls are required to protect very high-risk patient populations, which may include hematopoietic stem cell transplant and solid organ transplant recipients, from HAIs.

Hospitalists should be able to:

• Perform consistent and optimal hand hygiene techniques at all indicated points of care.

• Identify and implement indicated isolation precautions for patients with high-risk transmissible diseases or highly resistant infections.

• Identify and use local hospital resources, including antibiograms and infection control officers.

• Perform indicated infection control and prevention technique during all procedures.

• Implement precautions and infection control practices to protect patients from acquiring HAIs.

• Implement antibiotic de-escalation when possible on the basis of microbiologic culture results.

• Adopt the use of care bundles when shown to reduce the incidence of HAIs.

• Avoid devices that are more likely to cause HAIs if alternatives are safe, effective, and available.

• Encourage removal of invasive devices, especially central venous catheters and urinary catheters, early during the hospital stay and as soon as is clinically safe to do so.

• Communicate effectively the rationale and importance of infection control practices to patients, families, visitors, other healthcare providers, and hospital staff.

• Communicate appropriate patient information to infection control staff regarding potentially transmissible diseases.

• Lead, coordinate, and/or participate in efforts to educate other healthcare personnel and hospital staff about necessary infection control prevention measures.

• Lead, coordinate, and/or participate in multidisciplinary teams that organize, implement, and study infection control protocols, guidelines, or pathways using evidence-based systematic methods.

• Lead, coordinate, and/or participate in multidisciplinary efforts to develop antibiotic stewardship programs. 

Hospitalists should be able to:

• Serve as a role model in adherence to recommended hand hygiene and infection control practices.

• Engage collaboratively with multidisciplinary teams, which may include infection control, nursing service, and infectious disease consultants, to rapidly implement and maintain isolation precautions.

• Engage collaboratively with multidisciplinary teams, which may include infection control, nursing service, care coordination, long-term care facilities, home healthcare staff, and public health personnel, to plan for hospital discharge of patients with transmissible infectious diseases.

Professionalism refers to attitudes, behaviors, and skills for physicians to serve the interests of the patient above his or her self-interest. This denotes a commitment to the highest standards of excellence in the practice of medicine and to the generation and dissemination of knowledge to sustain the interests and welfare of patients. Within the practice of hospital medicine, professionalism also includes a commitment to be responsive to the health needs of society and a commitment to ethical principles. 

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 ethical principles, which may include beneficence and nonmaleficence, justice, patient autonomy, truth-telling, informed consent, and confidentiality.

• Describe the concept of double effect.

• Define and distinguish competency and decision-making capacity.

• Explain the utility of power of attorney and advance directives in medical care.

• Describe the key elements of informed consent.

• Explain determination of decision-making capacity and steps required for surrogate decision-making.

• Describe local laws and regulations relevant to the practice of hospital medicine.

• Explain medical futility.

• Recognize when consultation from others who have expertise in psychiatry and ethics will promote optimal care for patients and help resolve ethical dilemmas.

• Recognize the obligation to report fraud, professional misconduct, impairment, incompetence, or abandonment of patients.

• Recognize potential conflicts of interest in accepting gifts and/or travel from commercial sources.

• Recognize potential individual and institutional conflicts of interest with incentive-based contractual agreements with pharmaceutical companies and other funding agents.

Hospitalists should be able to:

• Observe doctor-patient confidentiality and identify family members or surrogates to whom information can be released.

• Communicate with patients and family members on a regular basis and develop a therapeutic relationship in both routine and challenging situations.

• Recommend treatment options that prioritize patient preference, optimize patient care, include consideration of resource use, and are formulated without regard to financial incentives or other conflicts of interest.

• Evaluate patients for medical decision-making capacity.

• Obtain informed consent when indicated and ensure patient understanding.

• Review power of attorney and advance directives with patients and family members.

• Adhere to ethical principles and behaviors, including honesty, integrity, and professional responsibility.

• Respect patient autonomy. 

Hospitalists should be able to:

• Commit to lifelong self-learning, maintenance of skills, and clinical excellence.

• Promote access to medical care for the community, especially in underserved areas.

• Demonstrate empathy for hospitalized patients.

• Provide compassionate and relevant care for patients, including those whose beliefs diverge from those of the treating physician or from accepted medical advice.

• Remain sensitive to differences in patients’ sex, age, race, culture, religion, and sexual orientation.

• Appreciate that informed adults with decision-making capacity may refuse recommended medical treatment.

• Appreciate that physicians are not required to provide care that is medically futile.

• Endorse that physicians have an obligation not to discriminate against any patient or group of patients.

• Recognize and observe appropriate boundaries of the physician-patient relationship.

• Follow a systematic approach to risks, benefits, and conflicts of interest in human subject research.

• Serve as a role model for professional and ethical conduct to house staff, medical students, and other members of the multidisciplinary team.

Professionalism refers to attitudes, behaviors, and skills for physicians to serve the interests of the patient above his or her self-interest. This denotes a commitment to the highest standards of excellence in the practice of medicine and to the generation and dissemination of knowledge to sustain the interests and welfare of patients. Within the practice of hospital medicine, professionalism also includes a commitment to be responsive to the health needs of society and a commitment to ethical principles. 

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 ethical principles, which may include beneficence and nonmaleficence, justice, patient autonomy, truth-telling, informed consent, and confidentiality.

• Describe the concept of double effect.

• Define and distinguish competency and decision-making capacity.

• Explain the utility of power of attorney and advance directives in medical care.

• Describe the key elements of informed consent.

• Explain determination of decision-making capacity and steps required for surrogate decision-making.

• Describe local laws and regulations relevant to the practice of hospital medicine.

• Explain medical futility.

• Recognize when consultation from others who have expertise in psychiatry and ethics will promote optimal care for patients and help resolve ethical dilemmas.

• Recognize the obligation to report fraud, professional misconduct, impairment, incompetence, or abandonment of patients.

• Recognize potential conflicts of interest in accepting gifts and/or travel from commercial sources.

• Recognize potential individual and institutional conflicts of interest with incentive-based contractual agreements with pharmaceutical companies and other funding agents.

Hospitalists should be able to:

• Observe doctor-patient confidentiality and identify family members or surrogates to whom information can be released.

• Communicate with patients and family members on a regular basis and develop a therapeutic relationship in both routine and challenging situations.

• Recommend treatment options that prioritize patient preference, optimize patient care, include consideration of resource use, and are formulated without regard to financial incentives or other conflicts of interest.

• Evaluate patients for medical decision-making capacity.

• Obtain informed consent when indicated and ensure patient understanding.

• Review power of attorney and advance directives with patients and family members.

• Adhere to ethical principles and behaviors, including honesty, integrity, and professional responsibility.

• Respect patient autonomy. 

Hospitalists should be able to:

• Commit to lifelong self-learning, maintenance of skills, and clinical excellence.

• Promote access to medical care for the community, especially in underserved areas.

• Demonstrate empathy for hospitalized patients.

• Provide compassionate and relevant care for patients, including those whose beliefs diverge from those of the treating physician or from accepted medical advice.

• Remain sensitive to differences in patients’ sex, age, race, culture, religion, and sexual orientation.

• Appreciate that informed adults with decision-making capacity may refuse recommended medical treatment.

• Appreciate that physicians are not required to provide care that is medically futile.

• Endorse that physicians have an obligation not to discriminate against any patient or group of patients.

• Recognize and observe appropriate boundaries of the physician-patient relationship.

• Follow a systematic approach to risks, benefits, and conflicts of interest in human subject research.

• Serve as a role model for professional and ethical conduct to house staff, medical students, and other members of the multidisciplinary team.

Professionalism refers to attitudes, behaviors, and skills for physicians to serve the interests of the patient above his or her self-interest. This denotes a commitment to the highest standards of excellence in the practice of medicine and to the generation and dissemination of knowledge to sustain the interests and welfare of patients. Within the practice of hospital medicine, professionalism also includes a commitment to be responsive to the health needs of society and a commitment to ethical principles. 

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 ethical principles, which may include beneficence and nonmaleficence, justice, patient autonomy, truth-telling, informed consent, and confidentiality.

• Describe the concept of double effect.

• Define and distinguish competency and decision-making capacity.

• Explain the utility of power of attorney and advance directives in medical care.

• Describe the key elements of informed consent.

• Explain determination of decision-making capacity and steps required for surrogate decision-making.

• Describe local laws and regulations relevant to the practice of hospital medicine.

• Explain medical futility.

• Recognize when consultation from others who have expertise in psychiatry and ethics will promote optimal care for patients and help resolve ethical dilemmas.

• Recognize the obligation to report fraud, professional misconduct, impairment, incompetence, or abandonment of patients.

• Recognize potential conflicts of interest in accepting gifts and/or travel from commercial sources.

• Recognize potential individual and institutional conflicts of interest with incentive-based contractual agreements with pharmaceutical companies and other funding agents.

Hospitalists should be able to:

• Observe doctor-patient confidentiality and identify family members or surrogates to whom information can be released.

• Communicate with patients and family members on a regular basis and develop a therapeutic relationship in both routine and challenging situations.

• Recommend treatment options that prioritize patient preference, optimize patient care, include consideration of resource use, and are formulated without regard to financial incentives or other conflicts of interest.

• Evaluate patients for medical decision-making capacity.

• Obtain informed consent when indicated and ensure patient understanding.

• Review power of attorney and advance directives with patients and family members.

• Adhere to ethical principles and behaviors, including honesty, integrity, and professional responsibility.

• Respect patient autonomy. 

Hospitalists should be able to:

• Commit to lifelong self-learning, maintenance of skills, and clinical excellence.

• Promote access to medical care for the community, especially in underserved areas.

• Demonstrate empathy for hospitalized patients.

• Provide compassionate and relevant care for patients, including those whose beliefs diverge from those of the treating physician or from accepted medical advice.

• Remain sensitive to differences in patients’ sex, age, race, culture, religion, and sexual orientation.

• Appreciate that informed adults with decision-making capacity may refuse recommended medical treatment.

• Appreciate that physicians are not required to provide care that is medically futile.

• Endorse that physicians have an obligation not to discriminate against any patient or group of patients.

• Recognize and observe appropriate boundaries of the physician-patient relationship.

• Follow a systematic approach to risks, benefits, and conflicts of interest in human subject research.

• Serve as a role model for professional and ethical conduct to house staff, medical students, and other members of the multidisciplinary team.

Quality improvement (QI) is the process of continually evaluating existing processes of care and implementing/disseminating best practice. QI is influenced by objective data and focuses on systems change to optimize institutional performance and appropriate resource use. Since the Institute of Medicine released its report “To Err is Human” in 1999, the then fledgling field of hospital medicine and the QI movement have simultaneously evolved and worked synergistically. Hospitalists are uniquely positioned to improve the quality of inpatient care. Hospitalists should strive to lead or participate in QI efforts to optimize management of common inpatient conditions and improve clinical outcomes on the basis of standardized evidence-based practices.  

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 roles of quality and peer review committees in facilitating continuous QI processes. 

• Identify structure, process, and outcome measures appropriate for specific QI projects.

• List the characteristics of high-reliability organizations and learning healthcare systems.

• Describe the elements of effective teams and teamwork.

• Describe the relationships among value, quality, and cost.

• Explain different philosophies and techniques for thorough analysis of complex systems, such as root cause analysis, failure mode and effects analysis, Lean, Six-Sigma, Plan-Do-Study-Act, etc.

• Identify and categorize adverse outcomes including sentinel events, medical errors, and near-misses.

• Describe QI outcome measurements currently used by stakeholders and regulatory agencies.

• Identify guidelines and protocols supported by outcomes data to shape and standardize clinical practice.

• Identify the relative strengths and limitations of proposed interventions to address hospital-based QI concerns.

• Identify appropriate institutional systems used to report medical errors, patient safety events, and near-misses.

Hospitalists should be able to: 

• Use quality data to inform hospitalist practice and improve patient care at the individual and system levels. 

• Distinguish outcome measurements from process measurements. 

• Interpret patient satisfaction metrics.  

• Incorporate patient preference and satisfaction into the optimization of healthcare quality.

• Identify key stakeholders within individual institutions and work collaboratively in QI endeavors.

• Use common methods to understand, describe, and analyze QI initiatives such as the fishbone diagram and the 5 why’s.

• Apply the results of validated outcome studies to improve the quality of inpatient practice. 

• Structure QI initiatives that reflect evidence-based literature and high-quality outcomes data. 

Hospitalists should be able to:

• Practice patient-centered care and recognize its value in improving patient safety and satisfaction.

• Promote the adoption of new practices, guidelines, and technology as supported by best available evidence. 

• Engage in a collaborative multidisciplinary team approach to lead, coordinate, and/or participate in the design and implementation of QI initiatives at individual, practice, and system levels. 

• Appreciate the importance and need to align quality goals with institutional and system goals.

• Advocate for and foster a Just Culture around patient safety and QI.

Quality improvement (QI) is the process of continually evaluating existing processes of care and implementing/disseminating best practice. QI is influenced by objective data and focuses on systems change to optimize institutional performance and appropriate resource use. Since the Institute of Medicine released its report “To Err is Human” in 1999, the then fledgling field of hospital medicine and the QI movement have simultaneously evolved and worked synergistically. Hospitalists are uniquely positioned to improve the quality of inpatient care. Hospitalists should strive to lead or participate in QI efforts to optimize management of common inpatient conditions and improve clinical outcomes on the basis of standardized evidence-based practices.  

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 roles of quality and peer review committees in facilitating continuous QI processes. 

• Identify structure, process, and outcome measures appropriate for specific QI projects.

• List the characteristics of high-reliability organizations and learning healthcare systems.

• Describe the elements of effective teams and teamwork.

• Describe the relationships among value, quality, and cost.

• Explain different philosophies and techniques for thorough analysis of complex systems, such as root cause analysis, failure mode and effects analysis, Lean, Six-Sigma, Plan-Do-Study-Act, etc.

• Identify and categorize adverse outcomes including sentinel events, medical errors, and near-misses.

• Describe QI outcome measurements currently used by stakeholders and regulatory agencies.

• Identify guidelines and protocols supported by outcomes data to shape and standardize clinical practice.

• Identify the relative strengths and limitations of proposed interventions to address hospital-based QI concerns.

• Identify appropriate institutional systems used to report medical errors, patient safety events, and near-misses.

Hospitalists should be able to: 

• Use quality data to inform hospitalist practice and improve patient care at the individual and system levels. 

• Distinguish outcome measurements from process measurements. 

• Interpret patient satisfaction metrics.  

• Incorporate patient preference and satisfaction into the optimization of healthcare quality.

• Identify key stakeholders within individual institutions and work collaboratively in QI endeavors.

• Use common methods to understand, describe, and analyze QI initiatives such as the fishbone diagram and the 5 why’s.

• Apply the results of validated outcome studies to improve the quality of inpatient practice. 

• Structure QI initiatives that reflect evidence-based literature and high-quality outcomes data. 

Hospitalists should be able to:

• Practice patient-centered care and recognize its value in improving patient safety and satisfaction.

• Promote the adoption of new practices, guidelines, and technology as supported by best available evidence. 

• Engage in a collaborative multidisciplinary team approach to lead, coordinate, and/or participate in the design and implementation of QI initiatives at individual, practice, and system levels. 

• Appreciate the importance and need to align quality goals with institutional and system goals.

• Advocate for and foster a Just Culture around patient safety and QI.

Quality improvement (QI) is the process of continually evaluating existing processes of care and implementing/disseminating best practice. QI is influenced by objective data and focuses on systems change to optimize institutional performance and appropriate resource use. Since the Institute of Medicine released its report “To Err is Human” in 1999, the then fledgling field of hospital medicine and the QI movement have simultaneously evolved and worked synergistically. Hospitalists are uniquely positioned to improve the quality of inpatient care. Hospitalists should strive to lead or participate in QI efforts to optimize management of common inpatient conditions and improve clinical outcomes on the basis of standardized evidence-based practices.  

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Hospitalists should be able to: 

• Describe the roles of quality and peer review committees in facilitating continuous QI processes. 

• Identify structure, process, and outcome measures appropriate for specific QI projects.

• List the characteristics of high-reliability organizations and learning healthcare systems.

• Describe the elements of effective teams and teamwork.

• Describe the relationships among value, quality, and cost.

• Explain different philosophies and techniques for thorough analysis of complex systems, such as root cause analysis, failure mode and effects analysis, Lean, Six-Sigma, Plan-Do-Study-Act, etc.

• Identify and categorize adverse outcomes including sentinel events, medical errors, and near-misses.

• Describe QI outcome measurements currently used by stakeholders and regulatory agencies.

• Identify guidelines and protocols supported by outcomes data to shape and standardize clinical practice.

• Identify the relative strengths and limitations of proposed interventions to address hospital-based QI concerns.

• Identify appropriate institutional systems used to report medical errors, patient safety events, and near-misses.

Hospitalists should be able to: 

• Use quality data to inform hospitalist practice and improve patient care at the individual and system levels. 

• Distinguish outcome measurements from process measurements. 

• Interpret patient satisfaction metrics.  

• Incorporate patient preference and satisfaction into the optimization of healthcare quality.

• Identify key stakeholders within individual institutions and work collaboratively in QI endeavors.

• Use common methods to understand, describe, and analyze QI initiatives such as the fishbone diagram and the 5 why’s.

• Apply the results of validated outcome studies to improve the quality of inpatient practice. 

• Structure QI initiatives that reflect evidence-based literature and high-quality outcomes data. 

Hospitalists should be able to:

• Practice patient-centered care and recognize its value in improving patient safety and satisfaction.

• Promote the adoption of new practices, guidelines, and technology as supported by best available evidence. 

• Engage in a collaborative multidisciplinary team approach to lead, coordinate, and/or participate in the design and implementation of QI initiatives at individual, practice, and system levels. 

• Appreciate the importance and need to align quality goals with institutional and system goals.

• Advocate for and foster a Just Culture around patient safety and QI.

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. 

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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. 

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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. 

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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. 

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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.  

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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.  

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.  

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.