Pancreatic Cancer – A Disease in Need: Optimizing and Integrating Supportive Care

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that continues to be challenging to treat. PDAC has the lowest five-year relative survival rate compared to all other solid tumor malignancies and is expected to become the second-leading cause of cancer-related death in the United States by 2030. Given the high mortality, there is an increasing role for concurrent anti-cancer and supportive care in the management of patients with PDAC with the aims of maximizing length of life, quality of life (QoL), and symptom control.

Findings

Emerging trends in supportive care that can be integrated into the clinical management of patients with PDAC include standardized supportive care screening, early integration of supportive care into routine cancer care, early implementation of outpatient-based advance care planning, and utilization of electronic patient reported outcomes for improved symptom management and QoL. The most common symptoms experienced are nausea, constipation, weight loss, diarrhea, anorexia, and abdominal and back pain. This review article includes current supportive management strategies for these and others. Common disease-related complications include biliary and duodenal obstruction requiring endoscopic procedures and venous thromboembolic events.

Conclusion

Patients with PDAC continue to have a poor prognosis. Systemic therapy options are able to palliate the high symptom burden but have a modest impact on overall survival. Early integration of supportive care can lead to improved outcomes.

Precis:

Pancreatic cancer is an aggressive malignancy with a poor prognosis. Early involvement of supportive care with honest prognostication, outpatient advance care planning, and utilization of electronic patient reported outcomes is recommended for improvement in quality of life, symptom management, and overall survival.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high mortality rate that continues to be challenging to treat. Its characteristics of late presentation with non-specific symptoms, early metastasis, immune privilege, and complex heterozygous genetic alterations, collectively contribute to poor clinical outcomes. In line with current trends in oncology, there is an increasing role for concurrent anti-cancer and supportive care in the management of patients with PDAC with the aims of maximizing length of life, quality of life (QoL), and symptom control¹. This review article will explore the prognosis of pancreatic cancer, emerging trends in supportive care to best care for patients with PDAC, and current management recommendations for common symptoms and disease and therapy-related complications.

Pancreatic Cancer

In 2019, there are anticipated to be 56,770 new cases of PDAC and 45,750 deaths in the United States². Globally, those numbers were 458,918 and 432,242 respectively in 2018³. At the time of presentation, approximately 50% of patients have stage IV disease with systemic therapies having a real but relatively modest impact on outcome^4,5. PDAC has the lowest five-year relative survival rate relative to all other solid tumor malignancies and is expected to become the second-leading cause of cancer-related death in the United States by 2030⁴. The high mortality rate of PDAC stems from multifactorial challenges related to the collective lack of early diagnosis and effective screening process, identification of high-risk patient groups, validated biomarkers, and effective treatment for advanced disease⁵.

Current systemic therapies available for unresectable locally advanced or metastatic PDAC have been shown to ameliorate symptoms experienced by patients and a valuable tool for supportive care⁶. Gourgou-Bourgade et al. confirmed that FOLFIRINOX (fluorouracil, folinic acid, irinotecan, and oxaliplatin) significantly reduced health-related QoL impairment compared with gemcitabine and both improved emotional functioning, pain, insomnia, anorexia, and constipation⁷. Unfortunately, immunotherapy options have not translated well into the treatment of PDAC, except for the small subset of patients (approximately 1–2%) with mismatch repair deficiency. Immune resistance is in part due to the dense immunosuppressive tumor microenvironment and lack of tumor antigenicity^8,9.

Current Trends in Supportive Care

Included in this section are emerging trends in the field of supportive care that are of potential benefit to patients with PDAC to try to optimize QoL and overall survival (Table 1).

Table 1.

Current Trends in Supportive Care

Trend	Utilization in Practice
Standardization	• Supportive care curriculum development and integration into medical education and training
	• Supportive care simulations with standardized patients
	• Supportive care screening tools
	• Supportive care interdisciplinary team structure
	• Community-based supportive care programs
Early Involvement	• Honest prognostication by medical staff
	• Outpatient clinic advance care planning
	• Goals of care informational videos
	• Early referral to supportive care interdisciplinary team
Integration of Technology	• Electronic patient reported outcomes for symptom management optimization
	• Videoconferencing multidisciplinary supportive care services
	• Online documentation of end-of-life decisions
	• End-of-life virtual reality

Standardization

Over the past decade, palliative care education has been systematically integrated into medical education and become a standardized competency for medical training¹⁰. Simulation-based medical education with standardized patients has emerged as a promising modality to teach key palliative care skills and close the education gap^11,12. In the VOICE trial, patient-centered communication about advanced cancer diagnosis, treatment options, prognosis, and QoL was enhanced with individualized training for both the clinician and patient¹³.

Another standardized process is the implementation of supportive care screening tools for patients with PDAC. A systematic review of supportive care screening in the emergency room was identified to be both feasible and cost-effective¹⁴. In the inpatient setting, supportive care screening tools as part of a nursing assessment have been validated to identify unmet supportive care needs and improve access to services¹⁵. A supportive care consultation consists of the assessment and management of physical symptoms, psychological, and spiritual needs, the assessment of the patient’s support system and caregiver’s needs, communication about prognosis, assisting patients to identify personal goals for care, including end-of-life care, and where indicated for discharge planning¹⁶. Adelson et al. found that among inpatients with advanced cancer, the standardized use of triggers for supportive care consultation was associated with a substantial impact on 30-day readmission rates, chemotherapy following discharge, hospice referrals, the use of support services, and the mortality index¹⁷. However, the results of other studies have not always been concordant; Pantilat et al. found that proactive inpatient supportive care consultations were not better than usual care¹⁸. Studies have further shown that the standardization of an interdisciplinary supportive care consultation team with a physician, nurse, social worker, and chaplain led to improved outcomes, satisfaction, and QoL in the inpatient and outpatient setting^19–21. Additionally, the standardization of community-based supportive care programs has increased the access, efficiency, and efficacy of supportive care in the underserved or less populated areas²².

Early Supportive Care Involvement

Integrating early supportive care in patients with advanced cancer is an increasing trend that can lead to improved mood and QoL, better patient outcomes, less aggressive end-of-life care, and longer survival^23–25. The Early Palliative Care Italian Study Group found that metastatic PDAC patients that received early supportive care had an increased number of supportive care visits, a higher use of hospice services, and received less chemotherapy in the last 30 days of life²⁶. As part of this investigation, patient-centered supportive care discussions of advance directives (AD), end-of-life care, and advance care planning (ACP) were conducted in the outpatient setting and facilitated by all healthcare professionals²⁷. Early ACP discussions are recommended by the American Society of Clinical Oncology and early specialty palliative care is proven to increase overall survival, yet there is no standard for patient-centered ACP^23,24. At Memorial Sloan Kettering, Epstein et al. tested a 10-question patient-centered ACP paradigm called the Person-Centered Oncologic Care and Choices with positive results²⁸. Included in this model is the emerging trend of using video educational tools, including for subjects such as goals-of-care. In a randomized controlled trial, cancer patients that viewed a goals-of-care video were better informed and more likely to prefer comfort care and avoid cardiopulmonary resuscitation²⁸. More recently, Desai et al. published findings of their initial experience of introducing supportive care upstream of the advanced disease setting, specifically in all patients, regardless of stage, prognosis, or treatment, including through structured assessment and response to patient symptoms, illness, and treatment understanding²⁹, and finally, nurse-led brief discussions of patient values³⁰.

For early supportive care interventions to be successful, the medical team must effectively communicate accurate expectations about the disease, treatment objectives, potential complications, prognosis, and life expectancy^31,32. In a study of 258 physicians caring for 326 terminally ill cancer patients, physicians only disclosed an accurate prognosis 37% of the time and knowingly provided overestimated/underestimated prognosis to 40.3% of patients³³. When patients have an honest understanding of their prognosis, they appear to be more fully informed and able to better choose their desired level of care with a lower level of anxiety^34,35. Disclosing a terminal prognosis allows patients to better cope with their illness and complete ACP, along with provide caregiver satisfaction with end-of-life care³⁶. In a pilot randomized controlled trial of monthly scheduled early specialty palliative care visits in patients with advanced PDAC, patients and caregivers reported acceptability and perceived effectiveness of the intervention while oncologists and palliative care specialists recommended tailoring the frequency and content of visits to patient/caregiver needs³⁷.

Supportive Care and Technology

In medical oncology, the use of electronic patient reported outcomes (ePROs) have been demonstrated to improve patient’s QoL, reduce hospitalizations and healthcare costs, and improve overall survival^38,39. ePROs provide an efficient standardized assessment of continuous data collection of the patient and their medical condition that allow for enhanced patient-centered care and increased patient satisfaction⁴⁰. In a national supportive care study of 19,747 patients using ePROs, there were statistically significant improvements in all domains of both patient and clinician-reported outcomes⁴¹. In PDAC patients, ePROs have been validated as an effective and reliable tool for symptom management and assessing QoL^42,43. In 2016, the Dutch Pancreatic Cancer Group performed a Delphi survey of PDAC patients and healthcare providers that identified a core set of PROs to enable enhanced and personalized care, as well as, create a nationwide prospective multidisciplinary pancreatic cancer registry for the development of pancreatic cancer-specific ePRO questionnaires⁴⁴. This study was further expanded into an international, multicenter Delphi study of 501 participants from the US, Europe, and Asia⁴⁵.

In rural and underserved areas, videoconferencing has become increasingly important to extend access to specialist multidisciplinary supportive care services⁴⁶. A study by Watanabe et al. found that videoconferencing with cancer patients was feasible, improved symptoms, reduced costs to the patient/families, and was satisfactory among users⁴⁷. In Taiwan, elderly patients are encouraged to complete specific end-of-life decisions online that are linked with their insurance card and used during hospital registration. Included in these decisions is a question about cardiopulmonary resuscitation⁴⁸. Another evolving technology is the use of virtual reality to help healthcare professionals, hospice staff, patients, and families experience end-of-life care through a dying patient’s perspective.

Pancreatic Cancer-related Symptom Management

Common symptoms experienced by PDAC patients include nausea, dyspnea, abdominal distension/bloating, constipation, anxiety, and depression. Nausea is often successfully controlled with serotonin antagonists alone or added with dopamine-receptor antagonists and first or second-generation antipsychotics⁴⁹. Opioids are a well-documented effective choice for dyspnea⁵⁰. Abdominal distension that is secondary to peritoneal metastases and associated ascites, is typically managed with a therapeutic paracentesis with/without a permanent drainage catheter, tumor-directed therapy, and sometimes, diuretics or a peritoneovenous shunt, depending on clinical context⁵¹. Often the best strategy for constipation, including when opioid-induced, is a multiple drug regimen that combines different mechanisms of action. The management of anxiety and depression includes adequate pain control and the use of anxiolytics like non-liver metabolized benzodiazepines, antidepressants like a serotonin-norepinephrine-reuptake-inhibitor (SNRI), and psychological support⁵².

Weight loss, malnutrition, steatorrhea, diarrhea, and anorexia are very common. Eighty percent of patients will suffer significant weight loss and develop cachexia, which further decreases their QoL, treatment response, and survival^53–55. Patients that are able to maintain a stable weight and body composition have a better prognosis⁵⁶. A well-balanced diet of vegetables and protein-rich foods consumed in small meals every two to three hours is recommended with ample fluids and avoidance of high-fat foods, refined/simple carbohydrates, and excessive alcohol. Pancreatic enzyme replacement therapy has been shown to significantly improve malabsorption, abdominal pain, bloating, steatorrhea, diarrhea, and QoL^56,57. In multiple randomized comparison studies, megestrol acetate and synthetic tetrahydrocannabinol have been shown to be useful appetite stimulants^58,59. In a randomized, double-blind, placebo-controlled study, advanced cancer patients that received dronabinol had increased appetite, appreciation for food, protein consumption, and total caloric intake, as well as quality of sleep, relaxation, and QoL⁶⁰. Similar results were seen in a 2018 study with nabilone⁶¹.

Abdominal and back pain are among the most common symptoms (Table 2). A 2016 comprehensive review concluded that the World Health Organization’s (WHO) Cancer Pain Relief guidelines continue to be the most effective method for managing cancer-related pain⁶². The core principle is a “pain/analgesia ladder” with escalation in management based on the severity of symptoms. The initial treatment consists of non-opioid medications like acetaminophen or non-steroidal anti-inflammatory drugs for mild pain, followed by the introduction of mild/moderate opioids like tramadol and codeine, and then stronger opioids like morphine, oxycodone, hydromorphone, and fentanyl. Throughout each level of management, adjuvant therapy with an SNRI, anticonvulsant, or alpha-2-adrenergic agonist can be incorporated for a potential additive effect^62,63.

Table 2.

Pancreatic Cancer-related Pain Management

Severity of Pain	Recommended Management
Mild	• Acetaminophen and non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, indomethacin, naproxen, etc.)
	• Complementary approaches (acupuncture, massage therapy, mindfulness, art therapy, etc.)
Moderate	• Adjuvant therapy (duloxetine, amitriptyline, tizanidine, gabapentin, baclofen, steroids, etc.)
	• Mild/Moderate opioids (tramadol and codeine)
Severe	• Stronger opioids (morphine, oxycodone, hydromorphone, fentanyl, etc.)
	• EUS-guided CPB
	• EUS-guided CPN
	• VSPL
	• IDDS

Note: Medical providers should start with recommendations for mild pain and then escalate use in a stepwise approach based on the severity of pain with complementary and adjuvant therapy used throughout.

EUS = endoscopic ultrasound, CPB = celiac plexus block, CPN = celiac plexus neurolysis, VSPL = video-thoracoscopic splanchnicectomy, IDDS = intrathecal drug delivery systems

In the setting of a nationwide opioid epidemic, patients and licensed independent practitioners (LIPs) are increasingly hesitant in the use of opioids for cancer-related pain management. At present, there are no studies that have explored patients with PDAC and opioid misuse, abuse, or related death. However, in a ten-year analysis by Chino et al., opioid-associated deaths were ten times less likely in cancer patients than the general population⁶⁴. LIPs should attempt to prescribe non-opioid and adjuvant medications for mild to moderate pain, screen for those at risk for non-medical opioid addiction, and counsel all patients on the prevalence of cancer-related pain and the relatively low prevalence of opioid addiction in cancer patients. In a study of 566 patients with unresectable PDAC, a higher initial opioid dose, and the rate of opioid dose escalation were both significantly negatively correlated with overall survival⁶⁵. As per the NCCN guidelines, LIPs should attempt opioid dose reductions in patients with well-controlled chronic pain followed by referral to a supportive care interdisciplinary team for a comprehensive pain management plan⁶⁶. In a 2018 study, the interdisciplinary team at MD Anderson decreased the median number of non-medical opioid use from 3 to 0.4/month and the morphine-equivalent daily dose from 165 to 112mg/day⁶⁷.

For severe pain that is refractory to oral and parenteral opioids, interventional therapies are sometimes beneficial for localized PDAC. The most common method is a celiac plexus block (CPB), which involves a disruption of visceral pain innervation from the pancreas and surrounding structures through an injection of corticosteroids or long-acting anesthetic⁶⁸. In two randomized comparison studies of endoscopic ultrasound (EUS) and percutaneous computed tomography (PC)-guided CPB, EUS provided superior and prolonged pain control than PC and was preferred among participants^69,70. A celiac plexus neurolysis (CPN) is permanent destruction of the plexus that is equally effective and suitable for patients with a short life expectancy and may provide symptomatic relief for 3–6 months⁷¹. In a 2018 retrospective cohort study of 200 PDAC patients at Johns Hopkins that underwent a CPN, both EUS and PC were effective at reducing post-procedural pain, however, at one-month EUS had a better pain response and significantly higher QoL⁷². An additional option with possible increased precision is a video-thoracoscopic splanchnicectomy (VSPL), which may avoid the potential side effects with local diffusion of neurolytic solutions⁷³. In a comparison of two non-randomized, prospective, case-controlled studies, both EUS-guided CPN and VSPL provided significant reduction of pain and improvement of QoL but EUS was able to improve all domains of QoL studied while VSPL only improved pain and fatigue⁷⁴. In addition, intrathecal drug delivery systems (IDDS) may be placed for improved pain control and a significant decrease in opioid consumption. In an 11-year follow-up observational study of 93 patients with refractory pancreatic cancer-related pain, IDDS were associated with statistically significant pain improvement at 1 week, 1 month, and 3 months in unresectable PDAC⁷⁵.

Other pain management treatment options include corticosteroids and radiation therapy⁷⁶. Complementary methods for chronic pain management include massage therapy, reiki, meditation/mindfulness, hypnosis, yoga, tai-chi, acupuncture, music or art therapy, and are of great interest to patients^77,78.

Pancreatic Cancer Disease-related Complications and Management

Symptomatic biliary obstruction develops in approximately 80% of patients with pancreatic head tumors. Traditionally the mainstay of treatment was palliative surgical biliary bypass with/without gastrojejunostomy, however, endoscopic therapies with stent placement are now primarily utilized for both biliary and duodenal obstructions⁷⁹. Biliary stents are most useful when pruritus is present, or if there is an indication for liver function to be improved to allow the safe administration of cancer treatment. Based on tumor anatomy, stents are successfully placed in over 90% of patients, with potential early post-procedure complications of pancreatitis, bleeding, or cholangitis occurring in 5% of cases^80,81. Late complications are common and related to stent obstruction/migration and in part dependent on the material of the stent⁸². Plastic stents are cost-efficient but experience a twofold increase in stent dysfunction requiring multiple subsequent procedures and higher overall costs compared to metal stents^80,83. In a recent review, endoscopic biliary stents are equally effective compared to surgery with less procedural cost, complications, and morbidity but higher rates of recurrent jaundice⁸⁴. Although, in a patient with a life expectancy of >6 months, a surgical biliary bypass could reduce the potential for subsequent procedures and hospital costs⁸⁵.

Pancreatic tumor invasion into the duodenum leading to ‘gastric outlet’ obstruction (GOO), or more accurately termed ‘duodenal obstruction’, can cause intractable reflux, nausea, vomiting, malnutrition, and cachexia. As per the SUSTENT study, the choice of therapy depends on performance status and predicted length of survival⁸⁶. Gray et al. identified four risk factors that correlated with <6 months of survival after a palliative surgical bypass and if ≥1 are present, then a non-operative intervention would be recommended. These factors include the presence of distant metastasis, poor tumor differentiation, severe preoperative nausea and vomiting, and absence of a preoperative biliary stent⁸⁷. In the short-term, supportive endoscopic stent placement is associated with a shorter length of hospitalization and faster return to oral intake but in the long-term, a laparoscopic gastrojejunostomy has superior durability and a longer duration of oral intake^83,84,88.

In 2008 the Khorana Risk Score (KRS) was created and predicts thrombosis risk based on the type of cancer, body mass index, and complete blood count. Patients with a KRS of ≥3 were considered high risk for a venous thromboembolism (VTE) and proposed that such patients might benefit from prophylactic anticoagulation. However, a 2016 validation study at the Moffitt Cancer Center found that the KRS did not appropriately stratify patients for VTE and that additional stratification methods are needed before cancer patients can be recommended for prophylactic strategies⁸⁹.

VTEs are another well-established complication of advanced PDAC with an incidence of ≥27%, which is four times higher than any other malignancy and fifty times higher than the average person⁹⁰. Thrombosis, especially early, in PDAC patients is a poor prognostic factor for early death⁹¹. PDAC patients have the highest rates of fatal pulmonary emboli and VTEs are the second-leading cause of death^92,93. The current guidelines for management include the use of low molecular weight heparin (LMWH) with contraindications of life-threatening bleeding, platelet counts < 20,000, or severe uncompensated coagulopathy^94,95. Recent studies have explored the use of direct oral anticoagulants (DOACs) in the treatment of cancer-associated thrombosis (CAT). In a 2017 prospective cohort study of 200 patients by Mantha et al., rivaroxaban was found to be safe and effective for CAT with 4.4% VTE recurrence and 2.2% major bleeding⁹⁶. These findings are lower than the reported values of 7–9% and 6–7% respectively for LMWH^97,98. Equivalent findings were seen in subsequent prospective randomized trials comparing DOACs with enoxaparin^99,100 and warfarin¹⁰¹. However, in similar studies between DOACs and dalteparin, DOACs were noninferior but had an increased risk of bleeding^102,103. As per the NCCN guidelines, DOACs have been associated with urinary and intestinal tract bleeding and should be used with caution in patients with urinary or gastrointestinal tract lesions, pathology, or instrumentation¹⁰⁴.

The role of prophylactic anticoagulation in this patient population is an area of active debate⁹⁰. In the CLOT trial, LMWH was shown to be more effective than warfarin in reducing recurrent VTEs without a significantly increased risk of bleeding and the CONKO-004 trial demonstrated that LMWH reduced the incidence of symptomatic VTEs but did not affect progression-free or overall survival^97,105. Most recently, the CASSINI trial was unable to show an overall statistical significance of rivaroxaban therapy for thromboprophylaxis of VTE and death due to a VTE, but did show a reduced rate of VTE over placebo during the period of anticoagulation¹⁰⁶. However, in the AVERT trial, the use of apixiban therapy resulted in a significantly lower rate of VTEs than placebo among intermediate-to-high-risk ambulatory patients with cancer and all-cause mortality was similar between the two treatment groups¹⁰⁷. The prevention of VTE remains an important topic among patients with active cancer with guideline committees currently evaluating this data and debating implications for optimal practice. Presently, there are not sufficient data to recommend that PDAC patients undergo prophylactic anticoagulation.

Conclusion

PDAC is an aggressive malignancy with a very challenging prognosis. For patients with a preserved performance status, systemic therapy can usually improve overall survival and effectively palliate the high symptom burden, for a modest period of time. However, as the disease evolves and cancer therapy resistance emerges, PDAC patients will require additional medical and endoscopic management for improvement of gastrointestinal symptoms, pain control, and QoL. Early recognition and involvement of supportive care with honest prognostication, outpatient advance care planning approaches, and utilization of electronic patient reported outcomes, collectively serve to best understand patient’s values and goals and provide care in alignment with those objectives.