Pancreatic cancer—A disease in need: Optimizing and integrating supportive care
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that continues to be challenging to treat. PDAC has the lowest 5-year relative survival rate compared with 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 anticancer and supportive care in the management of patients with PDAC with the aims of maximizing length of life, quality of life, and symptom control. 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 quality of life. 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. 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.
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 nonspecific 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 anticancer 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.1 This review article explores 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-related and therapy-related complications.
Pancreatic Cancer
In 2019, it is anticipated that there will be 56,770 new cases of PDAC and 45,750 deaths in the United States.2 Globally, those numbers were 458,918 and 432,242, respectively, in 2018.3 At the time of presentation, approximately 50% of patients have stage IV disease, and systemic therapies have a real but relatively modest impact on outcome.4, 5 PDAC has the lowest 5-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 2030.4 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 disease.5
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 care.6 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 constipation.7 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 because of 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).
| Trend | Utilization in Practice |
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| Standardization |
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| Early involvement |
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| Integration of technology |
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Standardization
Over the past decade, palliative care education has been systematically integrated into medical education and has become a standardized competency for medical training.10 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 (Values and Options in Cancer Care), patient-centered communication about advanced cancer diagnosis, treatment options, prognosis, and QoL was enhanced with individualized training for both the clinician and the patient.13
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 as both feasible and cost-effective.14 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 services.15 A supportive care consultation consists of the assessment and management of physical symptoms, psychological needs, and spiritual needs; the assessment of the patient's support system and the caregiver's needs; communication about prognosis; assisting patients to identify personal goals for care, including end-of-life care; and, where indicated, for discharge planning.16 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 after discharge, hospice referrals, the use of support services, and the mortality index.17 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 care.18 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 settings.19-21 In addition, the standardization of community-based supportive care programs has increased the access, efficiency, and efficacy of supportive care in underserved or less populated areas.22
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 patients with metastatic PDAC who received early supportive care had an increased number of supportive care visits, had a higher use of hospice services, and received less chemotherapy in the last 30 days of life.26 As part of this investigation, patient-centered supportive care discussions of advance directives, end-of-life care, and advance care planning (ACP) were conducted in the outpatient setting and were facilitated by all health care professionals.27 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 Person-Centered Oncologic Care and Choices with positive results.28 Included in that model is the emerging trend of using video educational tools, including for topics such as goals of care. In a randomized controlled trial, patients with cancer who viewed a goals-of-care video were better informed and more likely to prefer comfort care and to avoid cardiopulmonary resuscitation.28 More recently, Desai et al published findings from 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; in response to patient symptoms, illness, and treatment understanding29; and, finally, nurse-led brief discussions of patient values.30
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 patients with cancer, physicians only disclosed an accurate prognosis 37% of the time and knowingly provided overestimated/underestimated prognoses to 40.3% of patients.33 When patients have an honest understanding of their prognosis, they appear to be more fully informed and able to choose their desired level of care better with a lower level of anxiety.34, 35 Disclosing a terminal prognosis allows patients to cope better with their illness and to complete ACP, along with providing caregiver satisfaction with end-of-life care.36 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 needs.37
Supportive Care and Technology
In medical oncology, the use of electronic patient-reported outcomes (ePROs) has been demonstrated to improve patient's QoL, reduce hospitalizations and health care costs, and improve overall survival.38, 39 ePROs provide an efficient, standardized assessment of continuous data collection on the patient and their medical condition that allows for enhanced patient-centered care and increased patient satisfaction.40 In a national supportive care study of 19,747 patients using ePROs, there were statistically significant improvements in all domains of both patient-reported and clinician-reported outcomes.41 In patients with PDAC, 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 patients with PDAC and health care providers that identified a core set of PROs to enable enhanced and personalized care and to create a nationwide, prospective, multidisciplinary pancreatic cancer registry for the development of pancreatic cancer-specific ePRO questionnaires.44 That study was further expanded into an international, multicenter Delphi study of 501 participants from the United States, Europe, and Asia.45
In rural and underserved areas, videoconferencing has become increasingly important to extend access to specialist multidisciplinary supportive care services.46 A study by Watanabe et al found that videoconferencing with patients was feasible, improved symptoms, reduced costs to the patient/families, and was satisfactory among users.47 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 resuscitation.48 Another evolving technology is the use of virtual reality to help health care 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 patients with PDAC include nausea, dyspnea, abdominal distension/bloating, constipation, anxiety, and depression. Nausea is often successfully controlled with serotonin antagonists alone or added to dopamine-receptor antagonists and first-generation or second-generation antipsychotics.49 Opioids are a well documented effective choice for dyspnea.50 Abdominal distension that is secondary to peritoneal metastases and associated ascites is typically managed with therapeutic paracentesis with or without a permanent drainage catheter, tumor-directed therapy, and sometimes diuretics or a peritoneovenous shunt, depending on clinical context.51 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 nonliver metabolized benzodiazepines, antidepressants like serotonin-norepinephrine–reuptake inhibitors, and psychological support.52
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 who are able to maintain a stable weight and body composition have a better prognosis.56 A well balanced diet of vegetables and protein-rich foods consumed in small meals every 2 to 3 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, patients with advanced cancer who received dronabinol had increased appetite, appreciation for food, protein consumption, and total caloric intake, as well as quality of sleep, relaxation, and QoL.60 Similar results were seen in a 2018 study with nabilone.61
Abdominal pain and back pain are among the most common symptoms (Table 2). A 2016 comprehensive review concluded that the World Health Organization's cancer pain relief guidelines continue to be the most effective method for managing cancer-related pain.62 The core principle is a “pain/analgesia ladder,” with escalation in management based on the severity of symptoms. The initial treatment consists of nonopioid medications like acetaminophen or nonsteroidal 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 a serotonin-norepinephrine–reuptake inhibitor, anticonvulsant, or α-2-adrenergic agonist can be incorporated for a potential additive effect.62, 63
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- Abbreviations: CPB, celiac plexus block; CPN, celiac plexus neurolysis; EUS, endoscopic ultrasound; IDDS, intrathecal drug delivery systems; VSPL, videothoracoscopic splanchnicectomy.
- a 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.
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. Currently, there are no studies that have explored patients with PDAC and opioid misuse, abuse, or related death. However, in a 10-year analysis by Chino et al, opioid-associated deaths were 10 times less likely in patients with cancer than in the general population.64 LIPs should attempt to prescribe nonopioid and adjuvant medications for mild-to-moderate pain, screen for those at risk for nonmedical opioid addiction, and counsel all patients on the prevalence of cancer-related pain and the relatively low prevalence of opioid addiction in patients with cancer. 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 survival.65 According to the National Comprehensive Cancer Network 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 plan.66 In a 2018 study, the interdisciplinary team at The University of Texas MD Anderson Cancer Center decreased the median number of nonmedical opioid uses from 3 to 0.4 per month and decreased the morphine-equivalent daily dose from 165 to 112 mg daily.67
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, which involves a disruption of visceral pain innervation from the pancreas and surrounding structures through an injection of corticosteroids or long-acting anesthetic.68 In 2 randomized comparison studies of endoscopic ultrasound (EUS)-guided and percutaneous computed tomography (PC)-guided celiac plexus block, EUS provided superior and prolonged pain control compared with 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 who have a short life expectancy and may provide symptomatic relief for 3 to 6 months.71 In a 2018 retrospective cohort study of 200 patients with PDAC at Johns Hopkins who underwent CPN, both EUS and PC were effective at reducing postprocedural pain; however, at 1 month, patients who underwent EUS had a better pain response and significantly higher QoL.72 An additional option with possible increased precision is a videothoracoscopic splanchnicectomy (VSPL), which may avoid the potential side effects with local diffusion of neurolytic solutions.73 In a comparison of 2 nonrandomized, 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, whereas VSPL only improved pain and fatigue.74 In addition, intrathecal drug delivery systems 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, intrathecal drug delivery systems were associated with statistically significant pain improvement at 1 week, 1 month, and 3 months in unresectable PDAC.75
Other pain-management treatment options include corticosteroids and radiation therapy.76 Complementary methods for chronic pain management include massage therapy, Reiki, meditation/mindfulness, hypnosis, yoga, tai chi, acupuncture, music therapy, and 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 who have pancreatic head tumors. Traditionally, the mainstay of treatment was palliative surgical biliary bypass with or without gastrojejunostomy; however, endoscopic therapies with stent placement are now primarily used for both biliary and duodenal obstructions.79 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. On the basis of tumor anatomy, stents are successfully placed in >90% of patients, with potential early postprocedure complications of pancreatitis, bleeding, or cholangitis occurring in 5% of cases.80, 81 Late complications are common, are related to stent obstruction/migration, and depend in part on the material of the stent.82 Plastic stents are cost-efficient but have a 2-fold increase in stent dysfunction, requiring multiple subsequent procedures and higher overall costs compared with metal stents.80, 83 In a recent review, endoscopic biliary stents were equally effective as surgery, with less procedural cost, complications, and morbidity but with higher rates of recurrent jaundice.84 However, in a patient with a life expectancy >6 months, a surgical biliary bypass could reduce the potential for subsequent procedures and hospital costs.85
Pancreatic tumor invasion into the duodenum leading to “gastric outlet” obstruction (or more accurately termed “duodenal obstruction”) can cause intractable reflux, nausea, vomiting, malnutrition, and cachexia. According to the SUSTENT study (Surgical Gastrojejunosomy vs. Endoscopic Stent Placement for the Palliation of Malignant Gastric Outlet Obstruction), the choice of therapy depends on performance status and the predicted length of survival.86 Gray et al identified 4 risk factors that correlated with <6 months of survival after a palliative surgical bypass and, if ≥1 of the 4 factors are present, then a nonoperative intervention would be recommended. These factors include the presence of distant metastasis, poor tumor differentiation, severe preoperative nausea and vomiting, and the absence of a preoperative biliary stent.87 In the short term, supportive endoscopic stent placement is associated with a shorter length of hospitalization and a faster return to oral intake; however, 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 to predict the risk of thrombosis based on the type of cancer, body mass index, and complete blood count. Patients with a KRS ≥ 3 were considered at high risk for a venous thromboembolism (VTE), and it was 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 patients with cancer can be recommended for prophylactic strategies.89
VTEs are another well established complication of advanced PDAC, with an incidence of ≥27%, which is 4 times higher than any other malignancy and 50 times higher than the average person.90 Thrombosis, especially early, in patients with PDAC is a poor prognostic factor for early death.91 Patients with PDAC 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/µL, or severe, uncompensated coagulopathy.94, 95 Recent studies have explored the use of direct oral anticoagulants (DOACs) in the treatment of cancer-associated thrombosis. In a 2017 prospective cohort study of 200 patients by Mantha et al, rivaroxaban was identified as safe and effective for cancer-associated thrombosis, with 4.4% VTE recurrence and 2.2% major bleeding.96 These findings are lower than the reported values of 7% to 9% and 6% to 7%, respectively, for LMWH.97, 98 Equivalent findings were seen in subsequent prospective randomized trials comparing DOACs with enoxaparin99, 100 and warfarin.101 However, in similar studies between DOACs and dalteparin, DOACs were noninferior but had an increased risk of bleeding.102, 103 According to National Comprehensive Cancer Network guidelines, DOACs have been associated with urinary and intestinal tract bleeding and should be used with caution in patients who have urinary or gastrointestinal tract lesions, pathology, or instrumentation.104
The role of prophylactic anticoagulation in this patient population is an area of active debate.90 In the CLOT trial (Comparison of Low-Molecular-Weight Heparin Versus Coumadin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer), 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 (Pilot Study of Intensified Chemotherapy and Simultaneous Treatment With Heparin in Outpatients With Pancreatic Cancer) 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 (Rivaroxaban for Preventing Venous Thromboembolism in High-Risk Ambulatory Patients With Cancer) was unable to show an overall statistical significance of rivaroxaban therapy for thromboprophylaxis of VTE and death because of a VTE but did show a reduced rate of VTE over placebo during the period of anticoagulation.106 However, in the AVERT trial (Apixiban to Prevent VTE in Patients With Cancer), the use of apixiban therapy resulted in a significantly lower rate of VTEs than placebo among intermediate-risk to high-risk, ambulatory patients with cancer, and all-cause mortality was similar between the 2 treatment groups.107 The prevention of VTE remains an important topic among patients with active cancer, with guideline committees currently evaluating these data and debating the implications for optimal practice. Currently, there are not sufficient data to recommend that patients with PDAC 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, patients with PDAC will require additional medical and endoscopic management for the improvement of gastrointestinal symptoms, pain control, and QoL. Early recognition and involvement of supportive care with honest prognostication, outpatient ACP approaches, and utilization of ePROs collectively serve to best understand the patient's values and goals and provide care in alignment with those objectives.
Funding Support
This study was supported in part by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30CA008748.
Conflict of Interest Disclosures
Andrew S. Epstein receives royalties from Up-To-Date for peer reviewing gastrointestinal medical oncology and palliative care topic reviews. Eileen M. O’Reilly receives research funding to Memorial Sloan Kettering from Genentech, Roche, Bristol-Myers Squibb, Halozyme, Celgene, MabVax Therapeutics, Acta Biologica, AstraZeneca, Silenseed, Pfizer, and Polaris and personal fees from Cytomx, BioLineRx, Targovax, Celgene, Bayer, Polaris, and Sobi outside the submitted work. Gordon T. Moffat made no disclosures.
