Is every pancreatic cancer patient a palliative care patient?

Introduction

Sixty-two thousand patients are diagnosed annually in the United States with cancer of the exocrine pancreas, primarily adenocarcinoma that arises from the ductal epithelium. Fifteen to twenty percent of patients may have surgically resectable disease at the time of diagnosis, but most patients present with locally advanced or metastatic disease. Pancreatic cancer is a leading cause of cancer-related death, with relative 5-year survival rates of all stages approximately 11% (1). Cancer-directed therapies may include surgery, chemotherapy, radiation, and rarely targeted therapies. Clinical presentation and management vary based on location and stage of the tumor. Common symptoms at diagnosis include abdominal, epigastric and/or back pain, jaundice, diarrhea, weight loss, and anorexia.

Given the significant symptom burden and poor prognosis patients with pancreatic cancer face, early palliative care consultation is vital for management of symptoms, psychosocial distress, and medical decision making and advance care planning. Prior research has demonstrated that early palliative care involvement alongside standard oncology care may result in improved quality of life, symptom management, and potentially longer survival but also results in decreased use of chemotherapy, fewer hospitalizations, emergency department visits and intensive care stays in the 30 days prior to death, as well as increased duration of hospice enrollment (2,3). In addition to improving quality of life for the affected patient, effective palliative care has been shown to increase support for affected caregivers, which may also help to reduce prolonged grief in bereaved family members (3).

Treatment strategies

Surgical resection is the standard and only curative treatment for resectable pancreatic cancer but surgery alone is inadequate to effect a cure, as the risk of recurrence is 90% without adjuvant therapy (4). Pancreaticoduodenectomy is commonly known as a Whipple procedure and is a complex surgical procedure with potential acute and chronic complications. Following resection, the value of adjuvant chemotherapy has been established with six months of combination chemotherapy as the gold standard. As mentioned, most patients present with locally advanced or metastatic disease at diagnosis, thereby negating the option of curative intent treatment. In these cases, the role of cancer directed treatment is palliative in nature with the goal of lengthening survival and improving quality of life. FOLFIRINOX and combination gemcitabine and nab-paclitaxel are the most used palliative-intent chemotherapy regimens. Despite advancement in the cancer treatment landscape, there are no specific targeted therapies currently approved and median survival from metastatic pancreatic cancer remains low at 11 to 14 months.

Symptom management

Common symptoms patients with pancreatic cancer experience include abdominal pain, epigastric pain, back pain, jaundice, fatigue, nausea, diarrhea, anorexia, weight loss, anxiety, and depression. Systemic antitumor-therapies can prolong survival and decrease symptom burden but may also be accompanied by treatment-related side effects. Following a Whipple procedure, patients often experience changes to the gastrointestinal track, leading to serious long-term effects. Gastrointestinal malignancies in general, but specifically pancreatic cancer cause secondary maldigestion, especially following curative or palliative surgery. Even patients who did not undergo pancreatoduodenectomy can suffer from exocrine pancreatic insufficiency leading to malabsorption and resultant malnutrition, as well as altered pharmacokinetics of oral treatments. Early and concurrent involvement of palliative care can help to manage these symptoms to improve tolerance of cancer-directed therapies as well as improve quality of life for these patients. Management strategies for the most experienced symptoms are addressed below and summarized in Table 1.

Pain

Nearly all patients with pancreatic cancer experience pain during the disease course. For sixty percent of patients with pancreatic cancer, abdominal pain is the presenting complaint (5). Mid-epigastric pain with radiation to the back in the classic characterization of pancreatic cancer pain. The etiology of this appears to be multifactorial with visceral, somatic, and neuropathic elements depending on location and extent of disease. Pancreatic cancer causes direct pain in many ways: direct compression of adjacent structures, biliary or gastric outlet obstruction, and perineural invasion involving the celiac plexus. Pain can also arise as a secondary complication from treatment, such as chemotherapy induced peripheral neuropathy (CIPN) or from enteritis following radiation therapy. A thorough assessment of severity, timing, quality, aggravating and alleviating factors as well as impact on functional status and psychosocial wellbeing guides effective management with a multimodal and multidisciplinary approach.

Opioid medications are often required, but patients with mild pain may benefit from non-opioid medications, such as acetaminophen, in accordance with WHO analgesic ladder. NSAIDs have numerous contra-indications for patients receiving cancer treatment, so while effective as an adjuvant to opioids, they may not be an option and should be used cautiously. Adjunctive medications for the management of neuropathic pain which may arise from the malignancy itself or from CIPN include tricyclic antidepressants (nortriptyline or amitriptyline), serotonin and norepinephrine reuptake inhibitors (duloxetine and venlafaxine), and anti-convulsants (gabapentin and pregabalin). An effective approach typically starts with duloxetine or gabapentin for neuropathic pain and then includes dose titration prior to switching to pregabalin if ineffective (6). Choice of a neuropathic medication should include consideration of other symptoms and using medications that may treat multiple symptoms. The addition of a steroid, such as dexamethasone, is often helpful for pain from osseous or hepatic metastases, however, side effects prohibit long term steroid use.

When non-opioid medications are not fully effective for pain control, an opioid should be prescribed. Prescribers should start at the lowest effective dose of an immediate release opioid approximately every 4 hours as needed in oral tablet or liquid form. When a short-acting alone provides inadequate analgesia or a patient requires more than three doses in a 24-hour period to achieve analgesia, a long-acting opioid formulation should be started. If a patient cannot tolerate oral medications, alternate routes and forms of administration are available based on clinical situation, availability and location of the patient. Options may include transdermal buprenorphine or fentanyl, sublingual methadone or buprenorphine, and parenteral opioids with basal rate and as needed bolus dosing. Patients with a feeding tube can use extended-release abuse deterrent oxycodone which may be crushed or extended-release polymer coated morphine sulfate pellets as long-acting medications which can be opened and administered through the feeding tube while still maintaining continuous release properties. Typical formulations of extended-release oxycodone and extended-release morphine may not be crushed because it results in rapid absorption and uncontrolled delivery of the drug, potentially leading to opioid overdose.

Though opioids and adjuvant medications remain the mainstay of pain treatment, not all patients achieve adequate anesthesia or are limited by systemic toxicities (5). Due to the frequent involvement of the celiac plexus in pancreatic cancer, patients may also benefit from interventional procedures such as celiac plexus neurolysis (CPN). CPN has been found to be more effective than pharmacologic therapy alone and has been shown to reduce overall opioid requirements (7). CPN can be performed percutaneously, surgically, or endoscopically with the appropriate interventionalist. An initial celiac plexus block may be attempted with injection of a local anesthetic, and if analgesia is achieved, subsequent neurolysis may use dehydrated absolute alcohol for a longer lasting impact of 3-6 months. The procedure is generally performed on those patients with advanced disease, though it has been performed on patients with earlier disease stages with effect. Studies on survival post CPN have shown mixed results with some showing reduced survival time post treatment while others have shown improved survival time (8). Patient and providers should weigh the potential harms and benefits of CPN to determine referral and timing.

Palliative radiation therapy is another strategy to use for pain caused by localized areas of disease. The effects of radiation typically take 2 to 4 weeks to reach full benefits, so using radiation in conjunction with comprehensive medication management is essential. For pain control, palliative care providers should collaborate with the radiation oncologist to encourage use of hypofractionated radiation treatments, as prolonged courses of radiation may be physically and emotionally depleting for patients. Shorter courses of radiation provide equivalent symptomatic relief.

Ascites

Ascites is common in patients with advanced pancreatic cancer. Ascites can be malignant from peritoneal metastases or non-malignant from portal vein compression. Pharmacologic management of transudative ascites involves diuretics such as furosemide or spironolactone. Symptomatic patients or patients with exudative ascites routinely require paracentesis for both therapeutic and diagnostic purposes. Paracentesis may offer temporary relief of abdominal discomfort, but placement of a long-term drainage catheter can be an effective strategy for rapid reaccumulation of fluid.

Jaundice

Jaundice secondary to obstruction of the biliary tree develops in approximately 80% of patients with pancreatic head tumors and may cause abdominal pain as well as significant pruritus (9). Biliary stenting typically relieves obstructive symptoms of pain and pruritus but can also increase the risk of cholangitis. Bile acid sequestrants and rifampicin are initial medications used for pruritus associated with biliary cholestasis. Other ways of managing bothersome pruritus include 5-HT3 receptor antagonists, opioid antagonists, certain antidepressants and anticonvulsants and glucocorticoids. The use of topical or oral antihistamines is rarely beneficial due to lack of histamine release in biliary pruritus.

Nausea and vomiting

Symptoms of nausea and vomiting arise from both the disease and side effects of the treatments. Evaluation of the underlying etiology can help guide management. For example, FOLFIRINOX is a highly emetogenic chemotherapy regimen for pancreatic cancer that causes chemotherapy-induced nausea and vomiting (CINV). CINV is caused by receptor activation in the chemoreceptor trigger zone in the brain and responds to anti-emetic medicines that target 5HT3 and D2 receptors, including as ondansetron, prochlorperazine, olanzapine, and haloperidol. Anticipatory nausea may develop in the hours and days prior to chemotherapy and can be managed with anxiolytic medicines, such as benzodiazepines.

Many patients with pancreatic cancer experience gastroparesis leading to nausea and early satiety despite lack of overt tumor invasion (10). These patients may benefit from initiation of a prokinetic and anti-dopaminergic agent such as metoclopramide if there is not a complete bowel obstruction. Severe cases may require decompression with nasogastric or palliative venting PEG tube. Refractory vomiting occurs in gastric outlet obstruction in 15–20% of patients, and these patients may require a surgical gastrojejunostomy or an endoscopically placed duodenal stent, depending on an individual’s prognosis and performance status (11,12). Malignant bowel obstruction can also develop from peritoneal carcinomatosis and may require decompression; dexamethasone and octreotide are valuable in the medical management of bowel obstruction symptoms and can at times limit the need for surgical intervention.

Nutrition and bowel management

Significant weight loss is a common sign of pancreatic cancer. This may be due in part to malnutrition due to exocrine pancreas insufficiency and cancer related anorexia-cachexia syndrome with changes in nutrient metabolism. Patients with pancreatic cancer-induced anorexia and cachexia benefit from the supplementation of pancreatic enzymes with each meal. This is true even in absence of clinical steatorrhea, which rarely occurs until lipase levels are below 10% of normal (10). Orexigenic agents have also been investigated for anorexia-cachexia syndrome. Mirtazapine was found to have limited clinically significant benefit, while agents such as megestrol have unfavorable side effects such as increased risk of thromboembolism. Coordination of care with a nutritionist can help optimize nutrition. Between pancreatic insufficiency diarrhea, and opioid-induced constipation, patients with pancreatic cancer become skilled at careful titration of stimulant and osmotic laxatives agents, as well as anti-diarrheal agents.

Psychosocial support

The overall poor prognosis of pancreatic adenocarcinomas impacts patients and their caregivers in social, financial, spiritual and psychological ways. Palliative care utilizes a multidisciplinary approach to care that employs social workers, psychologists, psychiatrists, grief counselors, and chaplains to broadly support the patient and family. Palliative care providers are often the first members of the medical team to directly discuss the impact of the illness on the caregiver. Caregivers often express distress over their loved one’s disease, and doing so can lead to improved communication, reduction in burnout, and referrals to increase access to care such as home nursing or homemaking services.

Studies have shown that both pancreatic cancer patients and their caregivers have high levels of anxiety and depression in the three months following diagnosis (13). Several studies have also reported an increased incidence of depression in patients with pancreatic cancer prior to diagnosis in comparison to those with different cancer diagnoses as well as compared to the general population (14). This suggests that the symptoms of depression and anxiety might not only be related to the known overall poor prognosis following diagnosis, but it may also be a presenting symptom of the disease. Depression and anxiety are likely underdiagnosed in this patient population as some of the typical signs of depression, such as changes in sleep patterns, weight, oral intake, and fatigue may be falsely attributed to the disease alone. Specific questions geared towards assessing for anhedonia and depressed mood may be more effective for screening. If depression screening is positive, further history should be obtained from the patient and their family if appropriate regarding the impact of depression on daily functioning as well as assessment for possible suicidal ideation. Consultation with a social worker, psychotherapist and a psychiatrist for complex medication management may also be appropriate. Studies have shown that involvement of a mental health professional may improve overall quality of life and reduce psychosocial distress even in absence of pharmacologic therapies (14). Should medication management be required, SNRIs may serve dual purpose for both modulation of pain and mood symptoms and are often an excellent choice in pancreatic cancer. Stimulant medications such as methylphenidate can treat both cancer related fatigue and depression and serve as a bridge to allow antidepressants time to work.

Nonpharmacologic therapies including mindfulness, spiritual care, meditation, yoga, tai chi, hypnotherapy, acupuncture, acupressure, aromatherapy, massage therapy, pet therapy, and dietary supplements can be valuable for many patients. These complementary therapies may work in conjunction with conventional therapies to help reduce stress, fatigue, anxiety, nausea, and pain (15). These interventions have varying levels of evidence, and some interventions such as dietary supplementation may cause interactions with cancer-directed therapies. Palliative care providers can facilitate successful approaches to integrative oncology while maintaining high quality, safe, and patient centered care by using collaborative and nonjudgmental communication and counselling regarding benefits and risks of these complementary therapies.

Advance care planning

While anti-tumor therapies and aggressive symptom management are delivered with the intent of prolonging life and improving overall quality, pancreatic cancer portends a poor prognosis. In addition, patients often decline rapidly once the clinical change has started. The medical team must effectively communicate to patients and families the information about prognosis, treatment objectives, benefits and potential complications. Knowing this information allows patients and families an opportunity to engage in shared decision making, which promotes the creation of a care plan that is concordant with the patient’s personal goals and values. Studies have shown that patients who have a clear understanding of their illness have lower levels of anxiety and are better equipped to make advance care planning decisions as well as cope effectively with their illness (9). Advance care planning decisions may include designating a health care surrogate who can make medical decisions using substituted judgement for the patient should they lose capacity. Advanced directives specify the medical wishes in the event of irreversible clinical deterioration, such as whether to pursue cardiopulmonary resuscitation (CPR), mechanical ventilation, intensive care unit (ICU) escalation, hospitalization, artificial nutrition, or further caner-directed therapies. Each state uses a permutation of a MOLST (Medical Order for Life Sustaining Treatment) form to be signed by the patient and/or surrogate, as well as their medical provider. This form acts as a medical order (in contrast to an advanced directive which acts as a guide) to inform medical teams of the patient’s decisions surrounding end-of-life decisions and is especially important for patients with pancreatic cancer given the high rate of hospitalization and increased symptom burden at the end of life.

Having serious illness discussions also helps patients and families make deliberate decisions about transition to hospice care when a comfort focused approach is desired or warranted.

One study which analyzed a total of 574,522 pancreatic cancer hospitalizations from 2005 to 2011 in the United States to assess palliative care and hospice utilization revealed that palliative consultation has increased from 2.9% to 11.9%. Over this same period, discharges to hospice care increased from 10.2% to 12.7% with inpatient deaths decreasing from 11.2% to 8.1% (16). This study also noted that patients with metastatic disease were more likely to be discharged with hospice care. Other studies have shown that early referral to palliative care may decrease presentation to the emergency department and hospital admission and may increase duration of time enrolled in hospice care. Hospice care is beneficial for management of the patient’s symptoms at the end of life and provides support to caregivers for 13 months after the patient has died. This is especially vital in the case of caregivers of pancreatic care patients as they have been shown to exhibit prolonged grief and increased anxiety after the patient has died (13).

Conclusions

Patients with pancreatic adenocarcinoma of any stage benefit from early palliative care referral given high symptom burden and overall poor prognosis. Early referral may improve overall quality of life and communication while decreasing physical and emotional symptoms, alleviate caregiver burden, as well as decrease utilization of nonbeneficial disease-focused care at the end of life. Specialist palliative care referral in an embedded cancer center with a collaborative team may lead to the most comprehensive care; however, this continues to be a challenge to provide in many settings. Inpatient and community palliative care teams are also valuable in providing comprehensive and supportive services to patients and families in conjunction with their primary providers.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine for the series “Palliative Care in GI Malignancies”. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1457/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1457/coif). The series “Palliative Care in GI Malignancies” was commissioned by the editorial office without any funding or sponsorship. K.A. served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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