Palliative Care in Advanced Cancer in Older Adults: Management of Pain, Fatigue, and Gastrointestinal Symptoms
This article is the third in a continuing series on cancer in older adults. The goal of this series of articles is to highlight the ways in which the diagnosis and management of cancer in older adults differ from the diagnosis and management of cancer in younger patients.
Cancer is a common diagnosis in older adults,1 yet we lack evidence-based data to guide treatment in the elderly population.2 Treatment is further complicated by the heterogeneity of older adults, who vary in their functional status, comorbidities, and polypharmacy; have decreased physiologic reserves; and experience age-related physiologic changes that affect the pharmacokinetics and pharmacodynamics of medications. Due to this complexity, the ability to approach cancer diagnosis and treatment from a “geriatric perspective” is viewed as an essential part of oncologic care.2
Older adults with advanced cancer suffer; pain and other symptoms that negatively affect their quality of life are common and undertreated.3,4 Clinicians with geriatric expertise have an opportunity to improve care and quality of life for older cancer patients throughout the course of their disease, particularly when the primary goal is palliative.
Providing excellent palliative care begins with assessing the patient’s level of pain and other physical, psychosocial, and spiritual needs. The aim is to preserve quality of life for patients and their families, a central tenet of palliative care, by treating patients appropriately and offering support to them and their families throughout the illness and with bereavement.5 In this article, we provide a brief introduction to the steps involved in assessing and managing pain and selected nonpain symptoms in older adults with advanced cancer.
Central to palliation is promptly identifying troubling symptoms, implementing the appropriate interventions, and frequently reassessing the patient’s response so that treatment can be adjusted as needed to achieve symptom management goals. Self-report remains the gold standard for symptom assessment, even in patients with cognitive impairment.6 Validated symptom assessment scales, such as the Edmonton Symptom Assessment System,7 can also be useful.
Some patients with cognitive impairment may have difficulty communicating about their symptoms. Validated scales are available for assessing discomfort in nonverbal patients, and their use is recommended.8 If a patient with impaired communication has a condition commonly known to cause discomfort, such as a fracture, wounds, or a history of chronic pain, consider a trial intervention.
Although scales are useful, they are only part of a comprehensive clinical assessment. Symptoms such as pain are multidimensional constructs, in which other domains (eg, psychological state, other physical symptoms, and existential/spiritual and social concerns) interact to form the totality of a person’s experience and expression of symptoms (ie, “total pain”).9,10 To enhance quality of life, the interdisciplinary approach of hospice and palliative medicine programs requires consideration of all these domains.11
Pain Overview and Management
Pain with cancer is common. It reportedly affects 64% of patients with advanced disease, 59% of patients receiving antineoplastic therapy, and 33% of patients whose cancer has been cured.12 The undertreatment of cancer pain is also common and has been observed in nursing homes13 and in outpatient14 and inpatient settings.15 Multiple factors contribute to the undertreatment of cancer pain, including patients’ desires to avoid medications, especially opioids, providers’ difficulty with appropriate pain assessment and a widespread reluctance to prescribe opioids, and system barriers like short office visits leading to time pressures and difficulty scheduling monthly visits for refills of controlled substances.16 Pain management for geriatric patients is complex. Providers must consider geriatric issues, such as heterogeneity, differing pharmacokinetics, and a high prevalence of comorbidities and polypharmacy, and not allow these to inhibit appropriate pain management.
Nonpharmacologic treatment for malignant pain encompasses modalities such as physical therapy, transcutaneous electrical stimulation, administration of heat and cold, psychological and behavioral interventions, complementary and traditional Chinese medicine approaches, mind-body training, and therapeutic massage. Data is conflicted on the effectiveness of nearly all of these modalities, and many are currently being investigated in larger, more scientifically rigorous trials.17 Strong evidence exists that indicates radiotherapy of skeletal metastases provides pain relief.18
Since 1986, the basis of pharmacologic treatment has been the World Health Organization’s (WHO) Pain Ladder. Numerous studies have validated this three-step analgesic ladder for treating cancer pain.19 The conceptual framework of the pain ladder recommends nonopioids for mild pain, lower-dose or “mild” opioids for moderate pain, and higher-dose or “strong” opioids for severe pain, along with adjuvant medications and nonpharmacologic interventions.20,21 Although the original WHO analgesic ladder—also a three-step approach—suggested different opioids based on pain intensity (eg, codeine for moderate pain), there is no pharmacologic rationale for this approach, and opioids such as morphine or oxycodone can be prescribed at low enough doses to manage moderate pain safely.21
Nonopioid Medications. Recommendations for nonopioid pain relief have included the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) at medium to high doses.20 Due to the renal, cardiovascular, and gastrointestinal adverse events of NSAIDs in older adults, the American Geriatrics Society guidelines recommend acetaminophen as the first-line nonopioid analgesic for these patients.22
Acetaminophen has a ceiling dose of 4000 mg daily. Exceeding this amount increases the risk of severe liver injury, including liver failure.23 When calculating the patient’s daily intake of acetaminophen, it is important to include acetaminophen found in any over-the-counter cold and sleep preparations the patient uses and in acetaminophen-opioid preparations, such as hydrocodone plus acetaminophen. To mitigate the risk of acetaminophen overdose, the US Food and Drug Administration (FDA) has asked manufacturers of medications combining acetaminophen and opioids to limit the strength of acetaminophen in these formulations to 325 mg per dosage unit.23
To reduce the risk of acetaminophen overdose and improve background pain control, it should be prescribed “by the clock” (ie, scheduled administration), rather than on an as-needed basis. Patients should be reminded not to drink alcohol while taking acetaminophen-containing medication.23 Acetaminophen is contraindicated in patients with hepatic failure and relatively contraindicated in patients with hepatic insufficiency and past or present alcohol abuse.22
NSAIDs may be more useful than acetaminophen for managing chronic inflammatory pain and in the short-term treatment of osteoarthritis and low back pain22 though studies in elderly cancer patients are minimal. Chronic NSAID use increases the risk of gastrointestinal bleeding, renal failure, hypertension, and cardiovascular adverse events. Older patients have a dose-dependent risk of adverse gastrointestinal effects,24 and even low-dose aspirin or NSAIDs increase the risk for gastrointestinal bleeding two- to sixfold.25 Although cyclooxygenase-2 (COX-2) inhibitors have been shown to decrease the risk of gastrointestinal side effects, they are associated with an increased rate of cardiovascular events.26 Concomitant administration of a gastroprotective agent, such as a histamine-2 (H2) receptor agonist or a proton pump inhibitor, is recommended.22 NSAID use over 2 years in a noncancer population was associated with a 60% increase in the risk of stroke, even in those taking aspirin.27 Because there is limited research in NSAID use in elderly cancer patients and a high rate of frailty in this group, physiologic alterations in the renal, cardiovascular, and gastrointestinal systems related to aging offer a strong relative contraindication to NSAID use.21
Opioid Medications. Opioid therapy has been the mainstay of treatment for patients with moderate to severe cancer pain. Patients should be closely monitored during the initiation or titration of opioids.22 As a class, opioids have predictable adverse effects, the most common of which are constipation, sedation, pruritus, nausea, and vomiting. Side effects can often be minimized by decreasing the dose or changing the route of administration (eg, to rectal or intrathecal routes). Opioid rotation (changing opioids when side effects or nonefficacy make continuing current opioid therapy unwise) can minimize intolerance. More commonly, concomitant medications are prescribed to target opiate-induced adverse effects, such as prophylactic laxatives to prevent or lessen constipation.28
Opioids are available in different strengths and preparations. “Weak” opioids—those perched on the second rung of the WHO pain ladder—include codeine, tramadol, and, until recently, propoxyphene. Each carries its own risks when used in elderly patients, and all should be used sparingly. Codeine and tramadol are µ-receptor agonists, and their analgesic effects are negated in patients taking medications that inhibit CYP2D6, such as selective serotonin reuptake inhibitors (SSRIs), H2 blockers, and certain NSAIDs.29 Propoxyphene, which the body converts to a toxic metabolite called norpropoxyphene,29 has been removed from the market in the United States.30
When treating pain in older adults, clinicians should start with nonopioid analgesics and progress, without using the second-rung’s weak opioids, to low-dose “strong” opioids, which are pharmacokinetically more predictable and have better safety profiles than weak opioids.22 Morphine is the prototypical opioid and the one against which the potency of other opioids is compared. It is available in oral, parenteral, and rectal formulations. Morphine is metabolized by the liver into two metabolites that are excreted in the urine. Unless hepatic insufficiency is severe, it does not affect dosing. To prevent opioid toxicity, dose reduction is required for patients with impaired renal function, starting at a creatinine clearance of 50 mL/min.31
Hydromorphone, generally thought to be 7.5 times more potent than morphine, is also transformed by the liver into active metabolites that are excreted in the urine. It presents the same risk for toxicity as morphine in patients with impaired renal function.31
Oxycodone is only available as an oral preparation, and its efficacy and toxicities are not affected by age, renal function, or serum albumin levels.31 The pharmacokinetic profile of oxycodone does not change significantly in the setting of renal insufficiency.
Methadone is increasingly coming into favor as maintenance therapy for chronic cancer pain. Although its excretion is not contingent on renal function, its pharmacokinetic profile varies tremendously among users. This is likely because it is metabolized through the CYP450 pathway in the liver. Methadone has a propensity to accumulate, and patients should be monitored closely. Because methadone can increase QTc intervals and the risk of torsades de pointes (TdP), the patient’s QT interval should be evaluated before methadone is initiated, again at 30 days, and then yearly. If the QTc interval exceeds 500 msec, dose reduction or another agent should be considered. Structural heart disease and a history of arrhythmias are strong relative contraindications for methadone use.32 In retrospective case reports of methadone-induced TdP, most deaths were associated with multiple risk factors, including high daily methadone doses, use of other QTc-prolonging medications or CYP3A4 inhibitors, and electrolyte abnormalities.33 Consensus guidelines issued in 2008 on the use of methadone in palliative care recommend obtaining an electrocardiogram before initiating therapy, at 24 hours, and at 96 hours, but the guidelines do not advise clinicians on the appropriate response to changes in the QTc interval.34
Fentanyl is a synthetic opioid available as an injection, transdermal patch, lozenge, buccal soluble film or tablet, sublingual film or tablet, and a nasal spray. Fentanyl does not accumulate in patients with renal insufficiency. It is highly protein-bound, however, with an increased risk of accumulation and toxicity in patients with low serum albumin levels. This is of particular concern for patients with cancer, whose lean body mass-to-fat ratio is often low, because it increases the risk of toxicity once fat and muscle stores have been saturated.31 Transdermal fentanyl patches should not be used in cachectic35 and opioid-naïve patients. Transdermal fentanyl takes 3 to 5 days to reach a steady state; after patch removal, the drug continues to be released from fat stores and serum drug levels do not decrease significantly for 24 hours.31
Adjuvant Medications and Interventional Approaches
Medications with primary uses other than analgesia can have a beneficial effect on pain levels. Although tricyclic antidepressants (TCAs) are considered potentially inappropriate for use in older adults36 with an adverse effects profile that limits administering them at high doses in this population, they have been shown to reduce neuropathic pain.37 SSRIs do not possess analgesic properties, but they can be used to treat coexistent depression that may worsen pain perception. Gabapentin, pregabalin, and other antiepileptic drugs help alleviate neuropathic pain.22 Topical lidocaine patches are commonly used as adjuvant therapy for nociceptive or neuropathic pain, but data demonstrating their safety and effectiveness are limited to post-herpetic neuralgia38 and other neuropathic pain states.39 In a small crossover trial of cancer patients with postsurgical incisional pain, a lidocaine patch was ineffective at reducing pain intensity ratings.40 On their own, none of these medications provide sufficient relief of cancer pain, and they should only be used adjuvantly with nonopioid or opioid pain relieving agents.
Bisphosphonates are often helpful in patients with malignancy. They inhibit osteoclastic activity and can decrease metastatic bone pain, which is common in patients with multiple myeloma and breast, prostate, and lung cancers. Intravenous bisphosphonates that are approved for patients with skeletal metastases reduce skeletal morbidity, control malignancy-induced hypercalcemia, and possibly possess antitumor effects.41 Intravenous administration of bisphosphonates is associated with an increased risk of osteonecrosis of the jaw, a condition that occurs more often in older patients who have coexisting dental or periodontal disease and receive high doses of the therapy over a long period of time.42 Bisphosphonates used in conjunction with radiation therapy for those with pain from bony metastases have been found to decrease pain scores and increase quality of life and functional status.43 Bisphosphonates are contraindicated in patients with severe renal insufficiency or uncorrected vitamin D deficiency.42 Denosumab, an inhibitor of RANK ligand, was recently found to be noninferior to zoledronic acid at delaying or preventing skeletal-related events in those with advanced cancer, with less acute phase reactions and renal adverse events.44
Interventional approaches to managing cancer pain should be considered, particularly when medications are poorly tolerated or pain is refractory.21 These include injections, neural blockade, and intraspinal administration of opioids, including implanted delivery systems.21,45 Celiac plexus neurolysis for intra-abdominal cancer and intercostal nerve blocks for post-thoracotomy intercostal neuralgia45 are examples of neurolytic blockades for cancer pain syndromes.
Fatigue Overview and Management
Cancer patients commonly experience fatigue,46,47 which can markedly detract from their quality of life.48 Although a thorough examination of the pathophysiology and etiology of
cancer-related fatigue (CRF) is beyond the scope of this review, it is thought to be a multifactorial process in older adults. One proposed model demonstrates how cancer, comorbidities, and antineoplastic treatments lead to a negative energy balance, while hypothalamic-pituitary axis dysfunction from stress and increased levels of TNF-α and IL-1 act centrally to drive CRF symptoms.49
The first step toward improving fatigue symptoms is to identify and treat underlying factors that contribute to fatigue, such as pain, emotional distress, sleep disturbance, anemia, depression, and infection. Once these contributing factors have been addressed, treatments to remedy CRF can be split broadly into two categories: nonpharmacologic and pharmacologic.
To reduce the risk of adverse drug reactions in older adults, evidence-based nonpharmacologic treatments are recommended as first-line therapy for CRF. Patients may find the following strategies useful in managing their fatigue: energy conservation techniques, such as prioritizing activities; activity pacing (alternating physically demanding activities with more sedentary ones); scheduling demanding activities for times of peak energy; and following a routine.50 Physical exercise has demonstrated a modest but consistent ability to stop the progression of CRF or reverse CRF in patients who are undergoing or have completed chemotherapy.51
Broadly classified as psychosocial interventions, participation in support groups,52 stress management training,53 and acupuncture and acupressure54 are modestly effective at ameliorating fatigue symptoms. Exercise programs incorporating mindfulness, such as yoga and tai chi, may also improve CRF or health-related quality of life.55,56 The randomized controlled GROUP-HOPE trial found that combining psychosocial interventions with moderate exercise improved CRF.57
Although data do not support a direct association between anemia and fatigue in patients with advanced cancer,58 pharmacologic interventions are sometimes used to address anemia in patients with CRF, including erythropoiesis-stimulating agents (ESAs). The use of red blood cell transfusions to treat anemia in patients with cancer has demonstrated only short-lived improvement in fatigue (<15 days),59 which may reflect the multifactorial nature of CRF.
In patients with chemotherapy-induced anemia, epoetin alfa has been found to increase hemoglobin levels and improve functional status and fatigue,60 and darbepoetin has been shown to improve fatigue.61 Multiple studies have demonstrated that ESAs significantly shorten overall survival and/or increase the risk of tumor progression and thrombotic events in patients with cancer; thus, the FDA has implemented a Risk Evaluation and Mitigation Strategy to ensure safe administration of ESAs.62 It is now recommended that they only be used in patients with anemia due to myelosuppressive chemotherapy that is not being administered with the intent to cure.63
Depression is highly prevalent in cancer patients and can cause fatigue.64 A large review found that TCAs and SSRIs improved depressive symptoms and reduced symptoms of major depression after an average of 6 to 8 weeks of treatment.65 SSRIs are associated with fewer side effects than TCAs in elderly patients and are therefore preferred for treating depression in this patient population.36
Methylphenidate, a centrally-acting stimulant, and modafinil, a nonamphetamine stimulant, have also been investigated in the treatment of CRF. Although none of the studies to date have looked exclusively at elderly patients with cancer, these medications have been found to improve short-term fatigue symptoms in the general population of patients with cancer.66,67 Methylphenidate is contraindicated in people with glaucoma and is associated with an increased risk of death in patients with structural heart disease.68 Modafinil has been linked to Stevens-Johnson syndrome and hypersensitivity.69
Gastrointestinal Effects of Cancer
Patients with cancer frequently experience nausea, vomiting, and constipation. Nausea is evident in 21% to 68% of patients with advanced cancer.70 Although older patients recover more slowly than younger patients from cancer and treatment-related side effects (eg, nausea), adequate prescribing of antiemetics in the elderly is often lacking.71
The causes of nausea and vomiting in cancer patients are often multifactorial. Medications, such as opioids and chemotherapy agents, can produce nausea by direct activation of the chemoreceptor trigger zone in the medulla. Other causes of nausea include poorly treated constipation, gastrointestinal (GI) dysmotility, vestibular dysfunction, elevated intracranial pressure, metabolic abnormalities, dehydration, and malignant bowel obstruction. Infections of the upper GI tract, which are common in patients with neutropenia or who are receiving radiation therapy, and psychological concerns, such as anxiety and anticipation of nausea with highly emetic therapy, can also trigger nausea.72
Careful assessment and frequent reassessment—again noted as central tenets of good palliative care—are vital. Clinicians should take a complete history, determine whether there has been a change in bowel movements, search for emetogenic or constipating medications, and use laboratory and imaging modalities when appropriate to identify possible causes of nausea, vomiting, and constipation.72
The National Comprehensive Cancer Network (NCCN) and other organizations have issued evidence-based guidelines for treating chemotherapy-induced nausea and vomiting,73 which are beyond the scope of this review. These guidelines do not outline specific recommendations for older adults, but, as with other aspects of cancer symptom management, therapeutic considerations include drug interactions and increased susceptibility to side effects.74
The NCCN has also issued recommendations on the treatment of nonchemotherapy-induced nausea and vomiting as part of its published guidelines for patients with cancer who are receiving palliative care.75 Based on available evidence, the guidelines recommend maximal titration first of dopamine receptor antagonists, including prochlorperazine, haloperidol, or metoclopramide.75 The NCCN guidelines caution that prochlorperazine is associated with a lack of efficacy and an increased risk of adverse events in older adults and should not be used in these patients. Dopamine receptor antagonists work at the level of the chemoreceptor trigger zone; metoclopramide also increases GI motility. These medications should be initiated at low doses to minimize the risk of adverse effects, but can be rapidly titrated upward if needed.75
Strong evidence for the use of dopamine receptor antagonists is lacking. For example, one systematic review of the literature on managing opioid-induced nausea and vomiting in cancer patients concluded that the evidence was too limited to establish recommendations on antiemetic use.76 The authors did find a weak level of evidence to suggest that nausea and vomiting in cancer patients taking opioids might be lessened by changing the opioid or route of administration.76 Although one study reported that 50% of cancer patients receiving metoclopramide had a significant decrease in nausea, it was retrospective.77 A Cochrane systematic review was unable to find any randomized clinical trials investigating the effectiveness of haloperidol at treating nausea and vomiting in palliative care patients.78
If the use of dopamine receptor antagonists to treat nausea is contraindicated by adverse effects or poor efficacy, a number of medication classes are available for second-line therapy. At this point, 5-HT3 antagonists such as ondansetron, which are the mainstay of treatment for chemotherapy-induced nausea, are recommended.75 Available as standard and orally dissolving tablets and in intravenous preparations, 5-HT3 antagonists are more expensive than metoclopramide and data do not indicate any improved efficacy when used in patients who are not undergoing chemotherapy.79 In addition, the FDA issued a safety warning for ondansetron in September 2011, cautioning that it might prolong QT intervals.80
Anticholinergic agents, such as scopolamine, can be useful if there is a vestibular component to the patient’s nausea, although sedation and dizziness may limit dosing. Like prochlorperazine, the NCCN recommends against using chlorpromazine and promethazine to control nausea in elderly patients with cancer because the risk of distressing side effects exceeds the evidence for their efficacy.75 Prochlorperazine can cause sedation and hypotension; chlorpromazine can also have a sedating effect and lowers the seizure threshold; promethazine may produce sedation, dizziness, and headache, and lower the seizure threshold.81
Malignant bowel obstruction is common in patients with advanced abdominal or pelvic cancers or metastases and often causes nausea, vomiting, pain, and colickiness.82 Various mechanisms contribute to the risk of bowel obstruction, including pseudo-obstruction due to intestinal motility disorders or constipation. Metoclopramide may be useful in treating intestinal motility disorders, but it is relatively contraindicated in patients with complete mechanical bowel obstruction.83 Constipation in patients with cancer should be assessed and treated.
Evaluation for surgical treatment or stenting is appropriate for patients whose bowel obstruction has a potentially reversible cause and is largely supported by case series.82 However, a recent randomized trial showed no advantage to colonic stenting as a bridge to elective surgery and the trial was stopped early due to increased morbidity in the stenting group.84 When surgical interventions or stent placements are not possible, a decompressive percutaneous endoscopic gastrostomy tube is an alternative, with case series reporting high rates of symptom resolution.82 Interventional decompression may not be feasible, effective, or consistent with a patient’s goals of care, however. In advanced cancer patients who have an irreversible, inoperable obstruction, use of a nasogastric tube may worsen distress and create additional complications.75
Pharmacologic management for bowel obstruction includes analgesics (nonopioids and opioids), antiemetics, antispasmodics, corticosteroids, and octreotide, a synthetic somatostatin analog. Opioids are used to treat pain associated with bowel obstruction. Although they may have adverse effects on intestinal
motility if the goal is normalizing gut function, such as with ileus, pain management and relief of suffering is the paramount goal in palliative medicine. As summarized in one review, “if a patient needs an opioid for pain, give it.”85
Several small randomized trials reported significant decreases in nausea and vomiting and GI secretions in patients taking octreotide.82,86 The addition of an anticholinergic agent, such as scopolamine, is sometimes recommended to reduce colic and further decrease secretions,83,87 but these agents convey the risk of multiple adverse events in older adults. A Cochrane systematic review found a trend for resolution of bowel obstruction with use of corticosteroids and a low incidence of side effects; the dose range in the three small studies that were included was dexamethasone 6 to 16 mg intravenously.88
Cancer has a high prevalence among older adults, and palliative interventions can help reduce its physical and psychological symptoms. Providers should ask about patients’ levels of pain, fatigue, nausea, and vomiting and treat these symptoms with evidence-based interventions. These efforts have been shown to decrease suffering and improve quality of life. It is important to stay mindful of the differences in how medications are metabolized, the anticholinergic load, and whether the effects of certain agents may contraindicate their use in elderly adults to ensure better therapeutic outcomes and reduce the risk of iatrogenic harms.
Much work is needed to establish the best practices for palliative treatment in patients with cancer. Since older adults develop cancer at a higher rate than younger patients, it is imperative that they be included in clinical trials. All clinicians caring for individuals with cancer must develop geriatric competencies and learn to combine curative and palliative modalities to reduce the burden of cancer on older adults.
Dr. Jones is from the Department of Medicine; and Dr. Elbert-Avila is from the Department of Medicine and the Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC. Dr. Elbert-Avila is also affiliated with the Geriatric Research and Education Clinical Center (GRECC), Durham Veteran Affairs Medical Center, NC.
Dr. Suh is Associate Professor, Division of Community Geriatrics, Department of Family and Community Medicine, University of Texas Health Science Center in San Antonio, and Medical Co-Director, Acute Care of the Elderly (ACE) Unit, Christus Santa Rosa City Centre Hospital, San Antonio.
The authors and series editor report no relevant financial relationships.
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