NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Overview
The aim of the NCCN Guidelines for Palliative Care is to help ensure that each patient with cancer experiences the best quality of life possible throughout the illness trajectory by providing guidance for the primary oncology team. The NCCN Palliative Care Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical oncologists, hematologists, and hematologic oncologists, pediatric oncologists, neurologists and neuro-oncologists, anesthesiologists, psychiatrists and psychologists, internists, palliative care and pain management specialists, and geriatric medicine specialists. These guidelines were developed and are updated annually by the collaborative efforts of these experts based on their clinical experience and available scientific evidence.
The NCCN Guidelines for Palliative Care were developed to facilitate the appropriate integration of palliative care into oncology practice. The guidelines outline procedures for screening, assessment, palliative care interventions, reassessment, and after-death care.
Palliative Care Screening
The primary oncology team should screen all patients at every visit for one or more of the following: 1) unmanaged symptoms; 2) moderate to severe distress related to cancer diagnosis and therapy; 3) serious comorbid physical, psychiatric, and psychosocial conditions; 4) life expectancy of 6 months or less; 5) metastatic solid tumors; 6) patient or family concerns about the course of disease and decision-making; and/or 7) patient or family requests for palliative care. Patients who meet these screening criteria and those who make a specific request for palliative care should undergo a full palliative care assessment.
Patients who do not meet these screening criteria should undergo re-screening at the next visit. In addition, the oncology team should inform patients and family members about palliative care services. Anticipation of palliative care needs and prevention of symptoms should also be discussed, and conversations regarding advance care planning should be initiated.
Palliative Care Assessment
Patients who meet screening criteria (see previous section) should undergo a comprehensive palliative care
NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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NCCN Clinical Practice Guidelines in Oncology: Palliative Care, Version 1.2016
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Assessment for Benefits and Burdens of Anticancer Therapy
Many cancer symptoms can be relieved by controlling the cancer with anti-cancer therapy. Assessment of the benefits and burdens of anticancer therapy for each individual is based on the existing NCCN disease-specific guidelines (the most recent version of all guidelines can be found on the NCCN Web site at NCCN.org). Special attention should be given to the natural history of the specific tumor; the potential for response to further treatment; the meaning of anticancer therapy to the patient and family; the potential for treatment-related toxicities, including impairment of vital organs and performance status; and serious comorbid conditions. Specific recommendations regarding anticancer therapy for patients with various life expectancies are discussed in Palliative Care Interventions (see next column).
Assessment of Personal Goals, Values, and Expectations
Patients and families should also be asked about personal goals, values, and expectations. Their priorities for palliative care, including their goals and the perceived meaning of anticancer therapy and the importance they place on quality of life, should be assessed. Goals and expectations that might be better met by the hospice model of palliative care should be identified. When appropriate, it is important to determine the patient's understanding of the incurability of their disease and whether patients wish to know survival statistics.
Assessment of Physical Symptoms
The most common symptoms that need to be assessed are pain, dyspnea, anorexia, cachexia, nausea, vomiting, constipation, malignant bowel obstruction, fatigue, weakness, asthenia, insomnia, daytime sedation, and delirium.4 Palliative interventions for these symptoms are discussed individually in subsequent sections.
Assessment of Psychosocial Distress
Assessment of psychosocial distress should focus on illness-related distress and psychosocial, spiritual, or existential issues according to the NCCN Guidelines for Distress Management (available at NCCN.org). Special problems with social support and resources (ie, home, family, community, or financial issues) must also be assessed. Recommendations for the management of psychosocial distress can be found in subsequent sections and in the NCCN Guidelines for Distress Management (available at NCCN.org).
Assessment of Educational and Informational Needs and Cultural Factors Affecting Care
The values and preferences of patients and families about information and communication should also be assessed. The oncology team should inquire about cultural factors affecting care and perceptions of the patient/family regarding the patient's disease status.
Palliative Care Interventions
The oncology team should start palliative treatments following the specific recommendations described in these guidelines for common symptoms. Comorbid physical and psychosocial conditions should be treated by appropriate clinicians. Consultation or collaboration with palliative care specialists or teams is recommended for patients with more complex problems to improve their quality of life and survival.5,6 Referrals should be made as needed to mental health and social services, pastoral care, health care interpreters, hospice services, or other specialists. Finally, the oncology team can be helpful in mobilizing community support through religious organizations, schools, or community agencies.
The panel divided patients into 3 groups to address the effect of life expectancy on the delivery of palliative care interventions: 1) patients with years to months to live; 2) patients with months to weeks to live; and 3) dying patients in their final weeks to days. Patients in their final hours of life are referred to as “imminently dying” and may require special interventions. The panel recognizes the lack of precision in estimating life expectancy but believes that this delineation will be useful for the delivery of appropriate palliative care interventions. The patient and family's personal, spiritual and existential, cultural, and religious goals, values, and expectations may change throughout these timeframes. Optimal provision of palliative care requires ongoing reassessment and modification of strategies, as well as ongoing communication between the patient, family, and health care team.
Indicators that patients are in their last 6 months of life include decreased performance status (ECOG score ≥3; Karnofsky Performance Score ≤50), persistent hypercalcemia, central nervous system metastases, delirium, superior vena cava syndrome, spinal cord compression, cachexia, malignant effusions, liver failure, kidney failure, or other serious comorbid conditions. Many patients with stage IV cancers, especially those with metastatic lung cancer, pancreatic cancer, and glioblastoma multiforme, would benefit from palliative care beginning at diagnosis, because expected survival is limited.7–9
Anticancer Therapy
A recent Institute of Medicine (IOM) report, “Communicating with Patients on Health Care Evidence,” found that 90% of Americans surveyed want to know their options for tests and treatments and to be involved in decision-making for their health, with almost 50% wanting to discuss the option of doing nothing.10,11 However, the report also found that far fewer respondents had such discussions with their physicians.
Patients who have years to months to live and a good performance status are likely to be interested in continuing anticancer therapy to prolong survival and reduce cancer-related symptoms.12–15 Anticancer therapy may be conventional evidence-based treatment as outlined in the NCCN disease-specific guidelines (available at NCCN.org) or treatment in the context of a clinical trial. In some of the advanced-stage cancers, chemotherapy may be superior to best supportive care and may prolong survival.16,17 Furthermore, patients with advanced non-small cell lung cancer who are not eligible for systemic chemotherapy may benefit from targeted therapies that are effective for relieving symptoms, maintaining stable disease, and improving quality of life without the adverse events that may be associated with cytotoxic cancer therapies.18 Physicians, patients, and their families should discuss intent, goals, and range of choices; benefits and burdens of anticancer therapy; and possible effects on quality of life. In addition, the oncology team should prepare the patient psychologically for possible disease progression.
Anticancer therapy may at times go beyond what is evidence-based. Interestingly, data from a CanCORS study of 1574 patients with metastatic non-small cell lung cancer suggested that many patients received higher doses and a greater number of palliative radiation treatments than is supported by current evidence.19 Additionally, a study of patients with metastatic colorectal cancer revealed that more than 90% of patients consulted with a medical oncologist, and 82% of these patients received chemotherapy.20
Patients with months to weeks to live should be provided with guidance regarding the anticipated course of the disease. Physicians should confirm patient understanding of goals of therapy and preferences regarding prognostic information. Patients at this point are typically tired of therapy, homebound, and concerned about the side effects of more treatment. The focus of treatment for these patients shifts from prolonging life toward maintaining quality of life. These patients should consider potential discontinuation of anticancer treatment and be offered best supportive care, including referral to palliative care or hospice.21,22 To avoid demeaning the value of end-of-life care, palliative care and/or hospice care should not be described as “giving up,” but instead reframed as “fighting” for better quality of life.
In general, patients with weeks to days to live (ie, dying patients) should not be given anticancer therapy but should be given intensive palliative care focusing on symptom management and preparation for the dying process.
Symptom Management
Special considerations in the implementation of these guidelines based on life expectancy are delineated in the algorithms (see page 84). The major focus of these special considerations is the withholding and withdrawal of aggressive interventions; prevention and elimination of side effects associated with pharmacologic pain management; the acceptance of loss of function for the sake of relief of symptoms; and the treatment of the unique symptoms of patients in their final hours of life.
With regard to symptoms, the management of pain, dyspnea, anorexia/cachexia, nausea and vomiting, constipation, diarrhea, malignant bowel obstruction, fatigue, delirium, and psychologic distress is fundamental.23–25 These symptoms are discussed in detail in subsequent sections. As a general principle, if/when appropriate, providers should try to use palliative interventions that may address multiple symptoms.
Pain: See the NCCN Guidelines for Adult Cancer Pain (available online at NCCN.org) for more detail. In addition, it is important to note that dying patients in their last weeks of life have several specific requirements. For instance, opioid dose should not be reduced solely for decreased blood pressure, respiration rate, or level of consciousness when opioid is necessary for adequate management of dyspnea and pain. In fact, opioids can be titrated aggressively for moderate/severe acute/chronic pain.26 In addition, palliative sedation can be considered for refractory pain (see next section) after consultation with pain management/palliative care specialists.
Dyspnea: Dyspnea is one of the most common symptoms in patients with advanced lung cancer.27 The American Thoracic Society consensus statement defines dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.”28
Symptom intensity should first be assessed in all patients. Symptom intensity in noncommunicative patients with weeks to days to live should be assessed using physical signs of dyspnea. Underlying causes or comorbid conditions should then be treated using chemotherapy or radiation therapy; therapeutic procedures for cardiac, pleural, or abdominal fluid;29–31 bronchoscopic therapy; or bronchodilators, diuretics, steroids, antibiotics, transfusions, or anticoagulants for pulmonary emboli.
Both pharmacologic and nonpharmacologic interventions have been investigated in the management of dyspnea. A recent review concluded that little definitive data evaluating the effectiveness of dyspnea interventions exist and that randomized controlled trials are needed.32 Other reviews have determined that there are sufficient data to make treatment recommendations.30,33 Pharmacologic interventions may include opioids with or without benzodiazepines.30,34–39 Benzodiazepines can be tried for treatment of dyspnea if it is associated with anxiety; the beneficial effect of benzodiazepines on dyspnea in patients with advanced cancer is small.39
Of the opioids, morphine has undergone the most extensive investigation for treating dyspnea in patients with cancer, but recent studies have also looked at opioids such as fentanyl and oxycodone. A single-institution trial of nebulized fentanyl in patients with cancer with dyspnea showed improved oxygenation and reduced tachypnea, and 79% of patients said it improved their breathing.40 An attempted randomized, placebo-controlled trial at the same institution was not successful, because the practice had already diffused widely, with more than 1000 doses being prescribed.41
Multiple case reports show promising data about fentanyl, but further research is needed.42 In a small, randomized controlled trial, prophylactic subcutaneous fentanyl was effective for improving dyspnea and fatigue at rest and after a 6-minute walk test.43 A study revealed that nebulized fentanyl reduced intensity and unpleasantness of dyspnea in patients with chronic obstructive pulmonary disease (COPD).44 Nebulized fentanyl has not yet been studied in patients with cancer, but it can be considered in patients who do not respond well to the other interventions in these guidelines. Additionally, an observational study of 136 patients with terminal cancer also suggested that continuous infusion of subcutaneous oxycodone may provide relief of dyspnea in addition to relief of pain.45 For patients receiving chronic opioids, the panel recommends consideration of a 25% dose increase to manage dyspnea.
Scopolamine, atropine, hyoscyamine, and glycopyrrolate are options to reduce excessive secretions associated with dyspnea.46–50 Glycopyrrolate does not effectively cross the blood brain barrier and is less likely than the other drug options to cause delirium, but this agent can produce anticholinergic side effects.51–53 Scopolamine can be administered subcutaneously or transdermally; physicians should be aware that the onset of benefit for transdermal scopolamine patches is about 12 hours,54 and they are thus not an appropriate choice for imminently dying patients. A subcutaneous injection of scopolamine can be administered when the patch is applied or if management of secretions is inadequate.
Nonpharmacologic interventions include the use of handheld fans directed at the face, supplemental oxygen, and mechanical ventilation. A randomized, controlled, crossover trial demonstrated that breathlessness was reduced in patients when they directed a handheld fan toward their faces.55 Another randomized controlled trial examined the effects of room air versus palliative oxygen delivered via nasal cannula in patients with refractory dyspnea. Dyspnea scores were no different among patients receiving palliative oxygen versus room air, encouraging the use of less burdensome interventions.56 In a recent feasibility study of 200 patients with solid tumors randomized to receive either noninvasive positive-pressure ventilation (biphasic positive airway pressure, BiPAP) or oxygen therapy, patients in the ventilation group had greater improvements in dyspnea symptoms and required lower doses of opiates than patients in the oxygen group.57 However, a smaller phase II randomized trial comparing high-flow oxygen to BiPAP for persistent dyspnea in patients with advanced cancer revealed no significant differences between the two approaches.58
A time-limited trial of mechanical ventilation, as clinically indicated, and/or oxygen therapy for hypoxia may be beneficial. High-flow nasal oxygen and BiPAP may temporarily improve hypoxemia, but these are never available outside the hospital setting. As life expectancy decreases, the role of mechanical ventilation and oxygen diminishes and the role of opioids, benzodiazepines, glycopyrrolate, and scopolamine increases. If fluid overload is a contributing factor, enteral and parenteral fluids should be decreased or discontinued, and low-dose diuretics can be considered.
Anorexia/Cachexia Cachexia is physical wasting with loss of skeletal and visceral muscle mass and is very common among patients with cancer.59,60 Many patients with cancer lose the desire to eat (anorexia), which contributes to cachexia. Cachexia can also occur independently from anorexia, as proinflammatory cytokines and tumor-derived factors directly lead to muscle proteolysis.59,60 Cachexia leads to asthenia (weakness), hypoalbuminemia, emaciation, immune system impairment, metabolic dysfunction, and autonomic failure. Cancer-related cachexia has also been associated with failure of anticancer treatment, increased treatment toxicity, delayed treatment initiation, early treatment termination, shorter survival, and psychosocial distress.59–61 A recent study that examined cancer cachexia in a cohort of 1473 patients across all weight ranges showed that muscle depletion conveys a similarly poor prognosis as involuntary weight loss, regardless of body mass index.62
Reversible causes of anorexia, such as oropharyngeal candidiasis and depression, should be addressed. Treatment includes the relief of symptoms that interfere with food intake (eg, pain, constipation, nausea/vomiting), as well as metoclopramide for early satiety.30,33
For patients with months-to-weeks or weeks-to-days life expectancy, consider the use of appetite stimulants (eg, megestrol acetate, dexamethasone, olanzapine) if increased appetite is an important aspect of quality of life.63–67 A recent systematic review and meta-analysis of megestrol acetate revealed improved appetite and slight improvements in weight gain when using this drug to treat anorexia/cachexia in patients with cancer.64 Although 1 of 4 patients treated with megestrol acetate will have an increase in appetite and 1 of 12 will have an increase in weight, clinicians need to know that 1 of 6 will develop thromboembolic phenomena and 1 of 23 will die.64
A combination therapy approach may yield the best possible outcomes for patients with cancer cachexia. A randomized phase III trial in 332 patients with cancer-related anorexia/cachexia revealed superior outcomes for patients receiving a combination regimen that included medroxyprogesterone, megestrol acetate, eicosapentaenoic acid and L-carnitine supplementation, and thalidomide, versus therapy with any of the previously discussed single agents.68 Another phase III trial of 104 patients with advanced gynecologic cancers and cachexia supported the merits of combination therapy; compared with megestrol acetate alone, patients receiving megestrol acetate plus L-carnitine, celecoxib, and antioxidants had improved lean body mass, appetite, and quality of life.69
Although cannabinoid-based interventions (eg, dronabinol, cannabis) have some demonstrated efficacy for treating chemotherapy-induced nausea and vomiting and AIDS-related anorexia, the data to support cannabinoid-based interventions for treating anorexia/cachexia in patients with cancer are very limited.70 A randomized clinical trial of cannabis extract and delta-9-tetrahydrocannabinol in patients with cancer-related anorexia-cachexia syndrome did not demonstrate a benefit of these agents over placebo on appetite and quality of life.71 Another randomized trial comparing megestrol acetate to dronabinol in treating cancer-associated anorexia revealed megestrol acetate to be superior for promoting weight gain (75% vs 49% of patients) and appetite (11% vs 3%) in patients with advanced cancer.72 However, to a lesser extent, dronabinol did improve appetite and weight gain in some study patients. Ultimately, for some patients with cancer-related anorexia, cannabinoids could be helpful. However, it is important to note that cannabinoid administration in elderly patients may induce delirium, and providers should be aware of the local state rules and regulations regarding medicinal cannabinoid use.
Nutrition consultation should also be considered, because calorie-dense, high-protein supplementation has demonstrated some efficacy for weight stabilization,30,59,73–75 although some studies show nutritional interventions to be ineffective.76 A meta-analysis found that although nutritional intervention does not significantly affect weight gain or energy intake, it can improve some aspects of quality of life, including emotional functioning, dyspnea, and hunger.77 Nutritional support, including enteral and parenteral feeding as appropriate, should also be considered when the disease or treatment affects the ability to eat and/or absorb nutrients and the patient's life expectancy is months to years.78 The goals and intensity of nutritional support change as life expectancy is reduced to weeks to days. Overly aggressive enteral or parenteral nutrition therapies can actually increase the suffering of dying patients.78–81 In addition, a recent randomized controlled trial of patients with cancer enrolled in hospice found that parenteral hydration had no effect on dehydration symptoms such as fatigue and hallucination and had no effect on quality of life or survival.82 Therefore, instead of artificial hydration and nutrition, palliative care in the final weeks of life focuses on treating dry mouth and thirst, and providing education and support to the patient and family regarding the emotional aspects of withdrawal of nutritional support. Family members should be informed of alternate ways to care for dying patients.
Nausea and Vomiting: Chemotherapy-induced nausea and vomiting has a major impact on a patient's quality of life.83 Nausea and vomiting induced by chemotherapy or radiation therapy should be managed as outlined in the NCCN Guidelines for Antiemesis. Patients can also experience nausea and vomiting unrelated to chemotherapy and radiation, resulting from gastric outlet obstruction, bowel obstruction, constipation, opioid use, or hypercalcemia.84 These causes should be identified and treated. Proton pump inhibitors and histamine-2 (H2) receptor antagonists can be used to manage gastritis or gastroesophageal reflux. Gastric outlet obstruction may benefit from treatment with corticosteroids; alternative treatment options include endoscopic stenting or insertion of a decompressing G-tube. Many medications can also cause nausea and vomiting, and blood levels of possible culprits, such as digoxin, phenytoin, carbamazepine, and tricyclic antidepressants, should be checked.85,86
Nonspecific nausea and vomiting can be managed with dopamine receptor antagonists (eg, prochlorperazine, haloperidol, metoclopramide, olanzapine) or benzodiazepines (anxiety-related nausea). Persistent nausea and vomiting can be treated by titrating dopamine receptor antagonists to maximum benefit and tolerance.87–91 For persistent nausea, adding 5-HT3 (5-hydroxytryptamine 3) receptor antagonists92,93 and/or anticholinergic agents and/or antihistamines,94 corticosteroids,94,95 continuous or subcutaneous infusion of antiemetics, antipsychotics (eg, olanzapine or haloperidol),96 and/or cannabinoids can also be considered.97 Opioid rotation may also help alleviate symptoms.98 Agents that target the cannabinoid system may offer some efficacy in treating refractory chemotherapy-induced nausea and vomiting.99 Dronabinol and nabilone are 2 cannabinoid agents approved for treating chemotherapy-induced nausea and vomiting that are refractory to standard antiemetic therapies. Alternative therapies (eg, acupuncture, hypnosis, cognitive behavioral therapy) can also be considered.100–102 Palliative sedation (see subsequent section) can be considered as a last resort if intensified efforts by specialized palliative care or hospice services fail.
A systematic review assessed the level of evidence for antiemesis unrelated to chemotherapy.103 Although the authors concluded that antiemetic recommendations have moderate to weak evidence at best, the strongest evidence supports the use of metoclopramide; studies of multidrug combination therapies do not support their effectiveness.
Constipation: Constipation occurs in approximately 50% of patients with advanced cancer and most patients treated with opioids.104 Although several drugs, including antacids, anticholinergic drugs (antidepressants, antispasmodics, phenothiazines, and haloperidol), and antiemetics are known to cause constipation,105 opioid analgesics are most commonly associated with constipation. Providers should discontinue any nonessential constipating medications. In addition to physical discomfort, constipation in patients with advanced cancer can cause psychological distress and anxiety regarding continued opioid use.106 Opioid-induced constipation should be anticipated and treated prophylactically with a stimulating laxative to increase bowel motility with or without stool softeners.107 Although little evidence exists on which is the best initial bowel regimen in patients with cancer,108 one small study compared the use of senna alone versus a senna-docusate combination. The results demonstrated that the addition of the stool softener docusate was not necessary.109 Increasing intake of fluid and physical activity should also be encouraged, when appropriate. Added dietary fiber may be considered for patients with adequate fluid intake.
If constipation is present, the cause and severity must be assessed. Impaction, obstruction, and other treatable causes, such as hypercalcemia, hypokalemia, hypothyroidism, and diabetes mellitus, should be assessed and treated. Constipation may also be treated by adding bisacodyl 10 to 15 mg, 2 to 3 times daily with a goal of 1 nonforced bowel movement every 1 to 2 days. If impaction is observed, glycerine suppositories may be administered or manual disimpaction may be performed. If constipation persists, adding other laxatives may be considered, such as rectal bisacodyl once daily or oral polyethylene glycol, lactulose, magnesium hydroxide, or magnesium citrate.108 If gastroparesis is suspected, the addition of a prokinetic agent, such as metoclopramide, may be considered.
Peripherally acting μ-opioid receptor antagonists may help to relieve opioid-induced constipation (OIC) while maintaining pain management. Recent studies have shown that methylnaltrexone provided effective relief of OIC while preserving opioid-mediated analgesia.110,111 Naloxegol, a similar peripherally-acting μ-opioid receptor antagonist, has also been studied for treating OIC in patients receiving chronic opioids for noncancer pain.112,113 Gastrointestinal specialists have reported some success using erythromycin for constipation symptoms that do not respond to peripherally acting μ-opioid receptor antagonists such as methylnaltrexone.
Several newer agents have also been examined for treating constipation. Lubiprostone is an orally active prostaglandin analog that activates select chloride channels to enhance intestinal fluid secretion.114,115 This agent was shown to be effective for treating OIC in patients with chronic noncancer pain. Lubiprostone could be used in combination with a peripherally acting μ-opioid receptor antagonist such as methylnaltrexone. Linaclotide is a selective agonist of guanylate cyclase-C receptors in the intestines to enhance intestinal secretions and has been effective in the treatment of constipation associated with irritable bowel syndrome and chronic idiopathic constipation.116,117 The American Gastroenterological Association includes lubiprostone and linaclotide as recommended options for treating constipation associated with irritable bowel disorder.118
Based on these results, the NCCN Palliative Care Panel recommends considering 0.15 mg per kilogram of body weight of methylnaltrexone every other day (no more than once/day) for patients experiencing constipation that has not responded to standard laxative therapy. Methylnaltrexone should not be used in patients with a postoperative ileus or mechanical bowel obstruction.
Diarrhea: In patients with cancer, diarrhea can be caused by a number of potential factors, including anticancer treatment-related side effects, infection, antibiotic use, dietary changes, or fecal impaction.119 Diarrhea is a common side effect of various chemotherapeutics (eg, fluorouracil and irinotecan),120,121 as well tyrosine kinase inhibitors and certain biologic agents (eg, ipilimumab, cetuximab, panitumumab).122 Abdominal and pelvic radiation therapy (alone or as part of chemoradiation regimens) can also induce gastrointestinal toxicity resulting in diarrhea.120
The National Cancer Institute Common Toxicity Criteria are typically used for measuring diarrhea in this patient population.119 The panel recommends that patients be screened to determine the grade of diarrhea. Providers should provide immediate intervention for dehydration based on grade and assess for potential cause(s).
For patients with years, years to months, or months to weeks of estimated life expectancy who have grade 1 or 2 diarrhea, recommendations include hydration and electrolyte replacement (oral or intravenous fluids as appropriate), antidiarrheal medications, and a bland/BRAT (bread, rice, applesauce, toast) diet. For treating grade 2 diarrhea, anticholinergic agents such as hyoscyamine or atropine can be considered. Infection-induced diarrhea should be treated with the appropriate antibiotic. If diarrhea persists, the use of low doses of morphine concentrate can be considered and would be more cost effective than tincture of opium. Patients with persistent grade 2 or grades 3 or 4 diarrhea should receive inpatient treatment. In addition to fluid replacement, antidiarrheal therapy, and anticholinergics, octreotide can also be considered.
For patients with weeks to days of estimated life expectancy, the previously discussed interventions can be considered consistent with the goals of care. At-home intravenous hydration may be considered in addition to scopolamine or hyoscyamine. If diarrhea persists, consider octreotide or glycopyrrolate. Patients should begin around-the-clock opioids or receive an increased dose of ongoing opioid regimens.
Malignant Bowel Obstruction: Malignant bowel obstructions are usually diagnosed clinically and confirmed with radiography. For patients with years to months to live, surgery after CT scan is the primary treatment option. Altthough surgery can lead to improvements in quality of life, surgical risks should be discussed with patients and families. Although surgery is the primary treatment for malignant obstruction, some patients with advanced disease or patients in generally poor condition are not fit for surgery and require alternative management to relieve distressing symptoms. Risk factors for poor surgical outcome include ascites, carcinomatosis, palpable intra-abdominal masses, multiple bowel obstructions, previous abdominal radiation, advanced disease, and poor overall clinical status.123 In these patients, medical management can include pharmacologic measures, parenteral fluids, endoscopic management, and enteral tube drainage (silicone tubing may offer superior comfort over vinyl).
Pharmacologic management of malignant bowel obstruction can be seen as different for 2 groups of patients: those for whom the goal is to maintain gut function and those for whom gut function is no longer possible. When the goal is maintaining gut function, patients can be treated with opioids, antiemetics, and corticosteroids, alone or in combination. When gut function is no longer considered possible, pharmacologic options also include somatostatin analogs (eg, octreotide) and/or anticholinergics.124–129 If octreotide is helpful and the patient has a life expectancy of at least 1 month, it may be beneficial to consider a depot form of octreotide once an optimal dose is established. Antiemetics that increase gastrointestinal mobility such as metoclopramide should not be used in patients with complete obstruction, but may be beneficial when obstruction is partial. Use of octreotide is recommended early in the diagnosis because of its efficacy and tolerability.130,131 Despite positive findings from several smaller randomized trials, a recent phase III trial of octreotide in 86 patients with malignant bowel obstruction failed to demonstrate a significant effect of this drug on days free of vomiting, number of vomiting episodes, symptom management, and other secondary endpoints.132
A venting gastrostomy tube (inserted by interventional radiology, endoscopy, or surgery departments), a percutaneous endoscopic gastrostomy tube, or an endoscopically placed stent can also palliate symptoms of malignant bowel obstruction.133,134 Total parenteral nutrition can be considered to improve quality of life in patients with a life expectancy of years to months. These interventions have been shown to have little positive impact on survival time, but may improve quality of life.7,8
Fatigue/Weakness/Asthenia: The data on methylphenidate for treating cancer-related fatigue have been mixed.135 Although some trials have suggested a dose-dependent benefit of this agent on fatigue symptoms,136,137 other studies have failed to produce positive results.138 Phase III randomized trials of modafinil for treating cancer-related fatigue suggested that modafinil had a modest efficacy and was most effective for those with severe fatigue.139,140 For more information, see the NCCN Guidelines for Cancer-Related Fatigue (available at NCCN.org).
Sleep/Wake Disturbances: Patients with cancer often suffer from insomnia or daytime sedation.141–143 In a recent study of 442 patients with advanced cancer, 330 (75%) patients were noted to have baseline sleep disturbance as assessed using the Edmonton Symptom Assessment System (ESAS) sleep item.144 Patients should first be evaluated for sleep/wake disturbances using, for example, the Epworth Sleepiness Scale.145 If patients have a history of sleep-disordered breathing (eg, excessive snoring, gasping for air, observed apneas, frequent arousals, sudden involuntary movement of arm or legs during sleep, unexplained daytime drowsiness), polysomnography should be considered. Polysomnography should also be considered for patients with head and neck cancers, because obstructive sleep apnea (OSA) is prevalent in patients with this disease.146,147 Primary sleep disorders, such as OSA and periodic limb movement disorder, should be treated with continuous positive airway pressure (CPAP) or BiPAP.148 Restless leg syndrome, if present, can be treated with ropinirole, pramipexole with pregabalin, or carbidopa-levodopa.149–157 Fears and anxiety regarding death and disease should be explored, and other contributing factors to sleep/wake disturbances should be treated, including pain, depression, anxiety, delirium, and nausea. Cognitive behavioral therapy may be effective in treating sleep/wake disturbances in patients with cancer.33,158–162
For refractory insomnia, pharmacologic management includes the short-acting benzodiazepine lorazepam, the nonbenzodiazepine zolpidem, antipsychotic medications such as chlorpromazine, quetiapine, and olanzapine, and sedating antidepressants such as trazodone and mirtazapine.163 The panel suggests that mirtazapine may be especially effective in patients with depression and anorexia. Benzodiazepines should be avoided in older patients and in patients with cognitive impairment, because they have been shown to cause decreased cognitive performance.164 Caution should be exercised when administering zolpidem due to the known risk of next-morning impairment. In 2013, the US FDA required lower recommended doses of zolpidem (ie, from 10 to 5 mg for immediate-release products and from 12.5 to 6.25 mg for extended-release formulations).165
For refractory daytime sedation, the guidelines suggest several options. The central nervous system stimulants methylphenidate or dextroamphetamine should be given with a starting dose of 2.5 to 5 mg orally with breakfast. If the effect of the drug does not last through lunch, a second dose can be given at lunch, preferably no later than 2:00 pm. Doses can be escalated as needed.166 Another option for refractory daytime sedation is the psychostimulant modafinil, which has been approved in adults for excessive sleepiness associated with OSA/hypopnea syndrome (OSAHS), shift work sleep disorder, and narcolepsy.167 The panel also recommends caffeine and dextroamphetamine as additional options for refractory daytime sedation. The last dose of caffeine should be given no later than 4:00 pm.
Dying patients should be assessed for their desire to have their insomnia or sedation treated. The doses of their pharmacologic therapies can be adjusted as appropriate. The addition of an antipsychotic drug (chlorpromazine or quetiapine) can be considered in patients whose insomnia is refractory.
Please also see the NCCN Guidelines for Adult Cancer Pain and the NCCN Guidelines for Cancer-Related Fatigue for their discussions on sleep/wake disturbances (available at NCCN.org).
Delirium: Delirium should be assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.168 Reversible causes should be identified and treated appropriately.169 Delirium may present as either a hypoactive or a hyperactive subtype.170 Recent studies have suggested that hypoactive delirium was the most prevalent subtype in patients under palliative care and that this condition is often underdiagnosed due to its presentation.171,172
Two comprehensive reviews describe the evidence base for recommended pharmacologic and nonpharmacologic treatments for delirium in patients with cancer.33,173 Nonpharmacologic interventions (eg, reorientation, cognitive stimulation, sleep hygiene) should be maximized before pharmacologic interventions are used. Delirium-inducing medications (ie, steroids, anticholinergics) should be reduced or eliminated as much as possible.174 Benzodiazepines should not be used as initial treatment for delirium in patients not already taking them.
The symptoms of moderate delirium can be managed with oral haloperidol, risperidone, olanzapine, or quetiapine fumarate.175–177 The symptoms of severe delirium (ie, agitation) should be managed with antipsychotic, neuroleptic drugs such as haloperidol, olanzapine, or chlorpromazine.178 Because of its hypotensive side effect, intravenous chlorpromazine should only be used in bed-bound patients. A benzodiazepine, such as lorazepam, may be added for agitation that is refractory to high doses of neuroleptics.179 The presence of therapeutic levels of neuroleptics usually prevents the paradoxic excitation sometimes seen when delirious patients are given lorazepam. The dosages of these symptom-management medications should be titrated to optimal relief. Opioid dose reduction or rotation can also be considered for patients with severe delirium. Caregivers should be supported in caring for their loved one and coping with this distressing condition.
Delirium in patients with advanced cancer and limited life expectancy may shorten prognosis.180 In these patients, iatrogenic causes should be eliminated whenever possible. Opioid rotation can be considered (see NCCN Guidelines for Adult Cancer Pain) if the delirium is believed to be caused by neurotoxicity of the current opioid. If delirium is a result of disease progression, palliative care must be focused on symptom management and family support. Neuroleptic and benzodiazepine medications should have their dose increased and/or their route of administration changed to ensure adequate delirium symptom management.181 Unnecessary medications and tubes should be removed. For refractory delirium in dying patients, palliative sedation can be considered after consultation with a palliative care specialist and/or psychiatrist. Please also see the NCCN Guidelines for Distress Management (available at NCCN.org) for further discussion of delirium in patients with cancer.
Conclusions
These guidelines are intended to help oncology teams provide the best care possible for patients with incurable cancer. Patients with advanced disease frequently are overly optimistic about their chances of cure, treatment response, symptom relief, and survival. One study found that those who overestimated their survival were more likely to die a bad death.182 Using a decision aid, Smith et al183 found that most patients want honest information, even if it is bad news. Although use of the decision aid typically took 20 minutes and was challenging for oncologists, it did not cause patients to give up hope or become distressed. Physician-led discussion of disease progression and death can improve quality of care and quality of life for both patients and families.184 Providing information in a collaborative manner protects the autonomy of patients to make informed decisions based on potential treatment outcomes.185 Palliative care can help patients and families set realistic expectations and meet short- and longer-term goals, such as important life-cycle events. Much of the care outlined in these guidelines is geared toward a different hope than that for cure of the disease itself.183,186,187 Even when cure is no longer possible, hope remains: hope for dignity, comfort, and closure and for growth at the end of life. It is our hope that these guidelines will help oncology and palliative care professionals together create a better future for patients, families, and providers.
Individual Disclosures of the NCCN Palliative Care Panel
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