Palliative care and pain management

Cardinale B. Smith, MD, MSCR

Overview

Palliative care is an essential component of comprehensive cancer care. Palliative care is given concurrently with other disease–modifying, life–prolonging, and curative therapy. Palliative medicine specialists focus on helping patients and their families with a variety of care needs including symptom control, psychosocial support, physician–patient communication, addressing care goals in relation to the patient’s condition, prognosis, values, and preferences, as well as with transitions in care. Cancer patients often experience significant symptom distress either from the illness itself or from the associated treatments. The beneficial effects of palliative care have been well documented. When integrated into early oncologic care, palliative care is associated with a significant improvement in quality of life, depression, and survival. As such, palliative care should be given throughout the trajectory of cancer care whether during early stage disease in which the focus is on cure or in more advanced disease when the focus is on maximizing quality of life. Currently, national and international organizations have clinical guidelines that recommend palliative care be routinely integrated into comprehensive cancer care.

Palliative care

Palliative care is medical care focused on the relief of suffering and support for the best possible quality of life for patients and their families facing serious, life-threatening illness.¹ It aims to identify and address the physical, psychological, and practical burdens of illness and is provided as an extra layer of support for seriously ill patients. Palliative care is delivered simultaneously with all appropriate curative and life-prolonging interventions. Palliative care specialists provide assessment and treatment of pain and other symptoms; employ communication skills with patients, families, and colleagues; support complex medical decision making and goal setting based on identifying and respecting patient wishes and goals; promote medically informed care coordination, continuity, and practical support for patients, family caregivers, and professional colleagues across health care settings and through the trajectory of an illness. Palliative care in cancer patients should begin at the time of diagnosis. The emphasis of care will vary over the course of illness, with anticancer therapy provided concomitantly with supportive care and symptom management.

Several randomized studies have demonstrated a benefit of incorporating early palliative care into standard oncologic care.^{2, 3} In these studies, palliative care has been shown to improve mood, quality of life, and potentially survival among patients with advanced cancer. As such, oncology guidelines now recommend the routine integration of palliative care into routine oncologic care. In 2012, the American Society for Clinical Oncology (ASCO) issued a provisional opinion recommending incorporation of palliative care “for any patient with metastatic cancer and/or high symptom burden.”⁴ In 2013, The Institute of Medicine’s report, Delivering High-Quality Cancer Care, recommended that cancer care teams “place primary emphasis on palliative care, psychosocial support and timely referral to hospice for end of life care.”⁵

There are several core components involved in providing quality palliative care for oncology patients. These include the following:

Whole patient assessment
Effective communication
Advanced care planning
Symptom management
Care at the end of life
Grief and bereavement support

Whole patient assessment

The whole patient assessment is guided by the National Comprehensive Cancer Network (NCCN) guidelines and core elements of palliative care as detailed in the National Quality Forum and involves evaluating all aspects of the impact of cancer and its treatments on the patient and family.⁶ In addition to routine medical history, patient assessment explores the patients’ social and community support, impact of the cancer diagnosis and treatment on patients’ quality of life, spiritual and social well-being, as well as patients’ expectations of therapy and goals of care. The whole patient assessment improves patient–physician communication and assists the physician in understanding potential barriers to patient adherence with treatment plans. This assessment is optimized by utilization of the interdisciplinary team to attend to all medical and psychosocial aspects of diagnosis, treatment, and to assist with patient and family distress.

Communication

Effective communication is an important component of the oncologist–patient relationship and assists in providing the highest quality cancer care. In an ASCO survey conducted in 1998, approximately 60% of respondents indicated that they broke bad news to patients from 5 to 20 times per month. Despite these challenges, <10% of respondents received formal training in breaking bad news.⁷ Similarly, in a survey conducted at the 2004 ASCO meeting, oncology fellows reported being more likely to have observation and feedback on bone marrow biopsies than on goals of care discussions.⁸ This lack of training can have a negative impact on cancer patients and providers. Poor communication skills have been associated with decreased patient participation in decision making,⁹ missed opportunities to respond empathically to patient concerns, ignored patient wishes to discuss health-related quality of life issues, and an increased likelihood of receiving anticancer treatment at the end of life.¹⁰ Alternatively, effective communication has been shown to influence desirable outcomes such as patient satisfaction, adherence with treatments, decreased patient distress, and reduces physician burnout.^{11, 12}

There are existing protocols to help deliver bad news and address goals of care (Table 1).^{13, 14} These protocols can be applied to most situations including a new diagnosis of cancer, cancer recurrence, progression of disease, and transition to hospice. This communication process attempts to achieve four main goals: gathering information from the patient to elicit readiness to hear the news; providing information in accordance with the patient’s needs and desires; reducing the emotional impact and isolation experienced by the recipient of the bad news; and developing a treatment plan that aligns with patient preferences. When communicating with patients and families, it is important to use open-ended questions such as “What are your hopes and fears?” and “What is important in your life?”¹⁴ It is important to avoid language with unintended consequences such as “There is nothing more we can do for you” and “Do you want everything done for you?”¹⁴ Instead, try saying “We will do everything to give you the best quality of life” or “We will manage your symptoms very aggressively.” Additionally, it is important to avoid jargon or euphemisms, and instead use plain, simple language. Once the goals of care are established, it becomes much easier to construct a plan of care centered on those preferences. There are currently training programs that are offered to train oncologists in these specific skills, a list if available resources can be found in Table 2.

Table 1 Protocol for breaking bad news and addressing goals of care

Recommendation	Comments
Create the proper setting	Prior to the meeting determine the most appropriate participants (family members and other health care providers) Allow adequate time Determine what to say prior to the meeting
Clarify what the patient and family already know	“What have you been told about your medical situation so far?” This allows you to correct any misinformation and tailor the conversation based on their prior knowledge
Explore hopes and expectations of patient and family	Allows you to distinguish between attainable and unattainable goals
Suggest realistic goals	Suggest attainable goals based on the present clinical scenario and how they can best be achieved Review appropriateness of disease-modifying treatments Try to explain using simple language why unrealistic goals cannot be met
Use empathic responses	Very important to allow silence and to listen Let patient and family express emotions Once emotions are expressed use a connector such as “I can see how upsetting this is to you”
Make a plan and follow through	Summarize the plan to ensure that your interpretation of the conversation and decisions is in concordance with patient and family and how the plan of care will meet their goals Make a plan for continued follow-up Inform the patient and family how to contact you if they have further questions or concerns Continue to review and revise the plan as needed

Source: Data from Refs [13] and [14].

Table 2 Palliative care Internet resources

www.capc.org: Center to Advance Palliative Care: Educational-based content to learn primary palliative care skills. Technical assistance for clinicians and hospitals seeking to establish or strengthen a palliative care program
www.vitaltalk.org: Website to help providers learn communication skills
www.epeconline.net: Education on Palliative and End of Life Care (EPEC): Comprehensive curriculum covering fundamentals of palliative medicine; free downloadable power point and teaching guides
www.palliativedrugs.com: Extensive information on pharmacologic symptom management
www.aahpm.org: American Academy of Hospice and Palliative Medicine: Physician membership organization; board review courses, publications
www.hms.harvard.edu/cdi/pallcare: Center for Palliative Care at Harvard Medical School: Faculty development courses, other educational programs
www.nationalconsensusproject.org: National Consensus Project for Quality Palliative Care: Clinical practice guidelines
http://endoflife.stanford.edu/: Joint project of the US Veterans Administration and SUMMIT, Stanford University Medical School. Curriculum covering fundamentals of palliative medicine

Advance care planning

Once the patients’ goals of care are established, they should be documented in the form of advance directives. Advance directives consist of two main components: the health care proxy or durable power of attorney for health care and treatment directives.¹⁵ A commonly used comprehensive advance directive is the medical orders for life-sustaining treatment (MOLST) or physician orders for life-sustaining treatment (POLST) and is currently in use or under development in over 40 states.¹⁶ POLST is appropriate for people with cancer and a prognosis measured in 1–2 years. It specifically addresses medical decisions and options that are likely to arise in the near future, including cardiopulmonary resuscitation, antibiotics for infections, artificial food and fluids, and whether or not the patient would want to be re-hospitalized. Additionally, it can be transported across care settings. POLST appears to be associated with better receipt of medical care reflecting patient treatment preferences (decreased hospitalization and life-sustaining treatments) when compared to traditional practices, improved surrogate understanding of patient goals and preferences and an improved prevalence, clarity, and specificity of preferences documented.^17–19 It is important for every cancer patient to have advance directives to help avoid confusion and conflict, to prepare for future medical care, and to ensure that patients’ wishes will be followed.

Symptom management

Patients with cancer experience many physical and psychosocial symptoms either as a consequence of therapy or as a result of the disease itself. The essential components of symptom management include (1) routine and repeated formal assessment, (2) expertise in prescribing medications, including the safe use of opioid analgesics, adjuvant approaches to pain management, and management of a wide range of other common and distressing symptoms and syndromes, and (3) skillful management of treatment side effects. Currently, there is no gold standard for symptom assessment in palliative care. Although several tools exist, the most commonly used is the Edmonton Symptom Assessment System, which consists of nine visual analog scales or numerical rating scales that evaluate a combination of the most common physical and psychological symptoms.²⁰ The most common symptom experienced by cancer patients is pain.²¹ The most frequent nonpain symptoms are constipation, nausea and vomiting, anorexia/cachexia, dyspnea, delirium, and anxiety.²¹ The management of some of these symptoms will be discussed in the following sections.

Pain

The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”²² Although the cause of the pain and the type of injury vary, the constellation of complex neurophysiologic phenomena of pain includes two broad categories, nociceptive pain, which include both somatic and visceral pain, and neuropathic pain.²³ Somatic pain is characterized as well localized, intermittent, or constant and is described as aching, gnawing, throbbing, or cramping (e.g., bone metastases). Visceral pain is mediated by discrete nociceptors in the cardiovascular, respiratory, gastrointestinal (GI), and genitourinary systems. It is usually described as deep, squeezing, or colicky and is commonly referred to cutaneous sites, which may be tender. Neuropathic pain is clinically described as a burning, tingling, or numb sensation with paroxysms of shock-like pain. Cancer history should include description of the pain complaint, including the patient’s description of pain and intensity; its quality, exacerbating, relieving factors, and its radiation if any; its exact onset and temporal pattern. Impact of pain on the activities of daily living, sleep, mood, and affect should be assessed.

The guiding principles of a therapeutic strategy for cancer pain should include (1) detailed assessment of the patient’s pain, (2) making a pain diagnosis, (3) understanding the goals of care and the patient’s preferences, (4) developing and implementing the best therapeutic and diagnostic strategy, (5) continual reassessment of the degree of pain and analgesia, and (6) expertise to provide alternative therapeutic strategies. Of greatest importance, no patient should be inadequately evaluated because of patient’s experiencing “too much pain.” A series of algorithms have been developed for the management of cancer pain.^{24, 25} The World Health Organization Cancer Pain and Palliative Care Program advocates a three-step approach, which advocates starting with nonopioid analgesia [e.g., nonsteroidal, anti-inflammatory drugs (NSAIDs)] and then titrating up to low- then high-potency opioids.²³ Similarly, NCCN pain management guidelines provide an algorithm of a stepwise approach to the treatment of mild, moderate, and severe pain and strategy of rapid but safe opioid titration to provide analgesia.²⁶ General guidelines of cancer pain treatment are listed in Table 3. Management of cancer pain can be divided into pharmacologic approaches, interventional approaches, and psychological management.

Table 3 Guidelines for the use of analgesic drugs in cancer pain management

Start with a specific drug for a specific type of pain

1. Clarify the patient’s pain, its nature, site, duration, and intensity, and the degree of pain relief from prior nonopioid and opioid drug use
2. Complete a careful medical and neurologic history and examination. Assess the potential role of radiotherapy, surgery, and/or chemotherapy in pain control
3. Assess the psychological factors contributing to the pain complaint and understand the meaning of the pain for the patient
4. Choose the route of administration to fit the needs of the individual patient
1. i. Choose the oral route as the simplest approach
2. ii. Consider the buccal or rectal routes for patients who cannot tolerate oral drugs and refuse parenteral routes. Start intravenous intermittent boluses or continuous infusions in patients requiring rapid escalation of opioids for pain control
3. iii. Use intermittent boluses or continuous subcutaneous infusions for patients without venous access or in patients at home
4. iv. Choose the epidural or intrathecal route in patients who develop limiting side effects from systemic opioids
5. v. Use PCA pumps for selected patients in hospital and at home
5. Know the pharmacology of the available opioid drugs. Titrate the dose to the individual needs of the patient
1. i. Start with a dose that is at least equivalent or slightly greater than the equianalgesic dose of the previous analgesic used
2. ii. Order the medication on a regular basis (oral–every 3–4 h, intravenous–every 15–60 min as needed)
3. iii. Instruct the patient to take the medication on a PRN basis if the patient is opioid naive
4. iv. Order “rescue medication” equivalent to 10% of the standing 24-h dose to begin with on a PRN basis
5. v. Inform the patient of options in taking the medication and request that he or she report side effects of excessive sedation or confusion. Monitor the side effects closely
6. Use a combination of drugs to provide additive analgesia to reduce side effects or to control other symptoms
1. i. Know the various adjuvant drugs that provide additive analgesia, for example, anticonvulsants, corticosteroids
2. ii. Use neurostimulants to reduce sedative effects, for example, caffeine, dextroamphetamine, methylphenidate, modafinil
3. iii. Use antidepressant, anticonvulsant, and other analgesics to manage neuropathic pain
7. Anticipate and treat side effects
1. i. Watch for respiratory depression and use naloxone if needed (in diluted doses to prevent acute withdrawal)
2. ii. Counteract sedation with neurostimulants
3. iii. Use antiemetics to suppress the emetic effect of opioids
4. iv. Define an individualized bowel regimen to prevent and manage constipation
5. v. Treat myoclonus by switching to an alternative analgesic, or suppress it with anxiolytic drugs
8. Watch for the development of tolerance
1. i. Distinguish tolerance from progression of tumor
2. ii. Recognize that there is no limit to tolerance
3. iii. Switch to an alternative opioid if the dose of the current opioid cannot be escalated
4. iv. Consider opioid rotation if one or more intractable side effects are noted

Abbreviations: PCA, patient-controlled analgesia; PRN, pro re nata (according as circumstances may require).

Pharmacological approaches are the most commonly used method for managing cancer pain. The brief outline of pharmacologic approach is detailed in Table 4. The selection of the right analgesic to maximize pain relief and minimize adverse effects begins with the use of nonopioids for mild pain. In patients with moderate pain that is not controlled with nonopioids such as acetaminophen, NSAIDs, and adjuvant medications (WHO step 1), the so-called weak opioid agonists (codeine, hydrocodone, and tramadol) alone or in combination are prescribed (step 2). In patients with severe pain, a strong opioid (morphine, hydromorphone, fentanyl, methadone, oxycodone, oxymorphone, or levorphanol) is the drug of choice (step 3). At all levels, certain NSAIDs and adjuvant drugs may be used for specific indications. A number of opioid analgesics is available for clinical use and are listed in Table 4.

Table 4 Opioid analgesics commonly used for moderate to severe pain narcotic agonists

	Parenteral (mg)	Oral (mg)	Conversion factor (IV to PO)	Comments
Morphine	10	30	1 : 3	Standard of comparison for opioid analgesics; lower dose for aged patients
Hydromorphone	1.5	7.5	1 : 5	Slightly shorter-acting
Fentanyl	25 µg = 1 mg morphine IV	—	—	Short half-life; transdermal and transmucosal preparations available
Codeine	130	200	1 : 1.5	Often used in combination with nonopioid analgesics; biotransformed, part, to morphine
Oxycodone	—	20	–	Also in combination with nonopioid analgesics that limit dose escalation
Oxymorphone	1	10	1 : 10	Not available orally
Methadone^a	—	—	—	—

^a Methadone has a complex pharmacokinetic and pharmacodynamic profile that makes equianalgesic dosing particularly difficult. Consult with an experienced clinician before initiating or adjusting the dose of methadone.

Selection of the opioids should be based on patient’s analgesic history, renal and hepatic function (Table 5), side effects, and severity of pain. Short-acting opioids are usually used for opioid titration and as needed (PRN, pro re nata) for breakthrough pain. After an effective stable 24-h opioid requirement is established, a switch to a long-acting formulation should be considered. Long-acting opioids allow patients to achieve more consistent blood levels, reduce pain recurrence, improve compliance, and reduce the iatrogenic dependence. Rescue medications equivalent to 10% of the standing 24-h dose should also be made available to patients.^{27, 28} Overall, opioid dose, route, and titration schedule should be tailored to the patient’s medical needs, treatment goals, and side-effect profile. There is no minimum or maximum dose. The opioid dose needs to be titrated to maintain the patient’s desired balance between pain relief and opioid-related side effects.

Table 5 Guidelines for opioids in kidney and liver disease

	Kidney disease^a		Liver disease
	Renal failure	Dialysis	Stable cirrhosis	Severe disease
Morphine	Do not use	Do not use Not dialyzed	Caution ↓ dose ↓ frequency^b	Do not use
Oxycodone	Caution ↓ dose ↓ frequency^b	Caution	Caution ↓ dose ↓ frequency^b	Caution ↓ dose ↓ frequency^b
Hydromorphone	Preferred ↓ dose ↓ frequency^b	Preferred Not dialyzed, but minimal toxicity	Caution ↓ dose ↓ frequency^b	Caution ↓ dose ↓ frequency^b
Fentanyl	Preferred	Preferred Not dialyzed, but minimal toxicity	Preferred	Preferred
Codeine	Do not use	Do not use	Do not use	Do not use
Methadone^c	Preferred—with consultation only	Preferred—with consultation only. Not dialyzed, but minimal toxicity	Preferred—with consultation only	Preferred—with consultation only

^a Avoid sustained release oral opioids and fentanyl patches in kidney disease. Note that even the “safest” opioids are not dialyzable.

^b ↓ dose means reduce dose by 25–50%. ↓ frequency means reduce standing orders for short-acting opioids from q4h to q6h.

^c Consult with an experienced clinician before initiating or adjusting the dose of methadone.

Interventional approaches can be divided into six major types: (1) trigger-point injections, (2) peripheral nerve blocks, (3) autonomic nerve blocks, (4) epidural and intrathecal infusions, (5) surgical approaches, and (6) neurostimulatory approaches. The techniques for each of these procedures are outside the scope of this chapter, but have been described in detail elsewhere.²⁹

Psychological management of cancer pain includes the use of psychotherapeutic, cognitive-behavioral, and psychopharmacologic interventions. These techniques are most useful in three clinical situations: (1) in the management of patients with intermittent predictable pain (such as pain associated with procedures), (2) in the management of incident pain (e.g., in the patient with pain on movement), and (3) in the management of chronic cancer pain.^{30, 31}

Constipation

Constipation is defined as the infrequent and difficult passage of hard stool. It is a common cause of morbidity in the palliative care setting and affects more than 95% of patients who are treated with opioids for cancer-related pain.¹⁵ The two most common etiologies are related to the side effects of opioids and the effects of progressive disease. Severe constipation can lead to bowel obstruction and perforation and can be a cause of severe morbidity. In patients who are neutropenic, severe constipation can lead to bacterial transfer across the colon, resulting in bacteremia and potentially sepsis. The Rome criteria defines constipation as the presence of two or more of the following symptoms³²:

Straining at least 25% of the time
Hard stools at least 25% of the time
Incomplete evacuation at least 25% of the time
≤2 bowel movements per week.

Assessment of constipation should involve a history of the patient’s bowel pattern, fluid intake, recent dietary changes, review of current medications, and a thorough physical examination, including a rectal exam—with caution in patients with neutropenia. In addition, abdominal radiography can be performed to look for the presence of stool if the diagnosis remains unclear.

Constipation can be managed with nonpharmacologic measures as well as pharmacologic interventions. Nonpharmacologic measures include increasing fluid intake if possible and regular toileting as colonic activity is highest early in the morning, after walking, and 30 min after meals. Pharmacologic interventions for the management of constipation may be administered orally or rectally and are summarized in Table 6. There is no single correct management approach to laxative prescribing. Initial regimens often include a stimulant, such as senna, given once or twice per day and titrated according to response. Stool-softening agents, such as docusate, are commonly prescribed, but they have not been shown to be efficacious in this setting.³³ Whichever bowel regimen is initiated should be individualized and titrated to response. It is important to note that the best treatment of constipation is prevention. A prophylactic bowel regimen should be initiated at the time opioids are initially prescribed and should be continued for as long as the patient remains on opioids.

Table 6 Laxatives commonly used to treat constipation

Class of drug	Preparation	Starting dose	Mechanism of action	Comments
Oral
Lubricant	Mineral oil	5–10 mL/day	Lubricates stool surface, allows easier passage	Adverse effects include lipoid pneumonia, leakage of oily fecal material. 255 paraffin and magnesium hydroxide considered safest
Bulk-forming agents	Methycellulose, bran, psyllium	Bran 8 g daily Others 3–4 g daily	Increases stool bulk, stimulating peristalsis	Good for mild constipation. Caution as needs to be taken with at least 200–300 mL of water. May precipitate obstruction in a debilitated patient by forming a viscous mass
				May cause flatulence and bloating
Osmotic (poorly absorbed sugars)	Lactulose	15–30 mL daily	Retention of water in the lumen via osmotic effects	Sweet taste that may not be well tolerated. Bloating, abdominal cramping, and flatulence are common
Saline	Magnesium hydroxide Sodium bisphosphonate	2.4–4.8 g daily	High osmolarity compounds causes retention of water in the lumen throughout the entire gut. Directly stimulates peristalsis	Strong cathartic. Mostly used as a bowel prep for endoscopic procedures. May alter fluid and electrolyte imbalance. Caution in patients with heart failure or renal insufficiency
Anthraquinones	Senna	Max 100 mg/day	Direct stimulation of myenteric plexus causing induction of peristalsis	Often combined with docusate. May cause abdominal cramping. Do not use if obstruction is suspected
Polyphenolic	Bisacodyl	10 mg daily	Stimulates secretion and motility of small intestine and colon	May cause abdominal cramping
Rectal
Lubricant	Mineral oil enema	One enema	Used as retention enema to allow evacuation or manual removal of impacted stool	Efficacy is dependent on ability to retain the oil
Osmotic	Glycerin	One suppository	Softens stools via osmosis
Saline	Sodium phosphate	One enema or suppository	Releases bound water from feces. May stimulate rectal or distal colonic peristalsis	May alter fluid and electrolyte balance. Caution in patients with heart failure or renal insufficiency
Polyphenolic	Bisacodyl	10 mg suppository	Promotes colonic peristalsis	Activity depends on bisacodyl reaching the rectal wall
Subcutaneous
Peripheral opioid receptor antagonist	Methylnaltrexone	<38 kg:0.15 mg/kg 38 to <62 kg: 8 mg 62–114 kg: 12 mg >114 kg: 0.15 mg/kg (round up)	Selectively blocks opioid binding at the mu receptor, in the GI tract	Only for opioid-induced constipation

Nausea and vomiting

Nausea and vomiting are reported to affect between 40% and 70% of patients with cancer.³⁴ Nausea and vomiting can cause substantial psychological distress for patients and families and impact overall quality of life.³⁵ Nausea is subjective and is defined as an unpleasant sensation of the need to vomit and can be associated with autonomic symptoms, including pallor, cold sweats, tachycardia, and diarrhea. Vomiting is the forceful discharge of gastric contents via the mouth resulting from the contraction of the abdominal musculature and diaphragm. The pathophysiology of nausea and vomiting is complex and involves four pathways (chemoreceptor trigger zone, cortex, peripheral pathways in the GI tract, and vestibular system), which when stimulated can induce nausea and vomiting.^{36, 37}

The etiology of nausea and vomiting are varied, but it is important to determine the exact cause in order to select targeted and effective treatment. The most common etiologies in patients with cancer are chemotherapy-induced nausea and vomiting (CINV) and opioid-induced, bowel obstruction and constipation. Once the likely etiology of nausea and vomiting is identified, directed therapy can begin. There are guidelines for the prevention and treatment of CINV in patients on antineoplastic therapy.³⁸ The most commonly used approach is based on identifying the etiology and administering the most potent antagonist targeted toward the implicated receptors. This strategy has been shown to be effective in up to 80–90% of patients. Some practitioners recommend starting an empirical antiemetic regimen, typically with a dopamine antagonist, regardless of the presumed etiology.^39–41 No direct comparisons currently exist between mechanism-based and empirical therapy.

Therapy should consist of nonpharmacologic and pharmacologic measures aimed at alleviating the cause of the symptoms. Nonpharmacologic measures include avoiding strong smells or other nausea triggers, eating small, frequent meals, limiting oral intake during periods of extreme emesis,⁴² relaxation techniques,⁴³ acupuncture, and acupressure.⁴⁴ Progressive muscle relaxation and guided mental imagery during periods of chemotherapy have also shown beneficial effects.⁴⁵ The most commonly used antiemetics worldwide are metoclopramide, dexamethasone, haloperidol, hyoscine butylbromide, and cyclizine. Antiemetics are available in the form of pills, orally dissolvable tablets, intravenous infusion, rectal suppositories, and subcutaneous infusions. Thought should be given to selection of the appropriate route of administration of the antiemetic to ensure maximum efficacy. A list of antiemetics, routes of administration, and their properties can be found in Table 7.

Table 7 Antiemetics commonly used to treat nausea and vomiting

Receptor site of action	Drug name	Dosage/route	Adverse effects
Dopamine antagonists (D₂)	Chlorpromazine	10–25 mg PO every 4–6 h, 25–50 mg IM every 3–4 h	Dystonia, akathisia, sedation, and postural hypotension
	Haldol	10–20 mg PO, IV/SQ before meals and at bedtime or every 6 h	Dystonia and akathisia
	Metoclopramide	10–20 mg PO every 6 h, 5–10 mg IV every 6 h or 25 mg rectally every 6 h	Dystonia, akathisia, abdominal cramping in obstruction
	Prochlorperazine	5–10 mg PO every 6–8 h or 25 mg rectally every 12 h	Dystonia, akathisia, and sedation
	Olanzapine	5–10 mg PO once daily for up to 5 days
Histamine antagonists (H₁)	Cyclizine	25–50 mg PO/SQ or rectally every 8 h	Dry mouth, sedation, skin irritation at SQ sites may occur
	Diphenhydramine	25–50 mg PO/IV/SQ every 4–8 h
	Promethazine (also has activity on D₂ and ACH)	12.5–25 mg PO, IV/IM rectal every 4–6 h	Sedation, dry mouth, and urinary retention Dry mouth, dystonia, akathisia, and sedation
Acetylcholine antagonists (ACH)	Glycopyrrolate	0.2 mg IV/SQ every 4–6 h	Dry mouth, blurred vision, confusion, urinary retention, ileus
	Hycosamine	0.125–0.25 mg PO/SL every 4 h or 0.25–0.5 mg IV/SQ every 4 h	Dry mouth, blurred vision, confusion, urinary retention, ileus
	Scopolamine	0.1–0.4 mg IV/SQ every 4 h or 1.5 mg transdermal patch every 72 h	Dry mouth, blurred vision, confusion, urinary retention, ileus
Serotonin antagonists (5HT₃)	Dolasetron	100 mg PO daily	Headache, diarrhea
	Granisetron	2 mg PO daily or daily	Headache, constipation, weakness
	Ondansetron	4–8 mg PO/IV or dissolvable tablet IV every 4–8 h (max 32 mg/day)	Headache, constipation, weakness
	Palonosetron	0.25 mg IV prior to start of chemotherapy^a	Headache, constipation
Substance P antagonist	Aprepitant	125 mg PO on day 1 of chemotherapy	Headache
		80 mg PO on days 2 and 3^a
	Fosaprepitant	150 mg IV day 1 of chemotherapy	Headache, infusion site pain
Other
Corticosteroids	Dexamethasone	10–20 mg PO/IV each treatment day	Hyperglycemia, GI bleeding, insomnia, psychosis
Cannabinoids	Dronabinol	2–20 mg PO daily in divided doses	Dizziness, euphoria in the young and dysphoria in the elderly, paranoid reaction, somnolence
Benzodiazepines	Lorazepam^b
Somatostatin analog	Octreotide	0.5–2 mg PO/IV every 4–6 h	Sedation, respiratory depression
		100 mcg every 8–12 h IV/SQ or 100 mcg/h as continuous IV infusion	Bradycardia, headache, malaise, hyperglycemia

^a Have not been shown to be effective in terminating nausea or vomiting once it occurs and should not be used for this purpose.

^b Best used for anticipatory nausea and vomiting.

Anorexia/cachexia syndrome (ACS)

ACS (anorexia/cachexia syndrome) is characterized by disproportionate and excessive loss of lean body mass. ACS may occur in up to 80% of patients with advanced cancer.⁴⁶ ACS is usually a marker of disease progression. In a multicenter retrospective review of 3047 cancer patients enrolled on clinical trials from the Eastern Cooperative Oncology Group, weight loss of more than 5% of premorbid weight prior to the initiation of chemotherapy was predictive of early mortality.⁴⁷ Weight loss was independent of disease stage, tumor histology, and patient performance status in its predictive value.⁴⁷

Management of this syndrome should first focus on trying to treat any of the contributing secondary causes. Because anorexia is a prevalent and distressing symptom suffered by most cancer patients, the basis of pharmacologic treatment has focused on alleviating this symptom. The two classes of drugs that have been shown to be effective in phase III clinical trials are corticosteroids and progestational agents.^{48, 49} These drugs do not appear to improve survival, but may improve quality of life. Corticosteroids, usually in the form of dexamethasone at a dose of 4 mg/day (although doses of 2–20 mg/day can be used), has been shown to alleviate cancer anorexia on a short-term basis. This finding has been replicated by other studies and both prednisolone and methylprednisolone have been shown to be effective.⁵⁰ As the duration of appetite stimulation is short lived, and the side effects increase over time, it is most useful for patients with a life expectancy of <6 weeks. Megestrol acetate has been shown to result in dose-dependent improvements in appetite, which usually occur in about 1 week. Improvement in overall well-being has been demonstrated in more than 60% of patients starting at doses of 160 mg/day. The optimal dosing for weight gain appears to be between 480 and 800 mg/day. Effects are seen after several weeks in only 25% of patients.⁵¹ It is important to start at a lower dose and titrate upwards as adverse events are dose related. Adverse events include deep vein thrombosis, especially in those concomitantly on chemotherapy, edema, hyperglycemia, and elevated liver enzymes. Cannabinoids, in its synthetic form of dronabinol, may have some limited effects on improving appetite, but it does not contribute to significant weight gain. In a randomized trial comparing dronabinol to megestrol acetate, significantly more patients had improvement in appetite and weight gain with megestrol acetate.⁵² Combined therapy with both megestrol acetate and dronabinol had no benefit beyond that obtained with megestrol acetate alone. Adverse events with dronabinol include sedation, confusion, and perceptual disturbances.

Dyspnea

Dyspnea is the awareness of an uncomfortable or unpleasant sensation of breathing. The prevalence of dyspnea varies greatly and ranges from 21% to 79% depending on primary disease site, stage of disease, and location of metastasis.⁵³ The sensation of dyspnea is a subjective experience with numerous etiologies. The presence of tachypnea and hypoxia does not adequately reflect the severity of symptoms felt by the patient.⁵⁴ It is not uncommon that patients with moderate to severe tachypnea will not complain of dyspnea. In contrast, patients who are not tachypneic may report severe dyspnea. It is therefore of utmost importance that assessment be based on patient report. The goal of treatment is symptomatic relief of the patient’s expression of dyspnea, rather than the correction of objective variables (tachypnea and low oxygen saturation).

The most common modalities used to treat dyspnea include oxygen therapy and opioids. Three randomized controlled crossover studies have evaluated the use of oxygen (4 or 5 L/min) versus air in advanced cancer patients with dyspnea. Two of these studies evaluated patients with hypoxemia on room air and found that oxygen therapy was more beneficial.^{55, 56} The third evaluated nonhypoxemic cancer patients and found that there was no difference between oxygen therapy and air in reducing the intensity of dyspnea.⁵⁷ Opioids are the pharmacologic treatment of choice in the management of dyspnea. Several randomized controlled trials in cancer patients with dyspnea have demonstrated their benefit. In opioid-naive patients, a starting dose of morphine sulfate 2.5–5 mg orally or its equivalent intravenously every 4 h can be effective. In those patients already on opioid therapy, an increase of 25% in the baseline dose may provide relief.⁵⁸

The terminal phase

Death is a natural process that will occur for every patient. About 10% of people will die suddenly and unexpectedly, while the other 90% die after a period of illness with gradual deterioration until an active dying phase occurs signifying the end of life.⁵ There are “two roads to death,”⁵⁹ the usual road that occurs in most patients and presents as decreasing level of consciousness that leads to coma and death, and the difficult road. The difficult road is marked by terminal delirium, which can manifest as restlessness, confusion, and agitation; it can be a source of great distress for patients, family, and loved ones.⁵⁹ The most common symptoms reported by families in the last week of life are fatigue, dyspnea, and dry mouth, while the most distressing are fatigue, dyspnea, and pain.⁶⁰ The Clinical Practice Guidelines for Quality Palliative Care emphasize that families should be educated regarding the signs and symptoms of approaching death in a manner that is developmentally, age, and culturally appropriate.⁶ While patients and families may still be focused on glucose or blood pressure control, such preventive measures must be taken into the context of the patients’ life expectancy. Discontinuation of such medications often involves a detailed discussion about the risks and adverse effects outweighing the probable lack of benefit. The least invasive rate of medication administration should be attempted initially using the most invasive route only when absolutely necessary. A variety of physiologic changes occur in the last hours to days of life and the following is a summary of the most common changes that occur^{61, 62}:

1. Weakness and fatigue. Weakness and fatigue usually increase as the patient is approaching death. Patients will begin to spend all of their time in bed and will be less interested in participating in usual activities, including visiting with others.
2. Decreased oral intake. Most dying patients lose their appetite and stop drinking. Many caregivers interpret this as a patient “giving up” or “starving to death.” It is important to explain to patients and their family members that there is a decreased need for food and drink during this phase. There is some evidence suggesting that prolonged anorexia is not uncomfortable. One study found that 97% of dying patients who stopped eating experienced no hunger or hunger only initially.⁶³ It has been proposed that terminal anorexia induces a ketosis that contributes to a sense of well-being and diminished discomfort and may in fact be beneficial to dying patients.^{61, 64} Two meta-analyses of studies of both parenteral⁶⁵ and enteral⁶⁶ nutrition in patients with metastatic cancer found that neither therapy resulted in an improvement in morbidity or mortality and actually resulted in an increased total complication rate. The evidence with respect to hydration in dying patients is less straightforward with many differing expert opinions.^{61, 67–69} Some studies suggest that parenteral hydration prevents and treats some cases of terminal delirium,^{67, 68, 70} and others correlate dehydration with adverse symptoms such as thirst.^{69, 71, 72} Still others believe that the data does not support a correlation between dehydration and symptoms and that rehydration does not improve patient comfort.^{63, 70} A randomized control trial of advanced cancer patients within weeks of death demonstrated no improvement in symptoms, quality of life, or survival when compared to placebo.⁷³ It is important that each individual patient be evaluated to determine the risk benefit ratio. Attention should be placed on minimizing the sense of thirst and maintaining patient comfort even when dehydration is present, with oral hygiene. This can be achieved by using lollipop sponges dipped in cold fluids such as water, a lemon-flavored drink or sorbet.
3. Delirium. While reversible factors may be identified in up to half of cases, terminal delirium management typically focuses on symptom control with medications.⁷² Treatment should be aimed at the symptoms of delirium while simultaneously attempting to treat reversible causes. Although delirium is most often associated with the last hours to days of life, in some episodes it may be reversible with therapeutic intervention.^{72, 74} Neuroleptic agents are the mainstay of pharmacologic treatment as they are effective in both hypoactive and hyperactive delirium. Of these agents, haloperidol is the agent of choice as it has lower sedating properties, less anticholinergic and cardiovascular effects. The pharmacologic agents commonly used in the management of delirium can be found in Table 8.

Table 8 Pharmacologic therapy of delirium

Drug name	Dosage/route	Comments
Haloperidol	0.5–5 mg PO/IV/IM/SC every 6–12 h	Most commonly used agent. Can prolong QT interval
Chlorpromazine	12.5–50 mg PO/IV/IM every 8–12 h	Has similar efficacy to haloperidol, but more sedating, anticholinergic and hypotensive effects
Lorazepam	0.5–2 mg PO/SL/IV every 4–8 h and titrate as needed	Most commonly used as a second agent in combination with haloperidol. Can also be used as a continuous infusion for refractory cases where deep sedation is needed. May worsen delirium in the elderly. Caution with liver failure
Risperidone	Start at 0.5–1 mg/day PO and titrate up to 4–6 mg/day	In one study shown to have no differences in side effects when compared to haloperidol. Limited use as only available in oral route
Olanzapine	5 mg PO qhs and titrated to effect (max 20 mg/day)	Risk factors for a poor response to olanzapine in cancer patients are: Age >70 History of dementia CNS metastases Hypoxia Hypoactive delirium
Midazolam	1 mg/h IV and titrated to effect	Most commonly used for refractory cases where sedation is needed

Grief and bereavement

Bereavement is the state of loss as a consequence of death.⁷⁵ Grief is defined as the emotional response to loss and mourning, and often refers to social expressions associated with loss.⁷⁵ Several types of grief exist: anticipatory grief, uncomplicated grief, and complicated grief. Anticipatory grief refers to the mourning that occurs in patients and families prior to death and is a way to facilitate the adjustment to bereavement. Uncomplicated grief is the most common type of grief reaction and is socially perceived as normal. Complicated grief involves the persistence of grief reactions over a long period of time and is characterized by an inability to return to the pre-loss level of functioning.⁷⁶ Palliative care provides grief and bereavement services to patients and their caregivers before, during, and after death to help promote healthy grieving.

Both hospice and palliative care have been shown to provide effective pre-loss interventions for preventing complicated bereavement. These interventions are associated with a reduced risk of major depressive disorder in caregivers.⁷⁷ The multidisciplinary palliative care team including physicians, social workers, nurses, psychologists, and chaplains performs a psychosocial assessment of the patient and caregiver in order to identify those that may be high risk for complicated grief. The palliative care team can provide basic practical help before death such as assisting with advanced directives, assistance with financial matters, and encouraging individual medical care of the caregiver as well as providing assistance after death by offering counseling or referral to other support services.

Hospice

Hospice is a philosophy of care. The goal of hospice is to focus on maintaining the best quality of life rather than length of life in patients who have a life expectancy of 6 months or less. It is different from palliative care in that palliative care is given simultaneously with other curative and life-prolonging therapies. Hospice services have been available in the United States since 1974 and have been funded by Medicare as part of the Medicare hospice benefit since 1982.⁷⁸

Hospice is the only Medicare benefit that includes medications, durable medical equipment, and continuous around-the-clock access to care and support. Bereavement services are also offered to family members after a patient’s death. The Medicare hospice benefit covers all care related to the cancer diagnosis. The patient can still receive Medicare benefits for the treatment of other illnesses.

Most hospice care is delivered at home. It is also provided in other settings such as inpatient hospice facilities, nursing homes, assisted living facilities, and hospitals. It is estimated that approximately 45% of all people who died in the United States in 2011 were under the care of a hospice program and of all patients enrolled, 38% had a diagnosis of cancer.⁷⁹ In a study comparing survival of hospice to nonhospice patients, hospice care prolonged the lives of some terminally ill cancer patients.⁸⁰ The mean survival period was significantly longer for hospice patients with lung cancer (39 days longer) and pancreatic cancer (21 days), while marginally significant for colon cancer (33 days).⁸⁰

Summary

Palliative care is patient- and family-centered interdisciplinary care that focuses on relieving suffering and providing the best quality of life for patients undergoing curative and life-prolonging treatments as well as for patients in whom cancer specific treatments are no longer available. It is estimated that 35% of patients with cancer will die from their disease.⁸¹ Increasing attention has been given to improvements in quality of life issues in oncology, for patients undergoing chemotherapy, patients at the end of life as well as cancer survivors. Prevalence of symptoms during cancer treatment can be substantial. Palliative care is an integral part of comprehensive cancer care. Palliative care is most effective when initiated at the time of diagnosis allowing for patients to be followed through the trajectory of illness. The oncologist plays a key role in discussing treatment options, curative or palliative, from the outset of the diagnosis. Assessing the patients’ goals is equally as important. Patients should be made aware that receiving anticancer treatments does not preclude them from access to palliative care services. Increasing the emphasis on palliative care in oncology should improve patient outcomes and can diminish some of the oncologist’s stress of caring for patients with serious and life-threatening illness.

Palliative care has experienced a rapid growth in the last two decades in response to the increasing number of patients living with serious illness, an increased demand for high-quality symptom control, desire for improved coordination of care across settings and increased need for advance care planning. The number of palliative care programs within hospital settings has increased by 138% since 2000.⁸² Expansion of palliative medicine education is supported by the Liaison Committee on Medical Education, which has mandated medical school education in palliative medicine, and the ACGME (accreditation council for graduate medical education), which requires oncology fellow training in palliative medicine. There is a plethora of Internet-based resources that provide physicians in practice with access to further information and education on palliative care (Table 2).

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Tags: Holland-Frei Cancer Medicine

Apr 12, 2017 | Posted by admin in ONCOLOGY | Comments Off

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