Eric E. Prommer, Lisa Thompson, and Dennis A. Casciato
I. PAIN
A. Barriers to optimal pain control. Pain is one of the most common and dreaded symptoms associated with cancer. Its prevalence ranges from 30% to 40% in those getting active therapy to nearly 90% of those with advanced cancer. Uncontrolled pain precludes a satisfactory quality of life. However, advances in pain management techniques have made it possible to control pain in most cancer patients. Barriers that exist to the achievement of optimal analgesia can be divided into patient, physician, and institutional components.
1. Patient-related barriers include
a. Reluctance to report pain (because of concerns about distracting physicians from treatment of the cancer and fears that pain means that the disease is worse)
b. Difficulty in following recommendations (health illiteracy)
c. Fear of addiction (or being thought of as an addict)
d. Worries about side effects (and the ability to manage them)
e. Fear of disease progression, injections, and a belief that pain must be accepted
2. Physician barriers include
a. Failure to appreciate the severity of pain
b. Knowledge deficit regarding specific treatment for pain (physicians largely underdose patients because of excessive concern about the dose and side effects of opioids and fear of patient addiction)
3. Institutional barriers for optimal pain management include
a. Lack of commitment to make pain treatment a priority
b. Lack of resources
c. Lack of use of instruments for pain assessment (but anyone can use a numeric pain rating scale)
B. Assessment of pain in cancer patients. Pain is a nonspecific symptom that can result from unrelated benign diseases, effects of treatment, paraneoplastic syndromes, or the direct mechanical effects of the cancer. Pain determined to result from direct mechanical effects of a cancer must be assessed in terms of whether the underlying disease can be treated to relieve the pain. To provide effective pain treatment, an appropriate differential diagnosis must be determined.
1. The following steps should be done in the assessment of cancer pain:
a. Believe the patient’s complaint.
b. Take a history of the pain, which should include the site, quality, onset, exacerbating and relieving features, associated symptoms, impact on quality of life and psychological state, and response to previous and current therapies.
c. Assess the pain as acute, chronic, intermittent, incident, or breakthrough.
d. Prioritize each complaint.
e. Assess for previous history of alcohol or drug dependence.
f. Perform medical and neurologic examinations.
g. Consider diagnostic procedures.
h. Treat and assess response to therapy.
i. Individualize therapy.
j. Communicate with the patient via pain intensity scales.
2. Patient self-assessment is the most reliable guide to both the cause of the pain and the effectiveness of pain treatment. A log should be kept to track the times that the pain is worst, the intensity of the pain, the times and doses of pain medications or other analgesic measures, and the response to these measures.
Numeric rating scales are probably the easiest for patients to use. An example is a pain scale of 0 to 10 (0 is for the absence of pain and 10 is for the most severe pain imaginable to the patient). The physician uses the information to adjust dosage and timing of analgesic medications or to change therapy.
3. Evaluation for depression is an essential part of pain management. Chronic pain leads to depression, which progressively lowers the pain threshold and creates a positive-feedback cycle of pain and depression. Solicit symptoms of depression, including loss of energy, abnormal sleep patterns, loss of appetite, loss of interest, and decreased ability for cognitive distraction. Some of these symptoms are mistaken for signs of progressive cancer.
C. Principles of pain management in cancer patients when the underlying cause cannot be treated effectively
1. Ideally, the goal of cancer pain management is complete relief of pain. Even when this is not possible, maximizing pain control improves overall functioning and quality of life.
2. Pharmacologic step management of cancer pain. The World Health Organization (WHO) has designed a three-step approach to the systemic management of pain.
Step 1: Patients with mild cancer-related pain can be treated with nonopioid analgesics. These can be combined with other adjuvant analgesics if necessary.
Step 2: Patients with moderate pain, or those who do not get analgesia with the step 1 agent, can be treated with opioids such as hydrocodone or oxycodone conjugated to acetaminophen. Tramadol, a weak opioid with effects on serotonin and norepinephrine uptake, is also a step 2 agent.
Step 3: Patients with severe pain and those who do not get relief with agents appropriate to step 2 should get an opioid designed for moderate to severe pain. This group includes morphine, hydromorphone, methadone, fentanyl, and oxycodone. Newer opioids, such as oxymorphone and its long-acting form (Opana), increase the available step 3 options. These can be combined with a nonopioid analgesic or an adjuvant agent. Sometimes it is necessary to go directly to a step 3 agent.
3. Intrathecal analgesics are often used when patients develop intolerable adverse effects to oral opioids or experience inadequate pain relief.
4. Blocks and neurosurgical procedures (see Section I.I.3)
5. Localized pharmacologic analgesics and nonpharmacologic interventions for pain, although not commonly required, are an important part of the armamentarium for pain control. These range from injections of glucocorticoid-lidocaine into isolated painful soft tissue areas to nerve blocks involving ganglia, such as the celiac or hypogastric plexus.
6. Placebos are never indicated for the treatment of cancer pain unless the patient is enrolled in a clinical trial in pain management.
7. Physical dependence and tolerance are common side effects of prolonged use of opiate analgesics in cancer patients. The development of addiction to opioid analgesics in patients with cancer pain is low. Terminology is as follows:
a. Tolerance is the need to increase the dose to maintain the same effect. Pharmacologically this is a rightward shift in the dose response curve.
b. Physical dependence is the state where continued administration is necessary to prevent the onset of withdrawal symptoms.
c. Psychological dependence describes compulsive drug-seeking behavior and overwhelming involvement with drug procurement and use.
d. Pseudoaddiction is when the patient with unrelieved pain develops what appears to be drug-seeking behavior to relieve that pain.
8. Ineffective analgesia is administered because of the barriers to optimal pain control (Section I.A), or persistent pain may mean that the underlying cancer is progressing.
9. Certain analgesics should be avoided. Analgesics with mixed agonist and antagonist properties, such as pentazocine (Talwin) or propoxyphene (Darvon), should not be used. Likewise, meperidine (Demerol) should not be used because it is not potent, and a risk exists of metabolite accumulation in the setting of renal insufficiency.
D. Nonnarcotic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAID)
1. Acetaminophen (AMP, paracetamol, Tylenol and others). As with aspirin, AMP is an antipyretic. Unlike aspirin, AMP has no anti-inflammatory or antiplatelet actions. The starting dose is 650 mg PO q.i.d. and the maximum is 4,000 mg/d.
2. Salicylates
a. Aspirin (ASA, acetylsalicylic acid) is the standard against which other NSAIDs are compared. This analgesic is significantly more effective than placebo in patients with pain from cancer. Aspirin should not be used in patients with a history of the syndrome of nasal polyps and asthma, gastritis, peptic ulcer disease, or bleeding diathesis (including severe thrombocytopenia or concomitant use of anticoagulants). Aspirin can inhibit platelet aggregation for 1 week or more.
b. Choline magnesium trisalicylate (Trilisate) is believed to have less gastrointestinal (GI) toxicity than other NSAIDs and no antiplatelet effect, but does have anti-inflammatory properties. The starting dose is 1,500 mg PO once, then 1,000 mg b.i.d. This drug is useful in patients with thrombocytopenia.
3. Cyclo-oxygenase (COX) inhibitors can be useful in the treatment of bony metastasis, paraneoplastic fever, and paraneoplastic periosteitis. They are divided into nonselective COX-1 and selective COX-2 inhibitors. COX-1 is present in most tissues, helps maintain gastric mucosa, and influences kidney and platelet function. COX-2 is induced in response to injury and is involved in the inflammatory cascade. Cox inhibitors can act synergistically with other analgesics such as opioids.
The nonselective inhibitors can cause gastric ulcers and GI bleeding as well as reversibly affect platelet function. The selective COX-2 inhibitors have relatively reduced the risk of GI toxicity and reduced antiplatelet effect associated with their use. NSAID-induced ulcer disease may be reduced by the coadministration of H2 blockers or proton pump inhibitors such as omeprazole (Prilosec, 20 mg PO daily). Misoprostol (Cytotec), 100 µg PO q.i.d. can also ameliorate the GI side effects.
a. Nonselective NSAID that are useful orally include (among others)
(1) Ibuprofen (Advil), 200 to 800 mg q.i.d. PO
(2) Naproxen (Naprosyn), 250 to 750 mg b.i.d. PO
(3) Indomethacin (Indocin), 25 to 75 mg t.i.d. PO
b. Selective COX-2 inhibitors include
(1) Celecoxib (Celebrex), 100 to 200 mg once or twice daily PO
(2) Meloxicam (Mobic), 7.5 mg once or twice daily PO
c. Ketorolac (Toradol) is an NSAID available in IM and IV forms. The dose is 30 mg IM or IV once, then 15 mg q6h (not to exceed 5 days).
E. Adjuvant drugs for cancer pain management
1. Corticosteroids are indicated in refractory neuropathic pain, bone pain, pain associated with capsular distension (painful hepatomegaly), duct obstruction, headache associated with central nervous system (CNS) metastasis, bowel obstruction, and ascites. The dose in these conditions is largely empiric.
2. Bisphosphonate infusion every 4 weeks is the treatment of choice for bone pain and fracture prevention from osteolytic lesions of multiple myeloma. It may also be helpful in controlling bone pain in up to 25% of patients with breast cancer or prostate cancer. Either pamidronate (Aredia, 90 mg IV over 3 hours) or zoledronate (Zometa, 4 mg IV over 15 minutes) can be used.
3. Anxiolytic agents
a. Benzodiazepines. Anxious or agitated patients often perceive anxiety as a painful sensation. Diazepam (Valium), alprazolam (Xanax), or lorazepam (Ativan) may be used if narcotic analgesics alone are not effective. These drugs should be avoided in patients with dementia and may produce paradoxical agitated, confusional states in some patients. They may interact with opioids to produce increased somnolence and thus they are looked for first when patients on opioids already develop “opioid” adverse effects, such as increased sedation.
b. Antihistamines, such as hydroxyzine (Atarax, Marax), 25 to 100 mg PO q.i.d., may be useful in the anxious patient as a mild anxiolytic agent with sedating, analgesic, antipruritic, and antiemetic properties.
c. Pain can be associated with increased delirium. Patients with dementia can become agitated and confused when they develop pain. These patients often benefit from a regimen of haloperidol (Haldol), 1 to 3 mg/d, with analgesics. This drug can cause extrapyramidal symptoms, torticollis, and swallowing problems. Haloperidol is contraindicated in patients with Parkinson disease. Diphenhydramine (Benadryl) and benztropine mesylate (Cogentin) rapidly reverse extrapyramidal symptoms. Another option in the demented patient who has delirium is to use the newer atypical antipsychotics, such a quetiapine (Seroquel), which have a more favorable side effect profile, at least when it comes to extrapyramidal symptoms and are very useful in patients with Parkinson disease.
F. Neuropathic pain syndromes, particularly if the pain is lancinating or burning, can often be treated with anticonvulsant drugs alone or in combination with tricyclic antidepressants. These drug combinations are often effective in treatment of peripheral neuralgias, postherpetic neuralgia, and tic douloureux. Gabapentin is considered to be the first-line agent in the treatment of neuropathic pain. Typical doses are as follows:
1. Antiseizure drugs used for neuropathic pain
a. Gabapentin (Neurontin), starting dose is 300 mg PO at bedtime (h.s.). The maximal dose is 3,600 mg/d/ with q.i.d. dosing.
b. Phenytoin (Dilantin), starting dose is 100 mg b.i.d.; titrate upward by 100-mg increments every 3 to 7 days and monitor for side effects.
c. Carbamazepine (Tegretol), starting dose is 100 mg b.i.d.; titrate to toxic level by 100-mg increments every 3 to 7 days.
d. Lamotrigine (Lamictal), 25 mg PO h.s.; increase dose q3d
e. Topiramate (Topamax), 25 mg PO h.s.; increase dose q3d
f. Valproic Acid (Depakote), 200 to 400 mg PO b.i.d. or t.i.d.
g. Antidepressant drugs (see Section I.F.2)
2. Antidepressants are useful adjuvant analgesics that provide relief at doses below that needed to treat depression. Trials suggesting efficacy have been done in patients with postherpetic neuralgia or diabetic neuropathy. There are few clear studies indicating efficacy in the cancer patient population.
a. Tricyclic antidepressants, which may have lost favor to gabapentin as first-line agents, include amitriptyline (Elavil), desipramine (Norpramin), nortriptyline (Pamelor), doxepin (Sinequan), and imipramine (Tofranil). These are started at 10 to 25 mg h.s. and titrated upward at 10- to 25-mg increments every 5 to 7 days.
b. Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and fluvoxamine (Luvox). These drugs have performed inconsistently in neuropathic pain trials.
c. Other antidepressants include venlafaxine (Effexor), bupropion (Wellbutrin), trazodone (Desyrel), nefazodone (Serzone), and mirtazapine (Remeron). Clinical experience suggests that these agents can be useful, but no controlled clinical trials have established their utility in the treatment of neuropathic pain.
3. α-Adrenergic agonists, such as tizanidine (Zanaflex, 2 mg PO h.s.), may be useful in refractory neuropathic pain but this is based on clinical experience not controlled trials. These agents are most commonly used intrathecally, along with opioids and local anesthetics.
4. Systemic local anesthetics
a. IV lidocaine. Controlled trials suggest that lidocaine is effective in neuropathy associated with diabetes. Response occurs at sub-antiarrhythmic doses but lasts only a few hours. Response to IV lidocaine may be predictive of a subsequent response to mexiletine.
b. Mexiletine (Mexitil) has been found effective in patients with diabetic neuropathy on the basis of controlled clinical trials. The starting dose is 50 mg t.i.d. PO (taken with meals) with titration upward every 5 to 7 days.
5. Topical agents
a. Lidocaine patch, 5% (Lidoderm). Controlled clinical trials showed efficacy in postherpetic neuralgia. Its use in other conditions is based on anecdotal data. The dose is up to three patches topically (12 hours on and 12 hours off). There are no clinically relevant serum levels.
b. Topical capsaicin (Zostrix) depletes substance P and may act as a counter-irritant. Results in trials are mixed for peripheral neuropathy and pain may actually worsen. It is not recommended.
c. Topical opioids are often used for painful ulcerations. Methadone and morphine can be compounded into topical preparations.
G. Opioids produce their analgesic effect through the interaction with specific opioid receptors. The only significant differences among the various opioids are duration of action and the dose needed to produce the same analgesic effect.
The best agents are the pure agonists. Agonists or antagonists, such as pentazocine (Talwin) or propoxyphene (Darvon), are not effective and should not be used. Meperidine likewise should not be used because it is not potent and its metabolites accumulate in the setting of renal insufficiency. Methadone is being used more often because research has suggested that it works on other receptors involved in pain perception.
No “ceiling” to opioid doses exists. Doses can be escalated to provide analgesia as long as there are no unacceptable toxicities. Ineffectiveness observed while using opioids usually indicates underdosing; the analgesic effect and the duration of that effect increase as the dose is increased. Ineffectiveness may also reflect progression of the underlying disease, but this will also respond to a dose increment.
1. Opioids for mild to moderate pain: short-acting opioids (WHO step 2; there are no step 1 opioids)
a. Codeine phosphate: 60 mg q3–4h PO. Also available as Tylenol #2 (15 mg codeine with AMP), Tylenol #3 (30 mg codeine with AMP), and Tylenol #4 (60 mg codeine with AMP). Do not exceed 4 g/d of AMP. Codeine is rarely used for analgesia as it is especially susceptible to producing constipation. Codeine is one-eighth as potent as morphine.
b. Hydrocodone bitartrate (with ASA or AMP; Lorcet, Lortab, Vicodin): 10 mg q3–4h PO. Hydrocodone is equivalent to morphine on a milligram per milligram basis. It is not available as a stand-alone opioid.
c. Oxycodone hydrochloride (Roxicodone as single agent or in combination with AMP or ASA as Percocet, Percodan, Tylox): 5 to 10 mg q3–4h PO.
d. Tramadol (Ultram or Ultracet [with AMP]). Maximum dose for cancer pain is 300 mg/d. The immediate release form is dosed q6h; the extended release form is dosed q12h.
2. Opioids for moderate to severe pain. Short-acting opioids (WHO steps 2 and 3). Oral immediate release opioids generally have an onset of action of approximately 1 hour and their duration of effect is approximately 4 hours.
a. Morphine sulfate (MS), immediate release, is the standard against which all other analgesics are measured. The starting dose of MS in the opioid-naive patient is 0.5 to 1 mg q3–4h IV or 15 to 30 mg q3–4h PO; it can be given more frequently for acute pain crises. MS is available as
(1) Tablets and capsules (MSIR, immediate release MS): 15 and 30 mg
(2) Elixirs (Roxanol): 10 mg/5 mL and 20 mg/mL
(3) Rectal suppositories (RMS): 1, 5, 20, and 30 mg
(4) Injectable: 0.5, 1, 10, and 25 mg/mL concentrations
b. Hydromorphone (Dilaudid). Duration of action is 4 hours but can be as short as 3 hours. Available as
(1) Tablets: 1, 2, 3, 4, and 8 mg
(2) Elixir: 5 mg/5 mL
(3) Rectal suppository: 3 mg
(4) Injectables: 1-, 2-, 3-, 4-, and 10-mg/mL concentrations
c. Oxycodone hydrochloride: Considered to be both a step 2 and a step 3 agent. Not available in IV form. Available as:
(1) OxyIR, Roxicodone: 5-mg tablets and capsules
(2) Oxyfast: 20-mg/mL elixir
3. Long-acting opioids are usually started after dose titration (achievement of pain relief with short-acting opioids). Analgesic onset is in 3 to 4 hours and lasts for 12 hours. No advantage to q8h dosing, but it is often done. To derive the long-acting opioid dose, divide the total 24-hour immediate-release dose by 2. Kadian is the only long-acting opioid that can be crushed, sprinkled, and put in a feeding tube.
a. Sustained release morphine: Available as
(1) MS Contin: 15-, 30-, 60-, 100-, and 200-mg tablets
(2) Oramorph SR: 30-, 60-, and 100-mg tablets
(3) Kadian: 20-, 50-, and 100-mg capsules
b. Sustained release oxycodone is available as OxyContin in 10-, 20-, 40-, and 80-mg tablets
c. Fentanyl (Duragesic) transdermal patches: Available at delivery rates of 25, 50, 75, and 100 µg/h. Therapeutic levels are not reached for 13 to 24 hours. Patches are changed q72h; some patients need the patch changed q48h. The recommended upward dose titration interval is q72h. A 100-µg patch is equivalent to morphine given IV at 4 mg/h. Another way to convert fentanyl to morphine and vice versa is to convert 2 mg of oral morphine for every 1 µg of fentanyl. Oral transmucosal fentanyl citrate (OTFC) is available in the form of fentanyl lollipops. They have a rapid onset of action (minutes) and have been shown to be superior to morphine for “incidental pain” (see below).
d. Methadone is useful for neuropathic or severe pain. It is also useful when opioids are required in the setting of renal failure. The N-methyl-D-aspartate (NMDA) blocking ability of the drug reverses opioid tolerance. Prospective studies have shown that currently available equianalgesic dosing tables are not accurate when switching from morphine to methadone. The dosing interval should not be less than q8h. The dose may be as little as 5% to 10% of the MS dose, especially in patients on chronic MS therapy.
e. Oxymorphone. Originally used as rectal form (Numorphan suppository), this drug is now available in oral form. The immediate release form is unique, in that it has a half-life of approximately 6 hours. A long-acting form is available (Opana). The drug is slightly more potent than morphine (1.2 times).
4. Side effects of opioids
a. GI effects include constipation, nausea, and vomiting. Define a prophylactic regimen for constipation and for nausea when the first opioid prescription is written.
(1) Constipation is the most common adverse effect of opioids. Constipation is not related to dose and can occur with small doses of opioids. It is caused by the opioid effect on motility, as well as decreased pancreatic, biliary, gastric, and intestinal secretions. Tolerance to this side effect usually does not occur (see Section IV.A.5).
(2) Nausea and vomiting caused by opioids is owing to stimulation of the chemoreceptor trigger zone. Thus, antiemetics with antidopaminergic properties are indicated. Agents such as prochlorperazine (Compazine), metoclopramide (Reglan), and haloperidol (Haldol) are good choices.
b. CNS side effects. Morphine-3-glucuronide is the morphine metabolite implicated in the development of CNS toxicity. Other manifestations of CNS toxicity include sedation, hallucinations, delirium, and myoclonus.
(1) Sedation is more common in the opioid naive patient. It rarely lasts more than 48 to 72 hours. If persistent, methylphenidate, 5 mg at 8 AM and at noon, or modafinil 200 mg/d may be useful.
(2) Myoclonus (spontaneous jerking movements) can occur in up to 45% of patients. This is an adverse effect seen with chronic opioid use. Treatment options include opioid dose reduction if pain is well controlled, opioid rotation if pain is poorly controlled, or adding clonazepam (Klonopin, 0.5 to 1 mg) or diazepam (Valium, 2 mg) PO q12h.
c. Respiratory depression is unusual and usually only occurs in patients who are either having rapid dose escalation or are in renal failure (due to accumulation of morphine-6-glucuronide). Respiratory depression is not common because morphine does not have good bioavailability and pain is an antidote to respiratory depression. Respiratory depression can occur when pain is rapidly reduced, such as after a nerve block. It can also occur when MS is given with other CNS depressants. Treatment is by dose reduction, such as stopping the infusion for 2 hours and then restarting at half the dose, or holding one or two doses of opioids and then restarting at a lower dose if possible. Naloxone is rarely necessary.
d. Other side effects of opioids include
(1) Noncardiogenic pulmonary edema occurs with rapid dose escalation and may be related to capillary permeability changes secondary to opioid release of histamine.
(2) Xerostomia is common with concomitant use of antidepressants and anticholinergic agents. Treatment includes sodium bicarbonate rinses or pilocarpine.
(3) Urinary retention is caused by the anticholinergic effects of opioids.
(4) SIADH (syndrome of inappropriate antidiuretic hormone) can be caused by opioids.
(5) Endocrine: hypothyroidism and hypercalcemia potentiate the CNS effects of opioids.
(6) Dermatologic: pruritus is more commonly seen with intrathecal opioids.
5. Drug interactions with opioids
a. Potentiators of MS effect generally work by interfering with morphine metabolism. These agents include H2 blockers, antidepressants, phenothiazines, and antianxiety agents.
b. Agents that decrease MS effect generally induce the metabolism of morphine. These agents include phenytoin, barbiturates, and rifampin.
c. MS effect on other agents. Morphine can increase gabapentin levels and reduce ciprofloxacin levels.
6. Management of narcotic withdrawal. The intensity of withdrawal symptoms is usually proportional to the duration of physical dependence. Symptoms develop within 2 to 48 hours after the last dose and usually peak at 72 hours. Opioid withdrawal is less life threatening and dangerous than withdrawal from other classes of controlled drugs. Reassurance, education, and perhaps mild sedatives may be all that is required for patients who develop physical dependence during hospitalization and who are not going to continue on the drugs. Small doses of clonidine, 0.05 to 0.1 mg PO t.i.d. (or weekly skin patches), may reduce symptoms of withdrawal, especially tremors, hypertension, anxiety, and fevers.
H. Administration of analgesics
1. Opioid dosage. There is no maximum dose or ceiling to MS or other opioids. As the dose is increased, analgesic effects increase. Increments in dosing are always balanced by monitoring for side effects. Once stable drug levels are achieved with immediate-release dosing, the patient can be switched to a long-acting agent. Rescue doses for breakthrough pain with immediate-release agents are made available as needed (p.r.n.). With elderly patients, “go low and go slow,” taking into account age-related sensitivity to opioids as well as age-related reductions in renal function.
a. Dose finding for oral opioids. The oral route is preferred because oral opioids can control pain in patients with advanced cancer 80% to 90% of the time. Doses are given regularly (“around the clock” [ATC]) and supplemental medications are provided p.r.n.
In the opioid naive patient, the initial dose of MS can be from 5 to 30 mg depending on the severity of pain. This dose is started at q4h. The p.r.n. dose is approximately 50% of the q4h dose and is provided once during the 4-hour dosing interval. The optimal dose is one that relieves the patient’s pain (to <4 on a 10-point scale) without causing side effects. In the elderly patient, it is always best to “go low” and “go slow.” This means lower starting doses and increased dosing intervals.
Once the optimal dose is found, the total opioid amount is calculated and then divided by 2 to yield the q12h, long-acting dose. The q2–4h p.r.n. dose is approximately 10% to 20% of the total 24-hour dose.
b. Dose finding for parenteral agents. In the opioid naive patient with severe pain, initial MS doses of 2 to 4 mg IV or SQ can be given every 15 minutes as necessary to control pain. When pain is controlled, the dose given over a 2- to 4-hour interval becomes the q4h dose and the p.r.n. dose (50% of the ATC dose) is given q1–2h.
c. Need for frequent p.r.n. doses. Patients needing more than four p.r.n. opioid doses per day most likely need an increase in the ATC dose. The ATC dose can be increased by 25% to 50% and adjustments of the p.r.n. dose can be made.
d. Incident pain. Pain with turning, bathing, and transporting can be managed with p.r.n. doses or more generous p.r.n. doses at the time the patient is likely to experience the incident pain.
e. Equianalgesic tables represent rough guidelines that are based on single-dose studies in otherwise healthy patients. The potency ratio of oral MS to oral hydromorphone is 5:1 (5 mg of MS is equivalent to 1 mg of hydromorphone orally). The potency ratio for IV or SQ MS to hydro-morphone is 7:1 (7 mg of MS is equivalent to 1 mg of hydromorphone IV or SQ). Oxycodone potency ranges from 1:1 to 1.5:1 compared with MS. Equianalgesic tables are not useful when converting from other step 3 opioids to methadone.
2. Subcutaneous opioids are reserved for those who cannot use the oral route for pain administration or who need rapid onset of analgesia. SQ dosing is identical to IV dosing. The limiting feature of this route is the infusion rate; in general, the SQ route can absorb up to 3 mg/h; with larger volumes, hyaluronidase (Wydase) can be given. The shoulder, abdomen, and thigh are ideal sites for infusion.
3. Pumps for patient-controlled analgesia (PCA) are occasionally useful for cancer patients. Begin with a 2- to 5-mg dose of MS with a delay interval of 10 minutes (“lockout”); the patient can thus receive this dose up to six times an hour. The amount given over 4 hours is determined and converted to an hourly dose. The new, every 10 minute demand dose becomes 50% of the hourly dose. For patients already on MS, the same method is used except that the 24-hour dose is converted to an hourly dose and then a new demand dose can be formulated.
4. Intravenous opioids are reserved for patients who cannot be given opioids by the oral route. It is also ideal for rapid titration of doses. Dosing is based on current analgesic requirements. The usual conversion from oral MS to SQ or IV MS is to divide the total oral requirement by 3 with this representing the total IV dose. This amount can be divided by 24 to give hourly rates.
5. Epidural and intrathecal anesthesia are considered when oral and parenteral routes have proven ineffective and/or there is excessive toxicity associated with opioid use.
a. Epidural analgesia. A catheter is placed close to the involved dermatome. The type of delivery system depends on prognosis of the patient. Tumor invasion of the spine is not a contraindication, because most tumors involve the body of the vertebra and not the spinous process. To calculate the epidural dose from an oral dose, divide the total 24-hour oral dose by 10. To calculate the epidural dose from an SQ dose, divide the total 24 hour SQ dose by 5. Analgesia can be improved when combined with bupivacaine (Marcaine) or clonidine. The addition of these agents is indicated for neuropathic pain, dysesthetic pain, midline pain below the umbilicus, or pain involving the sacral plexus.
b. Intrathecal analgesia has more effective pain control, uses less opioid, and has less incidence of catheter occlusion than the epidural route. Doses for intrathecal administration are 10% of the epidural doses.
6. Other routes for opioids
a. Rectal administration can also be used if the oral route is not available.
The oral–rectal potency ratio is 1:1.
b. Sublingual and buccal administration can be used if the oral route is not available. Ideal agents for this route are the more lipophilic opioids such as fentanyl (Actiq) lollipops and methadone. These agents have a greater Buccal or sublingual bioavailability than MS. The buccal–oral potency ratio is 1:1.
c. Topical opioids have been used for painful ulcerative lesions, cutaneous pain from tumor infiltration, and oral mucositis. It is available in a 1 mg/mL gel vehicle.
I. Other methods of pain management
1. Psychological methods of pain control. Behavioral modification, although not generally effective for moderate to severe chronic cancer pain, may be helpful for mild pain. Operant conditioning, hypnosis, guided imagery, and biofeedback are techniques that can be helpful for chronic mild pain, such as postoperative chest wall pain. Cognitive distraction is a useful adjunct for mild pain. These techniques can help patients restore self-control and act in a way that participates in their own care.
2. Physical methods of pain control, such as hot or cold packs for muscle and joint pain, various types of massage therapy, and exercise programs, may be helpful additions to drug therapy in patients with mild to moderate chronic pain syndromes, but are generally ineffective in treatment of severe cancer pain.
Transcutaneous electrical nerve stimulation (TENS) has demonstrated efficacy in the treatment of malignant disease, but the problems encountered were waning effect and sudden termination of effect. The results of clinical trials on acupuncture have been conflicting; retrospective data suggest that any efficacy of acupuncture for cancer pain is short lived.
3. Neuroablative procedures are considered when standard pain management methods and intraspinal analgesia have failed. These procedures are not for patients who have a short life expectancy or are in poor physical condition.
a. Unilateral chordotomy is the most effective neuroablative procedure and is particularly useful for patients with unilateral cancer pain below the shoulder. Radiofrequency lesions to spinothalamic tracts of the spinal cord are generally placed at the C-1 to C-2 level.
Contralateral loss of superficial, deep, and visceral pain is produced in >75% of patients treated with percutaneous chordotomy. The duration of analgesia is limited to only a few months; incapacitating dysesthesia may develop after several months. In experienced hands, unilateral chordotomy is associated with low morbidity and mortality and minimal incidence of motor weakness or loss of bladder function. Sleep apnea, fecal and urinary incontinence, loss of orgasm, and muscle weakness, on the other hand, frequently complicate bilateral chordotomy.
b. Nerve blocks may be useful in patients with pain restricted to a single somatic nerve or adjacent nerves (e.g., postthoracotomy pain may be relieved by subcostal blocks). Short-acting local anesthetics are initially used to determine the location for a permanent procedure.
c. Celiac plexus nerve block is effective in up to 85% of patients for treating upper abdominal visceral pain, particularly from cancers of the pancreas or stomach. The procedure is often accomplished with needle placement under CT or fluoroscopic guidance. It can also be performed endoscopically or at the time of laparotomy. Pretreatment hydration and postoperative observation for 4 to 6 hours (with fluid replacement as necessary) can prevent transient hypotension from this procedure.
d. Lumbar sympathetic blockade can be attempted for pelvic visceral pain. This procedure affects sphincter tone or lower extremity strength uncommonly.
e. Dorsal root entry zone lesions involve the destruction of dorsal horn neurons. It has been used to treat nonmalignant conditions such as brachial plexus avulsions, postparaplegic and postquadriplegic pain, and postamputation pain. Postherpetic neuralgia also responds to this procedure. Its usefulness in cancer pain needs to be studied further.
It is performed under general anesthesia. Proper placement of the lesion (in the cord) is important and can be difficult. Poor performance status, bleeding diathesis, infection, and poor cardiopulmonary reserve are contraindications to the procedure.
f. Intracranial procedures, such as medullary or pontine tractotomy, thalamotomy, cingulotomy, and hypophysectomy, are rarely performed.
II. ORAL SYMPTOMS
A. Stomatitis from chemotherapy can develop 2 to 10 days after treatment with many cytotoxic agents and during RT to the head or neck. Resolution of symptoms usually occurs 2 to 3 weeks after completion of therapy but may persist longer. Sucking on ice chips or popsicles during the short infusion of certain cytotoxic agents (e.g., methotrexate, 5-fluorouracil) or taking oral glutamine preparations may prevent the development of stomatitis.
1. Aggravating factors include poor oral hygiene (gingivitis, poorly maintained dentures), xerostomia, age- or RT-related mucous membrane atrophy, and aerobic or anaerobic bacterial infections. Infection with Candidasp. or herpesvirus can complicate or be confused with chemotherapeutic stomatitis; the index of suspicion for the infections is increased in patients with acquired immunodeficiency syndrome (AIDS) and in those taking high-dose or long-term glucocorticoids.
2. Symptoms and signs. Stomatitis is usually first noted by the patient as sensitivity to citrus juice, hot food, or spicy food. Erythema and then aphthous ulcers develop. In severe cases, lesions progress to extensive ulceration and sloughing of the oral mucosa. Candida albicans or herpesvirus infection can have a similar appearance and must be considered if the mouth lesions are longer lasting or recognized by their characteristic appearance.
3. Management of stomatitis. The following measures may relieve symptoms:
a. Avoid foods that trigger the pain
b. Abstain from alcohol
c. Suck on popsicles and cold beverages
d. Frequently rinse the mouth with solutions of saline or baking soda
e. Swish and expectorate certain commercial suspensions
(1) Ulcerease: glycerin, sodium bicarbonate, and sodium borate
(2) BAX: lidocaine, diphenhydramine, sorbitol, and Mylanta
(3) Stomafate: sucralfate, Benylin syrup, and Maalox
(4) Gelclair: contains none of the above ingredients; use undiluted
f. Formulations: rinse with 15 mL four to six times per day
(1) Mix 30 mL each of diphenhydramine hydrochloride (Benadryl, 12.5 mg/5 mL), viscous xylocaine (2%), and Maalox
(2) Mix 30 mL of Benadryl (12.5 mg/5 mL), 60 mL of tetracycline or penicillin (125 mg/5 mL), 45 mL of nystatin oral suspension (100,000 U/mL), 30 mL of 2% viscous lidocaine, 30 mL of hydrocortisone suspension (10 mg/5 mL), and 45 mL sterile water for irrigation
g. Medications
(1) Viscous 2% lidocaine (Xylocaine), 10 to 15 mL for 30 seconds before meals and q2h p.r.n.
(2) Sucralfate (Carafate), 1 g q.i.d.
(3) Opioids, especially parenteral opioids or Fentanyl lollipops (Actiq), may be useful. Elixirs may not be helpful because they contain alcohol, which can exacerbate mucositis.
(4) Appropriate antimicrobial treatment for bacterial, monilial, or herpesvirus infections
(5) Palifermin, a recombinant human keratinocyte growth factor, at 180 µg/kg given as a single dose 3 days before chemotherapy, was better than a placebo at reducing the incidence of moderate to severe mucositis in a small series.
B. Xerostomia
1. Causes. Xerostomia is a complication of RT to the head and neck area but also may be caused by commonly used medications (e.g., antihistamines and opioids) and by mouth breathing. The severity depends on the volume of exposed salivary glands, dosage, and location. Radiation decreases the amount of saliva produced, and alters the enzymatic content, pH, and viscosity of saliva. This can lead to the development of caries. Therapy consists of the following options:
2. Management of xerostomia
a. Maintain good oral hygiene and hydration
b. Amifostine ethyol, 200 mg/m2 IV over 15 to 30 minutes before radiation dose. Saliva production at 1 year was greater in those getting the treatment. Adverse effects include nausea and vomiting, but it is not certain whether the cancer may be protected by this drug as well.
c. Saliva substitutes (e.g., Xerolube, Salivart, Synthetic saliva spray) and Biotene chewing gum
d. Pilocarpine, 5 to 10 mg PO t.i.d. given before radiation starts. Pilocarpine is contraindicated in patients with glaucoma or asthma.
e. Others: hard candies (e.g., Life Savers, cinnamon, lemon drops), sugarless chewing gum, ice cubes
C. Taste alterations can occur as a reduction in taste sensitivity (hypogeusia), a distortion of taste (dysgeusia), or the absence of taste (ageusia). Patients with advanced cancer frequently lose taste for red meat, even without anticancer therapies.
1. Causes of taste alterations include carcinomatous involvement of the mouth, head and neck surgery, and CNS lesions. Dental pathology, poor oral hygiene, endocrine factors (hypothyroidism, hypophysectomy, adrenalectomy), stomatitis, xerostomia, malnutrition, drugs, and metabolic disturbances are other causes.
a. Chemotherapy can cause alterations in taste. Agents reported to cause taste alterations include bleomycin, cisplatinum, gemcitibine, interferon gamma, leuprolide, tamoxifen, docetaxel, and etoposide.
b. RT can alter taste by reducing and altering salivary gland output. Taste sensitivity to sweets is the least affected; sensitivity to bitter and salty is most affected. At 2,000 cGy and upward, taste loss increases rapidly. Taste acuity can partially return after 20 to 60 days. Taste can be fully restored 2 to 4 months following RT. Zinc, 25 mg PO q.i.d. before RT was reported to lessen hypogeusia, but controlled trials subsequently did not support this finding.
2. Management of taste dysfunction includes
a. Maintain good oral hygiene
b. Search for medications that can alter taste such as amphotericin, allopurinol, β-lactam antibiotics, chlorhexidine mouthwash, and pentamidine
c. Reduce the urea content (bitterness) of the diet by eating white meats, eggs, and dairy products
d. Mask the bitter taste of urea-containing foods by marinating meats, using more and stronger seasonings, eating food at cold or room temperatures, and drinking more liquids
e. Help overcome general poor taste by eating foods that are tart (lemonade frozen in ice trays, pickles, vinegar) or that leave their own taste (fruit, lemon drops, hard candy)
D. Halitosis occurs when exhaled air is combined with foul-smelling substances from the respiratory or GI tract. The exact incidence is unknown.
1. Causes of halitosis include diseases of the oral cavity, infections of the respiratory tract, diseases of the digestive tract, metabolic failure (diabetic ketoacidosis, uremia, and hepatic insufficiency), drugs (anything that can cause xerostomia, chemotherapy and RT, opioids), and foods (garlic, onions, meat, and fish).
2. Management of halitosis includes
a. Optimal dental hygiene and hydration
b. Gentle brushing of tongue with a soft toothbrush (the back of the tongue in particular collects malodorous bacteria)
c. Mouthwash, breath-freshening tablets
d. Treat infections appropriately
e. Prokinetic drugs for gastric stasis if indicated
E. Dysphagia is difficulty in transferring solids and liquids from the mouth to the stomach.
1. Causes of dysphagia include cancer infiltration or fibrosis of the esophagus, external compression, motor neuron damage, cranial nerve involvement by tumor, cerebellar damage, or neuromuscular dysfunction. Treatment (RT, chemotherapy), drugs (neuroleptics, anticholinergic agents), surgery, concurrent disease, and symptoms associated with advanced cancer (dry mouth, candida infections) are other causes of dysphagia. Treatment options depend on the patient’s prognosis. In patients with advanced cancer and a very short prognosis it may not be appropriate to subject a patient to IV hydration or feeding tubes. In the patient who has a new diagnosis or who is having a slow decline, the following options are available:
2. Management of dysphagia. After there is agreement about treatment and feeding goals, treatment possibilities include the following:
a. Evaluate aspiration for any reason with a videofluoroscopic barium swallow study and fibroendoscopy. Speech therapists could then work with dietitians to design foods with the proper consistency for safe swallowing and sufficient caloric intake.
b. Palliating an obstructed esophagus from esophageal cancer (see Chapter 9, Section VI.B)
c. If an esophageal stent becomes blocked, the patient should sip small amounts of water and, every 30 minutes, dilute hydrogen peroxide. Alternatively, the tube can be flushed with cola.
d. Strictures from RT require gradual dilation by experienced gastroenterologists. Antireflux regimens or reduction of stomach acid with famoti-dine (Pepcid), 10 mg b.i.d., or intermittent 4-week courses of omeprazole (Prilosec), 20 to 40 mg each morning, may be helpful.
e. Excessive saliva production when total esophageal obstruction produces sialorrhea and drooling can be treated with anticholinergics, alum mouth-washes, or irradiation of the salivary glands (400 to 1,000 cGy).
f. Nutritional support for chemotherapy or RT can be optimized for the short term with the use of feeding tubes. Patients of advanced age, with CNS disease, and low serum albumin are at high risk for early mortality and a feeding tube may not be appropriate.
III. NAUSEA AND VOMITING
A. Causes
1. Differential diagnosis. Nausea and vomiting in cancer patients occur most often as a result of cytotoxic chemotherapy. Other causes of nausea and vomiting include elevated intracranial pressure, anxiety, bowel obstruction, constipation, opioids, RT, benign gastric disease, metabolic abnormalities (hypercalcemia, renal or hepatic failure), autonomic dysfunction, and other drugs (e.g., NSAIDs and digoxin).
2. Cytotoxic drugs that are highly emetic include cisplatin, dactinomycin, anthracyclines; dacarbazine, nitrosoureas, nitrogen mustard, and high-dose cyclophosphamide (see Appendix B-1). The mechanisms for nausea and vomiting from chemotherapy are poorly defined but appear usually to be mediated by the CNS; some drugs may have peripheral activity. Acute chemotherapy-induced vomiting typically occurs 1 to 2 hours after treatment and usually resolves in 24 hours. Subacute vomiting occurs 9 to 18 hours after giving chemotherapy. Delayed vomiting occurs 48 to 72 hours after giving cisplatin (especially with doses of 100 mg/m2 or more) and diminishes in 1 to 3 days. Cyclophosphamide can also cause delayed nausea and vomiting; the peak occurs approximately 24 hours after administration.
3. Psychological and behavioral factors may induce or modify vomiting. Patients may vomit even before receiving chemotherapy (anticipatory vomiting) when the IV line is started, the syringe is seen, or even before leaving home on the day chemotherapy is scheduled. Emesis is more easily controlled, on the other hand, in patients with a history of chronic heavy alcohol use.
B. Management of nausea and vomiting
1. Prevention of vomiting. It is best to prevent nausea and vomiting with adequate doses of antiemetics, particularly when chemotherapy drugs known to induce vomiting are used.
a. Serotonin receptor (5-HT3) antagonists bind to type 3 receptors of serotonin (5-hydroxytryptamine [5-HT]) and are the drugs of choice to prevent emesis generated by highly emetic regimens. 5-HT3 blockers alone achieve complete abrogation of emesis in about 60% of patients and achieve major control of emesis in 75% of patients.
(1) Dosage. The following agents have about the same effectiveness and improved efficacy with the addition of a corticosteroid, and they are given 30 to 60 minutes before chemotherapy:
(a) Ondansetron (Zofran), 8 or 32 mg IV (0.125 mg/kg)
(b) Granisetron (Kytril), 0.01 mg (10 µg)/kg IV or 1 mg PO
(c) Palonosetron (Aloxi), 0.25 mg IV over 30 seconds, for acute and delayed nausea and vomiting
(2) Side effects are mild headache, constipation, and transient transaminase elevations. Extrapyramidal side effects do not occur.
b. Metoclopramide (Reglan), a procainamide derivative, acts both centrally (at the chemoreceptor trigger zone as a dopamine antagonist) and peripherally (by stimulating gastric and small bowel motility, thereby preventing gastric stasis and dilation). At high doses, metoclopramide also blocks 5-HT receptors.
(1) Dose: 1 to 3 mg/kg IV q2h for two to six doses.
(2) Side effects include mild sedation, dystonic reactions (especially in young patients), akathisia (restlessness), and diarrhea. The drug is given with lorazepam, diphenhydramine, and corticosteroids to prevent these complications.
c. Corticosteroids are effective for treating chemotherapy-induced vomiting by themselves or with 5-HT3 blockers. Recommended dosages are as follows:
(1) Dexamethasone, 10 to 20 mg IV for one or two doses
(2) Methylprednisolone, 125 mg IV for one or two doses
d. Lorazepam (Ativan), 1 or 2 mg IV or sublingually q3–6h, is very useful in patients who are treated with emetogenic chemotherapy or who have refractory or anticipatory vomiting. The drug’s amnesic effect is also helpful.
2. Agents used for nausea
a. Cannabinoids. Δ-9-tetrahydrocannabinol (THC) is the main active ingredient in marijuana and can relieve nausea and vomiting in some patients who do not respond to other antiemetic drugs. The drug should be prescribed cautiously for elderly patients and not at all for patients with cardiovascular or psychiatric illness. Cannabinoids are not as effective as serotonin inhibitors and they have frequent side effects.
(1) Dose
(a) THC, 2.5 to 10 mg PO q3–4h, is available as Marinol in 2.5-, 5.0-, and 10-mg capsules.
(b) Nabilone (Cesamet) is a cannabinoid that is now approved by the FDA for patients with nausea and vomiting who have not responded to conventional antiemetics. The dose is 1 mg PO b.i.d. to 2 mg t.i.d., beginning 1 to 3 hours before starting chemotherapy.
(2) Side effects include orthostatic hypotension, sedation, dry mouth, ataxia, dizziness, euphoria, and dysphoria. Maintaining a “high” is correlated with the antiemetic effect in younger patients.
b. Scopolamine (Transderm Scop). Patches are changed q3d.
c. Phenothiazines
(1) Prochlorperazine (Compazine), 5 to 20 mg PO q4–6h
(2) Thiethylperazine (Torecan), 10 mg PO t.i.d.
d. Haloperidol (Haldol), 0.5 to 1.0 mg PO q4–12h
e. Metoclopramide (Reglan), 10 to 20 mg PO q6–8h (if gastric stasis is suspected)
3. Delayed vomiting, occurring 1 to 2 days after treatment, is most often seen after high doses of cisplatin and is difficult to treat. The following may be tried:
a. Dexamethasone alone: 8 mg b.i.d. PO for 2 days, then 4 mg b.i.d. for 2 days
b. Metoclopramide: 0.5 mg/kg q.i.d. PO for 2 days with dexamethasone
c. Ondansetron: 4 or 8 mg b.i.d. to t.i.d. for 3 days with or without dexamethasone
d. Aprepitant (Emend) is a NK-1 receptor antagonist that blocks substance P and has been shown to decrease delayed nausea and vomiting by 20%. It is given for 3 days with a 5-HT3 inhibitor and dexamethasone. Give 125 mg PO 1 hour before chemotherapy on day 1, and then give 80 mg PO on the mornings of the second and third days of the chemotherapy cycle.
e. Palonosetron (Aloxi) (see above for dosing)
4. Anticipatory vomiting is exceedingly difficult to palliate. Prevention of emesis when chemotherapy is first given is the best way to prevent anticipatory vomiting. Antiemetics should be prescribed generously, and chemotherapy should be given as late in the day as possible. Symptoms may improve with the following:
a. Sedatives, including antihistamines or benzodiazepines
b. Hypnosis by an experienced psychologist
c. Progressive muscle relaxation, which involves learning to relax by actively tensing and then relaxing specific muscle groups
d. Cognitive distraction
e. Relaxation techniques with guided imagery
f. Operant conditioning (e.g., patients may be treated in an area and on a day different from their usual place and time)
IV. COLORECTAL SYMPTOMS
A. Constipation is extremely common in patients with advanced cancer. Straining, hard stools, infrequent stools, and abdominal discomfort associated with attempts at having a bowel movement are some of the ways it is described.
1. Causes of constipation include
a. Causes directly related to cancer such as bowel obstruction, spinal cord compression, and hypercalcemia
b. Causes owing to the secondary effects of cancer such as weakness, inactivity, confusion, depression, dehydration, and lack of privacy
c. Drugs, such as opioids, anticholinergics (antidepressants), antacids, anti-convulsants (Tegretol), antiemetics (5-HT3 inhibitors), chemotherapeutic agents (e.g., vincristine and thalidomide), abused laxatives, and barium from oral contrast radiographic studies
d. Concurrent disease, such as diabetes, hypothyroidism, anal canal disorders, and diverticulitis
2. Evaluation of the constipated cancer patient requires performing a rectal examination. If hard stools are present, institute stool softeners; manual disimpaction may be needed. If soft stool is present, a stimulatory drug may be needed. If there is no stool, a stimulatory drug may be beneficial. Evidence is that a combination of a softener and a stimulatory drug may be the best approach. Abdominal radiographs may be needed to exclude bowel obstruction.
3. Prophylactic measures include maintaining activity, hydration, fiber in the diet (within reason), and privacy for the patient. Review the patient’s medication list for potentially offending agents.
4. Preparations available include the following:
a. Bulk producers (e.g., Metamucil, Konsyl) are normalizers rather than true laxatives. They must be taken with adequate water; if not, a viscous mass may form leading to obstruction. Their taste is unacceptable. Their effectiveness in severe constipation has not been demonstrated (We do not use these agents).
b. Stool softeners, which are useful in the presence of hard stool, include
(1) Docusate sodium (Colace): 50- and 100-mg capsules
(2) Docusate calcium (Surfak): 50- and 240-mg capsules
c. Bowel stimulants, which are useful if there is soft stool, include
(1) Senna, sennosides (Senokot): 8.6-mg tablet (or syrup); starting dose is 15 mg h.s.
(2) Bisacodyl (Dulcolax): 5-mg tablet, 10-mg suppository; starting dose is 10 mg PO h.s.
d. Commercial combinations include sennosides and docusate sodium (Senokot-S), casanthranol and docusate sodium (Peri-Colace), danthron and docusate sodium (Doxidan), and many others
e. Lubricant laxatives have little role in chronic constipation and are mainly useful for acute impaction:
(1) Mineral oil, which is given as enema
(2) Liquid paraffin, 10 mL PO daily
f. Osmotic laxatives draw fluid into the bowel:
(1) Lactulose (Cephulac), starting dose is 15 to 20 mL b.i.d.
(2) Saline laxatives exert an osmotic effect drawing fluid into the lumen, which can lead to sodium overload, and should not be used in patients with renal failure. Examples are magnesium hydroxide (Milk of Magnesia), magnesium citrate, and sodium phosphates (Fleet Phospho Soda).
g. Rectal laxatives are undignified for the patient, but often give good results. Their mechanisms of action parallel the oral agents. They consist of
(1) Lubricant rectal laxatives, such as oil retention enemas, are good for fecal impaction.
(2) Osmotic laxatives, such as glycerin suppositories
(3) Saline laxatives, such as Fleet Phospho Soda enema
5. Prevention and management of narcotic-induced constipation. Patients who are receiving regular dosages of narcotics (or neuropathic chemotherapy agents such as vincristine) should be carefully questioned about bowel movements. They should be encouraged to drink liquids (e.g., water, prune juice, coffee) and to eat bran cereal daily.
These measures plus stool softeners are usually insufficient, however, and bulk producers are poorly tolerated. The combination of a stool softener and a bowel stimulant in parallel increasing doses is recommended to prevent opioid-induced constipation. Brand name preparations (e.g., Senokot-S, Peri-Colace) can cost 10 times more than generic preparations of these agents.
a. All patients starting on opioids should have senna or Dulcolax available to take h.s. Start all patients on two tablets of senna h.s.
b. If no response occurs, increase the dosage to two, three, or four tablets b.i.d. or t.i.d. as needed, or switch to Dulcolax, two tablets PO h.s. (or to t.i.d. if needed). Add sorbitol, 15 to 30 mL b.i.d., if needed. Reevaluate patients for other causes of constipation.
c. If these measures fail, consider a saline laxative.
d. The management of opioid-induced constipation that is refractory to laxa tives has been treated with oral naloxone, methylnaltrexone, and prokinetic agents, such as subcutaneous metoclopramide. Oral naloxone can reverse opioid-induced constipation without precipitating withdrawal because of its extensive hepatic first-pass metabolism, which leads to low plasma levels. Suggested starting doses are
(1) Oral naloxone, 0.8 mg PO b.i.d. with titration upward every 2 to 3 days, monitoring for laxative effect and withdrawal
(2) Methylnaltrexone and alvimopan (Entrareg) are being evaluated for opioid-induced bowel syndrome
(3) Metoclopramide, 10 mg SQ q6h
B. Rectal discharge can be caused by hemorrhoids, fecal impaction, tumor, radiation proctitis, and various rectal fistulas. After addressing the primary cause, inflammation may be reduced with corticosteroid suppositories or enemas. The skin of the perineum and genitalia must be protected and kept clean (without soap) and dry.
C. Enterocutaneous fistulas can be managed in the same manner as for surgical stomas with colostomy or ileostomy bags. The direction and advice of a stomal therapist are often warranted.
1. The skin surrounding the fistulae rapidly breaks down and limits bag attachment. Débrided skin should be kept clean using water with or without a mild soap; detergents and disinfectants aggravate the skin condition. Glucocorticoid creams (not ointments) can be used for local inflammation, and triple-antibiotic cream can be used for infected areas. Several sealants are available to protect the skin from fistula discharge, including newer plastic coverings that permit air but not liquids to reach the skin and sprays, such as Opsite.
2. Unless the volume of fecal material is large, it is sometimes possible to place a urinary catheter into the stoma, after assessing the anatomy by retrograde barium studies. The catheter can be used as a temporizing measure until abraded skin is sufficiently healed to provide secure attachment for a colostomy appliance.
D. Distal colon and rectal cancerous fistulas involving the bladder or vagina are best managed by a more proximal colostomy. This stops all drainage and allows long-term healing of inflamed tissues.
E. Chemotherapy-induced diarrhea (CID) can be debilitating and potentially life threatening. The risk for CID is significantly greater with regimens that contain fluoropyrimidines or irinotecan. The cause of diarrhea is most likely a multifactorial process that results in an imbalance between absorption and secretion in the small bowel. Irinotecan causes both an acute and a delayed type of diarrhea. The acute onset type is cholinergic in nature, occurs in the first 24 hours, and responds to atropine (0.25 to 1.0 mg IV). The late onset diarrhea occurs 3 to 11 days after treatment.
The opioids loperamide (Imodium) and diphenoxylate (Lomotil) are most commonly used for CID. These agents reduce diarrhea by decreasing peristalsis in the small and large intestines. NSAIDs, clonidine, and cyproheptadine control the diarrhea associated with bowel inflammation, bronchogenic carcinoma, and carcinoid syndrome, respectively. Octreotide is effective in controlling the diarrhea associated with islet cell carcinomas, acquired immunodeficiency syndrome (AIDS), and other secretory diarrheal syndromes. Octreotide also controls severe CID, but the optimal dose quantity and duration is unsettled, and the drug is expensive. The basis for treatment of CID is mostly anecdotal. Recommendations are as follows:
1. Avoid certain food products: milk and dairy products, spicy foods, alcohol, caffeine, prune and orange juices, high-fiber foods, and high-fat foods.
2. Avoid certain medications: laxatives, stool softeners, and promotility agents (metoclopramide, cisapride).
3. Evaluate stool for the presence of fecal leukocytes and pathogenic microbes in patients with persistent or severe diarrhea; treat accordingly.
4. Low-grade diarrhea (National Cancer Institute [NCI] grades 1 and 2; see Appendix B-2).
a. Observe for and correct any fluid and electrolyte imbalances
b. Loperamide given as an initial 4-mg dose followed by 2 mg q4h. If diarrhea persists, increase the dose to 2 mg q2h
c. Octreotide, 100 to 150 µg SQ t.i.d., is given for patients who are refractory to high-dose loperamide therapy; treatment is continued until diarrhea resolves.
5. Severe diarrhea (NCI grades 3 and 4; see Appendix B-2).
a. Hospitalize patients who have significant dehydration, blood in the stool, or abdominal pain, and treat accordingly
b. Octreotide, 100 to 150 µg SQ t.i.d., is given until diarrhea resolves. It is reasonable to increase the dose by 50-µg increments until diarrhea is controlled. Doses up to 2,000 µg SQ t.i.d. for 5 days have been used safely in CID.
V. URINARY SYMPTOMS
A. Dysuria
1. Causes. Inflammation of the urinary bladder or outlet
2. Management of dysuria includes treatment of infection if present and the following:
a. Phenazopyridine (Pyridium), 100 to 200 mg PO t.i.d.
b. Amitriptyline, 25 to 50 mg PO h.s. (especially for interstitial cystitis)
B. Bladder spasm
1. Causes. Vesicular irritation by cancer, postradiation fibrosis, indwelling catheter, cystitis, or anxiety
2. Management of bladder spasm. Cystitis is treated with antibiotics, catheter change, and bladder irrigation if a urethral catheter is present. Drugs of choice are as follows:
a. Flavoxate (Urispas), 200 to 400 mg PO q.i.d.
b. Oxybutynin chloride (Ditropan), 5-mg PO t.i.d. or q.i.d.
c. NSAIDs are reportedly helpful
d. Hyoscyamine sulfate
(1) 0.125-mg tablets (Levsin), 1 or 2 tablets PO or SL q4h
(2) 0.15-mg tablets (Cystospaz), 1 or 2 tablets PO q.i.d.
(3) 0.375-mg sustained release capsules (Levsinex, Cystospaz-M), 1 capsule q12h
e. Belladonna-opium suppositories (B & O Supprettes), one q4h
f. Propantheline bromide (Pro-Banthine), 15 mg PO h.s. or b.i.d.
g. Blocks of the lumbar sympathetic plexus may be effective for the management of intractable bladder pain.
C. Urinary hesitancy
1. Causes. Malignant or benign prostate enlargement, infiltration of the bladder neck, presacral plexopathy, drugs, intrathecal block, bladder denervation by surgery, loaded rectum, inability to stand to void, and asthenia
2. Management of hesitancy. Address the specific causes; a urethral catheter may be necessary. Drugs that may be useful include the following:
a. Terazosin hydrochloride (Hytrin), 1 to 10 mg PO h.s.
b. Bethanechol (Urecholine), 10 to 30 mg PO b.i.d. to q.i.d.
D. Urinary obstruction by tumor
1. Causes
a. Upper tract obstruction can be caused by tumor, stricture, calculi, clots, and retroperitoneal fibrosis.
b. Lower tract obstruction is caused by tumor, benign prostatic enlargement, clots, calculi, infection, stricture, fecal impaction, detrusor failure from anticholinergic side effects of drugs, and neurogenic disease.
2. Management of urinary obstruction
a. Lower tract obstruction management includes catheter placement in the urethra or suprapubically. Tumor-related obstruction can be treated by surgery, RT, or endoscopic resection depending on the disease stage.
b. Upper tract obstruction can be treated by nephrostomy tubes, cystoscopically placed stents, or stenting via nephrostomy tube.
c. Often patients are too debilitated for invasive procedures and supportive care measures become the priority.
E. Discolored urine can be caused by food or drugs and is of no concern, except for the anxiety provoked in the patient.
1. Pink or red urine: beets, blackberries, rhubarb; doxorubicin (Adriamycin); phenolphthalein (Ex-Lax), senna, cascara, danthron (e.g., in Doxidan); deferoxamine (Desferal); chlorzoxazone (Paraflex); phenothiazines; phenazopyridine (Pyridium)
2. Brown or black urine: phenacetin, salicylate; metronidazole (Flagyl); nitrofurantoin, chloroquine, quinine quinacrine, sulfonamides (yellow-brown); L-dopa, methyldopa (Aldomet); iron dextran (Imferon)
3. Blue or green urine: methylene blue, food coloring and other dyes; riboflavin; indomethacin, amitriptyline, danthron, mitoxantrone
4. Yellow: Suntinib malate (Sutent), rifampicin (Rifampin; orange)
VI. RESPIRATORY SYMPTOMS
A. Cough
1. Causes
a. Irritation of airway from dry air, tumor in airway, extrinsic compression, aspiration from vocal cord paralysis, reduced gag reflex, fistula, and gastroesophageal reflux. Infection, medications (e.g., angiotensin-converting enzyme [ACE] inhibitors), and excessive sputum must also be considered.
b. Lung pathology, such as infection, lymphangitic carcinomatosis, radiation pneumonitis, COPD, pulmonary edema, and pleural or pericardial effusion
c. Irritation of diaphragm, pleura, or pericardium
2. Management of cough is according to the cause
a. General measures include positioning the patient, and humidifying the air
b. Antibiotics to treat infection
c. Bronchodilators for bronchospasm
d. Drainage is facilitated by physiotherapy and postural drainage.
e. Mucolytics via steam or nebulized saline, or drugs such as acetylcysteine (Mucomyst)
f. Antitussives include
(1) Opioids, such as codeine, hydrocodone, MS, and dihydromorphone, are all options that have equivalent efficacy.
(2) Benzonatate (Tessalon Perles), 100 mg q4h
(3) Local anesthetics, such as inhaled lidocaine. The dose is empiric. The starting dose is 5 mL of 2% lidocaine q4h via handheld nebulizer.
(4) Dextromethorphan (Robitussin DM)
(5) Inhaled β2 agonists or anticholinergics such as ipratropium (Atrovent) for patients with bronchitic component
(6) Sedation in refractory cases (Valium)
B. Hiccups
1. Causes
a. Diaphragmatic irritation from tumor infiltration, subphrenic abscess or empyema, hepatomegaly, and ascites
b. Phrenic nerve irritation from mediastinal cancers
c. Gastric distention of any cause
d. Uremia, esophagitis, or brain tumors
e. Drugs, such as dexamethasone and barbiturates
2. Management of hiccups
a. Home remedies are numerous and usually involve pharyngeal stimulation. Methods used have included two teaspoons of granulated sugar, two glasses of liquor, a cold key down the back of a hyperextended neck, a nasopharyngeal tube, and drinking a glass of cool water through a straw while plugging both the patient’s ears with his or her fingers.
b. Reduction of gastric distention: nasogastric intubation, peppermint water (relaxes the esophageal sphincter), or antiflatulents (simethicone)
c. Induction of hypercarbia by breath-holding or using a paper bag
d. Potentially helpful pharmacologic measures
(1) Baclofen (Lioresal), 5 to 20 mg PO q6–12h (the only drug tested in a randomized, placebo-controlled manner)
(2) Chlorpromazine (Thorazine), 25 to 50 mg PO or IV q6h
(3) Metoclopramide (Reglan), 10 to 20 mg PO q4–6h
(4) Nifedipine, 10 to 20 mg PO q8–12h
(5) Benzonatate (Tessalon Perles), 100 mg q.i.d.
(6) Ondansetron, 8 mg PO t.i.d. or IV bolus
(7) Anticonvulsants: phenytoin, carbamazepine, valproic acid
(8) Stimulants: amphetamines, methylphenidate
C. Dyspnea
1. Causes
a. Tumor obstruction of trachea or bronchus
b. Infection of lung tissue or bronchus
c. Decreased functional lung tissue, such as following resection, tumor involvement, effusion, embolism
d. Decreased ventilatory movement due to debility, chest wall weakness, elevated diaphragm, ascites, hepatomegaly
e. Cardiovascular causes, such as congestive heart failure, cardiomyopathy, pericardial effusion
f. Other: Anemia, anxiety
2. Management of dyspnea
a. Oxygen is of benefit in hypoxemic patients
b. Opioids have shown positive effects in patients with COPD or advanced cancer
c. Nebulized opioids are controversial
d. Benzodiazepines when an anxiety component exists
e. Corticosteroids used in lymphangitic carcinomatosis
f. Bronchodilators, as indicated
g. Position the patient comfortably; open windows and use fans
3. Management of respiratory panic involves the use of anxiolytics together with opioids. Oxygen may be beneficial for the hypoxemic patient.
4. Management of “death rattle,” which results from the weakened patient being too ill to expectorate, includes
a. Positioning on the left side
b. Hyoscine (Scopolamine) patch, 1.5 mg q72h
c. Hyoscine hydrobromide, 0.2 to 0.4 mg SQ q2–4h
d. Hyoscine butylbromide, 20 mg SQ q2–4h (not available in the United States)
e. Atropine, 0.4 to 0.8 mg SQ q2–4h
f. Suctioning is uncomfortable for the patient and should be minimized
VII. SKIN PROBLEMS
A. Pruritus
1. Causes. Generalized pruritus can develop as a result of the following:
a. Scabies, dry flaky skin, or other primary skin conditions
b. Biliary tract obstruction
c. Paraneoplastic syndrome, lymphomas, cutaneous metastases
d. Renal failure
e. Drugs, such as opioids, amphetamines, intraspinal morphine
f. Hypersensitivity to drugs
g. Autoimmune disorders (systemic lupus erythematosus, Sjogren syndrome)
h. Iron deficiency, polycythemia vera, systemic mast cell disease
i. Thyroid disease, hyperparathyroidism
j. Psychiatric causes
2. Management of pruritus. Control of the underlying cancer may relieve itching. Drugs suspected of causing hypersensitivity reactions should be stopped. Factors that increase the perception of pruritus include dehydration, heat, anxiety, and boredom.
a. Instructions to patients. Patients should be told to avoid traumatizing the skin by alcohol rubs, woolen clothing, or frequent bathing. Excessive bathing, especially with detergents and hot water, results in dry skin, which causes itching in itself. The use of baby oil, olive oil, lanolin, bland creams, emollient creams, or petroleum jelly should be encouraged. The skin should be “oiled” after each bath or shower, blotting in the agent while toweling dry. The use of soap should be stopped and situations that result in increased sweating avoided.
b. Topical therapy. Emollients with camphor and menthol (Sarna lotion), phenol, or pramoxine (PrameGel, Pramosone, or Aveeno anti-itch) can be effective. Cool compresses and oatmeal baths (Aveeno) can be helpful. Topical steroids, such as hydrocortisone 1% or 2.5%, and triamcinolone 0.1%, can be useful provided that they are prescribed in amounts necessary to cover affected skin.
c. Oral medications include antihistamines, anxiolytics, corticosteroids, and antidepressants
d. Specific treatments for specific disorders
(1) Naloxone for intraspinal morphine associated pruritus
(2) Cholestyramine (4 g PO q6h) for cholestatic pruritus
(3) Methyltestosterone (25 mg PO q8h) for cholestatic pruritus
(4) Stenting and anticancer therapy for tumor-related cholestasis
(5) Topical and systemic steroids for inflammatory skin diseases
(6) Pruritus associated with polycythemia vera responds to disease therapy, and H2 blockers
(7) Pruritus associated with lymphoma can respond to corticosteroids and therapy of the disease
(8) Urticaria responds to antihistamines and corticosteroids
B. Preventive skin care in dying patients is extremely important to their comfort. The following are recommendations extracted from Twycross RG and Lack SA. Therapeutics in Terminal Cancer. London: Pitman, 1984.
1. Prevent decubiti by redistributing pressure
a. At home, obtain a camping mattress and fill it with water instead of air to create a waterbed.
b. For wheelchairs, use an inflatable cushion or egg-crate foam.
c. Elbow and heel pads, sheepskin mats, self-adhering urethane foam, pillows, and bed cradles may be helpful.
d. Turn or reposition patients frequently.
e. Decubitus ulcers are sometimes impossible to prevent or treat in terminal patients, regardless of frequent and meticulous care. Cachexia, skin atrophy, incontinence, and pain on movement are some of the contributing factors. Caring and conscientious nurses may need physician reassurance that decubiti in this setting are impossible to prevent or treat.
2. Provide optimal hydration and hygiene
a. Avoid soap on dry, fragile skin; creams and ointments in intertriginous areas; and trauma (from restraints, tape, and so forth).
b. On normal skin, use mild soaps, pat dry, use gentle massage with bland cream, and use petroleum jelly on elbows and heels.
c. On dry skin, use fine talc.
d. On chafed areas, use silicone spray or Opsite.
e. Change bed linen often.
C. Hair loss
1. Causes. Irradiation to the scalp and administration of certain cytotoxic drugs result in marked alopecia. Hair loss begins 2 to 3 weeks after these therapies are started. Hair usually regrows after therapy is discontinued. The relative risks of hair loss caused by chemotherapeutic agents are shown in Appendix B-1.
2. Management
a. Emotional support. Patients need to be forewarned. Hair loss should be discussed openly and sympathetically and its importance compared with the potential benefits of therapy. Inform patients about the relative risks of the specific regimen for alopecia. Explain that hair loss is preceded by scalp itching or pain and that hair is often curly when it regrows.
b. Wigs should be obtained as soon as hair loss becomes evident (or before). Complimenting patients’ appearance in a wig (if sincere) aids in adjustment. Prescribe scalp prosthesis for insurance carriers.
c. Other measures. Suggest the use of hats and colorful scarves, soft-bristle brushes, mild shampoos, and satin pillowcases. Discourage the use of blow-dryers, hot rollers, and exposure of the scalp to the sun.
VIII. NECROTIC, MALODOROUS TUMOR MASSES
A. Pathogenesis. Progressively growing tumor masses may erode through the overlying skin and ulcerate. The center of the mass becomes necrotic with the formation and release of malodorous polyamines, such as putrescine and cadaverine. These polyamines are reactive and adhere to almost anything with which they come in contact, including skin, clothing, and hospital equipment, leaving a residual nauseating odor in the room. The smell worsens if the mass becomes infected with anaerobic organisms. The stench makes it difficult for others to enter the room. When visitors leave, the smell stays on their clothing and skin; as a result, patients become isolated from contact with others. Patients themselves often do not notice the odor.
B. Management
1. RT. Large masses that may invade the overlying skin should be irradiated to prevent skin breakdown.
2. Amputation may be necessary for tumors that do not respond to RT or chemotherapy (e.g., an extremity that is ravaged with sarcoma).
3. Skin metastases confined to one small area of the body may be amenable to local resection. However, recurrences are likely.
4. Chemotherapy or endocrine therapy should be used appropriately for the primary tumor.
5. Local care
a. Frequent dressing changes with highly absorbent, nonadhesive material. Alginates can absorb exudates.
b. Tumor bleeding may be ameliorated with a hemostatic dressing, such as Mepitel, or by applying 1:1,000 epinephrine solutions to the tumor surface before applying the new dressing.
c. Flushing. Necrotic tumor masses and fistulas should be generously irrigated at least t.i.d. with large volumes of 3% hydrogen peroxide.
d. Silver nitrate, 1% solution soaked in large gauze pads, may be applied to necrotic areas by a gloved operator every day or two to help reduce oozing and odor. Absorbed silver may cause renal damage.
e. Maggots actually débride necrotic tissue; however, the sight of maggots in wounds is usually more than nursing staff, physicians, and visitors can tolerate, although patients often do not appear to notice them. Diethyl ether in generous amounts is applied to the tumor surface with 4 × 4 inch gauze; the gauze is wrung out onto the lesion so that it reaches the deeper ulcerated areas. Maggots rapidly recur if treatment with ether is stopped.
6. Measures to control odor
a. Isolate patients with malodorous tumors in private rooms. An outward facing fan is placed to blow air out of the window. Normal areas of skin should be kept clean, and malodorous masses should be kept covered.
b. Room deodorizers should be used. The deodorant aromas should be changed every few days to avoid conditioning of the staff, who soon identify the smell of the product with the rather thinly disguised stench of necrotic cancer.
c. Metronidazole (Flagyl), 250 to 500 mg q.i.d., may be helpful, particularly if anaerobic bacterial infection is present. Crushed metronidazole tablets on soaked gauzes can be applied topically.
d. Chloresium, a 22% chlorophyll–copper complex in isotonic saline, is a true deodorizing agent and can be poured directly onto the necrotic tissues.
e. Disposable protective gowns and gloves should be worn by caregivers.
IX. FEVER
A. Causes. The diagnosis of tumor-induced fever is one of exclusion. It can develop in the course of nearly any malignancy but is especially common in the following conditions:
1. Lymphomas and myeloproliferative disorders
2. Retroperitoneal cancer
3. Metastatic cancer to the liver
4. Hepatocellular and renal cell carcinoma
5. Gastric and pancreatic cancers
6. Osteosarcomas
B. Management
1. Controlling the underlying tumor, when possible, is the most effective means of controlling fever from tumors.
2. Aspirin and acetaminophen may be alternated q2h p.r.n.
3. Indomethacin, 25 to 50 mg PO t.i.d., is often helpful.
4. Corticosteroids may be helpful but are generally not necessary.
X. LYMPHEDEMA is defined as lymphatic production exceeding transport capacity. Most often this is caused by obstruction of lymphatic drainage but also has a component of vascular damage.
A. Patients at risk
1. Breast cancer patients who have had nodal dissection, as well as RT
2. Melanoma patients who have had nodal dissection
3. Prostate cancer patients who have had surgery or whole pelvic radiation
B. Types
1. Acute, transient, and mild, occurring a few days after surgery
2. Acute and painful, occurring 4 to 6 weeks after surgery as a result of acute lymphangitis or phlebitis
3. Erysipeloid form, which occurs after minor trauma and is superimposed on chronic edema
4. Insidious and painless is the most common form. There is no erythema and it occurs years after primary treatment.
C. Assessment
1. Attempt to classify the type of edema
2. How does the edema affect the patient in terms of function? Assess for depression.
3. Examine pulses, sensory and motor functions, and document the size of extremities
D. Management of lymphedema
1. Education involves reporting any areas of breakdown, weeping, or erythema to the doctor. The patient should avoid heavy lifting with the affected limb, avoid hot tubs and saunas, and cuts and burns to the extremity, wear gloves while doing gardening, avoid venipuncture and blood pressure checks in the extremity, and wear a compression sleeve while exercising or traveling. Self-massage should be taught to the patient.
2. Manual lymphatic drainage involves lightly massaging the affected limb to move edema fluid through lymphatic anastomoses to functional lymph nodes. Elastic stockings can be applied after the massage.
3. Extremity pumps can be helpful.
4. Exercise and elevation are never harmful.
5. Antibiotics for evidence of infection.
6. Diuretics may be helpful if a significant vascular component is thought to be present.
7. Corticosteroids are helpful if enlarged nodes are the cause of the edema.
XI. VENOUS ACCESS PROBLEMS
A. Administering chemotherapy to patients with poor venous access
1. Switching to oral agents. Many of the available chemotherapeutic agents are absorbed, although incompletely, when given orally.
2. Difficulty finding veins may be alleviated by several techniques:
a. Hang the arms (wrapped in hot, moist towels, with tourniquets lightly applied) for 10 minutes below the level of the heart.
b. Use a blood pressure cuff expanded halfway between systolic and diastolic pressures. Tight tourniquets are never helpful.
c. Search other places to find veins, such as the upper arm or legs.
d. Advise patients to drink plenty of liquids on the day before treatment and to wear a sweater on the day of treatment to keep the arm warm.
e. Place hot packs over the site before venipuncture.
3. Vein training. Patients with inaccessible veins are instructed to sit in a chair with the arms held below heart level and to squeeze tennis balls, Nerf balls, or household sponges t.i.d. for 10 minutes or until fatigued. The arms may be wrapped periodically with warm towels.
4. Other methods for securing venous access include arteriovenous fistula (see Section XI.C) and right atrial Silastic catheters (see Section XI.E).
B. Heparin lock. A plugged, short catheter may be used in patients requiring intermittent IV infusions. The catheter is flushed regularly with heparin.
C. An arteriovenous fistula can be established in patients who have inaccessible veins and a reasonably long expected survival. Administration of viscous solutions through the shunt promotes thrombosis.
D. Hypodermoclysis. Dehydration in patients with difficult venous access can be treated with parenteral fluids administered by clysis. A 21-gauge needle is inserted at a slight angle to the skin of the lateral thigh and then further inserted 1 to 2 inches into the subcutaneous tissue. One vial (150 U) of hyaluronidase (Wydase) is administered through the needle; the enzyme should not be infused into inflamed or cancerous areas. Ringer’s lactate solution and mineral additives can then be given at a rate of 100 to 150 mL.
E. Prolonged central venous catheterization. Polymerized silicone rubber (Silastic) catheters inserted into the right atrium through the cephalic vein can provide prolonged venous access for administering IV fluids, blood products, and drugs, and for sampling blood. Both external and subcutaneously implanted types are available.
1. A nonfunctioning catheter is usually the result of obstruction of the catheter tip by either the right atrial wall or a clot. Repositioning the patient usually dislodges the catheter from the atrial wall. A chest radiograph should be taken to evaluate the position of the catheter tip, if it is questionable.
a. Heparin, 3 mL of 1:1,000 solution, should be injected into the line with a tuberculin syringe to provide extra pressure; leave it in place for 15 to 60 minutes before flushing. Repeat the procedure four more times or until successful.
b. Urokinase, 5,000 IU (Abbokinase “Open Cath”) may also be tried if a clot is suspected.
c. An infusion of urokinase directly into the dysfunctional catheter may also successfully dissolve clots. The dose is 40,000 U/h for 1 to 12 hours. Patients should be observed for bleeding for 48 hours.
d. Alternatively, Alteplase, a tissue plasminogen activator for local fibrinolysis that is manufactured by recombinant DNA technology, can be used. When instilled into a catheter at a dose of 0.5 to 1.0 mg/h, circulating levels would be expected to return to endogenous circulating levels within 30 minutes of stopping the infusion.
2. Complications. Catheter-related deaths are rare. The most frequent problems are severing the catheter (if external), infections, and clotting. Differences in the incidence of documented infections between external catheters and subcutaneous ports are arguable; if infections do occur, they may be treated successfully with antibiotics without removing the catheter in the appropriate circumstances (see Chapter 35, Section III.G). No differences exist in the incidence of clotting between external and subcutaneous catheter devices.
3. Indications for removing venous catheters include persistent fever, unexplained hypotension, entrance-site infection, air leak, axillary; jugular, or superior vena cava thrombosis; or pleural effusion (due to misplacement of the catheter into the pleural space).
XII. NUTRITIONAL SUPPORT
A. Mechanisms of malignant cachexia are poorly understood. The characteristics of cancer cachexia that differ from starvation cachexia include equal mobilization of fat and skeletal muscle (rather than preferential mobilization of fat), normal or increased basal metabolic rate (rather than decreased), increased liver metabolic activity, normal or increased glucose turnover (rather than decreased), and increased protein breakdown (rather than decreased). Related factors include but are not limited to the following:
1. Metabolic abnormalities in cachexia of malignancy
a. Carbohydrate metabolism: decreased blood glucose levels, glycogen stores, and sensitivity to insulin; increased gluconeogenesis, Cori’s cycle activity, glucose turnover, and serum lactate
b. Fat metabolism: decreased lipoprotein lipase activity, lipid stores; increased lipolysis, serum triglyceride levels, and glycerol turnover
c. Protein metabolism: decreased skeletal muscle synthesis; increased skeletal muscle catabolism and protein turnover; negative nitrogen balance
d. Cytokine abnormalities involve tumor necrosis factor, IL-1, IL-6, interferon gamma, leukemia inhibitory factor, and others
2. Decreased intake
a. Anorexia. Many tumors are associated with anorexia, typically manifested by an aversion to meat. Poorly controlled pain, stomatitis, chemotherapy, RT, and altered sense of taste and smell contribute to the loss of appetite. GI causes of malnutrition or anorexia include decreased gastric reservoir from tumor or extrinsic compression (hepatomegaly), dysphagia from tumor or treatment, and fistula formation. Depression and organ failure are other causes.
b. Mechanical obstruction of any portion of the intestinal tract makes oral intake impossible. In advanced stages, tumors of the head and neck or ovary frequently make eating impossible.
c. Nausea and vomiting. See Section III.
d. Diagnostic studies often require fasting; if such studies are not conducted efficiently, patients can become nutritionally further compromised.
3. Increased losses
a. Biochemical abnormalities. See Section XII.A.1.
b. Diarrhea. Severe diarrhea or malabsorption syndromes are associated with carcinoid syndrome, gastrinoma, medullary thyroid carcinoma, pancreatic carcinoma, small bowel lymphatic obstruction, excessive bowel resection, certain cytotoxic agents, and radiation enteritis.
c. Lactase deficiency is common in protein starvation and after some chemotherapies, making milk products unsuitable.
4. Natural history. Increasing loss of body protein leads to progressively worsening anemia, hypoalbuminemia, hypotransferrinemia, loss of cell-mediated immunity, decreased work tolerance, decreased deep-breathing ability, increased risk for pneumonia, inability to ambulate, and then inability to sit up. Other signs include hair loss, scaling skin, brittle nails, and decubitus ulcer. Death occurs when 30% to 50% of body protein stores are lost.
B. Assessment of nutritional status. Serial measurements of the following parameters provide prognostic information about the risk for sepsis and death:
1. Weight and serum albumin concentration. Substantial protein-calorie malnutrition is characterized by a recent loss of >10% of the stable preillness weight and by significant hypoalbuminemia (<3.0 g/dL). Albumin has a serum half-life of about 3 weeks, and albumin levels change in direct proportion to improvement or deterioration of nutritional status.
2. Transferrin has a half-life of about 1 week and changes more rapidly than albumin with changes in nutritional state. Serum transferrin is also less affected than albumin by factors unrelated to nutritional state, such as hydration and infection.
3. Skin tests. Poor nutrition with weight loss of >10% of usual body weight results in anergy and depression of immune competence. Nutritional status and immunocompetence are adequate if two or more of the following skin test antigens produce a positive intradermal reaction: tuberculin, mumps, Candida sp., and streptokinase-streptodornase.
4. Nutritional requirements. The healthy person requires 2,000 to 2,700 (25 cal/kg) calories per day distributed as follows: 15% protein (1 g/kg body weight), 50% carbohydrate (3 g/kg), and 35% fat (1 g/kg). To achieve a positive nitrogen balance and sustain weight, cachectic patients would require hyperalimentation with 2,700 to 4,000 calories and twice the recommended daily allowance of amino acids and essential nutrients. These calculations are for patients with cancer who warrant hyperalimentation (see below).
C. Treatment of anorexia and cachexia
1. Palliative care of the anorectic or cachectic patient. Progressive weight loss is part of the biology of progressive cancer. Nutritional therapy does not prolong survival if the tumor cannot be controlled. Most patients and families, however, believe that nutritional status is essential, regardless of the underlying disease.
a. Physician interest in dietary support often provides psychological palliation, especially when active cancer treatment is not helpful. Useful techniques include referral to dietitians, and “folksy” dietary advice, such as the use of caloric supplements and the measures described in Section XII.C.2, below, which give patients and families the feeling that they are doing something positive. The physician must recommend against unhealthful diets and potentially toxic doses of “health food” preparations.
b. It is important that the physician support the wishes of the dying patient who is becoming exhausted by well-meaning family members and friends trying to force food intake. Advise family that, although the intentions are appreciated, pushing a patient to eat is exhausting and adds to that person’s misery. The physician should reiterate the futility and harmful psychological effects of forcing food. The refusal to eat is the patient’s biology and decision.
2. Some measures that may be helpful in patients who refuse food include the following:
a. Provide small, frequent feedings, up to six times a day, as tolerated.
b. Take a dietary history. Are there times of the day when the patient has an appetite? If so, the major caloric intake should occur at these times.
c. A small helping looks better on a small plate; do not use large dinner plates.
d. Have food available whenever the patient is hungry.
e. Have the patient dress for meals and sit at the table, if possible.
f. Attend to stomatitis, dry mouth, and foul taste.
g. Vitamins may be used if not excessive. Vitamin C is ineffective therapy against tumors, but is usually harmless unless substituted for proven therapy or if the doses ingested produce dysuria, diarrhea, or satiety.
h. Do not routinely weigh the patient.
3. Appetite stimulants that may be helpful include the following:
a. Megestrol acetate, 400 to 800 mg/d (10 to 20 mL/d of Megace Oral Suspension, which contains 40 mg/mL in 240-mL bottles). Side effects include high cost, venous thrombosis, edema, hypertension, and hyperglycemia.
b. Dexamethasone, 4 mg in the morning after food. This dose is empirically derived. Side effects include proximal myopathy, fluid retention, mental status changes, and immunosuppression.
c. Metoclopramide (Reglan), 10 mg PO before meals and bedtime, may be indicated in patients who are experiencing anorexia, nausea, early satiety, and manifestations of dysmotility. Side effects include dystonic reactions and restlessness.
d. THC, 2.5 to 7.5 mg after breakfast and lunch, starting with the lower dose, which is then escalated. Side effects include dizziness, fluid retention, somnolence, and dissociation, particularly in the elderly. A recent placebo-controlled trial suggests no benefit for cannabinoids in the anorexia-cachexia syndrome.
e. Antidepressants may be useful with anorexia caused by depression.
f. Hydrazine sulfate, cyproheptadine, anabolic steroids, dronabinol, and pentoxifylline have been shown to be ineffective for cancer patients in controlled trials.
g. Psychostimulants, such as methylphenidate (Ritalin), may actually improve appetite when used in the setting of depression.
4. Other measures
a. Dental relining improves chewing abilities and facial appearance.
b. An old photograph helps the new caregivers recognize the essential humanness of the emaciated patient.
c. New photographs of the patient with family, friends, and caregivers help legitimize the value of this “new” person.
d. The patient should have at least one new set of well-fitting clothes, if affordable.
D. Hyperalimentation in cancer patients. Nutritional deficiency leads to decreased immunocompetence, poor wound healing, and decreased tolerance to antitumor therapy. For cancer patients whose prognosis warrants nutritional support, enteral feeding (EF) or parenteral hyperalimentation (PH) may be given.
1. Indications for EF. “If the gut works, use it.” Patients who have a functional GI tract but are unable to ingest adequate nutrients orally are candidates for EF. EF is far less expensive, more physiologic, and associated with fewer complications than PH.
2. Indications for PH
a. The patient has a curable neoplasm, but recovery likely will be protracted from treatment (e.g., extensive bowel resection).
b. The patient is cured of tumor but is awaiting surgical intervention and has residual nutritional problems (e.g., enterocutaneous fistulas).
c. The patient requires prolonged postoperative nasogastric suction (>4 to 7 days) for conditions that necessitate avoidance of oral intake.
d. Patients with severe malabsorption, vomiting, esophageal obstruction from benign causes, or severe dysphagia not amenable to dietary manipulation
e. Patients with chemotherapy-associated severe diarrhea or prolonged stomatitis leading to weight loss
3. Contraindications to hyperalimentation
a. Contraindications to EF are intractable vomiting, upper GI bleeding, or intestinal obstruction.
b. Hyperalimentation is not useful for patients with any of the following conditions:
(1) Minimal nutritional deficits
(2) Weight loss caused by progressive cancer that is unlikely to respond to therapy
(3) Aggressive tumors that respond dramatically to therapy (e.g., lymphoma and small cell lung cancer)
c. PH is strongly discouraged in most patients receiving chemotherapy because the 12% complication rate is unacceptable. Complications include pneumothorax, thrombosis, and catheter-related septicemia.
E. Enteral feeding provides liquid formula diets into the GI tract orally or by means of feeding tubes. Gastrotomy tubes and other tube enterostomies are used when a nasogastric feeding tube cannot be placed or is not tolerated by the patient. Percutaneous endoscopic placement has the advantages of speed and minimal surgical incision.
1. Preparations. Many enteral products are available, but a standard formula is usually sufficient for patients with an intact digestive system. Isotonic solutions that contain high nitrogen and a medium caloric density (1 to 2 kcal/mL) are satisfactory in 90% of patients. Preparations that contain a high concentration of amino acids are often unacceptable for patients with cancer-related meat aversion.
High-calorie preparations are offered as caloric supplements, but they often cause diarrhea and are so rich that many patients refuse them. Asking patients for flavor preference, diluting each can with an equal amount of water, and serving no more than half this amount on ice can make these preparations more acceptable to patients. This cooled dilution can provide up to an additional 1,000 cal/d when given after patients have eaten what they can of a meal, between meals, and h.s. as tolerated.
2. Administration. Start tube feedings with a full-strength solution at about 30 mL. Increase the infusion rate to tolerance by increments of 10 to 25 mL over 12 to 24 hours for 2 to 3 days.
3. Complications of EF
a. Frequent complications and corrections
(1) Vomiting and bloating: reduce the flow rate.
(2) Diarrhea and cramping: reduce the flow rate; dilute the solution; treat with an antidiarrheal drug; consider a different type of solution. Diarrhea is especially likely in patients who have been given broad-spectrum antibiotics.
(3) Hyperglycemia: reduce the flow rate; give insulin.
(4) Edema: usually requires no treatment; diuretics may be used.
(5) Offensive smell or taste: add flavorings.
(6) Nasopharyngeal discomfort: encourage the use of sugarless gum, gargling with warm water and mouthwash, topical anesthetics.
(7) Abnormalities of serum levels of sodium, potassium, calcium, magnesium, or phosphorus: adjust the formula’s ingredients.
b. Infrequent complications and corrections
(1) Congestive heart failure: administer fluids more slowly and treat cardiac decompensation.
(2) Fat malabsorption: use low-fat formulas; add pancreatic enzymes.
(3) Elevated serum transaminase: decrease carbohydrate content of formula.
(4) Acute otitis media: administer antibiotics; change nasogastric tube to other nostril.
(5) Clogged tube lumen: flush with water or replace tube.
c. Rare complications that necessitate discontinuing therapy
(1) Aspiration pneumonia (unlikely to occur if the head of the bed is elevated to 45 degrees, volume overload is avoided, and the cough reflex is intact)
(2) Esophageal erosion from nasogastric tube
(3) Acute purulent sinusitis
(4) Hyperosmolar coma
XIII. CANCER-RELATED FATIGUE
A. Definition. A history of fatigue, diminished energy, increased need to rest disproportionate to any recent change in activity level occurring every day during the same 2-week period in the last month plus five of the following:
1. Weakness
2. Diminished concentration or attention
3. Insomnia or hypersomnia
4. Unrefreshing sleep
5. Need to struggle to overcome inactivity
6. Difficulty completing daily tasks
7. Problems with short-term memory
8. Postexertional malaise lasting several hours
9. Symptoms cause difficulty in everyday functioning
10. Symptoms are a consequence of cancer or cancer-related therapy
11. Symptoms are not a consequence of depression, somatization disorder, or delirium
B. Causes
1. Cancer, cancer therapies, biologic response modifiers
2. Systemic disorders, such as anemia, infection, pulmonary infections, liver and renal failure; malnutrition, dehydration, electrolyte disorders, endocrine dysfunction
3. Sleep disorders
4. Immobility and lack of exercise
5. Chronic pain
6. Centrally acting drugs, such as opioids
7. Psychosocial problems
C. Evaluation. Take a history focusing on severity, provocative palliative factors, and impact on quality of life. Look for causes and manifestations of fatigue.
D. Management of cancer-related fatigue
1. Establish reasonable expectations
2. Correct potential causes, such as depression, anemia, fluid and electrolyte disorders, endocrine deficiencies, and hypoxia
3. Treat deconditioning; consider referral to a rehabilitation specialist
4. Pharmacologic interventions
a. Methylphenidate (Ritalin), 2.5 or 5.0 mg PO at 8:00 AM and noon (has been proven not to be helpful)
b. Dextroamphetamine, 2.5 or 5.0 mg PO once or twice daily.
c. Modafinil (Provigil), 100 to 200 mg PO each morning
d. Corticosteroids, such as dexamethasone (1 to 2 mg b.i.d.) or prednisone (5 to 10 mg PO b.i.d.)
5. Nonpharmacologic approaches
a. Educating the patient
b. Individualizing exercise programs if possible
c. Maintaining a diary
d. Educating about sleep, hygiene, stress management, proper nutrition, and hydration may help
Suggested Reading
Bruera E, Kim HN. Cancer pain. JAMA 2003;290:2476.
Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. J Palliat Med 2002;5:127.
Bruera E, Valero V, Driver L, et al. Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial. J Clin Oncol 2006;24:2073.
Caraceni A, Cherny N, Fainsinger R, et al. Pain measurement tools and methods in clinical research in palliative care: recommendations of an expert working group of the European Association of Palliative Care. J P Symptom Manage2002;23:239.
Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol 2001;19:2542.
Davis MP. The opioid bowel syndrome: a review of pathophysiology and treatment. J Opioid Manag 2005;1:153.
Estfan B, LeGrand S. Management of cough in advanced cancer. J Support Oncol 2004;2:523.
Foldi E. The treatment of lymphedema. Cancer 1998;83(12 Suppl American):2833.
Grocott P. The palliative management of fungating malignant wounds. J Wound Care 2000;9(1):4.
Hanks GW, Conno F, Cherny N, et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer 2001;84(5):587.
Mitchell SA, Berger AM. Cancer-related fatigue: the evidence base for assessment and management. Cancer J 2006;12:374.
Navari RM. Prevention of emesis from multiple-day and high-dose chemotherapy regimens. J Natl Compr Canc Netw 2007;5:51.
Stearns L, Boortz-Marx R, Du PS, et al. Intrathecal drug delivery for the management of cancer pain: a multidisciplinary consensus of best clinical practices. J Support Oncol 2005;3:399.
Sykes NP. The pathogenesis of constipation. J Support Oncol 2006;4:213.
Twycross R, Greaves MW, Handwerker H, et al. Itch: scratching more than the surface. QJM 2003;96:7.
Vadhan-Raj S, Trent J, Patel S et al. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer. Ann Int Med 2010;153(6):358.
Williams CM. Dyspnea. Cancer J 2006;12:365.
Yan BM, Myers RP. Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer. Am J Gastroenterol 2007;102:430.
Zell JA, Chang JC. Neoplastic fever: a neglected paraneoplastic syndrome. Support Care Cancer 2005;13:870.