Symptoms

Individuals presenting with lung cancer are usually highly symptomatic. Most patients with advanced disease have at least four distressing symptoms. Their average pain severity is 6 to 7, which is considered moderate, based on a numerical rating scale with 0 being no pain and 10 being severe pain. The most frequently reported symptoms are anorexia, cough, dyspnea, fatigue, pain, and insomnia. Individuals with lung cancer experience a greater prevalence of depression and anxiety than individuals with other cancers and also have more frequent and prolonged fatigue compared with patients with other cancers. Breathlessness occurs in 70% of patients, is associated with a substantially greater symptom burden, and can adversely influence the experience of caring for a loved one. Symptom burden may, in fact, be greater than patients indicate. That is why it is important to use a standardized symptom questionnaire. Studies have shown that, when presented with a symptom checklist, patients report three to four times more symptoms than they volunteer.

Even individuals with relatively early-stage lung cancer (stages I–IIIB) have substantial symptoms. When using the Lung Cancer Symptom Scale at disease presentation, patients reported an average of 11 symptoms, and, even when successfully treated, they reported an average of 6 to 7 symptoms still present a year after treatment. As mentioned previously, individuals with early-stage lung cancer experience lack of energy, worry, dyspnea, cough, and insomnia. The Karnofsky performance status often remains impaired at 36 to 52 weeks after treatment, but symptom distress gradually declines by 1 year. Symptom distress is the primary reason for clinical encounters in the outpatient setting and the primary reason for unscheduled admissions. Despite treatments for NSCLC, there is gradual deterioration in physical function, activities of daily living, and cognitive function and an increasing need for social support.

Physicians frequently believe that tumor reduction is a surrogate for improved patient-related outcomes. However, based upon a systematic review of quality of life associated with standard chemotherapy for advanced NSCLC, there are no major changes in the global quality of life for patients on standard chemotherapy regimens. There is only a modest correlation (0.35) between objective tumor size and symptoms. Improved patient-related outcomes with treatment last a much shorter time (3.8 months on average) than duration of objective tumor response (6.4 months). Objective tumor response and patient-related outcomes contribute unique, independent information. One cannot be substituted for the other. Unfortunately, most oncologists are unfamiliar with standard symptom questionnaires, and most are not aware of clinically meaningful differences in patient-related outcome measures. However, having patients complete quality-of-life and symptom questionnaires gives patients a sense of better continuity with their physician and the feeling that their treating oncologist has considered their daily activities and emotional state. Patients think that such questionnaires are helpful and not burdensome. Longitudinal assessment of symptoms is also important because treatment reduces certain symptoms but increases others.

At least 40% of outpatients with cancer are undertreated for pain, as measured by the Pain Management Index. This reflects inadequate analgesic choices based on pain severity, but does not reflect pain response. Despite the fact that greater than 60% of patients have substantial pain, there is no change in the Pain Management Index score with follow-up. Oncologists self-rate their ability to manage pain as high (7 to 10, with 10 being the best management), but rate their colleagues’ ability to control pain lower (3 to 10). Oncologists perceive lack of assessment, time constraints, and patient reluctance to complain as barriers to pain management. Most oncologists know the WHO analgesic stepladder and prescribe opioids around-the-clock for chronic pain. However, most (greater than 60%) fail to correctly answer questions regarding opioid management (dose, schedule, conversion and rotation ratios, and titration) when tested through clinical scenarios. This has been documented in several studies. Symptom burden increases in intensity and number of symptoms as cancer progresses and then plateaus in the last month of survival. Eighty percent have increasing fatigue, dyspnea, and anorexia, and most have chest pain in the last 3 months of life. Left poorly managed, these individuals experience a painful death, and families experience complicated grief or depression in bereavement. Integrating palliative care into outpatient oncology practice early in the course of cancer reduces symptom burden, improves quality of life, and provides the care and support patients and families want (see Box 58.3 ).

Communication

Honest communication is important but can be marred when a patient and physician maintain false hope in anticancer therapy. Good communication includes discussions about alternative therapies, prognosis, the goals of therapy, advance directives, and end-of-life care. Giving bad news requires some special skills, and few oncologists have had that type of communication training. In the US Cancer Care Outcomes Research and Surveillance (Can CORS) study, only half of patients with advanced cancer had discussions about hospice care, and yet greater than 70% died within 6 months. Of the more than 4000 physicians caring for Can CORS patients, most would not initiate discussions about prognosis, advance directives, resuscitation, and hospice care, even if death was expected within 6 months and despite national guidelines. Most physicians stated that they would postpone these discussions until the patient was highly symptomatic or failed disease-modifying therapy. Some will not conduct these discussions unless initiated by the family or patient. Medical oncologists explain the disease course in 53% of consultations and discuss the absence of cure in 84%. However after consultation, most patients with advanced lung cancer still believe there is some chance of cure with chemotherapy. Even after being fully informed using decision aids, one-third of patients with incurable cancer feel that their cancer has some chance of being cured with chemotherapy. Patients do want to be fully informed about the stage at diagnosis and the prognosis, but comprehension often lags behind. Within consultations, oncologists address symptoms in 35% of patient encounters and discuss prognosis in 39%. Patients may perceive prognosis differently than incurability, which has no time line. Even when prognosis is discussed, physicians tend to be overly optimistic. Documentation of discussions about prognosis appears in less than 40% of medical charts. However, documented discussions about prognosis are also associated with documented discussions about options regarding ongoing anticancer therapy (odds ratio 5.8), and documented do-not-resuscitate (DNR) orders (odds ratio, 2.2). Individuals with advanced cancer who overestimate their prognosis or who are given an overly optimistic estimate of survival are more likely to choose therapies for which the burden outweighs the benefit, are less likely to discuss preferences with surrogates, and are less likely to obtain information that would improve the quality of end-of-life care.

The picture may be a bit different from the patient’s perspective. In a study involving 276 patients from four major medical centers, 40% of patients rated communication with their oncologist about the potential for cure of their lung cancer low, and 80% gave low ratings about communication regarding resuscitation, life-sustaining treatments, and preparation of advance directives. Over half of patients reported that communication with their oncologist was inadequate. These findings may be related to a patient’s perception and inability to comprehend the seriousness of the situation, which is only realized as cancer progresses.

A large number of patients choose palliative chemotherapy at the end-of-life, for little to no benefit, because it helps them maintain a sense of control. Adverse effects are less of a concern for patients who value quantity of life. In this situation, alternatives are frequently not discussed. There are few, if any, decision aids to help patients make choices when considering palliative chemotherapy. Patients who have a priority of a longer life rather than better quality of life and who have had a previous response to anticancer treatment are likely to choose aggressive treatment. Patients experience cognitive dissonance when oncologists attempt to discuss end-of-life care and palliative chemotherapy within the same visit. Few patients with advanced cancer have completed advance directives, and less than one-quarter of patients want to discuss advance directives with their oncologists. Sixty percent of oncologists prefer not to discuss advance directives and end-of-life care, including resuscitation and hospice, until anticancer treatments are exhausted.

A collusion of hope surrounding anticancer therapy is maintained by continuing aggressive anticancer therapies despite little or no benefit. Although once important, patients seem to disregard quality of life and give precedence to quantity of life in choosing salvage chemotherapy. Physicians are inclined to continue anticancer therapy, despite lack of benefit, to maintain hope rather than provide supportive and palliative care. Paradoxically, this occurs despite the fact that there is little survival benefit with chemotherapy given within 1 to 3 months of death. In fact, chemotherapy may shorten survival, and early palliative care and hospice care may prolong survival.

As a result, the average time from the last chemotherapy to death is 50 to 60 days, and the time from the last targeted therapy to death is 40 to 50 days. Fourteen to eighteen percent of individuals receive chemotherapy or targeted therapy within 30 days of dying. The most common targeted agents used at the end of life are erlotinib and bevacizumab. Patients with lung cancer had greater odds (2.6) of being on a targeted agent within the last 30 days of life than individuals with other advanced cancers. In one study at a large cancer center, the median time from palliative care consult to death was 1.4 months (interquartile 0.5 to 4.2 months) but the median length of time from the first encounter with an oncologist to consultation about palliative care was 20 months (interquartile 6 to 45). Therefore, there were multiple missed opportunities to include palliative care as part of patient care earlier in the course of disease. Half of patients with lung cancer are within 2 months of death before end-of-life care and hospice are mentioned. The average stable performance score of patients with lung cancer, as measured by the Palliative Prognostic Index, a modification of the Karnofsky performance score, is 8 to 9 months. Once the Palliative Prognostic Index has dropped to 30 or less, the average survival is 0.38 months. At this stage, very few patients (less than 5%) will have improvement in their performance score. Consulting palliative care services after the patient has become bedridden, or has a poor performance score, provides little time to manage symptoms and primarily requires crisis intervention. Offering additional anticancer therapy when a performance score improves is unlikely to occur and, if discussed with the patient, will lead to a false sense of hope and will delay advanced care planning and hospice referral. Even patients with technically treatable small cell lung cancer and an Eastern Cooperative Oncology Group performance score of 3 or 4 do poorly. Only 20% of them will finish the standard four cycles. With a performance score of 4, the median survival is 7 days, and, with a performance score of 3, it is 64 days.

The end results of poor communication and a collusion of hope in anticancer therapy are aggressive care at the end of life, chemotherapy in the last 14 days of life, intensive care unit admissions in the last 30 days of life, and acute hospital-based care in the last 30 days of life. About half of patients with advanced lung cancer will have aggressive therapy at the end of life. The detrimental effect of aggressive care at the end of life is not just economic. It also creates a greater risk of caregiver depression and complicated grief. In retrospect, many patients and families regret their choices of aggressive therapy near the end of life.

In general, patients feel that advance directives should be discussed earlier than physicians do, and the majority of families wished palliative care had been involved earlier in the course of cancer treatment. In one study, end-of-life care discussions took place a median of 33 days before death. In hospitalized patients with advanced cancer, palliative consults usually occur late within the hospital stay, when death is imminent, after a substantial hospital stay, or after admission to an intensive care unit. Consultations often involve the transfer of care.

Most patients in large cancer centers do have a DNR directive in place at the time of death. The average time of signing a DNR directive is less than 3 days before death, and one-third are signed by surrogates. As few as 5% of individuals with advanced cancer who die in the hospital have signed outpatient DNR directives.

Symptom Management, Prognostic Information, and Hope

One of the benefits of integrating palliative care into outpatient oncology is decreased symptom burden. The use of symptom assessment questionnaires will uncover more bothersome symptoms, which can then be managed by the palliative care team. Individuals referred to palliative care early in the course of treatment are more likely to perceive and retain accurate information about prognosis and are less likely to receive aggressive chemotherapy at the end of life. Prognostic discussions do not dampen hope. They empower individuals by providing realistic expectations to help them make informed choices about their medical care. Early palliative care is associated with longer intervals between the last chemotherapy and death and increased hospice enrollment more than 7 days before death (60% compared with 33%). Individuals who have less than 30 days of exposure to palliative care are more likely to receive chemotherapy within 30 days of death. Hope is more influenced by a caring relationship between patient and physician than by prognostic disclosure. The great majority of caregivers feel that avoiding discussions about prognosis is an inappropriate way of maintaining hope.

Communication, Quality of Life, and Patient-Related Outcomes

Palliative care programs use quality-of-life questionnaires that have been shown to improve communication. Providing palliative care during anticancer therapy improves quality of life. Patient-centered communication takes time and involves sensitivity. Physicians must be able to respond to emotive verbal and nonverbal cues. Oncologists respond to approximately 20% to 30% of emotional cues and are quite responsive to informational cues. Within family meetings, physicians often do most of the talking (71%) compared with family members (29%). One of the core competencies required of physicians completing a fellowship in palliative medicine is to be able to conduct a family meeting. Therefore, when compared with oncology trainees, palliative medicine specialists are more likely to be better equipped to effectively communicate within the family conference. Emotional and psychosocial issues assume greater importance at the end of life. Communication training, which is part of a palliative medicine fellowship, can improve physicians’ attitudes and their responses to emotions, as well as the satisfaction of the patients’ families. Time constraints are a major issue for cancer specialists because cancer treatment and related issues need to be addressed. Paradoxically, despite the intensive involvement oncologists have with their patients, patients prefer to have conversations and communications about end-of-life care with physicians other than their oncologist. They want their oncologist to remain “optimistic” and focused on treating their cancer.

Rehabilitation

General rehabilitation, exercise with strength training, and aerobics and pulmonary rehabilitation are often neglected in the various phases of treating patients with lung cancer. Many individuals with lung cancer have chronic obstructive lung disease (COPD), and evidence indicates pulmonary rehabilitation in chronic lung disease improves quality of life, dyspnea, and fatigue and empowers patients to be involved in their own therapy. Although moderate physical activity reduces fatigue and improves symptoms, function and quality of life three-fourths of patients with lung cancer in the United States do not meet physical activity guidelines, and 51% do not participate in moderate activities. For some individuals with cancer who have undergone potentially curative therapy, physical exercise can actually reduce recurrences and all-cause mortality. Physical exercise is safe and feasible and may even potentially benefit individuals with advanced incurable cancer. There is an open trial that is investigating the benefits of 2 months of a physical exercise intervention on fatigue and quality of life in patients with unresectable lung cancer. Rehabilitation and physical exercise are most often discussed in palliative care, interdisciplinary team meetings rather than in oncology tumor boards. Therefore, patients who are seen by the palliative care team are more likely to be considered for pulmonary rehabilitation and exercise training.

Research and complementary therapies of integration of palliative care into cancer treatment have resulted in supportive and complementary therapeutic trials during standard chemotherapy. In one trial, patients using American ginseng had improved cancer-related fatigue, particularly during chemotherapy. In another trial, patients using omega-3 fatty acids during chemotherapy for NSCLC experienced improved muscle mass compared with standard treatment.

Health-Care Economics

Early integration of palliative care into cancer care not only reduces aggressive care at the end of life, but also has economic advantages, without adversely influencing survival. Nearly 40% of Medicare dollars are spent in the last months of life. Even when palliative care is used as crisis intervention, transfer of appropriate patients from inpatient acute care to inpatient palliative care reduces costs by 66%. Palliative care inpatient consult teams reduce daily inpatient costs by US $239. The authors of two randomized trials and a cohort study found that care provided in inpatient palliative care units reduced costs by 38% to 50% compared with care provided in regular hospital wards. Likewise, using in-home palliative care teams reduces readmissions to the hospital and emergency department compared with standard outpatient cancer care. The average costs per day for in-home outpatient care was $95, which was substantially less than the usual care ($213). Financial comparisons of acute care hospital services have been possible using the Centers for Medicare & Medicaid Services case mix index (CMI) and All Patient Refined-Diagnosis Related Group (APR-DRG) data. Based on CMI and APR-DRG data, Cleveland Clinic’s Inpatient Palliative Medicine acute care unit’s total mean charges per admission are $7800 lower than at peer institutions without palliative care inpatient units, despite an equivalent severity of illness, longer length of stay, and higher mortality. The lower charges are due primarily to lower laboratory and pharmaceutical charges. A systematic review of costs and cost-effectiveness of palliative care has been published, but the quality of the studies varied, studies used different methods, and some studies were small. Cohort studies were at risk of bias through potentially unobserved confounding variables. However, all palliative care service structures (inpatient, home, and outpatient palliative care) were found to have economic advantages, largely due to reduced health-care utilization (readmissions and referral to hospice) and direct-care cost savings. For example, earlier palliative care enrollment reduced acute care days.

Survival

Early integration of palliative care into cancer care does not shorten survival, and may actually prolong survival. Early palliative care also leads to earlier hospice transition, which has a short-term survival advantage for patients with lung cancer. The survival advantage of palliative care needs to be confirmed by other studies because this information was based on a post hoc analysis in the Boston Study, and there has been much speculation about the mechanism used to calculate the survival advantage. Quality of life and mood are associated with survival; reduced quality of life and depression are associated with shortened survival; and improved quality of life is associated with improved survival. Interventions such as palliative care improve quality of life and reduce depression, and may have a biologic effect related to prolonged survival. It is interesting to note that, in the Boston Study, mood was improved without increased use of antidepressants. Survival benefits also may be related to reduced aggressive care at the end of life. Lastly, greater social support fostered by the palliative care team and the integration of the family into the plan of care may improve survival.

Fatigue

Fatigue is almost universally experienced by individuals with advanced cancer and is the main symptom that detrimentally influences quality of life. Fatigue is a distressing persistent sense of tiredness or exhaustion that interferes with daily activities. Unlike normal physical fatigue, it occurs with normal activity and can occur without any physical activity. It is pervasive and lasts beyond the normal expected recovery time. Descriptors for fatigue, such as tiredness, induration, lack of vigor, and asthenia, may not exactly describe every patient’s experience. Fatigue can be screened through a numerical rating scale (0 = no fatigue, 10 = severe fatigue), with fatigue ratings greater than 4 being clinically significant. People with cancer who have fatigue should be screened for depression. Cancer-related fatigue is not associated with anhedonia, hopelessness, or worthlessness. Insomnia and pain should be treated. Patients with obstructive sleep apnea will also experience fatigue and may benefit from continuous positive airway pressure while sleeping. Anemia, hypothyroidism, and hypogonadism will contribute to the severity of fatigue, and treatment for these conditions may improve fatigue. Comorbidities, such as heart failure and COPD, should be assessed and treatment maximized.

In one randomized double-blind trial, cancer-related fatigue was improved with corticosteroids. However, the long-term use of corticosteroids is associated with side effects, including osteoporosis, myopathy, insomnia, thromboembolism, and psychotomimetic side effects. Dexamethasone (4 mg in the morning and at noon) was used in this trial. Doses should be tapered to the lowest effective dose, or discontinued if no response is observed after a 2-week trial period. In a second randomized, double-blind trial, American ginseng was effective in reducing cancer-related fatigue. The side effects were similar to those with placebo, and ginseng had few drug interactions. Psychostimulants were reported to be effective in prospective, single-arm studies, but these positive results have not been duplicated in randomized trials. Strength and endurance training may help to address fatigue and loss of physical function during chemotherapy, as such training has been shown to increase the 6-minute walk time, stair climbing, strength capacity, and, in patients with dyspnea, perception of shortness of breath during submaximal walking.

Dyspnea

Dyspnea can be described as chest tightness, rapid shallow breathing, air hunger, and not getting enough air, and each descriptor reflects a different pathophysiology. Chest tightness is associated with coronary artery disease. Rapid shallow breathing is the result of a mismatch between respiratory drive and lung capacity. Air hunger is associated with increasing retention of carbon dioxide. Not getting enough air is associated with hyperinflation. Most patients with cancer have dyspnea at the end of life.

In advanced cancer, particularly lung cancer, there are usually a multitude of reasons for dyspnea. These reasons include loss of lung volume from treatment and tumor size, pleural effusions, cardiac tamponade, COPD, coronary artery disease, thromboembolism, pneumonia and wasting, anxiety and depression, and uncontrolled pain. Wasting is associated with quantitative and qualitative changes in the diaphragm muscle, which leads to reduced tidal volume with exertion and inspiratory capacity.

Dyspnea can be screened by the numerical scale within the Edmonton Symptom Assessment System. The Cancer Dyspnea Scale and the Dyspnea Numeric Scale, which assess dyspnea interference with activities, may also be used.

Depending on the underlying etiology, treatment for cancer-related dyspnea may include surgery, chemotherapy, radiotherapy, thoracentesis, pericardiocentesis, the use of drainage tubes, bronchoscopy with laser or stenting, brachytherapy, corticosteroids and antibiotics, and transfusions. Nonintervention approaches may also reduce dyspnea. Pulmonary rehabilitation and walking aids that activate accessory muscles can improve dyspnea. Oxygen should be used for patients who are hypoxic (oxygen saturation of less than 90%). Blowing air across the face, by way of a room or handheld fan, may reduce dyspnea in those who have normal oxygen levels. Noninvasive ventilation, using bilevel positive airway pressure, reduces dyspnea and avoids intubation. It does not require sedation.

Morphine reduces dyspnea without causing hypercapnia. Initial dose is 2.5 mg to 5 mg every 4 hours, as needed. If patients are opioid tolerant, a 25% increase in the opioid dose may be helpful. Nebulized opioids and furosemide should not be used as standard therapy, because of lack of evidence supporting their effectiveness. Most individuals with chronic dyspnea also have episodes of worsening dyspnea, or air hunger, that should be treated with an opioid, as needed. Benzodiazepines and sedating phenothiazines have been used to treat dyspnea, but there is conflicting evidence. There are negative and positive trials with few high-quality randomized studies. Both benzodiazepines and sedating phenothiazines may be added or substituted for opioids if patients are intolerant of opioids or wish not to go on opioids. Lastly, for patients with refractory dyspnea, palliative sedation, using subcutaneous phenobarbital, or using parenteral haloperidol plus a benzodiazepine (e.g., midazolam or lorazepam), may be necessary to control dyspnea. Palliative sedation should be discussed with patients and families before instituting treatment. The patient should have a DNR order, and, if gastric tube feedings are in place, they should be removed.

Cough

Symptomatic cough will occur in at least half of patients with lung cancer. Patients with advanced lung disease have greater dependence on cough for mucus clearance than healthy individuals. In patients with lung cancer, the cough response is prompted by excessive noxious stimulation of afferent sensory fibers through the vagus. There also can be central sensitization of neurons governing the cough reflex. Evaluation of cough should include whether the cough is productive or not, what triggers the cough, the timing of the episodes (daytime or nocturnal), the patient’s medications, (e.g., angiotensin-converting enzyme inhibitors), and the underlying comorbidities. A cough scale can be used to gauge frequency and severity. The Manchester Cough and Lung Cancer Scale uses 10 items to assess cough in lung cancer. It is presently being validated. Chest radiographs and computed tomography (CT) images may demonstrate an obstructive bronchus, pleural or pericardial effusions, atelectasis, pneumonia, bronchopleural or bronchoesophageal fistula, lymphangitic carcinomatosis, superior vena cava obstruction, or treatment-related pneumonitis.

Radiotherapy, laser therapy, brachytherapy, or stenting may relieve an obstructive bronchus. Thoracentesis, chest tube drainage plus pleurodesis, or placement of tunnelled indwelling pleural catheter can reduce cough and dyspnea associated with pleural effusions. Pericardiocentesis may be relieved with a cardiac tamponade. Simple hydration, humidification, and mucolytics may be helpful, particularly with mobilization of secretions. However, there are no well-conducted randomized trials that support the use of mucolytics in the management of cough. There is also sparse evidence for chest wall vibration and manual clearance of secretions. Flutter valve oscillation through a mouthpiece has been used. Positive end-expiratory pressure, via face mask, for 45 minutes per day improves cough and dyspnea.

Cough suppression is desirable when cough is no longer useful as a function or if cough produces pain or is fatiguing. Opioids commonly used as cough suppressants include codeine, dextromethorphan, and morphine. Dextromethorphan controls the intensity of cough better than codeine. Sustained-release morphine reduces cough severity by 40%. There is no evidence of a dose–response relationship when using morphine, or of one opioid being superior for the treatment of cough.

Proton-pump inhibitors can reduce cough caused by gastric reflux, and gabapentin has been shown to reduce cough stemming from central sensitization. Prednisone (30 mg daily for 2 weeks) may reduce cough associated with bronchospasm, or pleural, pericardial, or diaphragmatic irritation caused by the tumor or treatment. Baclofen may also work, if standard therapies have been ineffective. For patients who are imminently dying, treatment with a cholinergic inhibitor, such as glycopyrrolate, may reduce secretions and the so-called death rattle. The recommended glycopyrrolate dose is 0.1 mg to 0.2 mg (IV or subcutaneous) every 6 to 8 hours. It is best given around-the-clock because it prevents, rather than treats, secretions. Glycopyrrolate is a quaternary scopolamine derivative that does not cross into the central nervous system, thus preventing anticholinergic-induced cognitive dysfunction or delirium. Alternatives are inhaled ipratropium or scopolamine ophthalmic solution dropped onto the tongue.

Cachexia and Anorexia

Cachexia is most often recognized as involuntary weight loss. Precachexia is defined as a weight loss of less than 5%, and cachexia is defined as weight loss greater than 5%. However, if the body mass index (BMI) is less than 20, then a greater than 2% body weight loss would be defined as cachexia. Symptoms associated with cachexia include sarcopenia, loss of fat mass, anorexia, fatigue, and elevated inflammatory cytokines and acute phase reactants. Anorexia is a cluster of symptoms that includes bloating, early satiety, taste and smell changes, dysgeusia, and diurnal variations in food intake.

Peripheral and central mechanisms generate cachexia and anorexia. Inflammatory cytokines upregulate the transcription factor NF kappa-B in muscle that in turn, upregulates myostatin, proteasomes, and prostaglandins. Satellite cell proliferation is inhibited and muscle synthesis, through MyoD and mTOR/Akt, is blocked. Mitochondrial function and calcium metabolism) are also adversely affected, leading to reduced oxidative phosphorylation. In addition, there is an increase in reactive oxygen species. Anorexia results from increased neurotransmission of proopiomelanocortin-containing neurons within the arcuate nucleus of the hypothalamus. There is also a simultaneous reduction of neuropeptide Y signals. Neurotransmission through proopiomelanocortin neurons is increased through activation of serotonin receptors (5-HT2C) as well as throughout regulation of interleukin-1.

Inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1, and interleukin-6) increase production of C-reactive protein from the liver and muscle. Hypoalbuminemia develops from loss of the endothelial barrier and extravasation into interstitial spaces. Elevated C-reactive protein is associated with progressive weight loss and is a poor prognostic indicator in lung cancer. Both serum albumin and C-reactive protein are combined in the Glasgow Prognostic Score. Pretreatment Glasgow prognostic score is a useful and important predictor of cancer-specific survival in patients with inoperable NSCLC. It is predictive of the most important aspects of platinum-related toxicity.

Assessment of cachexia is complex. Factors that have been used to follow the course of cachexia and sarcopenia include changes in weight, BMI, anthropometric measurements, bioelectrical impedance, dual-energy x-ray absorptiometry, and measurement of muscle area at the level of the L3 vertebral body. Using CT to measure muscle mass at the L3 vertebral body level has been validated. These measurements can be done routinely to follow the course of cancer. Assessment of anorexia can be made through the Edmonton Symptom Assessment Score. The Functional Assessment of Anorexia Cachexia Therapy scale, which is a 12-item module attached to the Functional Assessment of Cancer Therapy quality-of-life tool, can also be used. There are multiple other nutritional scales, but they do not separate starvation from cachexia. In a study evaluating use of the Mini Nutritional Assessment scale for individuals with lung cancer, the score on the scale correlated with laboratory parameters of inflammation and was independently associated with survival.

The best method for treating cancer-related cachexia is to cure the cancer. If this is not possible, then the goals of therapy are to maintain muscle mass, nutritional intake, and function. Because it is unlikely that a single drug will have a major impact on cancer cachexia and anorexia, treatment should be multimodal. Appetite stimulants include corticosteroids, progesterone, and olanzapine. In a randomized trial, the combination of megestrol acetate and olanzapine was superior to megestrol acetate as a single agent, with substantial improvements in appetite, nausea, weight gain, and quality of life. Cachexia has been treated with single-agent antioxidants, l-carnitine, omega-3 fatty acids, thalidomide, nonsteroidal antiinflammatory drugs (NSAIDs), and megestrol acetate, with little to marginal benefit. Recent trials of drug combinations have proven to be more effective than single agents in increasing lean body mass, decreasing energy expenditures, and improving appetite. Ghrelin analogs and selective androgen receptor modulators are presently in development.

Pain

At least half of individuals with advanced cancer will have chronic pain. There are well-described cancer pain syndromes. Approximately 75% of individuals with cancer have pain related to their cancer, and 25% have pain related to treatment or comorbid illnesses. Many individuals with cancer have cancer pain syndromes because of widespread metastases, and these syndromes have been well described. Clinicians can mistake existential suffering for physical pain. Characteristically, somatic pain does not respond to treatment with opioids.

To properly assess pain, clinicians need to know pain intensity, the point from where it radiates, temporal pattern, pain quality, and provocative and relieving factors. The cause, pathophysiology, and pain syndrome can be inferred from the history and confirmed by physical examination and radiographs. Pain intensity is largely used when choosing analgesics and adjusting doses, but interference with activity and function are equally important. Pain intensity may change little, but function, mood, sleep, and vitality may improve with treatment. Another area that needs to be assessed when considering treatment is the side effects associated with analgesics. Pain can be assessed on a numerical rating scale. Mild pain is less than 4 on an 11-point numerical rating scale; moderate pain is 5 to 7; and severe pain is greater than 7. A reduction of baseline pain severity between 30% and 50% is clinically significant. The Brief Pain Inventory is a validated tool and can be used in the initial assessment. Before prescribing opioids for moderate to severe pain, the patient’s substance abuse history, family substance abuse history, and the patient’s history of depression, anxiety disorder, or personality disorder should be obtained.

Classifying pain into somatic, visceral, or neuropathic is an oversimplification of clinical reality. There are features of neuropathic pain in patients who have visceral metastases, as demonstrated in animal models. Central sensitization can occur in all three subclasses of pain.

For mild pain, acetaminophen or NSAIDs can be used as the analgesics of choice, but should not be used for patients with coagulopathy, or heart or kidney failure. NSAIDs are also not recommended for treating older individuals. Prophylaxis with proton-pump inhibitors should be considered. There is evidence that the combination of NSAIDs and acetaminophen may improve analgesia.

For moderate pain, tramadol, tapentadol, codeine, or low doses of a potent opioid, such as morphine, are reasonable choices. Although it had been assumed that codeine is an analgesic—through conversion to morphine via the cytochrome CYP 2D6—newer evidence suggests that there is actually synergy between codeine and morphine. Therefore, codeine may have to be converted to morphine for analgesia. If patients were originally treated with nonopioid analgesics, such as acetaminophen or NSAIDs, these drugs can be added or continued.

For severe pain, potent opioids such as oxycodone, morphine, hydromorphone, or fentanyl may be used as first-line analgesics. Starting doses are as follows: morphine, 5 mg every 4 hours by mouth; oxycodone, 5 mg every 4 hours; hydromorphone, 1 mg every 4 hours; and transdermal fentanyl at 12 μg per hour. If pain is acute or unstable, transdermal fentanyl should not be used. Sustained-release morphine (15 mg every 12 hours) or oxycodone (10 mg every 12 hours) may be used in place of immediate-release preparations. Most patients have breakthrough pain. A rescue dose of one-sixth of the total daily opioid dose should be provided every 1 to 2 hours. Transient flares of pain may be related to activities (incident pain) or spontaneous. End-of-dose failure is considered suboptimal around-the-clock opioid dosing. If this occurs, the around-the-clock dose should be increased. There are considerable differences in dose requirements between patients who will require dose titration of no less than 25% and no more than 100% of the total daily dose. As an alternative, transmucosal, buccal, sublingual, or intranasal fentanyl have been approved for breakthrough pain. These preparations are expensive and should be reserved as second-line treatments for individuals whose breakthrough pain is unresponsive to oral, immediate-release opioids.

Titration of potent opioids is required to control pain in most individuals. To reach steady-state levels, the dose of immediate-release opioids should not be changed more often than every 24 hours. The dose of sustained-release opioids should not be changed more often than every 48 hours, and the dose of transdermal fentanyl should not be changed more often than every 48 to 72 hours. If pain remains a problem, then the rescue dose can be titrated to response, and the around-the-clock dose adjusted once steady-state is reached. Patients with severe liver disease should be treated with morphine or hydromorphone because these opioids are conjugated and glucuronidation is relatively spared. For patients who are in renal failure, methadone or buprenorphine are the opioids of choice. Because of its unique pharmacology, methadone should be used only by designated prescribers.

Adjuvant analgesics can improve pain and reduce opioid requirements. Antiseizure drugs, predominantly gabapentinoids, tricyclic antidepressants, and selective norepinephrine serotonin reuptake inhibitors (duloxetine and venlafaxine), can improve neuropathic pain. Because tricyclic antidepressants have substantial side effects, secondary amine tricyclic antidepressants may be better tolerated. When adjuvant analgesics are used, the number needed to treat to substantially reduce neuropathic pain in an individual patient ranges from three to five. Corticosteroids reduce symptoms and pain from tumor-related compressive neuropathy, brain metastases, and bowel obstruction. Bisphosphonates have been used for bone pain. For patients in whom pain does not respond to a first-line opioid, or in whom dose-limiting toxicity develops (e.g., confusion, myoclonus, hallucinations, nightmares, or severe nausea), switching to or rotating with an alternative opioid will improve pain control and reduce side effects. Because of noncross tolerance, doses that are 50% to 70% of the equianalgesic dose should be used and further dose adjustment should be made, based on clinical context, including potential drug interactions and organ function. Routine use of analgesic tables can be dangerous. As an alternative, switching to spinal opioids may improve the opioid therapeutic index by reducing side effects. Spinal adjuvant analgesics include bupivacaine and clonidine.

Side effects related to opioids can add symptom burden to patients or may be mistaken for progressive cancer. Constipation, if severe, not only produces nausea and vomiting, but can also resemble a bowel obstruction. Because there is no tolerance for constipation, stool softeners and laxatives should be started proactively when opioids are prescribed. Opioid-induced constipation that is unresponsive to laxatives and enemas should be treated with methylnaltrexone. Opioid-induced sedation may respond to a methylphenidate. The anticholinergic side effects of opioids, (dry mouth, urinary retention, and nausea) may require targeted approaches to management. Antiemetics, such as metoclopramide, prochlorperazine, or ondansetron, may be used to manage nausea. For most individuals, nausea is mild and tolerance develops over several days. Most opioids, except for buprenorphine, induce hypogonadotropic hypogonadism, which can result in altered mood, hot flashes, loss of libido and sexual function, and, over a period of time, loss of muscle and bone. When treatment with an opioid is started or doses are adjusted, there can be mild sedation and mild muddled thinking, which usually resolves over several days. Patients should be taking stable doses of opioids for approximately 2 weeks before they consider driving a car. Overt confusion and delirium induced by opioids require opioid rotation or change in route rather than antipsychotics. Nonpharmacologic modalities should be considered concurrently with analgesics. Mind-body approaches and integrative interventions can be helpful, both in improving pain and in reducing the opioid requirements. Correction of impending fractures of long bones; kyphoplasty; and brachial, celiac, or hypogastric blocks can improve pain and improve opioid responses.