The emerging role of palliative medicine in the treatment of lung cancer patients

CANCER-RELATED ANOREXIA AND CACHEXIA: TREATMENT IMPROVES APPETITE

The main hallmark of cancer-related anorexia and cachexia is weight loss; this symptom cluster is most often associated with hypophagia. The coexistence of anorexia and appetite-related anhedonia is common in lung cancer patients, such that 25% of lung cancer patients with anorexia report no distress with not eating, nor do they derive pleasure from eating. Others report that early satiety and changes in taste dramatically affect appetite. To some, anorexia is a distressful reminder of progression of their cancer.

Megestrol acetate and medroxyprogesterone acetate at least partially improve appetite in a subset of anorectic cancer patients. The use of medroxyprogesterone acetate has resulted in weight gain but not muscle mass in some patients with cancer-related anorexia, but has had less effect on fatigue and quality of life in these patients.

Olanzapine is an atypical antipsychotic with an affinity for multiple neurotransmitter receptors. Several of these, such as the serotonin receptors 5-HT₂ and 5-HT₃, histamine receptors, and dopamine receptors, are implicated in anorexia, nausea, and vomiting. Case reports suggest that olanzapine has antiemetic activity in patients with advanced cancer and usefulness as prophylaxis against chemotherapy-related nausea and vomiting.⁵ Reduced risk of extrapyramidal symptoms compared with standard antiemetics enhances the value of olanzapine for prevention of cancer-related anorexia.

Navari et al⁶ conducted a randomized trial to determine the effectiveness of megestrol acetate and olanzapine for the treatment of cancer-related anorexia. Eighty patients were randomized to receive oral megestrol acetate 800 mg/d, or oral megestrol acetate 800 mg/d plus olanzapine 5 mg once nightly, for 8 weeks. Patients were removed from the study if they did not take the study medication for a 48-hour period or if intolerable toxicity developed that was attributable to the study agents.

The MD Anderson Symptom Inventory (MDASI) was completed weekly to assess key symptom outcome variables. A change of 3 cm on the visual analog scale over two separate time periods for a symptom was considered sufficient to define a change in the symptom.

Quality of life was measured using a valid 28-item self-reported instrument (Functional Assessment of Cancer Therapy-General). Patients were examined by their physicians every 2 weeks.

In the group assigned to megestrol acetate, 15 patients had a weight gain of at least 5%—a change that was considered significant. Appetite improved in two patients, nausea decreased in three patients, and quality of life improved in five patients at both 4 weeks and 8 weeks. The improvements in appetite, nausea, and quality of life for the whole group on megestrol acetate alone were not significant, and there was no improvement in mean symptom scores measured by the MDASI.

There were incremental improvements of all measures in patients randomized to megestrol acetate plus olanzapine. Among patients receiving the combination, 33 had a weight gain of at least 5%; 25 reported an improvement in appetite, 21 experienced a reduction in nausea, and 23 had an improvement in quality of life at both 4 weeks and 8 weeks. All outcome variables were improved on the MDASI

CANCER AND DYSPNEA: NUMEROUS INTERVENTIONS HAVE BEEN ASSESSED

Reduced inspiratory capacity caused by weakened inspiratory muscles results in an increased Borg rating of perceived exertion (RPE) relative to oxygen levels. Both central nervous system activation of muscle and loss of muscle tissue contribute to dyspnea and fatigue in lung cancer patients.⁷ Cancer fatigue, also measured by the Borg RPE scale, appears to be a “central” mechanism that stems from a mismatch between efferent output for afferent inputs in the setting of ventilatory muscle weakness, thereby increasing the perception of dyspnea. Several interventions have been used to relieve dyspnea, ranging from oxygen therapy to treatment with opioids.

Oxygen saturation

The association between hypoxemia and dyspnea is poor.⁸ In a randomized prospective trial, Abernethy et al⁹ found no benefit to oxygen therapy compared with medical air without added supplemental oxygen in individuals who had normal oxygen saturation but symptomatic dyspnea.

Bilevel positive airway pressure

Bilevel positive airway pressure has been shown to reduce the need for invasive ventilation; improve oxygen saturation; and reduce dynamic hyperinflation, thus relieving dyspnea.¹⁰ It has been effective in dyspneic patients with motor neuron disease, cancer, heart failure, status asthmaticus, stroke, drug overdose, and interstitial lung disease.

Indwelling pleural catheters

Tunneled pleural catheters reduce the severity of dyspnea in 95% of patients.¹¹ These catheters are inserted on an outpatient basis, allowing for outpatient drainage. Autopleurodesis occurs in about 45% of patients, in which case the catheter can be removed. Adverse reactions are few (incidence < 10%), but consist of empyema, pneumothorax, cellulitis, or catheter obstruction. The disadvantage is the expense of catheter maintenance.

Nebulized furosemide

Case reports suggest that inhalation of nebulized furosemide, 20 mg four times daily, dramatically improves dyspnea in patients with advanced cancer and severe shortness of breath that is unresponsive to opioids.¹² Nebulized furosemide appears to have a direct effect on either pulmonary stretch receptors or irritant receptors in the airways; it also has a diuretic effect. Response occurs quickly with an onset of effect in 20 to 30 minutes.

B-type natriuretic peptide

The level of N-terminal precursor of B-type natriuretic peptide (NT-pro-BNP) can predict response to sunitinib in renal cancer,¹³ and the BNP level predicts 30-day mortality in pulmonary embolism.¹⁴ Measurement of BNP to detect dyspnea in patients with lung cancer is not useful, however, because the BNP level increases with cardiac and pericardial metastases. The BNP level is also persistently elevated after chest radiation therapy, and it increases with anthracycline cardiotoxicity. It is not a useful marker for distinguishing pulmonary from nonpulmonary or cardiac from noncardiac causes of dyspnea.

Lung ultrasound

Portable diagnostic lung ultrasound can be used to detect pneumonia, pleural effusions, pulmonary emboli, pneumothorax, atelectasis, and lung abscesses as potential causes of dyspnea.^15–18 In addition to the advantage of portability, there is no radiation exposure and the technology permits echocardiography to be conducted.

Opioids

Evidence supports opioids for pharmacologic relief of dyspnea in the palliative care of patients with chronic obstructive pulmonary disease and cancer. Studies have been conducted with morphine sulfate, hydromorphone, dihydrocodeine, intranasal and transmucosal fentanyl, oxycodone, and diamorphine.^19–21

The response to opioids is unrelated to the severity of dyspnea.²² Responses and safe administration occur even in patients with reduced oxygen saturation or elevated carbon dioxide partial pressure.²⁰ Opioids can be used safely in the opioid-naïve population.²⁰ Recommended dosages in these patients are 2.5 to 5.0 mg of morphine sulfate every 4 hours, 5 mg of oxycodone every 4 hours as needed, and 1 mg of hydromorphone every 4 hours in the opioid-naïve. In opioid-tolerant patients, it is recommended that therapy start with these doses and then be increased in 25% increments every 24 hours, as needed.