Dyspnea in Patients With Advanced Cancer
Dyspnea is defined as an uncomfortable awareness of breathing. It is a subjective experience involving many factors that modulate the quality and intensity of its perception. Patients with comparable degrees of functional lung impairment and disease burden may describe varying intensities of dyspnea. Patients use a host of different words and phrases to describe the sensation of breathlessness. Terms such as tightness and suffocating are sometimes used.
Reports on the frequency of dyspnea also vary, depending on the setting and the extent of disease. In one study, 49% of a general cancer population reported breathlessness, and 20% rated their breathlessness as moderate to severe. Patients with advanced cancer experience this symptom more frequently and more intensely than do patients with limited disease. One study found that 75 of 135 patients with advanced cancer reporting to an outpatient palliative care clinic were experiencing moderate-to-severe dyspnea. Breathlessness was a complaint at presentation in 60% of 289 patients with lung cancer. Results of a large study showed that 70% of patients suffered from dyspnea in the last 6 weeks of life. About one-third of patients who could report the intensity of their dyspnea rated it as moderate to severe. Another study revealed that half of patients with advanced cancer scored their dyspnea as moderate to severe.Pathophysiology and Etiology
The pathophysiological mechanisms of breathlessness are numerous and complex. Peripheral and central mechanisms as well as mechanical and chemical pathways are involved with a variety of sensory afferent sources.[9-11]
The qualities of dyspnea can be appreciated as work/effort, tightness, and air hunger. The experience of excess work and effort is caused by sensory-perceptual mechanisms similar to those involved in muscles exercising. Tightness is caused by stimulation of airway receptors with bronchoconstriction. Intensity of air hunger and unsatisfied inspiration is caused by imbalances of respiratory drive, outgoing signals from the brain, and feedback from afferents in the respiratory system.
The direct causes of dyspnea in patients with advanced cancer are numerous; categorizing them can assist in the etiologic work-up. One approach is to divide direct causes into the following four groups:
- Direct tumor effects such as intrinsic or extrinsic airway obstruction, pleural involvement, parenchymal involvement either by primary or metastatic disease, superior vena cava syndrome, lymphangitic carcinomatosis, and pericardial effusion.
- Indirect tumor effects such as pneumonia, a pulmonary embolus, paralysis of a hemidiaphragm, or weakening of the respiratory muscles from sarcopenia.
- Treatment-related causes such as pulmonary fibrosis secondary to radiation therapy or chemotherapy or chemotherapy-induced cardiomyopathy.
- Causes unrelated to the cancer. These include chronic obstructive airway disease, congestive heart failure, anemia, certain acidotic states, and bronchospasm.
- Functional causes (e.g., anxiety).
One study found that in patients experiencing dyspnea from advanced cancer, a median of five different abnormalities could have contributed to their shortness of breath. Spirometry was abnormal in 93% of 100 patients examined, with 5% having obstructive patterns, 41% restrictive patterns, and 47% mixed patterns; 49% of patients had lung cancer, 91% had abnormal chest radiographs, and 65% had parenchymal or pleural involvement. These results indicate that a subset of patients will experience shortness of breath without any apparent lung involvement. The potentially correctable causes of dyspnea included hypoxia (40%), anemia (20%), and bronchospasm (52%). No significant association between the type of respiratory impairment and the degree of dyspnea was found. Most of these patients were current or former smokers. Most patients also had a significant lowering of their maximum inspiratory pressures, suggesting severe respiratory muscle dysfunction. This finding was duplicated in another study. Of patients admitted to hospice care, 34% had histories of cardiac disease and 24% had histories of respiratory disease. Only 39% of terminally ill patients who reported dyspnea had lung or pleural involvement. The etiology of dyspnea could not be clearly identified in approximately one-quarter of patients. Another study found that 49% of lung cancer patients presented with airflow obstruction.[7,13]
Respiratory muscle dysfunction is an underrecognized factor contributing to dyspnea. Causes of respiratory muscle dysfunction include neuromuscular disease, malnutrition, and deficiencies of potassium, magnesium, and inorganic phosphate. Poor oxygenation, muscle fatigue, abnormal cortisol and catecholamine levels, and circulating cytokines are also implicated.
Although it is commonly believed that anxiety is associated with breathlessness, researchers found that anxiety and shortness of breath do not invariably go together. One study demonstrated that the involvement of the lungs by cancer, anxiety, and poor maximal inspiratory pressures were correlates of the intensity of dyspnea in patients with advanced cancer.Assessment
The multidimensional nature of dyspnea must be noted in the complicated assessment of this symptom. Patient-reported outcome is the gold standard for assessment of dyspnea. There is no consensus on what constitutes the best instrument for assessing dyspnea. Visual analog and numerical rating scales appear to be useful and are commonly utilized.[8,15-17] The Borg Scale is occasionally utilized. The Cancer Dyspnea Scale is a multidimensional instrument, initially developed in Japan for patients with lung cancer and later translated into Swedish. This scale has been shown to be valid and reliable in patients with advanced lung cancer. The subscales measure sense of effort (physical dimension), sense of anxiety (psychological dimension), and sense of discomfort. These tools are limited, however, because they are unidimensional and do not account for the relative contribution of different factors to a patient’s perception of breathlessness. Assessment should include the impact of dyspnea on the patient’s functional status and appreciation of the dynamic component of dyspnea—namely, exertional dyspnea.
Objective signs such as tachypnea or the use of accessory breathing muscles frequently do not match a patient’s perception of dyspnea and the degree of functional impairment it causes. Numerous factors, including psychosocial issues, may affect a patient’s experience of dyspnea. Pulmonary function tests, with few exceptions, play a limited role in the assessment of this syndrome. Lack of a clear understanding of the pathophysiological mechanisms underlying dyspnea hampers the clinician’s overall ability to effectively manage it.[8,15]
A comprehensive history and examination are essential to an accurate assessment of dyspnea.[8,15] The temporal onset, qualities of the symptom, associated symptoms, precipitating and relieving events or activities, and responses to medications should be reviewed. Sudden onset may herald a pulmonary embolism or infection, whereas gradual onset may suggest the development of a pleural effusion. A history of obstructive airways or cardiac disease can shed some light on possible underlying causes. Investigations such as measuring oxygen saturation can be useful in determining whether a patient is hypoxic. In the setting of advanced, incurable cancer, arterial blood gasses play a limited role.
Diagnostic tests that may help to determine the etiology of dyspnea include chest imaging by radiography, computer-assisted tomography, complete blood counts, oxygen saturation at rest and with exercise and, to a much lesser extent, pulmonary function tests. Maximal inspiratory pressure (MIP) measurements may be helpful, particularly if no apparent cause can be found. MIP is a reliable functional test of the strength of the diaphragm and other respiratory muscles. Functional assessments such as the 6-minute walk test and exercise ergometry may also provide valuable information about the severity and impact of dyspnea.[19,20]Management of Dyspnea
Management of underlying causes
As with all symptoms, it is essential to identify and treat the underlying cause(s) of dyspnea if possible and when appropriate. Examples of specific underlying causes (some of them potentially reversible) and their treatments include the following:
- Tumor obstruction (upper airways, bronchus, or superior vena cava): Radiation therapy, hormone therapy, or chemotherapy for sensitive tumors. Bronchoscope-guided cauterization or laser ablation of intraluminal masses in large airways can be considered when such technology and expertise is available. Stenting of large airways with expandable stents when the obstruction is extraluminal has been described.
- Carcinomatous lymphangitis: A trial of corticosteroids, e.g., dexamethasone. The optimal dose is not clear. Chemotherapy should be considered in sensitive cancers.
- Superior vena cava obstruction: Chemotherapy for sensitive tumors, radiation therapy, stenting, opioids for dyspnea, and/or steroids as appropriate for the clinical context.
- Bronchospasms: Bronchodilators. The indiscriminate use of bronchodilators, particularly in the absence of bronchospasm, is discouraged. The treatment of underlying chronic obstructive disease should be optimized with bronchodilators and inhaled corticosteroids as appropriate, particularly because many patients may be current or former smokers.
- Pleural effusions: Pleural aspiration by thoracentesis or chest drain. Pleurodesis in selected patients with recurrent effusions should be considered. Indwelling catheters are now available for patients with recurrent effusions who are not suitable for pleurodesing.
- Pericardial effusions: Drainage for immediate relief and possibly intrapericardial chemotherapy or definitive surgery, depending on the clinical context and goals of care.
- Gross ascites: Abdominal paracentesis to relieve the diaphragmatic splinting.
- Cardiac failure: Diuretics and other drugs as appropriate.
- Chest infections: Antibiotics and chest physiotherapy when appropriate.
- Anemia: Blood transfusions in select patients.
- Pulmonary embolism: Anticoagulate when appropriate.
- Anxiety: Psychotropic medications and psychotherapy.
Symptomatic management of dyspnea is based primarily on oxygen therapy, opioids for palliation of dyspnea, and treatment of underlying causes (e.g., superimposed infection) when appropriate.
Opioids represent an extremely effective treatment for dyspnea in cancer patients. Fear of side effects should not prevent the appropriate use of opioids in this setting. Most authorities believe that, if used appropriately, opioids do not hasten death in dyspneic cancer patients; rather, they reduce physical and psychological distress and exhaustion, and early use improves quality of life.[15,22] Clinically significant hypoventilation following opioid therapy depends largely on the history of previous exposure to opioids and the rate of increase of the opioid dose. As with opioid use in pain management, the principles of starting at a regular low dose in opioid-naïve patients followed by appropriate dose titration applies. Opioid therapy for dyspnea is administered similarly to, and often concurrent with, opioid therapy for pain control. Most of the available evidence supports the role of opioids in relieving dyspnea in malignant and nonmalignant conditions.[23,24][Level of evidence: I];[25-27][Level of evidence: II]
Anecdotal and experimental evidence suggest a role for nebulized opioid administration in the treatment of dyspnea.[28-30] Opioid receptors are present on sensory nerve endings in the airways; however, nebulization is an inefficient way of administering drugs. Pharmacokinetic studies suggest that the systemic bioavailability of nebulized morphine is extremely poor and erratic, varying from 4% to 8%. Some patients may experience claustrophobia. Available evidence does not support the clinical use of nebulized opioids. More clinical trials are needed to better determine the role of this mode of treatment.
Patients who are hypoxic on room air are likely to benefit from oxygen therapy, probably through a decrease in the chemoreceptor input to the respiratory center and the brain cortex. In two controlled trials, cancer patients with dyspnea who were randomly assigned in a crossover design showed significant improvement in their dyspnea.[32,33][Level of evidence: I] The role of supplemental oxygen has also been examined in patients without hypoxemia in a large randomized controlled trial. Supplemental oxygen given at 2 L/min did not significantly improve dyspnea, compared with supplemental air. Therefore, supplemental oxygen is recommended for cancer patients with hypoxemia but not for those who are nonhypoxemic.
Other investigators have examined the effect of other oxygen delivery modalities on dyspnea in cancer patients, such as high-flow oxygen and noninvasive ventilation with bilevel positive airway pressure (BiPAP). High-flow oxygen devices deliver up to 40 L of humidified and heated oxygen per minute, and may reduce the intensity of dyspnea in patients who do not respond to low-flow oxygen. BiPAP has also been shown in several randomized controlled trials to alleviate dyspnea among hospitalized cancer patients,[35,36] particularly in patients with hypoventilation. These interventions may be reasonable options for patients with hypoxemia and refractory dyspnea despite the use of low-flow supplemental oxygen.
Other options suggested for symptomatic treatment include methylxanthines, sedatives, tranquilizers, nebulized local anesthetics, and antiprostaglandins. The role of methylxanthines in cancer-related dyspnea has not been clarified. Chlorpromazine and promethazine have been shown to decrease dyspnea without affecting ventilation in noncancer patients, but their role in cancer-related dyspnea is unclear. Four out of five randomized controlled trials failed to demonstrate any benefit for using benzodiazepines in cancer patients.;[Level of evidence: I] One randomized single-blind study suggests that the combination of two scheduled medications (subcutaneous morphine and subcutaneous midazolam) and one as needed (subcutaneous morphine) for episodes of breakthrough dyspnea is more effective than the other evaluated combinations for controlling breakthrough dyspnea and requires further study.[Level of evidence: I] The role of benzodiazepines appears to be limited to treatment of dyspnea that is considered a somatic manifestation of a panic disorder or use when a patient has concurrent severe anxiety. No evidence supports the use of nebulized local anesthetics for the treatment of breathlessness.General support measures
In addition to adequate pharmacological therapies, a number of nonpharmacological measures are suggested. These include pursed-lip breathing, diaphragmatic breathing and muscle training, cold air directed across the cheek, meditation, relaxation training, biofeedback techniques, and psychotherapy. The effectiveness of these measures in relieving breathlessness appears to be variable.Current Clinical Trials
Check NCI’s list of cancer clinical trials for U.S. supportive and palliative care trials about dyspnea that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- Wilcock A, Crosby V, Hughes A, et al.: Descriptors of breathlessness in patients with cancer and other cardiorespiratory diseases. J Pain Symptom Manage 23 (3): 182-9, 2002. [PUBMED Abstract]
- Ripamonti C, Fulfaro F, Bruera E: Dyspnoea in patients with advanced cancer: incidence, causes and treatments. Cancer Treat Rev 24 (1): 69-80, 1998. [PUBMED Abstract]
- Dudgeon DJ, Kristjanson L, Sloan JA, et al.: Dyspnea in cancer patients: prevalence and associated factors. J Pain Symptom Manage 21 (2): 95-102, 2001. [PUBMED Abstract]
- Bruera E, Schmitz B, Pither J, et al.: The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manage 19 (5): 357-62, 2000. [PUBMED Abstract]
- Muers MF, Round CE: Palliation of symptoms in non-small cell lung cancer: a study by the Yorkshire Regional Cancer Organisation Thoracic Group. Thorax 48 (4): 339-43, 1993. [PUBMED Abstract]
- Reuben DB, Mor V: Dyspnea in terminally ill cancer patients. Chest 89 (2): 234-6, 1986. [PUBMED Abstract]
- Dudgeon DJ, Lertzman M: Dyspnea in the advanced cancer patient. J Pain Symptom Manage 16 (4): 212-9, 1998. [PUBMED Abstract]
- Ripamonti C, Bruera E: Dyspnea: pathophysiology and assessment. J Pain Symptom Manage 13 (4): 220-32, 1997. [PUBMED Abstract]
- Widdicombe J: Lung afferent activity: implications for respiratory sensation. Respir Physiol Neurobiol 167 (1): 2-8, 2009. [PUBMED Abstract]
- Lee LY: Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respir Physiol Neurobiol 167 (1): 26-35, 2009. [PUBMED Abstract]
- Undem BJ, Nassenstein C: Airway nerves and dyspnea associated with inflammatory airway disease. Respir Physiol Neurobiol 167 (1): 36-44, 2009. [PUBMED Abstract]
- Parshall MB, Schwartzstein RM, Adams L, et al.: An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 185 (4): 435-52, 2012. [PUBMED Abstract]
- Congleton J, Muers MF: The incidence of airflow obstruction in bronchial carcinoma, its relation to breathlessness, and response to bronchodilator therapy. Respir Med 89 (4): 291-6, 1995. [PUBMED Abstract]
- Mancini DM, LaManca J, Henson D: The relation of respiratory muscle function to dyspnea in patients with heart failure. Heart Fail 8: 183-9, 1992.
- Dudgeon DJ, Rosenthal S: Management of dyspnea and cough in patients with cancer. Hematol Oncol Clin North Am 10 (1): 157-71, 1996. [PUBMED Abstract]
- Bausewein C, Farquhar M, Booth S, et al.: Measurement of breathlessness in advanced disease: a systematic review. Respir Med 101 (3): 399-410, 2007. [PUBMED Abstract]
- Dorman S, Byrne A, Edwards A: Which measurement scales should we use to measure breathlessness in palliative care? A systematic review. Palliat Med 21 (3): 177-91, 2007. [PUBMED Abstract]
- Henoch I, Bergman B, Gaston-Johansson F: Validation of a Swedish version of the Cancer Dyspnea Scale. J Pain Symptom Manage 31 (4): 353-61, 2006. [PUBMED Abstract]
- American Thoracic Society, American College of Chest Physicians: ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167 (2): 211-77, 2003. [PUBMED Abstract]
- ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories: ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 166 (1): 111-7, 2002. [PUBMED Abstract]
- Mantovani G, Astara G, Manca G, et al.: Endoscopic laser ablation as palliative treatment of endobronchial, nonresectable, or recurrent lung cancer: assessment of its impact on quality of life. Clin Lung Cancer 1 (4): 277-85; discussion 286, 2000. [PUBMED Abstract]
- Bruera E, Ripamonti C: Dyspnea in patients with advanced cancer. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 295-307.
- Bruera E, MacEachern T, Ripamonti C, et al.: Subcutaneous morphine for dyspnea in cancer patients. Ann Intern Med 119 (9): 906-7, 1993. [PUBMED Abstract]
- Allard P, Lamontagne C, Bernard P, et al.: How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial. J Pain Symptom Manage 17 (4): 256-65, 1999. [PUBMED Abstract]
- Bruera E, Macmillan K, Pither J, et al.: Effects of morphine on the dyspnea of terminal cancer patients. J Pain Symptom Manage 5 (6): 341-4, 1990. [PUBMED Abstract]
- Cohen MH, Anderson AJ, Krasnow SH, et al.: Continuous intravenous infusion of morphine for severe dyspnea. South Med J 84 (2): 229-34, 1991. [PUBMED Abstract]
- Boyd KJ, Kelly M: Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. Palliat Med 11 (4): 277-81, 1997. [PUBMED Abstract]
- Zeppetella G: Nebulized morphine in the palliation of dyspnoea. Palliat Med 11 (4): 267-75, 1997. [PUBMED Abstract]
- Farncombe M, Chater S: Clinical application of nebulized opioids for treatment of dyspnoea in patients with malignant disease. Support Care Cancer 2 (3): 184-7, 1994. [PUBMED Abstract]
- Farncombe M, Chater S, Gillin A: The use of nebulized opioids for breathlessness: a chart review. Palliat Med 8 (4): 306-12, 1994. [PUBMED Abstract]
- Masood AR, Thomas SH: Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmacol 41 (3): 250-2, 1996. [PUBMED Abstract]
- Bruera E, de Stoutz N, Velasco-Leiva A, et al.: Effects of oxygen on dyspnoea in hypoxaemic terminal-cancer patients. Lancet 342 (8862): 13-4, 1993. [PUBMED Abstract]
- Bruera E, Schoeller T, MacEachern T: Symptomatic benefit of supplemental oxygen in hypoxemic patients with terminal cancer: the use of the N of 1 randomized controlled trial. J Pain Symptom Manage 7 (6): 365-8, 1992. [PUBMED Abstract]
- Abernethy AP, McDonald CF, Frith PA, et al.: Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 376 (9743): 784-93, 2010. [PUBMED Abstract]
- Hui D, Morgado M, Chisholm G, et al.: High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized trial. J Pain Symptom Manage 46 (4): 463-73, 2013. [PUBMED Abstract]
- Nava S, Ferrer M, Esquinas A, et al.: Palliative use of non-invasive ventilation in end-of-life patients with solid tumours: a randomised feasibility trial. Lancet Oncol 14 (3): 219-27, 2013. [PUBMED Abstract]
- Moroni M, Porta C, Gualtieri G, et al.: Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients. Br J Cancer 74 (2): 309-11, 1996. [PUBMED Abstract]
- Navigante AH, Cerchietti LC, Castro MA, et al.: Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage 31 (1): 38-47, 2006. [PUBMED Abstract]