Treatment of Dyspnea in Cancer Patients

June 1, 2002

A 54-year-old female seeks medical attention with a complaint of worsening exertional dyspnea of 3 to 4 weeks’ duration. She has a history of small-cell lung carcinoma, first diagnosed 3 months previously, and has had an excellent response to treatment, which included both chemotherapy and external-beam radiation. Consistent with her cancer diagnosis, she has a 30 pack-year history of cigarette smoking, and her pulmonary function tests indicate mild airflow obstruction, slight hyperinflation on lung volumes, and a mildly decreased diffusion capacity. In addition to her dyspnea with exertion, the patient describes symptoms of an intermittently productive cough, fatigue, and, recently, a poor appetite.

A 54-year-old female seeks medical attention with a complaint of worseningexertional dyspnea of 3 to 4 weeks’ duration. She has a history of small-celllung carcinoma, first diagnosed 3 months previously, and has had an excellentresponse to treatment, which included both chemotherapy and external-beamradiation. Consistent with her cancer diagnosis, she has a 30 pack-yearhistory of cigarette smoking, and her pulmonary function tests indicate mildairflow obstruction, slight hyperinflation on lung volumes, and a mildlydecreased diffusion capacity. In addition to her dyspnea with exertion, thepatient describes symptoms of an intermittently productive cough, fatigue, and,recently, a poor appetite.

This could be a typical case encountered by an oncologist,pulmonary/critical-care physician, or primary-care physician. Variations on thetheme of dyspnea and cough are two of the most common problems that thepulmonary specialist deals with on an outpatient basis, and it would not beunusual for the above patient to be referred to us or one of our colleagues atsome point for further evaluation. In this issue of ONCOLOGY, Jay R. Thomas andCharles F. von Gunten provide a succinct template for the treatment of suchpatients.

A Complex, Integrated Process

As the authors state in their first paragraph, dyspnea is defined as asensation of difficult or uncomfortable breathing and has been reported to occurin 21% to 90% of cancer patients. For some individuals, dyspnea is described asbreathlessness, while others feel a sense of restriction in their breathing oreven a vague feeling of chest discomfort. Drs. Thomas and von Guntenappropriately emphasize that this subjective sense of discomfort while breathingis the physiologic manifestation of a complex and integrated process involvinginput from several sources—ie, from the airway and lung parenchyma as well asthe brain’s respiratory center, the cerebral cortex, peripheral musculature,and the central and peripheral chemoreceptors.

Although the subjective feeling of dyspnea is a common symptom amongindividuals with advanced primary lung cancer or those with metastatic spread tothe lung, it is also found in individuals with no demonstrable pulmonary orpleural involvement. It is not surprising that the National Hospice Study[1]found that 24% of oncology patients experienced dyspnea with no knowncardiopulmonary process.

Etiology of Dyspnea

The authors state that it is important to initiate a reasonable evaluation ofthe cause of the patient’s dyspnea. As they point out, dyspnea in cancerpatients is usually multifactorial, with more than one potential cause perpatient. Their review suggests that, as potential causes of dyspnea, pulmonaryor pleural involvement should be at the forefront of such an evaluation.

They cite a prospective analysis of 100 dyspneic cancer patients in which 65%had lung or pleural involvement and 40% were hypoxic with an oxygen saturation< 90%.[2] An interesting aspect of this study was the finding that the medianmaximum inspiratory pressure was 16 cm H2O (lower limit of normal: > 50cm H2O), suggesting evidence of significant respiratory muscle weakness in someindividuals. Although the authors do not elaborate on this specific observation,the cited abnormal value for maximum inspiratory pressure may, in part, berelated to the etiology of the dyspnea observed in these individuals.

The study also raises the question of whether there may be similaritiesbetween the wasting patient with cancer and the advanced emphysema patient, bothof whom tend to experience chronic dyspnea. Like cancer patients, patients withemphysema tend to suffer from muscle wasting as a consequence of hypermetabolismas well as, in some cases, reduced dietary intake.[3,4]

The altered energy and substrate metabolism in patients with chronicobstructive pulmonary disease (COPD) are clearly connected to the dyspnea andexercise intolerance that are prominent symptoms of this syndrome. Indeed,studies have shown that peripheral skeletal muscle mass is reduced anddiaphragmatic mass and contractility are also depressed in individuals withCOPD.[4,5] Some, but not all, studies have also indicated an improvement indiaphragmatic contractility in patients with COPD after a period of aggressivenutritional support.[3,5] Thus, it is tempting to suggest that, like patientswith emphysema, cancer patients with advancing disease may demonstrate evidenceof peripheral and diaphragmatic muscle wasting. This muscle wasting may, inturn, be related to the low median maximum inspiratory pressure values reportedby Dudgeon et al, and described in the review by Thomas and von Gunten.[2]

Although the causes for this reduction in muscle mass may ultimately differbetween these diseases, the end results may be similar—ie, a progressivedysfunction of the peripheral and diaphragmatic muscles leading clinically to anenhanced sensation of dyspnea. In addition, this notion is consistent withobservations that the cytokine tumor necrosis factor-alpha is elevated in bothpatients with advanced cancer and those with COPD.[6] Because this cytokine isassociated with systemic inflammation, a hypermetabolic state, and thepathogenesis of muscle wasting, it may play a common role in the loss of proteinmuscle mass, muscle weakness, and dyspnea that are shared by these diseases.

The Deconditioned Patient

One point that could have been better developed in this review concerns thepotential role of physical conditioning in cancer patients. During the treatmentof a malignancy, it is possible that a variable loss of physical conditioningwill occur from the combined effects of serious illness and treatment modalitiessuch as surgery, radiation, or chemotherapy. In the case of advancing diseasethat is coupled with a decline in performance status, overall physicalconditioning is likely to decline as well.

Thus, the deconditioned patient may become dyspneic for the first time whenperforming certain activities, or may feel more dyspneic during these activitiesthan earlier perceived. Furthermore, if such a patient has significant muscleweakness or pulmonary involvement due to tumor or underlying lung disease, theseactivities (as well as concomitant deconditioning) may have an additive effecton the dyspnea.

As the cancer progresses, it may be increasingly difficult and thusunrealistic, to address the issue of deconditioning in an affected individual.It is a factor, however, that is sometimes taken for granted during theassessment of the dyspneic patient with a serious illness. Moreover, although itis important to assess oxygenation and lung function, subjective symptomsincluding dyspnea may not correlate well with physiologic measurements of lungfunction, arterial oxygen saturation, or arterial blood gas values.

This lack of a consistent correlation between subjective and objectiveindicators of respiratory status has become increasingly appreciated in patientswith COPD and asthma.[7] Collectively, these issues can cloud the overallpicture even further and thereby make the clinician’s task of assessing andmanaging the dyspneic cancer patient a difficult one.

Cancer-Related Dyspnea

The authors provide a long list of potential causes of dyspnea related tocancer but, understandably, do not expand on this list in detail. It should beemphasized that other causes of breathlessness are sometimes forgotten in suchan evaluation. These factors include electrolyte abnormalities,hypophosphatemia, hypomagnesemia, and hypercalcemia. Such conditions can elicitmuscle weakness and contribute to a sensation of dyspnea, yet are potentiallycorrectable causes of this problem. Furthermore, thromboembolic conditions suchas pulmonary embolism are sometimes overlooked, even in the hypercoagulablecancer patient, and pericardial effusions secondary to tumor metastasis shouldalso be considered, especially in those with thoracic disease.

The management of the cancer patient with dyspnea may take different routesdepending on the cause. For example, the inoperable patient with persistentendobronchial tumor obstruction may be best served by palliative measures thatinclude the placement of an airway stent, whereas a large malignant pleuraleffusion may require the placement of a chest tube or indwelling pleuralcatheter and subsequent pleurodesis. In the cancer patient with no clearpleural/pulmonary disease, the search may turn to a cardiac evaluation with afocused approach in that area. Alternatively, it may be concluded that there areseveral reasons for the patient’s dyspnea, including significant muscleweakness and deconditioning.

The authors state that, as in the patient with COPD, an overallcognitive/behavioral approach—including pursed-lip breathing, relaxationtechniques, and psychosocial support—may help cancer patients suffering fromchronic dyspnea. Of interest is the concept that opioids be used as first-linetherapy for the symptomatic relief of cancer-related dyspnea. Data on patientswith cancer and COPD suggest that opioids can relieve breathlessness withoutcausing overt respiratory depression.[8] However, in patients with COPD, opioidsare obviously not considered first-line therapy.

It should also be emphasized that the goal of therapy with opioids and/ormedications such as benzodiazepines is to relieve uncomfortable symptoms such asdyspnea. Sedation may also be appropriate in those with refractory dyspnea, butthe goal is relief of breathlessness and calming without hastening the patient’sdeath.

Conclusions

Thus, it is clear that dyspnea is a significant problem for cancer patients,from initial diagnosis to the deathbed. The authors provide a salient argumentfor conducting an aggressive evaluation in order to find and remove theunderlying cause whenever possible. Unfortunately, symptomatic control may stillbe the end result in terms of management. In this case, opioids are the firstline of therapy for symptomatic control of dyspnea, with benzodiazepines andsupplemental oxygen often useful as adjuncts. In refractory cases, sedation maybe appropriate, but as in the case of other end-stage illnesses, ethicalstandards need to guide the use of these medications.

References:

1. Reuben DB, Mor V: Dyspnea in terminally ill cancer patients. Chest89:234-236, 1986.

2. Dudgeon DJ, Lertzman M: Dyspnea in the advanced cancer patient. J PainSymptom Manage 16:212-219, 1998.

3. Schols AM, Wouters EF: Nutritional abnormalities and supplementation inchronic obstructive pulmonary disease. Clin Chest Med 21(4):753-762, 2000.

4. Creutzberg EC, Schols AM, Bothmer-Quaedvlieg FC, et al: Prevalence of anelevated resting energy expenditure in patients with chronic obstructivepulmonary disease in relation to body composition and lung function. Eur J ClinNutr 52:396-401, 1998.

5. Bernard S, LeBlanc P, Whittom F, et al: Peripheral muscle weakness inpatients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med158:629-634, 1998.

6. de Godoy I, Donahoe M, Calhoun WJ, et al: Elevated TNF-alpha production byperipheral blood monocytes of weight-losing COPD patients. Am J Respir Crit CareMed 153:633-637, 1996.

7. Teeter JG, Bleecker ER: Relationship between airway obstruction andrespiratory symptoms in adult asthmatics. Chest 113:272-277, 1998.

8. Poole PJ, Veale AG, Black PN: The effect of sustained-released morphine onbreathlessness and quality of life in severe chronic obstructive pulmonarydisease. Am J Respir Crit Care Med 157:1877-1880, 1998.