Treatment of Dyspnea in Cancer Patients

Dyspnea is defined as a sensation of difficult or uncomfortable breathing.[1] Its prevalence at different stages of cancer has been reported to range from 21% to 90%.[2-4] It is a common symptom among patients who have primary or metastatic involvement of the lung, but it is also a common complaint of patients with no direct lung involvement. The National Hospice Study found that 24% of patients with dyspnea had no known cardiopulmonary process to explain the condition.[4] Moreover, cancer is often superimposed on patients with significant underlying cardiopulmonary problems, such as chronic obstructive pulmonary disease (COPD) and congestive heart failure (CHF). Thus, dyspnea is a significant clinical problem throughout the entire spectrum of cancer, from first diagnosis to end stages.

Pathophysiology

The pathophysiology of dyspnea is still not well understood. Most studies have focused on either healthy volunteers with experimentally induced dyspnea or patients with COPD. Studies directly assessing dyspnea in cancer patients have been limited due to the practical constraint of recruiting cancer patients and to ethical constraints making placebo-controlled studies problematic.

Dyspnea is believed to be multifactorial, with central, peripheral, and cognitive/emotional components. The respiratory center in the medulla coordinates the activity of the diaphragm, the intercostal muscles, and accessory muscles of respiration. It receives information from central and peripheral chemoreceptors, peripheral mechanoreceptors, and the cerebral cortex. Respiratory effort, hypercapnia, hypoxia, pulmonary stretch, pulmonary irritants, and mismatch between what the brain expects and the feedback it receives are all variables that play a role in dyspnea.[5]

The following three clinical examples illustrate some of these underlying mechanisms.

First, breathing against increased resistance, as in COPD, or breathing with weakened muscles, as in cachexia, causes increased respiratory work that is perceived as dyspnea. Most studies point to this increased respiratory work as a major component of dyspnea.

Second, the chemical states associated with hypercapnia and hypoxia can increase dyspnea independently of increased respiratory effort.[6,7] Medullary chemoreceptors sense hypercapnia, and carotid body chemoreceptors sense hypoxia. Despite common belief, hypoxia appears to have a less significant role in dyspnea. Only moderate-to-severe levels of hypoxia trigger the peripheral chemoreceptors.[8]

Third, when researchers limit a subject’s inspiratory flow rate, dyspnea results despite no change in respiratory work or chemical status.[9]

These three examples demonstrate that dyspnea is indeed multifactorial, but they do not explain all cases of dyspnea. Given its multiple possible causes and our deficient knowledge, there is no reliable, objective measure of dyspnea. Respiratory rate, oxygen saturation, and arterial blood gas determinations do not correlate directly with dyspnea. For example, patients may be hypoxic but not dyspneic or dyspneic but not hypoxic. Therefore, the gold standard for the assessment and treatment of dyspnea must be patient self-report.

Visual analog[10] and Borg[11] scales are most commonly used to quantitatively rate dyspnea. These measures are simple, reproducible, and have been validated for use in clinical research. Visual analog scales typically have a 100-mm line with verbal descriptors such as "no breathlessness" and "worst possible breathlessness" at the ends. A patient merely marks his level of dyspnea on this line.

Diagnosis

For a patient presenting with dyspnea, the search for a cause begins with a thorough history and physical examination. Past medical history, smoking history, occupational history, and prior radiation or chemotherapy may provide important diagnostic clues. A physical examination in conjunction with simple studies such as pulse oximetry, complete blood count, and a chest x-ray will most often lead to a diagnosis. When the possible benefits of further investigation exceed the burdens, additional studies may include arterial blood gas determinations, pulmonary function tests, computed tomography scans, echocardiograms, or ventilation-perfusion scans.

Dyspnea in cancer patients may be due to the direct or indirect effects of tumors, the effects of anticancer therapy, or may be unrelated to the cancer. Possible specific etiologies of dyspnea are listed in Table 1. Despite this extensive list, few studies have systematically categorized the causes of dyspnea in cancer patients.

Dudgeon and Lertzman performed a prospective analysis of 100 advanced cancer patients with dyspnea in just such an attempt.[12] They found that 49% had lung cancer, 65% had lung or pleural involvement, 40% were hypoxic with O₂ saturation < 90%, 12% had PCO₂ ³ 45 mm Hg, 52% had a component of bronchospasm, 29% had evidence of cardiac ischemia, CHF, or atrial fibrillation, and 20% had hemoglobin levels < 10 g/dL.

Pulmonary function tests revealed that 5% had an obstructive pattern, 41% had a restrictive pattern, and 47% had a mixed obstructive/restrictive pattern. The median maximum inspiratory pressure was -16 cm H₂O (normal: ³ 50 cm H₂O), indicating significant muscle weakness. None of the patients had received chemotherapy linked to pulmonary disease, and 40% had undergone radiation therapy that encompassed at least a portion of the lungs. The average tally of potential causes of dyspnea per patient was five. Thus, it is clear that dyspnea in cancer patients is most commonly multifactorial.