STRATEGIES FOR THE PALLIATION OF DYSPNEA IN CANCER

Uncontrolled dyspnea is one of the most feared symptom any cancer patient can experience. This complex symptom presents a significant challenge to health providers as well as to caregivers with little consensus to inform management when compared to cancer pain.

In this issue of Cancer Pain Release Dr. Bruera (USA) and Dr. Currow (Australia) explain why dyspnea is challenging to manage and discuss clinically important findings that provide the best evidence to improve the symptomatic care of breathlessness.

There is increasing research and clinical interest in improving the accuracy of assessment of dyspnea to improve the palliation of this distressing symptom in cancer.

--Sophie M. Colleau, PhD




An interview with Eduardo Bruera, MD* & David Currow, B Med, MPH, FRACP**

* Professor Eduardo Bruera is the F. T. McGraw Chair in the Treatment of Cancer in the Department of Palliative Care and Rehabilitation Medicine at the University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.

** Professor David Currow is Chair of the Department of Palliative and Supportive Services at Flinders University, Adelaide, Australia.

Q: What is dyspnea?
Bruera: Dyspnea is a complex symptom, widely prevalent in the palliative care setting generally described as an uncomfortable awareness of breathing. Dyspnea is one of the most distressing symptoms for the patients as well as their caregivers. The term is used interchangeably with breathlessness in the medical literature.

Q: What is known about the patient’s experience of dyspnea in cancer?
Bruera: Episodes of breathlessness can be very frightening and patients use words such as suffocating, choking or tightness to describe the sensation. Qualitative work has shown that the symptom can be separated along three dimensions: air hunger – the need to breathe while being unable to increase ventilation; effort of breathing – physical tiredness associated with breathing; and chest tightness – the feeling of constriction and inability to breathe in and out. More research is needed to understand if such differences can be used in clinical practice in the same way we use patient descriptors to characterize pain mechanisms.

Q: Is the patient’s experience of dyspnea primarily a physical sensation?
Bruera: The experience of dyspnea encompasses physical, as well as psychological, social and spiritual domains. Recently the term “total dyspnea” has been proposed to capture the complexity of the symptom. It suggests a multidisciplinary approach centering on the patient’s psychological, social and spiritual needs as well as on the physical symptoms.

Q: What is the primary goal of treatment?
Bruera: Increasing the patient’s sense of mastery over the symptom is a key goal of treatment. As a clinician you want to see a significant improvement in the patient’s perception of breathing: you are trying to reduce distress, improve function and increase the patient’s quality of life.



Prevalence of dyspnea in cancer


Q: How prevalent is breathlessness in cancer?
Currow: In the general cancer population, dyspnea is estimated to occur in 15 to 55% at diagnosis. We also know that the prevalence of dyspnea varies with the primary tumor site, occurring more often in patients with lung cancer, but also described by patients even if their disease does not involve the lungs directly. In many cancers, dyspnea becomes increasingly prevalent as the disease progresses.

Q: Is there an association between dyspnea and end of life?
Currow: There is one large study that identifies breathlessness as an independent predictor for shorter survival among cancer patients. [1] Dyspnea has a propensity to worsen as functional status declines, often in proportion to the decline a person is experiencing.

Q: In advanced cancer, what are the causes of dyspnea?
Bruera: We know that the factors contributing to the genesis of dyspnea vary from person to person. Dyspnea may be caused by co-morbid conditions such as chronic obstructive pulmonary disease (COPD), heart failure or progressive neuromuscular disease. In advanced cancer, dyspnea is most commonly due to direct effects of the tumor on the lungs due to locally progressive disease, metastatic involvement or pleural effusion. It is not always possible to identify the cause of dyspnea.

Q: Is dyspnea associated with other symptoms?
Bruera: Dyspnea often co-exists with fatigue, depression and anxiety (see Henoch abstract). Anxiety may contribute to dyspnea but may also arise from dyspnea. Anxiety can aggravate the symptom leading to a progressive spiral of exacerbated breathlessness and greater psychological distress. The fear that each breath will be one’s last is related to the propensity of dyspnea to worsen as functional status declines.



Assessment of dyspnea in cancer


Q: Is there a standardized method to assess dyspnea in cancer?
Bruera: Currently there is no international consensus on how to measure breathlessness. From a clinical perspective we use a simple 0 (no shortness of breath) to 10 (worse possible) scale as part of the ESAS (Edmonton Symptom Assessment System). There is a growing interest in improving the accuracy of assessment and in standardizing the clinical assessment of dyspnea as is done in pain management.

Q: In your opinion, what should be included in the clinical assessment of dyspnea?
Currow: Four components: start with a comprehensive history about the onset, exacerbating and relieving factors; perform a physical examination to assess for possible causes such as a pleural effusion or an arrhythmia; assess the intensity and separately the unpleasantness of breathlessness with a scale to establish a baseline measurement; track dyspnea along with concomitant physical and psychological symptoms to evaluate its impact on quality of life.

Q: Is this four-pronged approach appropriate to all cancer patients regardless of performance status?
Currow: For all cancer patients the assessment should be multi-dimensional and include physical and psychological symptoms. For people with advanced cancer in the palliative setting, objective measures such as respiratory rate or oxygen saturation may not correlate closely with the sensation of dyspnea and results of pulmonary function tests are unlikely to change the symptomatic therapies offered.

Q: What are the potential benefits of the comprehensive physical examination?
Currow: An examination of the cardiac and respiratory systems and tests of lung function help reveal the abnormalities causing breathlessness: obstructive lung disease or pleural effusion cause an abnormal increase in respiratory effort; neuromuscular weakness in the diaphragm or cancer cachexia causes severe impairment in respiratory muscle strength; hypoxemia and hypercapnia create an abnormal increase in ventilatory requirements.

Q: Are these abnormalities indicative of the severity of dyspnea?
Currow: Because dyspnea is a subjective symptom, blood gas evaluation and lung function tests are unlikely to reflect the person’s experience. Asking patients how short of breath they feel is the most accurate measure of dyspnea severity.

Q: A number of patient-rated scales have been developed for measuring dyspnea. Are they suitable for clinical practice?
Bruera: The visual analog scale (VAS) [2] and the modified Borg scale[3] are commonly used to measure distress from dyspnea. However, there is no clear agreement on what constitutes a clinically important difference on dyspnea scales and this makes the interpretation of scales problematic. Nevertheless, it is helpful to ask the patient to rate the severity of dyspnea categorically (mild-moderate-severe) or numerically (0-10) as this can establish a baseline and help monitor the patient’s response to palliative interventions. The problem with scales is that many exist but none are validated in cancer or palliative care (see Dorman abstract). At this time, validation of existing tools to measure dyspnea in palliative care seems more appropriate than development of new tools.

Q: Can you explain the difference between breakthrough dyspnea and continuous dyspnea?
Bruera: Dyspnea can appear as a continuous symptom or with breakthrough episodes. A recent study identifies cancer dyspnea as predominantly breakthrough symptom with more than 80% of the patients experiencing breakthrough episodes (see Reddy abstract). Because many episodes of breakthrough dyspnea are short, they are not easily managed with currently available therapies.



Barriers to the management of dyspnea


Q: Good symptom control is more difficult to provide for dyspnea than for pain or nausea. What makes dyspnea so challenging to manage?
Currow: The knowledge base for the management of breathlessness continues to evolve rapidly, but there are few studies when compared to pain management to help inform clinical decision making. More narrative reviews than randomized control trials have been published about cancer-related dyspnea, and the evidence that is available is often not implemented in clinical practice.

Q: How do you explain this scarcity of evidence?
Currow: It is difficult to recruit dyspneic patients with cancer to clinical trials because of the unstable nature of the symptom. Dyspnea often worsens late in the disease and advances rapidly at a time when patients’ physical and cognitive conditions are worsening. So measuring the multi-dimensional experience of breathlessness is difficult both in the research setting and in day-to-day clinical practice.

Q: Research is understandably difficult in a population with a high anticipated attrition rate. What other barriers have you identified in everyday practice?
Currow: I think the subjective aspects of the symptom are challenging to health professionals. Caring for a patient who struggles for breath makes clinicians and family feel helpless whether the patient is in hospital or at home. Physicians have expressed uncertainty about managing dyspnea and this is now documented in the literature (see Wiese abstract).



Management of breathlessness in daily practice


Q: Is it ever possible to relieve the underlying cause of dyspnea?
Bruera: In lung cancer, chemotherapy and radiation therapy may help to reduce dyspnea in some people. Dyspnea associated with pneumonia can be effectively treated with antibiotics. However, the recommendation to relieve dyspnea by treating the cause is often simply not possible in patients with advanced cancer. At this point, dyspnea is refractory and the primary goal should be symptom palliation to decrease the sensation of dyspnea.

Q: Are there clinical practice guidelines to guide therapy?
Bruera: The American College of Physicians, the American College of Chest Physicians, the National Comprehensive Cancer Network and the Program in Evidence-Based Care of Cancer Care Ontario have all published recommendations for clinical practice in the last two years based on available evidence (see Resources). However, there is currently no internationally agreed upon roadmap to guide treatment. A number of established therapies have symptomatic benefits. Comprehensive management requires both pharmacological and non-pharmacological approaches.



The role of opioids in the palliation of dyspnea


Q: What is the mechanism by which opioids relieve dyspnea?
Currow: Although the exact mode of action of opioids in dyspnea management is unknown, recent evidence has demonstrated that endogenous opioids lessen the sensation of breathlessness in people with COPD who are exercising.[4] In people with cancer, research evidence supports the beneficial effects of systemic opioids for dyspnea relief.

Q: Is one opioid superior to control dyspnea?
Currow: The ideal parenteral or oral opioid has not been defined although trials using morphine and dihydrocodeine have reported statistically significant beneficial effects in reducing the intensity of dyspnea reported by the patient (see Clemens abstract).

Q: Are opioids also helpful for patients who are naïve to opioids?
Currow: A double-blind crossover trial looked at the effect of morphine 5 mg in seven opioid-naïve elderly patients with cancer and 3.5 mg in addition to their regular dose in two patients already on 7.5 mg oral morphine every 4 hours. This study found a significant improvement in dyspnea following treatment with morphine as compared with placebo with no significant changes in oxygen saturation (see Mazzocato abstract).

Q: Are concerns about respiratory depression justified when palliating dyspnea with opioids?
Currow: Although systematic reviews continue to confirm that low-dose opioids are effective to relieve breathlessness and do not compromise respiration, many physicians continue to be concerned about respiratory depression. This concern stems from the erroneous assumption that evidence from the acute care setting where bolus doses of opioids are used for analgesia in postoperative care also applies in the palliative care setting. This is not the case. In fact, in studies of opioids for dyspnea, oxygenation and carbon dioxide levels do not change with the introduction of opioids. Whether patients are already on opioids or are opioid-naïve, there is no evidence of respiratory depression (measured by respiratory rate, oxygen saturation or levels of carbon dioxide) when morphine or hydromorphone are carefully titrated for dyspnea or pain (see Clemens abstract).

Q: Did these studies report any adverse effect of opioids?
Currow: The main systemic opioid adverse effects were constipation, drowsiness, nausea and vomiting which are expected with opioids although the latter three symptoms often settle soon after the introduction of the opioids.

Q: Has the optimal opioid dose been determined for cancer-related dyspnea?
Currow: We still need to understand the optimal dosing when opioids are titrated to relieve dyspnea and we also need to know whether long-term dosing can be maintained at a starting dose.

Q: A number of trials have examined the role of nebulized opioids in the management of dyspnea. Can you explain the advantages of this route of administration?
Bruera: Inhaling a drug as a fine mist which is deposited on the respiratory tract is an appealing route for managing dyspnea because the drug will bind to the sensory receptors in the respiratory tract with minimal systemic toxicity. Morphine sulfate, hydromorphone hydrochloride, and fentanyl citrate have been administered through inhalation for dyspnea but the evidence for their benefit does not exist. Until now only morphine has been studied in this form in controlled trials and nebulized morphine does not relieve dyspnea. The disadvantages of nebulized opioids include increased costs related to equipment, need for using preservative-free drug and a complicated method of delivery.

Q: Could morphine be beneficial because its pain-relieving effect impacts the patient’s perception of breathlessness?
Bruera: Because opioids reduce pain, the dyspneic patient may indeed feel more able to breathe if chest pain on movement is contributing to breathlessness.



The role of benzodiazepines in the palliation of dyspnea


Q: How do benzodiazepines work in relation to dyspnea?
Bruera: Benzodiazepines enhance the action of the neurotransmitter GABA (Gamma Amino Butyric Acid) and reduce anxiety. There is no evidence that benzodiazepines modify the sensation of dyspnea as there is with opioids. However there is some evidence that benzodiazepines may improve mood in patients with dyspnea.

Q: Would you agree that benzodiazepines help patients deal with the affective and emotional dimension of dyspnea?
Bruera: Anxiolytics may improve mood in patients with dyspnea and help to lessen the intensity of the sensation. At this time, there is no evidence to support the routine use of long-term benzodiazepines to manage dyspnea. The main problem with these agents is that they have serious central side effects including delirium, falls and severe sedation.



Is there a role for steroids?


Q: When are steroids useful in managing cancer-related dyspnea?
Bruera: Corticosteroids work by decreasing inflammation in the respiratory tract. Steroids are useful to manage dyspnea in cancer patients who have upper airway obstruction related to the tumor, radiation pneumonitis, superior vena cava syndrome, or an inflammatory component to their dyspnea.

Q: Are there any concerns associated with the use of steroids?
Bruera: Corticosteroids should be used cautiously because of side effects when used for long periods such as hyperglycemia, proximal myopathy, or psychotropic effects. A brief course of steroids may be trialed in people with airway obstruction.



The myth of palliative oxygen


Q: What is the latest evidence on the role of oxygen to palliate dyspnea in patients with cancer?
Currow: The assumption that oxygen therapy relieves dyspnea should be questioned as there is currently no evidence that palliative oxygen relieves the sensation of dyspnea in patients with cancer unless they have hypoxemia, although the use of oxygen remains a common practice. Oxygen did not improve dyspnea in a large trial of mostly cancer patients treated at home (see Currow abstract).

Q: Why do clinicians prescribe oxygen therapy for dyspnea even though it is not effective?
Currow: Oxygen has been found helpful to prolong survival in patients with COPD and severe hypoxemia. There has been a presumption that it would help dyspneic cancer patients who are not hypoxemic. In fact the interaction between hypoxemia and dyspnea remains elusive as not all patients with abnormal blood gases experience dyspnea and many patients with dyspnea have relatively normal blood gases.

Q: Are there any adverse effects to prescribing oxygen?
Currow: Oxygen is an invasive intervention requiring tubing, tanks, and it presents a risk of nosebleeds from the nasal cannula. In addition, it is a relatively expensive therapy that patients do not like unless they are deriving significant symptomatic benefit. The need to rely on a machine is unpleasant for many people.

Q: You have recently explored the relationships between home oxygen therapy, dyspnea management and caregiver support. What did you find?
Currow: We found that the presence of a caregiver at home enhances the likelihood that oxygen therapy will be initiated (see Currow abstract). Our study suggests that caregivers may have a role in driving the prescription of oxygen therapy because of a need to be able to do something when the patient is breathless.

Q: Are you saying that oxygen therapy helps the caregiver more than it helps the dyspneic patient?
Currow: Our study raises many hypotheses. It is clear that we need to better understand the role of caregivers who may feel helpless and distressed when watching a breathless family member at home.



The role of non-pharmacological interventions


Q: What principles should drive the treatment strategy when considering non-pharmacological interventions?
Bruera: It is extremely important to think about the patient’s goal of care when considering any palliative intervention. Non-pharmacological interventions generally have a low risk profile and have been shown to have great benefit in many people with breathlessness.

Q: Can you give examples of effective non-pharmacological palliative interventions?
Bruera: Patients often say that their breathing is more comfortable sitting upright rather than lying flat. This position allows the rib cage to form a barrel shape providing better efficiency of the diaphragm and allowing the lungs to expand. Directing cool air at the patient’s face with a fan and lowering room temperature are other effective interventions to help relieve a person’s dyspnea.

Q: What would you consider a higher risk intervention?
Bruera: Some cancer patients who have progressive muscle weakness may benefit from positive airway pressure ventilation through face or nasal masks. Since a trained chest therapist should monitor this intervention in an inpatient setting, it is more invasive, requires more equipment and is often tolerated poorly by patients as their condition deteriorates.

Q: Is there any evidence that cognitive-behavioral approaches are effective at reducing dyspnea in cancer patients?
Bruera: The effectiveness of these interventions has not been established in patients with cancer-related dyspnea in part because they are often too ill both mentally and physically to complete cognitive or behavioral programs. Breathing control, activity pacing, relaxation techniques and psychosocial support have improved breathlessness, functional ability and emotional states in lung cancer patients able to complete such programs in a few controlled trials (see Zhao abstract).

Q: How likely is it that breathing control or relaxation techniques can be easily implemented in routine clinical practice?
Bruera: Interventions that require instructing patients are complex and need to be provided by health professionals with adequate knowledge and skills. Tailoring the intervention to the individual patient is very important and a practice guideline would be useful to guide and standardize practice.

Q: What can be done to reduce the distress experienced by breathless patients and their caregivers?
Bruera: Effective care centers on the patient’s needs and goals. Explaining and addressing the fears of the patient and family is very important. One should anticipate the possibility of a crisis of respiratory failure and discuss this with the family, as this provides emotional support.

Q: What should drive the symptomatic care of dyspnea now and in the future?
Bruera: The multiple dimension model of pain is well developed and tested and has been in common use for decades; we are beginning to test a similar model for dyspnea. We recommend that dyspnea be assessed in conjunction with vital signs in the palliative care setting where relief of dyspnea – like pain relief – may result in improved quality of life.

References:
1. Quinten C, Coens C, Mauer M, et al. An examination into quality of life as a prognostic survival indicator. Results of a meta-analysis of over 10,000 patients covering 30 EORTC clinical trials. J Clin Oncol 2008; 26 (15S): 9516.

2. A 100-mm scale from zero (no breathlessness) to 100 (worst possible breathlessness).

3. A categorical scale from zero (no breathlessness) to 10 (maximal breathlessness).

4. Mahler DA, Murray JA, Waterman LA, et al. Endogenous opioids modify dyspnea during treadmill exercise in patients with COPD. Eur Respir J 2009; 33(4): 771-777.