Dyspnea in Advanced Cancer: 'Dying Long Before Death'

Kristen Jenkins

November 29, 2017

More than half of patients with advanced cancer have difficulty breathing, and this chronic dyspnea can be highly debilitating and challenging to manage, thanks to the lack of evidence-based treatment options or a standard of care, say experts interviewed by Medscape Medical News for this feature article.

Dyspnea is prevalent in 50% to 60% of patients with advanced cancer generally and in up to 74% of patients with lung cancer. Prevalence increases during the last 6 weeks of life and can cause significant psychological and emotional distress, they noted.

Many patients report feelings of suffocation or "air hunger,” while others describe a choking sensation or chest tightness that makes breathing difficult and exhausting. Chronic refractory dyspnea can lead to overwhelming feelings of helplessness, anxiety, and depression.

The social isolation that comes with breathlessness can be equally traumatic, said David C. Currow, MD, professor of palliative and supportive services at Flinders University in Adelaide, South Australia.

 
People describe dying a social death long before they die a physical death. Dr David Currow
 

“People describe dying a social death long before they die a physical death,” he commented in an interview. "Their symptoms are progressively worsening, their exercise tolerance is decreasing, and their friends aren't coming around anymore because breathlessness is very difficult to watch."

Even in the general population, dyspnea may be more prevalent than previously thought. In Australia, population studies independent of health service access revealed that 1 in 100 people had severe chronic breathlessness on a day-to-day basis, and 1 in 300 people had breathlessness so severe that it precluded them from leaving the house.

The primary underlying cause was related to lung disease, particularly chronic obstructive pulmonary disease (COPD), followed by cardiac failure, cancer, neuromuscular diseases, and other respiratory diseases.

"At present, optimum management involves pharmacological treatment that has not changed in years and consists of the use of opioids and, occasionally, oxygen and anxiolytics,” said Marcin Chwistek, MD, director of the Pain and Palliative Care Program at Fox Chase Cancer Center, Philadelphia, Pennsylvania, when asked to comment.

"More research is needed to discover new and more effective treatment options for cancer patients with dyspnea," Dr Chwistek told Medscape Medical News. “It is crucial, therefore, for all clinicians taking care of patients with cancer to routinely screen and assess for dyspnea in their practice.”

"We do not have an adequate number of effective and available treatments," confirmed Jennifer S. Temel, MD, associate professor of medicine at Harvard Medical School and director of the Cancer Outcomes Research Program at the Massachusetts General Hospital Cancer Center, Boston.

What's more, the lack of a standard of care for managing respiratory symptoms in cancer patients has likely resulted in a significant amount of variation between protocols used at various institutions, Dr Temel told Medscape Medical News.

The lack of routine screening for dyspnea using validated outcomes has contributed to the "underdetection, underdiagnosis, and undertreatment of dyspnea," said David Hui, MD, from the Department of Palliative Care, Rehabilitation and Integrative Medicine at the University of Texas MD Anderson Cancer Center, Houston.

The "paucity of research in this field" has resulted in "few evidence-based interventions," he told Medscape Medical News.

This year, two pilot studies looking at very different types of agents for the treatment of dyspnea in patients with cancer have been reported by Dr Hui and colleagues.

One of these was a double-blind, randomized, controlled pilot study of dexamethasone, which suggested that the corticosteroid may be associated with rapid improvement of dyspnea and was well tolerated by patients with cancer. “Further studies are needed to confirm our findings,” they concluded.

The second was a pilot study of prophylactic fentanyl buccal tablets for episodic exertion dyspnea. The drug was associated with a reduction in exertional dyspnea and was well tolerated, supporting "the need for larger trials to confirm the therapeutic potential of rapid-onset opioids," they said.

 
Dyspnea is a complex symptom that requires a team to manage it properly. Dr Arif Kamal
 

"Dyspnea is a complex symptom that requires a team to manage it properly," noted Arif Kamal, MD, associate professor of medicine at Duke University in Durham, North Carolina. "A team provides an expanded toolbox to address dyspnea across all its drivers, including the emotional, social, and physical components," he told Medscape Medical News.

Results from a UK study reported in 2014 show that an integrated palliative and respiratory care service for patients with advanced disease and refractory breathlessness has potential survival benefits for patients with COPD and interstitial lung disease.

Although the survival differences were not significant for the patients with cancer in this study, it still provides "some evidence of the immense value of an expanded team to address dyspnea," said Dr Kamal.

Every second counts when it comes to treating patients with intractable dyspnea, emphasized Gudrun Marie Ilse Kreye, MD, program director of palliative care at University Hospital Krems in Austria, when speaking to Medscape Medical News.

 
My primary message to clinicians is that dyspnea in palliative care patients is an absolute emergency. Dr Gudrun Kreye
 

"My primary message to clinicians is that dyspnea in palliative care patients is an absolute emergency. Every second the patient suffers from dyspnea is a second too much," she said in an interview.

While acute treatment may be needed, it should always come after all attempts are made to "remove the removable," she pointed out. This would include, for example, pleural puncture for pleural effusion, antibiotics for pneumonia, and standard treatment for COPD.

"If primary treatment of the cause is not possible," said Dr Kreye, "opioids as first-line treatment for patients with advanced cancer and refractory dyspnea have been shown to be safe and effective in many studies and thus are strongly recommended."

"At the palliative care unit as well as at the oncology department in Krems, the use of opioids for patients with refractory dyspnea is standard of care," she added.

Earlier this year, Dr Kreye and colleagues published a meta-analysis of nine clinical trials of drugs used for dyspnea (which included opioids, benzodiazepines, and steroids), and they concluded that opioids are the drug of choice for treating refractory dyspnea in patients with advanced cancer.

"Neither benzodiazepines nor oxygen showed significant benefit," they concluded. "In addition, there is insufficient literature available to draw a conclusion about the effectiveness of steroids for treating persistent dyspnea in advanced cancer patients."

Reducing Symptom Burden

High-level evidence shows that treating breathlessness systematically can result in significant reductions in symptom burden, said Dr Currow. "Most important, regular oral low-dose sustained release morphine is safe and effective for the relief of breathlessness."

Dr Currow cited results from his group's phase 3, randomized, double blind, placebo-controlled study in 282 opioid-naive patients with COPD and severe chronic breathlessness, published last year in the European Respiratory Journal.

The results showed that daily extended-release (ER) morphine was safe and improved symptoms compared with placebo. Breathlessness improved significantly, both in the whole patient population with COPD receiving ER morphine compared with placebo (6.30 mm; P = .012) and in the most severely affected patients, with COPD and a modified Medical Research Council score of 3 or 4 (11.47 mm; P < .001).

Although drowsiness and constipation were more frequent in patients treated with morphine, no treatment-emergent episodes of respiratory depression occurred.

"This has huge application for cancer patients," Dr Currow told Medscape Medical News.

His group is also looking at other agents and is conducting a phase 3 randomized trial investigating the clinical effect and cost-effectiveness of the sertraline (Zoloft, Pfizer), for palliation in chronic dyspnea. Sertraline is a selective serotonin reuptake inhibitor that is marketed as an antidepressant.

In the United Kingdom, mirtazapine (Remeron, Merck) is under study for the treatment of dyspnea; this drug is also an antidepressant but acts on both noradrenergic and serotonin receptors.

Dr Currow noted that benzodiazepines, which have anxiolytic as well as other properties, have been widely used for dyspnea, but their efficacy has still not been widely established.

He also noted recent negative results with the anxiolytic drug buspirone (Buspar. Bristol-Myers Squibb). That report, published last year in Supportive Care in Cancer, was the biggest single randomized control trial to date of buspirone in 432 patients with cancer and dyspnea who were undergoing chemotherapy.

"It's very clear that in the chronic setting, it is unlikely that anxiety is the major driver of breathlessness," he said.

In the meantime, clinicians need to base their clinical assessment on the patient's subjective perception of breathlessness, Dr Currow commented, and he emphasized that there is often a poor correlation between the physiologic measures of respiratory dysfunction and the patient's subjective perception.

 
Breathlessness isn't just a symptom, it's a distinct clinical entity. Dr David Currow
 

Most patients with lung cancer have significant respiratory compromise before they are even diagnosed with lung cancer, he added. "Breathlessness isn't just a symptom, it's a distinct clinical entity seen in many people with advanced disease."

Importantly, clinicians shouldn't expect to diagnose chronic dyspnea by simply asking patients if they feel breathless. Many patients adapt for years or even decades by cutting back on activities, he said.

Instead, when the index of suspicion is high in a patient with primary or secondary lung cancer, heart failure, or emphysema, ask, "What have you given up in order to avoid feeling breathless?"

"They shrink their world to avoid breathlessness,” Dr Currow explained. "You'll hear things like 'Well, I gave us gardening 6 months ago, sex 4 months ago and walking the dog 2 months ago but I don't feel breathless anymore.’”

About 24% of patients who experience breathlessness at the end of life present without symptoms of cardiorespiratory disease, while in patients with cachexia, respiratory muscle weakness may be a cause of dyspnea. There is also a group of patients for whom no underlying cause of dyspnea will be found, despite systematic and thorough examination, said Dr Currow.

Three-Step Plan

The Canadian Thoracic Society has produced guidelines that outline a three-step plan for the management of dyspnea in advanced COPD.

This is based on a modification of the World Health Organization's analgesic ladder for the treatment of pain, and it is useful for managing breathlessness in patients with cancer, Dr Currow suggested.

First, it is essential to treat any underlying conditions that may contribute to dyspnea, particularly given that many studies show that even when the patient is in significant distress, this isn't done, he said. "It should not be assumed that other physicians have identified the underlying cause or causes of breathlessness or optimized treatment."

Second, nonpharmacologic interventions with a strong evidence base should be considered. These include conditioning exercises for those who can tolerate them, use of a walker, and other options (such as medical air, fans, and techniques to optimize breathing).

Among the nonpharmacologic interventions that may help is cognitive-behavior therapy (CBT), noted Dr Temel. Her group reported in 2014 a single-group, nonrandomized pilot study conducted in 20 patients receiving outpatient chemotherapy for advanced lung cancer, in which patients were given two brief, nurse-delivered CBT interventions during visits to the infusion clinic. This intervention reduced symptoms of dyspnea and improved scores for quality of life and mood, Dr Temel and colleagues reported. In addition, the proportion of patients reporting depression symptoms plummeted from 50% to 12%.

"Based upon these encouraging results, we are currently conducting a randomized trial of the nurse-delivered intervention versus usual care in patients with advanced lung cancer," Dr Temel told Medscape Medical News.

To come back to the three-step plan, the third step, which is reached when other measures have failed, involves the use of opioids. Specifically, oral sustained-release morphine at doses between 10 mg and 30 mg every 24 hours is required to reduce breathlessness, said Dr Currow. Approximately two of three patients will notice an improvement at the initial dose of 10 mg daily, and a smaller number will require 20 or even 30 mg.

Patients should also have regular laxatives introduced at the same time as regular morphine, he said.

Medications to prevent nausea and emesis can also be prescribed for the first few days, said Dr Kreye, "as [they are] in treating pain."

For patients who are already receiving opioids for cancer pain, the dose can be increased by 25% to 50% until the patient reports a reduction of dyspnea, she suggested. If symptoms persist, a benzodiazepine, such as lorazepam (Ativan, Wyeth) 2.5 mg sublingually can be added with a half-tablet or one tablet every 3 hours.

In rare circumstances, breathlessness may be sufficient to warrant sedation in the terminal hours and days of life using higher doses of benzodiazepines in combination with other sedatives, said Dr Currow. "Their role as an anxiolytic as well as an amnesiac may be of benefit to some patients."

Dr Kreye also noted that in "rare situations, mostly at the end of life, we use syringe drivers with opioids to ameliorate severe refractory dyspnea."

Beyond the palliative care setting, however, clinicians may be hesitant to use opioids to treat refractory dyspnea because of concerns about respiratory depression, experts acknowledged. Such considerations are largely based on the concerns of health professionals, not their patients, said Dr Currow.

"In direct contrast to intravenous doses of opioids in opioid-naive patients in the emergency department or postoperatively, regular low-dose opioids have not been associated with respiratory depression, obtundation or hospitalization resulting from respiratory failure," he pointed out.

Recently, a large cohort study of oxygen-dependent patients with COPD demonstrated no increase in hospitalizations or risk for death in patients treated with up to 30 mg of morphine equivalents a day, Dr Currow noted. Qualitative studies also show that patients and their caregivers are not concerned about the use of low-dose morphine when it's recommended by a clinician they trust.

Still, the attention paid by regulators, lawmakers, public health officials, and law enforcement to the opioid prescribing practices of clinicians is the single most important challenge, said Dr Kamal.

"It remains unclear how prescribing opioids for cancer patients outside of a pain indication will be treated, if prescriptions will be filled, and whether clinicians will open themselves up to actions by medical boards, regulators, or litigators," Dr Kamal explained. "Outside of hospice, the concern is that clinicians will not prescribe this pharmacologic gold standard, which will swing the pendulum too far."

Dr Kreye, for one, knows only too well what that can look like.

"I will never forget when a colleague refused to give opioids to a patient, being afraid that the patient would die from respiratory depression, and instead the patient died suffocating," she told Medscape Medical News. "Education about the value of opioids for refractory dyspnea is of utmost importance," she emphasized.

Dr Currow reports relationships with Specialized Therapeutics Pharma , Helsinn Pharmaceuticals, and Mayne Pharma. Dr Chwistek, Dr Hui, Dr Temel, Dr Kamal, and Dr Kreye have disclosed no relevant financial relationships.

Follow Medscape Oncology on Twitter: @MedscapeOnc

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