Treatment Recommendations for Respiratory Symptoms in Cancer Patients: Clinical Guidelines from the Japanese Society for Palliative Medicine

Abstract

Background:

Respiratory symptoms, dyspnea, cough, and death rattle, are common and distressing in advanced cancer patients. Palliation of respiratory symptoms is important to improve quality of life in cancer patients and their families/caregivers. Currently published clinical guidelines for the management of these respiratory symptoms in cancer patients did not cover the topics comprehensively or were not based on formal process for the development of clinical guidelines.

Methods:

The Japanese Society for Palliative Medicine (JSPM) decided to develop comprehensive clinical guidelines for the management of respiratory symptoms in cancer patients following the formal guideline developing process.

Results:

This article provides a summary of the recommendations with the rationales, as well as a short summary of the developing process, of the JSPM respiratory symptom management guidelines. We established 26 recommendations and all recommendations are based on the best available evidences and expert consensus.

Discussion:

More future clinical researches and continuous guideline updates are required to improve the quality of respiratory symptom management in cancer patients.

Introduction

Respiratory symptoms, dyspnea, cough, and death rattle (or noisy breathing), are common in advanced cancer patients. Fifty-four percent to 76% of advanced cancer patients experience dyspnea,^1–4 and more than 65% of lung cancer patients have cough at the time of diagnosis.⁵ On average, 35% of cancer patients develop death rattle at the end of life.⁶ Moreover, these are one of the most distressing symptoms not only for cancer patients but also for their families/caregivers.^7–9 Thus, it is very important to palliate respiratory symptoms to improve quality of life (QOL) in cancer patients and their families/caregivers.

Several clinical guidelines have been published worldwide to improve the quality of the management of these respiratory symptoms in cancer patients.^10–12 The Japanese Society for Palliative Medicine (JSPM) first published Clinical Guidelines for Respiratory Symptoms in Cancer Patients in 2011.¹³ However, the first JSPM guidelines were more focused on dyspnea management, and guidelines from other countries did not cover the topics comprehensively or were not based on a formal scientific process for the development of clinical guidelines. Thus, the JSPM has decided to comprehensively revise the clinical guidelines covering the management of respiratory symptoms in cancer patients by using validated methodology.

Herein, we present a short summary of the JSPM recommendations for the management of respiratory symptoms in cancer patients, along with the rationales underlying the recommendations and their development process.

Development Process

The objective of developing these clinical guidelines is establishing standard palliative interventions for respiratory symptoms in cancer patients. The target patients of these guidelines are all cancer patients with respiratory symptoms (dyspnea, cough, and death rattle), and primary users are all healthcare providers who care for cancer patients, including palliative care physicians, oncologists, nurses, and pharmacists.

Systematic literature search

First, 26 clinical questions (CQs) were developed based on the previous JSPM guidelines and a consensus meeting of taskforce members (10 palliative care physicians and 1 epidemiologist). Then, we performed a systematic literature search for each CQ in two electric databases (i.e., PubMed and the Cochrane Central Register of Controlled Trials [CENTRAL]), with searches limited to articles published before August 2014 and written in English or Japanese. In addition, we searched Japanese articles not included in PubMed or CENTRAL by using Ichushi-Web of the Japan Medical Abstracts Society. The policy used to identify relevant articles based on study designs was as follows: First, we selected articles of controlled trials or systematic reviews including only cancer patients. If no or only one such article was identified, we extended the search to observational studies including only cancer patients. If no relevant articles were identified, we extended the search to controlled trials that included cancer patients in part. If no relevant articles were identified, we extended the search to controlled trials including only noncancer patients.

The primary screening process included reviewing titles and abstracts of all articles identified from the databases to select potentially relevant articles for each CQ. All potentially relevant articles underwent a secondary screening process, in which the full texts were reviewed. After the secondary screening process, we selected relevant articles to provide evidence for each CQ. Additional articles were identified from the reference lists of selected articles and major palliative care textbooks^14,15 by hand search. All the literature search processes for each CQ were performed independently by two taskforce members.

Drafting recommendations and Delphi method

First, draft recommendation statements for each CQ with rationales were written by two-member teams of the taskforce. We used the modified Delphi method to examine the validity of each draft recommendation statement.¹⁶ Delphi rounds were conducted by 10 palliative care physicians, 8 representatives from other specialties, including a pulmonologist (the Japanese Respiratory Society), an oncologist (Japanese Society of Clinical Oncology [JSCO]), a primary care physician (Japan Primary Care Association [JPCA]), a nurse (Japanese Society of Cancer Nursing), and a pharmacist (Japanese Society for Pharmaceutical Palliative Care and Sciences), and a representative of a cancer patient group. After two Delphi rounds and an external review by six external reviewers (three palliative care specialists [physician, nurse, and pharmacist from the JSPM], two oncologists [JSCO and the Japan Lung Cancer Society], and one primary care physician [JPCA]), the final version of recommendation statements was approved.

Evidence and recommendation levels

We used the grading system developed by the Medical Information Network Distribution Service (Minds) to articulate the level of evidence and the strength of the recommendations, following the concepts of The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system¹⁷ (Table 1).

Table 1.

Recommendation Table

Strength of recommendation
1 (strong)	Strong recommendation to do (or not to do). The benefit of the recommended treatment certainly overweighs the harm or burden. In the guideline, statements are described as “recommend.”
2 (weak)	Weak recommendation to do (or not to do). The benefit of the recommended treatment may be closely balanced with the harm or burden. In the guideline, statements are described as “suggest.”
Level of evidence
A (high)	The evidence is established on the basis of the results of studies. Further research is very unlikely to change our confidence in the estimate of effect. For example, high-quality randomized controlled trials with concordant results or a meta-analysis of randomized controlled trials
B (moderate)	Although some moderate-/high-quality studies support the result, evidence is not sufficient. Further research is likely to significantly impact our confidence in the estimate of effect and may change the estimate. For example, randomized controlled trials with inconsistent results, low-quality controlled trials, or high-quality observational trials with consistent results
C (low)	Although some low-quality studies support the result, evidence is insufficient. Further research is very likely to significantly impact our confidence in the estimate of effect and is likely to change the estimate. For example, low-quality observational trials with consistent results
D (very low)	There is insufficient or no scientific evidence for the result. Any estimate of effect is very uncertain. For example, observational trials with inconsistent results, case reports, or expert opinions

Recommendations

Management of dyspnea

Oxygen therapy

Oxygen therapy is recommended in hypoxemic patients (1B): A double-blind randomized crossover trial compared the response to oxygen (4 L/min of oxygen through a nasal cannula) and air in 51 cancer patients with dyspnea (Fig. 1).¹⁸ In subgroup analysis of 17 hypoxemic patients, although O₂ saturation increased significantly in the oxygen group, the mean change in dyspnea intensity did not differ significantly between the two groups. Another double-blind randomized crossover trial comparing the response to oxygen (5 L/min of oxygen through a nasal cannula) and air in 14 hypoxemic cancer patients with dyspnea showed significantly better improvement of dyspnea intensity in the oxygen group.¹⁹ Neither study reported any adverse events.

FIG. 1.

Overview of recommendations for the management of dyspnea. NPPV, noninvasive positive pressure ventilation; SVC, superior vena cava.

Although these two studies reported conflicting results, the study targeting more specific population (hypoxemic cancer patients only) showed significant improvement in dyspnea with oxygen therapy.¹⁹ Thus, we recommend that oxygen therapy be used in hypoxemic cancer patients with dyspnea.

Oxygen therapy is suggested not to be used in nonhypoxemic patients (2C): A randomized crossover trial compared the efficacy of Heliox 28 (72% helium/28% oxygen), oxygen (28% oxygen), and air on dyspnea intensity in 12 nonhypoxemic lung cancer patients with exertional dyspnea.²⁰ The result of this study showed nonsignificant difference in dyspnea intensity after a 6-minite walk test (6MWT) between the oxygen group and the air group. Another randomized crossover trial comparing the efficacy of oxygen (5 L/min of oxygen through a nasal cannula) and air in 33 nonhypoxemic cancer patients with dyspnea at rest or after minimal exertion also showed nonsignificant differences in dyspnea intensity after a 6MWT between the two groups.²¹

Overall, the available evidence shows no efficacy of oxygen therapy on dyspnea in nonhypoxemic cancer patients. In addition, a more recent large randomized controlled study on mostly noncancer patients showed no additional symptomatic benefit of oxygen therapy in improving dyspnea in nonhypoxemic patients compared with air.²² However, because improvements in dyspnea intensity were reported in all these studies after starting gas supplementation regardless of the type of gas (oxygen or air), the possibility that oxygen therapy may improve dyspnea in some individuals cannot be excluded entirely. Thus, we suggest that oxygen therapy not to be used in nonhypoxemic cancer patients with dyspnea.

Noninvasive positive pressure ventilation (NPPV) is suggested to be used in patients with hypoxemia and hypercapnea (2B): An observational study including 23 solid cancer patients with acute respiratory failure (ARF: PaO₂/FiO₂ < 250 or pH ≦7.35 with PaCO₂ ≧50 mmHg), which evaluated the efficacy of NPPV on dyspnea intensity, showed significant improvement in dyspnea intensity one hour after starting NPPV.²³ Another study is a randomized crossover trial that evaluated the effect of NPPV and high-flow nasal cannula oxygen therapy on 30 cancer patients with dyspnea that was refractory to supplemental oxygen.²⁴ This study aimed to evaluate the feasibility of conducting this kind of study and did not compare the difference between the two groups. In the NPPV group of this study, dyspnea intensity was significantly improved after starting NPPV. A recent high-quality nonblinding randomized controlled trial compared the effect of NPPV and supplemental oxygen in alleviating dyspnea in 200 patients with solid cancer and ARF (PaO₂/FiO₂ ≦250).²⁵ This study included only patients who could tolerate a 5–10 minutes run in NPPV trial. Although dyspnea intensity decreased in both groups, a significantly more rapid improvement was seen in the NPPV group. In subgroup analysis, although there was a nonsignificant difference between the two groups in the case of patients without hypercapnia, the reduction in dyspnea intensity was greater in the NPPV group than in the oxygen group in subgroup analysis of hypercapnic state (PaCO₂ > 45 mmHg).

The available evidence suggests the possibility of improving dyspnea in hypoxemic cancer patients. However, 11%–23% of participants in the NPPV group dropped out of these studies. In addition, most studies only enrolled patients with ARF, and only the hypercapnic subgroup showed significant improvement for NPPV compared with supplemental oxygen group. These findings suggest that NPPV is beneficial in a limited population. Thus, we suggest that NPPV be used in patients with hypoxemia and hypercapnia.

High-flow nasal cannula oxygen therapy is suggested to be used in patients with hypoxemia that is refractory to standard oxygen therapy (2C): One retrospective trial of 183 cancer patients receiving high-flow nasal cannula oxygen therapy showed an improvement in anecdotal composite outcome in 41% of participants.²⁶ However, this study did not evaluate dyspnea as a single outcome. Another study, a randomized crossover trial, evaluated the efficacy of high-flow nasal cannula oxygen therapy and NPPV in 30 cancer patients with dyspnea that was refractory to supplemental oxygen.²⁴ As already described, this study aimed to evaluate the feasibility of conducting this type of study and did not compare the difference between the two groups. In high-flow nasal cannula oxygen group, dyspnea intensity was significantly improved after starting therapy.

Although there have been no comparison studies performed to date, the available evidence suggests the possibility of improving dyspnea by high-flow nasal cannula oxygen therapy in cancer patients. In addition, no severe adverse events have been reported after high-flow nasal cannula oxygen therapy, and treatment is fairly well tolerated. Thus, we suggest that high-flow nasal cannula oxygen therapy be used in patients with hypoxemia that is refractory to standard oxygen therapy.

Opioids

Systemic morphine is recommended to be used (1B): Two small double-blind randomized placebo-controlled crossover trials evaluating the effect of bolus subcutaneous morphine injection on dyspnea in cancer patients reported significant improvement in dyspnea intensity in the morphine group compared with placebo, without severe adverse events.^27,28 The other single-blind randomized controlled trial on 101 cancer patients with dyspnea during the last one week of life compared the effect of three different treatment groups (regular subcutaneous morphine with midazolam rescue, regular subcutaneous midazolam with morphine rescue, and regular morphine and midazolam with morphine rescue) on dyspnea intensity.²⁹ In this study, there was a nonsignificant difference in dyspnea intensity after 24 and 48 hours between the regular morphine group and regular midazolam group. Another single-blind randomized controlled trial on 63 outpatient cancer patients with dyspnea compared the efficacy of oral morphine and oral midazolam on dyspnea intensity.³⁰ This study consisted of two phases: the fast titration phase (to find the effective dose that defined at least 50% reduction in dyspnea) and the follow-up phase (five days treatment with the effective dose of the study drugs every four hours). Although dyspnea intensity decreased significantly compared with baseline in both groups, dyspnea intensity in the midazolam group was significantly lower than in the morphine group during the follow-up phase.

Available evidence indicates significant improvement of dyspnea in cancer patients by systemic morphine treatment compared with placebo. Conversely, in studies using an active comparator, systemic morphine was not superior in relieving dyspnea in cancer patients. However, these studies were of low methodological quality and the potential risk of bias must be taken into consideration. In addition, the adverse events, including respiratory depression, associated with systemic morphine, reported in these studies were rare and not severe. Thus, we recommend that systemic morphine be used in cancer patients with dyspnea.

Nebulized morphine is suggested not to be used (2B): One double-blind randomized placebo-controlled crossover trial on 79 cancer patients with dyspnea evaluated the efficacy of nebulized morphine relieving dyspnea.³¹ In this study, there were nonsignificant differences in the improvement of dyspnea between the two groups. Another double-blind randomized crossover trial on 12 cancer patients with dyspnea compared the efficacy of nebulized and systemic morphine on dyspnea intensity.³² This study also failed to show any differences in dyspnea intensity between those receiving nebulized and systemic morphine.

From the available study results, there is insufficient evidence that nebulized morphine can improve dyspnea in cancer patients. Since there is evidence that systemic morphine improves dyspnea, the benefit of nebulized morphine over systemic morphine for dyspnea in cancer patients is doubtful. Thus, we suggest that nebulized morphine not to be used in cancer patients with dyspnea.

Systemic oxycodone is suggested to be used, as alternative to morphine (2C): Only two retrospective studies have reported the effects of systemic oxycodone on dyspnea in cancer patients. One case series, in which three cancer patients whose dyspnea was well controlled with continuous subcutaneous morphine were switched to oral oxycodone for several reasons, reported maintenance dyspnea control after switching to oxycodone.³³ A retrospective chart review of 44 cancer patients using continuous subcutaneous oxycodone for dyspnea reported an improvement in dyspnea evaluated with a nonvalidated tool in 87% of participants.³⁴

Although the evidence is insufficient, available evidence suggests the potential benefit of systemic oxycodone in improving dyspnea in cancer patients. Moreover, systemic oxycodone may be an alternative to morphine in the setting of renal impairment or intolerable adverse events associated with morphine administration. Thus, we suggest that systemic oxycodone is used in cancer patients with dyspnea, as an alternative to morphine.

Systemic fentanyl is suggested not to be used (2C): One double-blind randomized placebo-controlled trial on 20 cancer patients evaluated the effect of bolus subcutaneous fentanyl on exercise-induced dyspnea.³⁵ The authors conducted a 6MWT before and after administration of fentanyl or placebo and evaluated dyspnea intensity before and after each 6MWT. The difference in the change of the mean dyspnea numerical rating scale after the 6MWT, before and after administration of fentanyl and placebo, was 0.9 and 1.3, respectively. The aim of this study was to evaluate the feasibility of conducting this type of study, and statistical analysis was not performed for comparison of dyspnea intensity between the two groups. Another double-blind randomized placebo-controlled crossover trial on 13 cancer patients evaluated the efficacy of oral transmucosal fentanyl citrate on exercise-induced dyspnea.³⁶ There were nonsignificant differences in dyspnea intensity after 6MWT between the two groups.

All these studies evaluated the effect of systemic fentanyl only on exercise-induced dyspnea, and no benefits of systemic fentanyl were shown by these studies. In addition, a systematic review of the effects of fentanyl on dyspnea that included cancer patients, noncancer patients, and healthy volunteers concluded that there is a lack of sufficient evidence of the effects of fentanyl in relieving dyspnea, and more high-quality clinical researches are warranted.³⁷ Thus, we suggest that systemic fentanyl not to be used in cancer patients with dyspnea.

Systemic codeine/dihydrocodeine is suggested to be used (2C): We found only one study evaluating the effects of codeine/dihydrocodeine on dyspnea in cancer patients. This nonblind randomized crossover trial was conducted in opioid-naive cancer patients with pain, and compared the efficacy of dihydrocodeine and tramadol on pain and QOL.³⁸ In this study, dyspnea was evaluated as one of the subscales of QOL, and there was nonsignificant difference in dyspnea intensity between the two groups.

We also found four randomized controlled trials evaluating the efficacy of codeine/dihydrocodeine on exertional dyspnea in noncancer patients. In three of the four trials, codeine/dihydrocodeine showed significantly lower dyspnea intensity after exercise test than placebo, in patients with chronic heart failure or chronic obstructive pulmonary disease.^39–41 Conversely, the remaining one study that compared dihydrocodeine with promethazine did not show significant difference in exercise-induced dyspnea intensity between the two groups.⁴²

Although sufficient evidence of the benefits of codeine/dihydrocodeine in the treatment of dyspnea in cancer patients has been lacking, a potential benefit of codeine/dihydrocodeine against dyspnea in cancer patients is suggested by the result of most of the studies performed in noncancer patients, which showed the benefit of codeine/dihydrocodeine against exercise-induced dyspnea. In addition, adverse events associated with codeine/dihydrocodeine in these studies did not differ significantly with placebo or active comparator. Thus, we suggest that codeine/dihydrocodeine be used in cancer patients with dyspnea.

Benzodiazepines

Benzodiazepines are suggested not to be used alone (2C): One single-blind randomized controlled trial on 101 cancer patients with dyspnea during the last one week of life compared the efficacy of three different treatments (regular subcutaneous morphine with midazolam rescue, regular subcutaneous midazolam with morphine rescue, and regular morphine and midazolam with morphine rescue) on dyspnea intensity.²⁹ In this study, there was nonsignificant difference in dyspnea intensity after 24 and 48 hours between midazolam group and morphine group. Another single-blind randomized controlled trial on 63 outpatient cancer patients with dyspnea compared the efficacy of oral morphine and oral midazolam on dyspnea intensity.³⁰ This study consisted of two phases: the fast titration phase (to find the effective dose that defined at least 50% reduction in dyspnea) and the follow-up phase (five days treatment with the effective dose of the study drugs every four hours). In the follow-up phase, dyspnea intensity was significantly lower in midazolam group than in morphine group.

Although the available evidence is not consistent, meta-analysis including these two studies already mentioned and one unpublished study found no significant benefit of midazolam in relieving dyspnea in cancer patients compared with morphine or placebo.⁴³ Thus, we suggest that benzodiazepines are not to be used alone in cancer patients with dyspnea.

Benzodiazepines are suggested to be used in combination with opioids (2C): In one prospective observational study of 26 cancer patients, dyspnea intensity improved significantly after the concurrent use of opioids (morphine or hydromorphone) and lorazepam.⁴⁴ Another retrospective chart review of 115 patients (64% were cancer patients, the remainder were noncancer patients) with moderate to severe dyspnea who were receiving inpatient palliative care consultation service evaluated dyspnea intensity and pharmacological intervention that they recieved.⁴⁵ In this study, concurrent use of benzodiazepines with opioids significantly improved dyspnea more frequently than receiving no medication. Moreover, a single-blind randomized controlled trial on 101 cancer patients with dyspnea during the last one week of life compared the efficacy of three different treatments (regular subcutaneous morphine with midazolam rescue, regular subcutaneous midazolam with morphine rescue, and regular morphine and midazolam with morphine rescue) on dyspnea intensity.²⁹ In this study, although there was nonsignificant difference in dyspnea intensity among the groups, concurrent use of midazolam with morphine resulted in significantly more frequent dyspnea relief than midazolam or morphine alone. The adverse events associated with the concurrent use of benzodiazepines and opioids in these studies were reported as nonsignificant.

Although we should keep the risk of the adverse events such as increasing drowsiness in mind, the available evidence shows potential benefit of the concurrent use of benzodiazepines and opioids in relieving dyspnea in cancer patients. Thus, we suggest that benzodiazepines be added to opioids in cancer patients with dyspnea.

Nebulized furosemide

Nebulized furosemide is recommended not to be used (1B): One randomized placebo-controlled crossover trial on 15 cancer patients evaluated the effect of nebulized furosemide on dyspnea intensity after an exercise stress test.⁴⁶ In this study, the dyspnea intensity did not differ significantly between nebulized furosemide group and placebo group. Another randomized placebo-controlled trial of seven cancer patients evaluated the effect of nebulized furosemide on dyspnea.⁴⁷ In this study, nebulized furosemide did not result in significant improvement in dyspnea compared with placebo.

The available evidence shows no benefit of nebulized furosemide on relieving dyspnea in cancer patients. Thus, we recommend that nebulized furosemide not to be used in cancer patients with dyspnea.

Corticosteroids

Systemic corticosteroids are suggested not to be used routinely without consideration of dyspnea etiology (2D): One prospective observational study evaluated the effects of systemic corticosteroids in controlling various symptoms in 106 cancer patients.⁴⁸ Of these 106 patients, 15 patients were treated with corticosteroids for dyspnea, and 13 of them could be analyzed. Dyspnea was improved in 5 of these 13 patients (39%) as evaluated by a nonvalidated tool. Another similar prospective observational study of 50 cancer patients receiving home-visit service reported that systemic corticosteroids improved dyspnea evaluated by a nonvalidated evaluation tool in 13 of 18 dyspneic patients (72%).⁴⁹ In addition, we found two case reports regarding the effects of systemic corticosteroids on dyspnea in cancer patients. One reported two cases of dyspnea caused by major airway obstruction improved significantly after the administration of systemic corticosteroids.⁵⁰ Conversely, systemic corticosteroids had no significant effect on respiratory status in another report of a patient with lymphangitis carcinomatosa.⁵¹ Across all four studies, several adverse events, including insomnia, delirium, infection, and GI bleeding, were reported in up to 20% of cases receiving systemic corticosteroids, with 12% of patients experiencing severe adverse events.

Although the available evidence suggests a potential benefit of systemic corticosteroids in relieving dyspnea in cancer patients, the designs of all studies we found were of a very low quality and at high risk of bias. Moreover, adverse events from systemic corticosteroids are not negligible, and it remains uncertain what type of dyspnea etiology or patient's characteristics are associated with a response to systemic corticosteroids. Thus, we suggest that systemic corticosteroids not to be used routinely in cancer patients with dyspnea without considering dyspnea etiology.

Systemic corticosteroids are suggested to be used in patients with lymphangitis carcinomatosa (2D): One prospective observational study evaluated the effects of systemic corticosteroids on various symptoms in 106 cancer patients.⁴⁸ In this study, although corticosteroids were administered for lymphangitis carcinomatosa in 10 patients, no information was provided regarding dyspnea. In one case report of a patient with lymphangitis carcinomatosa, systemic corticosteroids showed no significant effect on respiratory status.⁵¹

Evidence from currently available studies regarding the benefit of systemic corticosteroids on dyspnea caused by lymphangitis carcinomatosa is insufficient. However, systemic corticosteroids are listed as a treatment option for palliation of dyspnea caused by lymphangitis carcinomatosa in a major palliative medicine textbook.¹⁴ In addition, systemic corticosteroids are commonly used for palliation of dyspnea caused by lymphangitis carcinomatosa in real-world clinical practice. Thus, we suggest that systemic corticosteroids be used in cancer patients with dyspnea caused by lymphangitis carcinomatosa. Simultaneously, anticancer treatment, such as chemotherapy, should be considered, if indicated.

Systemic corticosteroids are suggested to be used in patients with superior vena cava syndrome (2D): One systematic review of treatments for superior vena cava (SVC) syndrome did not find any study evaluating systemic corticosteroids.⁵² However, systemic corticosteroids were described as anecdotal treatment modality for SVC syndrome in two clinical review articles^53,54 and in a major palliative medicine textbook.¹⁴

Thus, we suggest that systemic corticosteroids be used in cancer patients with dyspnea caused by SVC syndrome. At the same time, anticancer treatment, such as chemotherapy, should be considered, if indicated.

Systemic corticosteroids are suggested to be used in patients with major airway obstruction (2D): One case series including two cases of systemic corticosteroids use for major airway obstruction showed significant improvement of dyspnea in both cases.⁵⁰

Although the evidence is insufficient, the results of only available observations suggest a potential benefit of systemic corticosteroids in relieving dyspnea caused by major airway obstruction in cancer patients. Thus, we suggest that systemic corticosteroids be used in cancer patients with dyspnea caused by major airway obstruction.

Management of malignant pleural effusion

Thoracentesis with drainage of pleural effusion is recommended (1B)

We found seven observational studies that included in total 901 cancer patients evaluating the effects of thoracentesis with or without indwelling catheter drainage of malignant pleural effusion in relieving dyspnea.^55–61 All seven studies reported that thoracentesis significantly improved dyspnea, with only 6.5% of participants developing nonsignificant adverse events. In addition, we found four controlled trials that compared the efficacy of thoracentesis with indwelling catheter drainage and pleurodesis in relieving dyspnea caused by malignant pleural effusion. Of those, two randomized controlled trials showed that thoracentesis improved dyspnea significantly better than pleurodesis.^62,63 Although the differences were not significant, the remaining one randomized controlled trial⁶⁴ and one nonrandomized controlled trial⁶⁵ also showed a trend in favor of thoracentesis. Moreover, integrated data from these four controlled trials showed nonsignificant difference in adverse events between thoracentesis and pleurodesis.

The available evidence shows the benefit of thoracentesis with drainage of pleural effusion in relieving dyspnea from malignant pleural effusion, with an acceptable adverse events profile associated with thoracentesis. Thus, we recommend thoracentesis with drainage be performed in cancer patients with dyspnea caused by malignant pleural effusion.

Pleurodesis is suggested to be performed (2C)

We found four controlled trials that compared the efficacy of pleurodesis and thoracentesis with indwelling catheter drainage in relieving dyspnea caused by malignant pleural effusion. Of those, one randomized controlled trial⁶⁴ and one nonrandomized controlled trial⁶⁵ showed nonsignificant difference in dyspnea intensity between the two groups, whereas the remaining two randomized controlled trials showed that thoracentesis improved dyspnea significantly better than pleurodesis.^62,63 Integrated data from these four trials showed nonsignificant difference in adverse events between pleurodesis and thoracentesis.

The available evidence does not show a benefit of pleurodesis over thoracentesis in relieving dyspnea caused by malignant pleural effusion. However, dyspnea improved in the majority of patients in whom pleurodesis was performed, and there was nonsignificant difference in adverse events between pleurodesis and thoracentesis in included studies. Moreover, pleurodesis, if successful, does not require catheter placement or repeated thoracentesis, which is a potential advantage of pleurodesis. Thus, we suggest that pleurodesis be performed in cancer patients with dyspnea caused by malignant pleural effusion, if patients meet all the following conditions: (1) repeated thoracentesis is required to relieve dyspnea, (2) patient's general condition is tolerable for pleurodesis, and (3) a monthly prognosis is expected.

Diuretics is suggested not to be used (2D)

We found no study regarding the effects of diuretics on malignant pleural effusion. Moreover, there is no sufficient pathophysiological or pharmacological basis to use diuretics for malignant pleural effusion, and the risk of developing volume depletion, electrolyte abnormalities, and renal insufficiency is not negligible. Thus, we suggest that diuretics are not to be used in cancer patients with dyspnea caused by malignant pleural effusion.

Management of cough

Morphine/codeine/dihydrocodeine is suggested to be used (2D)

One double-blind randomized controlled trial of 140 lung cancer patients compared the efficacy of dihydrocodeine and levodropropizine (not available in Japan) in relieving cough.⁶⁶ Although cough improved after starting dihydrodeine, there was nonsignificant difference between the two groups. Another double-blind randomized controlled trial of 119 patients with respiratory diseases (including respiratory malignancy) compared the efficacy of different doses of codeine and moguisteine (not available in Japan) in relieving cough.⁶⁷ Although cough improved in 77% of patients in the codeine group, there was nonsignificant difference between the treatment groups. No significant adverse event associated with codeine/dihydrocodeine was reported in these two studies. A systematic review of interventions for cough in cancer patients concluded that although all studies had significant risk of bias, there is some indication for morphine or codeine/dihydrocodeine for cough.⁶⁸

The available evidence does not show any advantages of opioids to relieve cough compared with active comparators. However, all studies showed an improvement in cough intensity after the administration of morphine or codeine/dihydrocodeine. Moreover, the adverse event associated with these opioids is considered acceptable. Thus, we suggest that morphine and codeine/dihydrocodeine be used in cancer patients with cough.

Dextromethorphan is suggested to be used (2C)

We found no study regarding the effects of dextromethorphan against cough in cancer patients. However, in two randomized controlled trials in a total of 40 patients with chronic cough, including cancer patients, dextromethorphan improved cough significantly better than placebo.^69,70 Conversely, another three randomized controlled trials in a total of 460 patients with chronic cough that compared the efficacy of dextromethorphan and other active comparators (levodropropizine, moguisteine, or clofedanol)^71–73 found nonsignificant difference in cough severity between dextromethorphan and comparators.

There is insufficient evidence that dextromethorphan relieves cough in cancer patients. However, based on results of studies in chronic cough patients, dextromethorphan may have potential benefit in relieving cough in cancer patients. Moreover, information regarding adverse events was reported in four of five included studies, with nonsignificant difference between dextromethorphan and placebo or active comparators. Thus, we suggest that dextromethorphan be used in cancer patients with cough.

Gabapentin/pregabalin is suggested not to be used (2D)

We found no study regarding the effects of gabapentin/pregabalin against cough in cancer patients. One retrospective chart review of 51 chronic noncancer cough patients showed improvement of cough intensity after four-week treatment with gabapentin.⁷⁴ In addition, one double-blind randomized placebo-controlled trial of 62 chronic cough patients excluding all peripheral etiologies evaluated the efficacy of gabapentin in relieving cough.⁷⁵ In this study, gabapentin improved the cough-specific QOL score significantly better than placebo, but adverse events were significantly more frequent in the gabapentin group. A systematic review of the effects of pharmacological therapy for chronic cough concluded that although gabapentin/pregabalin may have potential benefit, further studies are needed to confirm the benefit.⁷⁶

Currently, evidence for the use of gabapentin/pregabalin to relieve cough in cancer patients is lacking. Conversely, results of studies of chronic cough in noncancer patients suggest potential benefit of gabapentin/pregabalin in relieving cough. However, since these studies excluded peripheral etiologies of chronic cough that are the cause of cough in cancer patients, we cannot extrapolate these results into cancer patients. Thus, we suggest that gabapentin/pregabalin not to be used in cancer patients with cough.

Nebulized lidocaine is suggested not to be used (2C)

One case series of four terminally ill patients (including one cancer patient) with chronic cough reported that nebulized lidocaine improved cough, evaluated by nonvalidated tool, in 50% of patients.⁷⁷ One observational study evaluated the effects of nebulized lidocaine against cough in 165 noncancer patients⁷⁸ and found that, although data from only 60% of patients were analyzable, nebulized lidocaine improved cough intensity. One double-blind randomized controlled trial of 127 COPD patients compared the efficacy of nebulized lidocaine and bronchodilator (terbutaline) in relieving cough.⁷⁹ In this study, there was nonsignificant difference in cough intensity between the two groups.

Although there is a potential benefit of using nebulized lidocaine to relieve cough in cancer patients, the evidence is insufficient. Moreover, several adverse events, such as arrhythmia and pharyngeal discomfort, have been reported. Thus, we suggest that nebulized lidocaine not to be used in cancer patients with cough.

Management of death rattle

Anticholinergics are suggested not to be used (2B)

One double-blind randomized placebo-controlled trial of 160 terminally ill patients (43% cancer patients) evaluated the efficacy of sublingual atropine in reducing death rattle.⁸⁰ However, this study was stopped prematurely because of futility after interim analysis showed nonsignificant difference in death rattle intensity between atropine group and placebo group. Another double-blind randomized crossover trial of 10 cancer patients compared the efficacy of scopolamine hydrobromide and octreotide in reducing death rattle⁸¹ and found nonsignificant difference between the two groups.

The available evidence does not show any benefit of anticholinergics to reduce death rattle in cancer patients. Moreover, the conclusions of three systematic reviews including studies of noncancer patients do not support the use of anticholinergics for death rattle.^6,82,83 Thus, we suggest that anticholinergics are not to be used in cancer patients with death rattle.

Octreotide is recommended not to be used (1C)

One double-blind randomized crossover trial of 10 cancer patients compared the efficacy of octreotide and scopolamine hydrobromide in reducing death rattle⁸¹ and found nonsignificant difference between the two groups.

The available evidence does not show any benefit of using octreotide to reduce death rattle. Moreover, since octreotide is an expensive drug, issue of cost-effectiveness needs to be taken into consideration for using octreotide. Thus, we recommend that octreotide is not to be used in cancer patients with death rattle.

Suction is suggested not to be performed (2D)

One case report showed that deep suctioning with a laryngoscope under sedation improved death rattle.⁸⁴ Although this report suggested a potential benefit of suctioning in reducing death rattle, the procedure shown in this report is not generalizable. Moreover, there is the possibility that repeated suctioning would give significant discomfort. Thus, we suggest that suctioning be not performed in cancer patients with death rattle.

Discussion

To the best of our knowledge, this is the first published clinical guidelines for the management of respiratory symptoms in cancer patients that has been established following a formal guideline development process. The recommendations of the JSPM respiratory symptom guidelines presented here are based on the combination of the best available evidence and expert consensus. It is difficult to conduct high-quality clinical research of symptom control in advanced cancer patients because of the vulnerability of patients as well as the ethical conflict. In fact, the evidence levels for most of our recommendations were low. Because of the lack of rigorous evidence, recommendation statements based on expert consensus and the best available evidence, like our guidelines, have an important role in guiding the best possible clinical practice for healthcare providers.

Despite our best effort, we could not find sufficient data regarding treatment effect on QOL and pharmaco-economic outcomes. Thus, we discourage the use of the individual recommendations in isolation without consideration of patient's preference and the pharmaco-economic aspect of the treatment intervention.

Finally, more clinical researches need to be conducted in this field, and continuous guideline updates are required to improve the quality of respiratory symptom management in cancer patients.

Footnotes

Acknowledgments

We thank the Japanese Respiratory Society, Japanese Society of Clinical Oncology, Japan Primary Care Association, the Japan Lung Cancer Society, Japanese Society of Cancer Nursing, and Japanese Society for Pharmaceutical Palliative Care and Sciences for their cooperation and advices in establishing recommendation statements.

Funding: This work was funded by the Japanese Society for Palliative Medicine.

Author Disclosure Statement

No competing financial interests exist.

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