Potential Efficacy of Midazolam as Second-Line Treatment for Terminal Dyspnea in Patients with Cancer: Secondary Analysis of a Multicenter Prospective Cohort Study

Abstract

Introduction:

Opioids are widely used as first-line treatment for dyspnea in terminally-ill patients with advanced cancer (terminal dyspnea), but the merit of second-line treatment for persistent terminal dyspnea despite opioid titration is not clear.

Objectives:

To explore whether the adjunctive use of low-dose midazolam as second-line treatment for terminal dyspnea is associated with dyspnea relief compared with further opioid titration.

Methods:

In this preplanned secondary analysis of a multicenter prospective cohort study that consecutively enrolled patients with advanced cancer and terminal dyspnea, we included patients with persistent dyspnea despite opioid titration for whom palliative care physicians added low-dose midazolam (≤10 mg/day) continuously as adjunctive treatment (midazolam group) or titrated opioids further (opioid group). We examined dyspnea intensity (Integrated Palliative care Outcome Scale; IPOS) at the baseline and after six hours.

Results:

Of the 108 patients enrolled in the main study, 19 exhibited persistent dyspnea despite opioid titration. Four patients were treated with low-dose midazolam, and 15 were treated with further opioid titration. The mean dyspnea IPOS scores decreased from 3.3 [standard error (SE) = 0.2] to 1.3 (0.05) [difference = 2.0 (95% confidence interval [CI] = −0.1 to 3.9); p = 0.07] in the midazolam group and significantly decreased from 2.7 (0.1) to 1.3 (0.2) [difference = 1.4 (95% CI = 0.8 to 2.0); p < 0.001] in the opioid group. No significant between-group differences were noted in the mean IPOS scores at the baseline or after six hours. Treatment-related adverse events were rare.

Conclusion:

Continuous low-dose midazolam as adjunctive treatment to opioids may serve as second-line treatment for persistent terminal dyspnea. Future randomized-controlled trials are warranted.

Introduction

Dyspnea is one of the most common and distressing symptoms in patients with advanced cancer, with a reported prevalence of 10% to 70%.^1–4 Dyspnea in the last weeks to days of life (terminal dyspnea) in patients with advanced cancer may worsen as death approaches and is often resistant to palliative treatment, sometimes requiring palliative sedation.^2–4 International guidelines recommend opioids as the first-line treatment for dyspnea.^3,4 However, prior observational studies reported that 30% to 50% of hospitalized patients with terminal dyspnea remained dyspneic despite the titration of parenteral opioids.^5,6 The second-line treatment for patients with persistent terminal dyspnea despite opioid titration is yet to be established. According to international guidelines, the use of benzodiazepines may be considered when dyspnea persists despite opioids and other nonpharmacologic treatments, as dyspnea triggers anxiety, which exacerbates dyspnea.^3,4 Among benzodiazepines, midazolam has multiple pharmacological actions, including anxiolytic, hypnotic, sedative, muscle relaxant, anticonvulsant, and amnesic effects.⁷ Midazolam is the most frequently used benzodiazepine for terminal dyspnea due to its unique characteristics, including rapid onset of effects, short duration of action, and various administration routes, such as intravenous, subcutaneous, intramuscular, and intranasal.^7,8 Navigante et al. showed that the combination of midazolam and morphine significantly relieved dyspnea more than morphine monotherapy as first-line treatment for terminal dyspnea in patients with advanced cancer.⁹ However, there is controversy among palliative care experts about whether benzodiazepines are effective for dyspnea in severely ill patients, and some experts suggest that they may be effective as second-line treatment for persistent terminal dyspnea.¹⁰ A nationwide survey of palliative care physicians in Japan showed that low-dose midazolam as adjunctive treatment for dyspnea was more commonly used as second-line treatment than further opioid titration, when opioids failed to relieve dyspnea sufficiently.⁸ However, no empirical studies have explored the efficacy of low-dose midazolam as second-line treatment for terminal dyspnea in patients with advanced cancer.

In this study, we aimed to explore whether the adjunctive use of low-dose midazolam as second-line treatment for terminal dyspnea in patients with advanced cancer is associated with palliation of dyspnea compared with further opioid titration.

Methods

Design

We conducted a preplanned secondary analysis of a multicenter prospective cohort study designed to examine the feasibility, efficacy, and safety of a comprehensive pharmacological treatment algorithm, including opioids for patients with terminal dyspnea. The methodology of this study has been reported in detail.⁶ We enrolled consecutive inpatients with advanced cancer who were started on parenteral opioids for dyspnea by palliative care physicians in palliative care units and palliative consultant teams at five sites in Japan from February 2020 through June 2021. Study protocols were approved by the Institutional Review Boards (IRBs) of all the study sites. All assessments and interventions were performed in the context of routine practice. This study was conducted based on the ethical standards of the Helsinki Declaration and ethical guidelines for medical and health research involving human subjects issued by the Ministry of Health, Labor and Welfare in Japan. The requirement for written informed consent in this observational study was waived by IRBs based on ethical guidelines.

Participants

Inclusion criteria for the main study included: age ≥18 years old; advanced cancer; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3; moderate-overwhelming dyspnea [Integrated Palliative Care Outcome Scale (IPOS) score of 2–4];¹¹ maintained communication capacity [0–2 based on the Communication Capacity Scale (CCS), item 4];¹² and initiation of parenteral opioids by continuous administration the first time for dyspnea. Patients were excluded if they received treatment for dyspnea caused by etiologies unrelated to cancer or if they were scheduled to undergo an intervention that would markedly influence the dyspnea intensity. The patients were followed up for one month or until death, whichever came first. In this secondary analysis, we included patients who continued to suffer from dyspnea despite opioid titration and in whom further opioid titration would be considered clinically controversial because uncomfortable side effects developed (e.g., drowsiness, respiratory depression, delirium, myoclonus, nausea, and vomiting).

Treatment strategies

To standardize our approach across the study sites, we developed a pharmacological treatment algorithm that visualizes how palliative care specialists use parenteral opioids by continuous administration.⁶ The algorithm reflects a comprehensive treatment strategy that includes opioid initiation and titration, opioid switching, and the addition of low-dose benzodiazepines. We indicated in the study protocol that the recommended initial dose of parenteral opioids was 6–12 mg daily (parenteral morphine-equivalent dose) for opioid-naive patients, and a 20% to 50% increase of prior opioids for opioid-tolerant patients. Thereafter, the doses were maintained, increased by 20%, or decreased by 20%, as clinically appropriate. When patients continued to suffer from dyspnea despite opioid titration of parenteral opioids, and when further opioid titration was considered clinically controversial because uncomfortable side effects developed, palliative care physicians chose whether to add continuous low-dose midazolam (midazolam ≤10 mg/day) intravenously or subcutaneously as adjunctive treatment to opioids (midazolam group) or to titrate opioids further (opioid group).^8,13

Measurements

The data collection process has been reported in detail elsewhere.⁶ In addition to patients’ baseline characteristics, responsible physicians measured variables related to dyspnea and treatment at the time when they chose whether to add low-dose midazolam or titrate opioids further (baseline = T0) and six hours later (T1).

Efficacy

Dyspnea intensity was assessed with IPOS at T0 and T1 (worst over two hours at each time point). IPOS is a valid and reliable proxy symptom assessment scale that rates how much a patient is affected by dyspnea on a 5-point scale (0 = not at all, 1 = slightly, 2 = moderately, 3 = severely, 4 = overwhelmingly).¹¹ In addition, clinicians assessed improvement using the Clinical Global Impression scale-Improvement, a validated 7-point scale ranging from 1 (very much improved) to 7 (very much worse).¹⁴

Achievement of treatment goals

The achievement of treatment goals was operationally defined, based on clinical experience, as “the case where dyspnea is alleviated or is acceptable to the patient, and the patient does not wish for further adjustment of treatment for dyspnea”.⁶ If the patient had difficulty communicating, and his or her family was present, the responsible physician asked the family if the patient looked comfortable and would not wish for further adjustment based on observation. If the patient had difficulty communicating and the family was not present, the responsible physician determined whether the treatment goals shared by the patient/family at the initiation of treatment had been achieved.

Consciousness and communication

We assessed CCS item 4 to examine the communication capacity and the modified Richmond Agitation-Sedation Scale (RASS) to examine the consciousness level. CCS is a reliable and valid 5-item tool to evaluate the communication capacity of patients with advanced cancer.¹² Item 4 of CCS quantifies voluntary communication on a 4-point scale ranging from 0 (voluntary and explicit communication of complex contents) to 3 (unable to communicate).^5,6,15 The modified RASS is a reliable and valid tool that measures the severity of agitation and sedation on a 10-point scale (−5 = unarousable to +4 = combative).^15–17

Adverse events

The severity of adverse events, including nausea, delirium, apnea, and somnolence, was assessed with the Common Terminology Criteria for Adverse Events version 5.0 over six hours.

Statistical analyses

The main outcome was the dyspnea IPOS score. The secondary outcomes included other efficacy variables, achievement of treatment goals, CCS item 4, RASS, and adverse events at T1. We used descriptive statistics to summarize baseline data and outcomes over time. We then performed paired t tests to demonstrate changes over time in patients who remained alive at T1 compared with T0. Dyspnea relief at T1 was defined as a dyspnea IPOS score of 0 or 1.^5,6,18 The t test was also used to compare IPOS, CCS item 4, and RASS between the midazolam and opioid groups. For each statistical method, p < 0.05 was considered a significant difference. The Statistical Package for the Social Sciences, version 25.0 (SPSS Inc., IBM, JAPAN) was used for statistical analyses.

Results

A total of 108 patients were enrolled in the main study and started on parenteral opioids (median overall survival = six days). Of these, 19 patients continued to suffer from dyspnea despite opioid titration, and further opioid titration was considered clinically controversial because side effects developed. Four patients were treated with continuous low-dose midazolam as adjunctive treatment to opioids, and 15 patients were treated with further opioid titration. Patient characteristics are shown in Table 1. The mean age was 68.8 years (standard deviation [SD] 12.5), and the primary cancer was lung cancer in 11 patients (57.9%) and gastrointestinal cancer in four patients (21.2%). Fourteen patients (73.7%) had lung metastases, and 16 (84.2%) had ECOG PS of 4. The most common etiology of dyspnea was lymphangitis carcinomatosis in eight patients (42.1%), followed by a lung tumor in five (26.3%). Table 2 shows outcomes at T0 and T1. The median parenteral morphine-equivalent daily doses in the midazolam and opioid groups were 60 mg/day (interquartile range [IQR]: 48, 96) and 18.0 mg/day (IQR: 9, 30), respectively. The median midazolam dose in the midazolam group was 4.9 mg (IQR: 4.4, 5.3). In the opioid group, two patients died within six hours, and one patient was initiated on continuous midazolam after further opioid titration.

Table 1.

Patient Characteristics

Variables	Midazolam group (n = 4)	Opioid group (n = 15)	Total (n = 19)
Age (SD)	68.3 (6.8)	69 (13.6)	68.8 (12.5)
Sex, female, n (%)	1 (25)	10 (66.7)	11 (57.9)
Body weight, kg (SD)	44.8 (11.4)	49.1 (7.9)	48.0 (9.1)
Primary cancer, n (%)
Lung	2 (50.0)	9 (60.0)	11 (57.9)
Esophagus, stomach, colon, rectum	2 (50.0)	2 (13.3)	4 (21.1)
Breast	0 (0)	3 (20.0)	3 (15.8)
Peritoneal carcinoma	0 (0)	1 (6.7)	1 (5.3)
Metastatic lesions, n (%)
Any	4 (100.0)	14 (93.3)	18 (94.7)
Pleural effusions	1 (25.0)	11 (73.3)	12 (63.2)
Lung	2 (50.0)	12 (80.0)	14 (73.7)
Pleura	2 (50.0)	10 (66.7)	12 (63.2)
Liver	0 (0)	5 (33.3)	5 (26.3)
Central nervous system	0 (0)	2 (13.3)	2 (10.5)
Comorbidity, n (%)
Chronic obstructive pulmonary disease	0 (0)	1 (6.7)	1 (5.3)
Dementia	0 (0)	1 (6.7)	1 (5.3)
Cerebrovascular disorders	0 (0)	1 (6.7)	1 (5.3)
ECOG PS on initiation of
parenteral opioid for dyspnea, n (%)
3	1 (25)	2 (13.3)	3 (15.8)
4	3 (75)	13 (86.7)	16 (84.2)
Palliative Performance Scale, n (%)
10	1 (25)	0 (0)	1 (5.3)
20	1 (25)	7 (46.7)	8 (42.1)
30	1 (25)	6 (40.0)	7 (36.8)
40	1 (25)	2 (13.3)	3 (15.8)
Etiology of dyspnea, n (%)
Pulmonary tumors	1 (25.0)	4 (26.7)	5 (26.3)
(primary, metastasis)
Pleural effusions	1 (25.0)	3 (20.0)	4 (21.1)
Lymphangitis carcinomatosis	1 (25.0)	7 (46.7)	8 (42.1)
Cachexia/respiratory muscle fatigue	0 (0)	1 (6.7)	1 (5.3)
Respiratory infection	2 (50.0)	0 (0)	2 (10.5)
Unidentified cause	0 (0)	1 (6.7)	1 (5.3)
Prior use of regular opioid, yes, n (%)	4 (100)	10 (66.7)	14 (73.7)

ECOG PS, Eastern Cooperative Oncology Group Performance Status; SD, standard deviation.

Table 2.

Change in Outcomes among Patients over T1

	Midazolam group (n = 4)		Opioid group (n = 15)
Variables	T0	T1	T0	T1
Opioids, n (%)
Morphine	2 (50)	2 (50)	12 (80)	12 (80)
Oxycodone	2 (50)	2 (50)	2 (13.3)	2 (13.3)
Hydromorphone	0 (0)	0 (0)	1 (6.7)	1 (6.7)
MEDD iv/sc mg/day
Median (IQR)	60.0 (48,96)	60.0 (48,96)	18.0 (9,30)	24.0 (20,42)
Goal achieved, n (%)		4 (100)		10 (66.7)
IPOS (worst), n (%)
0	0 (0)	1 (25)	0 (0)	1 (6.7)
1	0 (0)	2 (50)	0 (0)	9 (60)
2	3 (75)	0 (0)	5 (33.3)	4 (26.7)
3	1 (25)	1 (25)	9 (60.0)	1 (6.7)
4	0 (0)	0 (0)	1 (6.7)	0 (0)
IPOS, mean (SE)	3.3 (0.2)	1.3 (0.5)	2.7 (0.1)	1.3 (0.2)
Physician-rated improvement, n (%)
Much improved		1 (25)		2 (13.3)
Improved		1 (25)		7 (46.7)
Sightly improved		1 (25)		4 (26.7)
Unchanged		1 (25)		2 (13.3)
Slightly worsened		0 (0)		0 (0)
Worsened		0 (0)		0 (0)
Much worsened		0 (0)		0 (0)
Respiratory rate, mean (SE)	13.8 (2.1)	15.8 (2.9)	19.5 (2.0)	16.6 (1.3)
CCS, item 4, mean (SE)	1.5 (0.3)	1.5 (0.3)	1.4 (0.2)	1.9 (0.3)
RASS, mean (SE)	−1.0 (0.0)	−2.0 (0.4)	−0.9 (0.3)	−2.1 (0.4)
Adverse events (CTCAE), n (%)
Nausea
1	0 (0)	0 (0)	0 (0)	0 (0)
2	0 (0)	0 (0)	0 (0)	1 (6.7)
3	0 (0)	0 (0)	0 (0)	0 (0)
Delirium
1	1 (25)	1 (25)	1 (6.7)	0 (0)
2	0 (0)	0 (0)	5 (33.3)	5 (33.3)
3	0 (0)	0 (0)	1 (6.7)	1 (6.7)
Apnea
3	0 (0)	0 (0)	2 (13.3)	2 (13.3)
Somnolence
1	2 (50)	1 (25)	3 (20)	5 (33.3)
2	2 (50)	1 (25)	3 (20)	2 (13.3)
3	0 (0)	2 (50)	4 (26.7)	5 (33.3)
4	0 (0)	0 (0)	1 (6.7)	2 (13.3)

CCS, Communication Capacity Scale; IPOS, Integrated Palliative Care Outcome Scale; IQR, interquartile range; MEDD, morphine-equivalent daily dose; RASS, Richmond Agitation Sedation Scale; SE, standard error.

Dyspnea intensity

Figure 1 shows changes in dyspnea intensity from T0 to T1. The mean dyspnea IPOS scores decreased from 3.3 (standard error [SE]: 0.2) to 1.3 (SE: 0.05) (difference = 2.0 [95% CI = −0.1 to 3.9]; p = 0.07) in the midazolam group and significantly decreased from 2.7 (SE: 0.1) to 1.3 (SE: 0.2) (difference = 1.4 [95% CI = 0.8 to 2.0]; p < 0.001) in the opioid group (Table 3). No significant between-group differences were noted in the mean IPOS scores at T0 (p = 0.13) or T1 (p = 0.86).

FIG. 1.

Changes in dyspnea intensity. Bars show standard error. Dyspnea intensity measured by Integrated Palliative Care Outcome Scale (IPOS), ranging from 0 to 4, with higher values indicating greater intensity.

Table 3.

Changes in Dyspnea Intensity, Communication Capacity, and Consciousness Level

	Midazolam group (n = 4)					Opioid group (n = 19)
	T0	T1	Difference	p value^*		T0	T1	Difference	p value^*
	Mean (SE)	Mean (SE)	Mean (95% CI)			Mean (SE)	Mean (SE)	Mean (95% CI)
Dyspnea IPOS	3.3 (0.2)	1.3 (0.05)	2.0 (−0.1, 3.9)		0.07	Dyspnea IPOS	2.7 (0.1)	1.3 (0.2)		1.4 (0.8, 2.0)	<0.001
CCS, item 4	1.5 (0.3)	1.5 (0.3)	0.0 (0.0, 0.0)	—	CCS, item 4	1.4 (0.2)	1.9 (0.3)	-0.5 (−0.9, 0.1)	0.03
RASS	−1.0 (0.0)	−2.0 (0.4)	1.0 (−0.1, 2.1)	0.09	RASS	−0.9 (0.3)	−2.1 (0.4)	1.2 (0.4, 2.0)	0.01

p-values calculated based on comparison with T0 using paired t tests.

CCS, Communication Capacity Scale; IPOS, Integrated Palliative Care Outcome Scale; RASS, Richmond Agitation Sedation Scale; SE, standard error.

Consciousness and communication

In the midazolam group, the mean CCS item 4 scores did not change over time (1.5 [SE: 0.3] at both time points) (n = 4, difference from T0 = 0.0 [95% CI = not applicable: NA]; p = NA). Mean RASS was −1.0 (SE: 0.0) at T0 to −2.0 (SE: 0.4) at T1 (n = 4, difference from T0 = 1.0 [95% CI = −0.1 to 2.1]; p = 0.09), with no significant difference. In the opioid group, mean CCS item 4 scores significantly decreased from 1.4 (SE: 0.2) at T0 to 1.9 (SE: 0.3) at T1, indicating more communication difficulties (n = 15, difference from T0 = −0.5 [95% CI = −0.9 to 0.1]; p = 0.03). Mean RASS significantly decreased from −0.9 (SE: 0.3) at T0 to −2.1 (SE:0.4) at T1 (n = 15, difference from T0 = 1.2 [95% CI = 0.4 to 2.0]; p = 0.01).

Achievement of treatment goals

At T1, four patients (100%) in the midazolam group and 10 patients (66.7%) in the opioid group achieved the treatment goal of dyspnea relief.

Distribution of other dyspnea outcomes

At T1, dyspnea relief (IPOS ≤ 1) was observed in three patients (75%) in the midazolam group and in 10 patients (66.7%) in the opioid group. Physicians rated dyspnea as slightly improved, improved, or much improved in 3 (75%) and 13 (86.7%) patients in the midazolam and opioid groups at T1, respectively.

Adverse events

The number of any adverse events remained the same in the midazolam group (five at T0 and T1) and increased from 20 to 23 in the opioid group (Table 2). Grade ≥3 somnolence increased from none at T0 to two (50%) at T1 in the midazolam group and increased from five (33.3%) at T0 to seven (46.7%) at T1 in the opioid group. Respiratory depression was not observed in either group.

Discussion

To the best of our knowledge, this is the first study indicating that the adjunctive use of midazolam as second-line treatment for dyspnea may be associated with a decrease in dyspnea intensity.

The first important finding is that midazolam as adjunctive treatment may be effective. In the midazolam group, IPOS showed a trend toward a decrease over six hours and dyspnea relief was observed in 75% of patients. In addition, physicians perceived improvement in dyspnea in 75% of patients, and treatment goals were achieved in all patients. These findings were largely comparable to those of the opioid group.

The Cochrane review concluded that there is no evidence that benzodiazepines have a beneficial effect on dyspnea in patients with life-limiting diseases, including advanced cancer.^19–21 Benzodiazepines, in general, may not be effective when used as monotherapy for dyspnea in patients with advanced disease. In contrast, benzodiazepines may be useful for patients with terminal dyspnea, in whom dyspnea and anxiety often co-occur.^8–10 Anxiety is often reported as a major exacerbator of dyspnea, and its association with anxiety leads to a progressive negative spiral.^22,23 International guidelines for the management of dyspnea in patients with cancer suggest that there is no high-quality evidence to support the use of benzodiazepines for relief of dyspnea and have proposed that benzodiazepines may be considered in patients with cancer experiencing dyspnea-related anxiety if opioids and other nonpharmacologic treatments are not effective.^3,4 One randomized trial showed that midazolam as adjunctive treatment for dyspnea in terminally-ill patients with advanced cancer significantly reduced dyspnea compared with morphine monotherapy.⁹ However, this study did not adequately reflect standard practice in palliative care for dyspnea. For example, the amount of midazolam utilized in the study (30 mg/day) was a dose typically considered for palliative sedation^24–26 and was much higher than that commonly used for symptom control (≤10 mg/day).^8,24 Although its efficacy as first-line treatment was suggested, the efficacy of midazolam as second-line treatment for dyspnea has remained unclear. Our findings suggest that the adjunctive use of midazolam for dyspnea may be a potentially useful option as the second-line treatment.

The second important finding was that no marked decline in communication capacity or consciousness level was observed compared with the baseline in the midazolam group, and the results were largely similar to or at least more favorable than those in the opioid group. Patients with cancer in the last weeks to days of life may experience cognitive dysfunction and decreased levels of consciousness not only due to the drugs needed to alleviate various symptoms but also due to the natural dying process.² Alleviating dyspnea without such changes becomes more difficult as death approaches. Physicians need to balance dyspnea relief and communication capacity/consciousness in relief of terminal dyspnea.^5,27 Of note, adverse events were generally tolerable. Adverse events were common, and most of them were also seen at T0. Drowsiness tended to worsen, but respiratory depression was not observed.

This study had several limitations. First, it was a secondary analysis of an observational study. Due to the small sample size and exploratory nature of the study, we did not perform statistical power calculations or comprehensive statistical analysis with the adjustment of baseline differences. To ensure some degree of comparability, we established the inception point a priori when further opioid titration was considered clinically controversial due to persistent dyspnea and the development of unpleasant side effects despite opioid titration. However, patients in the two groups may not have been highly comparable. The participating physicians decided who would receive midazolam and who would be titrated to a higher opioid dose, which may have introduced a selection bias and undermined comparability. Randomized-controlled trials (RCTs) or well-designed observational studies with comparison groups are needed to assess the efficacy of midazolam as second-line treatment for terminal dyspnea. Second, patient-reported outcomes and other subjective assessments were not available because patients progressively become unable to communicate. Third, we did not conduct any assessments of anxiety in this study. A link between dyspnea and anxiety has been noted, and differences in the effects of midazolam with or without anxiety need to be evaluated in further studies. In the main study,⁶ data were available on concomitant treatment for dyspnea only up to 48 hours after the initiation of continuous opioid treatment. Information on concomitant treatment for dyspnea at the inception point of this study was insufficient (e.g., how many patients used steroids for lymphangitic carcinomatosis and at what dosage) because this secondary analysis included situations after 48 hours. These may have had an impact on the results. Thus, the group of four patients taking midazolam may be too small to draw definitive conclusions. Overall, our results should be considered hypothesis-generating, potentially suggesting the efficacy of midazolam. Finally, our findings are not immediately generalizable to primary palliative care, as the treatment was performed by palliative care specialists in this study. In summary, continuous low-dose midazolam as adjunctive treatment for persistent terminal dyspnea in patients with advanced cancer may be as effective and potentially safe as further opioid titration. Our preliminary findings justify the need for future RCTs or well-designed observational studies to confirm the efficacy and safety of midazolam as second-line treatment for terminal dyspnea.

Footnotes

Acknowledgments

The authors are grateful to researchers involved in Health, Labor, and Welfare Sciences Research Grants (19EA1011, and 22EA1004) and the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (20K20618) for their useful advice.

Authors’ Contributions

S.M.: concept and design, data acquisition, analysis and interpretation of data, writing of original draft and revision, approval of the final version, and sufficient participation. M.M.: concept and design, data acquisition, analysis and interpretation of data, revision, approval of the final version, and sufficient participation. T.Y., K.S., Y.M., R.M., H.Q., T.I., Y.M., K.I., N.Y., T.Y., S.O., S.I., A.I., and T.M.: concept and design, data acquisition, interpretation of data, revision, approval of the final version, and sufficient participation. E.S.: concept and design, data acquisition, analysis and interpretation of data, revision, approval of the final version, sufficient participation, and acquisition of funding.

Author Disclosure Statement

M.M received honoraria from Daiichi-Sankyo Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., Shionogi & Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; T.Y. received honoraria from Daiichi-Sankyo Co., Ltd., EA Pharma Co., Inc., Hisamitsu Pharmaceutical Co., Inc., Nihon Zoki Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., and Terumo Co.; K.S. received honoraria from Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., and Mundipharma Co., Ltd.; Y.M. received consulting fees from AstraZeneca Co., Daiichi-Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Fujimoto Pharmaceutical Corporation, Hisamitsu Pharmaceutical Co., Inc., Nippon Boehringer Ingelheim Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; Y.M. received honoraria from Daiichi-Sankyo Co., Ltd.; and E.S. received honoraria from Daiichi-Sankyo Co., Ltd., Hisamitsu Pharmaceutical Co., Inc., Pfizer Co., Terumo Co., and Tsumura & Co. Other authors declare no relevant conflicts of interest.

Funding Information

This work was supported, in part, by the Japan Hospice Palliative Care Foundation and Health, Labor, and Welfare Sciences Research Grants (19EA1011, and 22EA1004) and the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (20K20618).

Abbreviations Used

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