A Retrospective Observational Study of Factors Affecting the Efficacy of Concurrent Prescription of Naldemedine for Opioid-Induced Constipation Caused by Oxycodone Tablets

Abstract

Naldemedine is indicated for the treatment of opioid-induced constipation (OIC), but reports on its efficacy in preventing OIC are few. Therefore, we retrospectively investigated factors affecting the efficacy of concurrent prescription of naldemedine on OIC. Outpatients with cancer who were started on oxycodone 10 mg/d were included in the study. The eligible patients were classified by their physicians into the following three groups: Group A used regular laxatives before the introduction of oxycodone and initiated naldemedine treatment simultaneously with oxycodone administration, Group B did not take laxatives before the introduction of oxycodone and started naldemedine simultaneously with oxycodone administration, and Group C had been administering regular laxatives before the introduction of oxycodone and were not prescribed naldemedine simultaneously with oxycodone treatment. The Support Team Assessment Schedule Japanese edition score for constipation, frequency of defecation, Bristol Stool Form Scale, sense of incomplete rectal evacuation, and development or worsening of straining to pass bowel movements were compared among the three groups before and after oxycodone administration. In Group B, there was significant worsening of the four parameters except for the sense of incomplete rectal evacuation, whereas Groups A and C did not present any changes. In logistic regression analysis, body weight ≥51.8 kg was a factor significantly decreasing the preventive effect of naldemedine on OIC, and regular use of laxatives was a factor significantly increasing the preventive effect of naldemedine on OIC. Thus, the initiation of naldemedine should be considered depending on the body weight and regular laxative use.

INTRODUCTION

Opioid analgesics such as morphine, oxycodone, and fentanyl (opioids) are effective in the treatment of moderate-to-severe cancer pain and chronic pain.^1–3) One of the most common side effects is opioid-induced constipation (OIC), which occurs in 60–90% of opioid-using patients.^4–7) Side effects of opioids not only decrease the QOL of patients, but may also lead to drug refusal; therefore, it is important to prevent them.⁸⁾

Naldemedine tosylate (naldemedine) was launched on June 2017 and is indicated for OIC.⁹⁾ Most opioid users do not develop tolerance to constipation,¹⁰⁾ and the “Guidelines for the Pharmacotherapy of Cancer Pain” recommend prophylactic administration of laxatives for OIC.¹¹⁾

The risk of diarrhea is increased when naldemedine is introduced to patients who have been on opioids for a period of time.^12–14) Naldemedine may be used from the time of opioid induction to prevent OIC in outpatients with cancer pain in whom the daily bowel movements are difficult to monitor by a medical personnel. In addition, many patients are already using regular laxatives for chronic constipation at the time of opioid induction.

However, there have been few studies on the efficacy of naldemedine in preventing OIC, and even fewer studies on the effect of regular laxative intake before the introduction of opioids. Therefore, in this study, we divided the patients into groups according to the presence or absence of naldemedine for the prevention of OIC at the time of introduction of oxycodone tablets and the presence or absence of regular laxative intake before introduction of oxycodone. We compared the pre and post defecation status of each group. Additionally, we investigated the factors that influence the prophylactic effects of naldemedine on OIC.

PATIENTS AND METHODS

Patients

Patients who were started on regular oral oxycodone tablets 10 mg/d and oxycodone powder as a rescue medication for cancer pain at Osaka-fu Saiseikai Noe Hospital during the study period from January 1, 2018 to April 30, 2022 were considered eligible for this study. Since 2014, the pharmacists in Osaka-fu Saiseikai Noe Hospital have established a consultation system for pharmacists’ interventions in patients receiving opioids.¹⁵⁾ Their side effects were assessed by three pharmacists certified by the Japanese Society of Palliative Medicine and Pharmacotherapy. We interviewed and evaluated the patients using the same template before the introduction of oxycodone tablets and at the next physician visit 1–2 weeks later.

Followings were the exclusion criteria: (1) patients who were prescribed a laxative other than naldemedine for preventing OIC at the time of introduction of oxycodone tablets, (2) patients who could not be evaluated for constipation before and after introduction of oxycodone tablets, (3) patients who had diarrhea symptoms and were taking antidiarrheal medication before the introduction of oxycodone tablets, and (4) patients whose laxative use was unknown because they are only prescribed an abortive laxative.

Data Collection

All data were retrospectively collected from the electronic medical records of the hospital. The following background factors were recorded: sex, age, body weight, cancer type, naldemedine use, types of laxatives used other than naldemedine, laxative dosage, analgesic types other than oxycodone, types of antiemetic medications used, concomitant chemotherapy use, and concomitant use of inhibitors and inducers of CYP3A4 and P-glycoprotein inhibitor. If the patients started oxycodone tablets during the period of chemotherapy withdrawal, the patients are considered to have concomitant chemotherapy use. The following five items were investigated before and after the introduction of oxycodone: (1) the Support Team Assessment Schedule Japanese edition (STAS-J)¹⁶⁾ score for constipation, (2) frequency of defecation (times/week), (3) stool characteristics using the Bristol stool form scale,¹⁷⁾ (4) sense of incomplete rectal evacuation, and (5) development or worsening of strain in passing bowel movements.

Statistical Analysis

The eligible patients were divided into the following four groups:

A: Patients who were taking regular laxatives before the introduction of oxycodone and were simultaneously prescribed naldemedine with oxycodone to prevent OIC.

B: Patients who were not taking laxatives before the introduction of oxycodone and were simultaneously prescribed naldemedine with oxycodone to prevent OIC.

C: Patients who were taking regular laxatives before the introduction of oxycodone and were not prescribed naldemedine or any other drug for OIC at the time of introduction of oxycodone tablets.

D: Patients who were not taking laxatives before the introduction of oxycodone and were not prescribed naldemedine or other OIC-preventive drugs simultaneously with oxycodone.

Patients’ characteristics in each group were compared using the Kruskal–Wallis test for age and body weight, and Fisher’s exact test for other items, with a significance level of p < 0.05. Patient’s defecation status when starting oxycodone was compared using the Kruskal–Wallis test for STAS-J, frequency of defecation, and Bristol Stool Scale, and the Fisher’s exact test for other items, with a significant level of p < 0.05.

(1) STAS-J, (2) frequency of defecation, and (3) Bristol Stool Form Scale were compared by the Wilcoxon signed-rank sum test. The McNemar test was used for other items.

Univariate logistic regression analysis was performed to analyze the factors related to the effect of naldemedine in preventing OIC. The dependent variable was absence or presence of a worsening STAS-J score, whereas the independent variables were the items indicated in the patient background. Multivariate logistic regression analysis was performed using the factors that were found to be significant (p < 0.05) in the preceding univariate analysis. For the continuous variables of age and weight, the data were binary transformed using the cut-off values obtained by receiver operating characteristic (ROC) curve analysis, and used for the univariate and multivariate analyses.

The software EZR ver1.55¹⁸⁾ was used for all statistical analysis.

Ethical Approval and Informed Consent

The study was performed in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects and was approved by the Ethics Committee of Saiseikai-Noe Hospital (approved on July 6, 2022). Informed consent was obtained in the form of an opt-out option at the hospital.

RESULTS

Table 1 shows the patients’ backgrounds. As there were no patients in Group D, data analyses were only performed for Groups A, B, and C. Differences in sex, age, and body weight among the three groups were not significant (sex: p = 0.824, age: p = 0.424, body weight: p = 0.402). Magnesium oxide doses ranged from 660 to 2640 mg/d. More than half of the patients received a dose of 990 mg/d.

Table 1. Patient Characteristics

	Total	A	B	C
Sex (male/female, total)	31/20 (51)	9/4 (13)	16/12 (28)	6/4 (10)
Age (y) *	69.5 ± 12.5	72.2 ± 8.7	66.5 ± 13.8	74.1 ± 12.0
Weight (kg) *	54.4 ± 11.7	53.9 ± 14.1	55.9 ± 11.6	51.0 ± 6.6
Cancer types
Colorectal	17 (33.3%)	5 (38.5%)	11 (39.3%)	1 (10%)
Lung	11 (21.6%)	1 (7.7%)	7 (25.0%)	3 (30%)
Liver	5 (9.8%)	2 (15.4%)	1 (3.6%)	2 (20%)
Breast	3 (5.9%)	2 (15.4%)	1 (3.6%)	0 (0%)
Gastric	5 (9.8%)	1 (7.7%)	4 (14.3%)	0 (0%)
Pancreatic	2 (3.9%)	0 (0%)	1 (3.6%)	1 (10%)
Cecum	2 (3.9%)	1 (7.7%)	1 (3.6%)	0 (0%)
Others	6 (11.8%)	1 (7.7%)	2 (7.1%)	3 (30%)
Regular laxatives for before the introduction of oxycodone tablets
Magnesium oxide	14 (27.5%)	10 (76.9%)	0 (0%)	4 (40%)
Sennoside	6 (11.8%)	2 (15.4%)	0 (0%)	4 (40%)
Linaclotide	1 (2%)	0 (0%)	0 (0%)	1 (10%)
Lactulose	1 (2%)	0 (0%)	0 (0%)	1 (10%)
Macrogol	1 (2%)	1 (7.7%)	0 (0%)	0 (0%)
No prescription	28 (54.9%)	0 (0%)	28 (100%)	0 (0%)
Other analgesics **
Loxoprofen sodium	20 (39.2%)	3 (23.1%)	13 (46.4%)	4 (40%)
Acetaminophen	16 (31.4%)	4 (30.8%)	9 (32.1%)	3 (30%)
Celecoxib	4 (7.8%)	0 (0%)	1 (3.6%)	3 (30%)
No prescription	12 (23.5%)	6 (46.2%)	6 (21.4%)	0 (0%)
Antiemetics
Prochlorperazine maleate	33 (64.7%)	8 (61.5%)	22 (78.6%)	3 (30%)
Domperidone	4 (7.8%)	1 (7.7%)	2 (7.1%)	1 (10%)
Metoclopramide	3 (5.9%)	2 (15.4%)	1 (3.6%)	0 (0%)
Diphenhydramine hydrochloride	2 (3.9%)	0 (0%)	1 (3.6%)	1 (10%)
No prescription	9 (17.6%)	2 (15.4%)	2 (7.1%)	5 (50%)
Anti-cancer agent (yes)	15 (29.4%)	4 (30.8%)	9 (32.1%)	2 (20%)
CYP3A4 inhibitor (yes)	3 (5.9%)	2 (15.4%)	1 (3.6%)	0 (0%)
P-glycoprotein inhibitors (yes)	1 (2%)	0 (0%)	1 (3.6%)	0 (0%)

* Mean ± standard deviation (S.D.). ** One patient was administered more than 2 medications.

Table 2 shows the distribution of the measured scores at the time of starting oxycodone in each group. There were no significant differences in any parameter among the three groups.

Table 2. Patients’ Defecation When Starting Oxycodone Tablets

	A	B	C	p-Value
(1) STAS-J
	n = 13	n = 28	n = 10	0.671
0	10 (76.9%)	22 (78.6%)	9 (90%)
1	2 (15.4%)	5 (17.9%)	1 (10%)
2	1 (7.7%)	1 (3.6%)	0 (%)
3	0 (0%)	0 (0%)	0 (0%)
4	0 (0%)	0 (0%)	0 (0%)
(2) Frequency of defecation (times/week)
	n = 10	n = 24	n = 10	0.595
0	0 (0%)	0 (0%)	0 (0%)
1	0 (0%)	0 (0%)	0 (0%)
2	0 (0%)	0 (0%)	0 (0%)
3	0 (0%)	2 (8.3%)	0 (0%)
4	3 (30%)	5 (20.8%)	5 (50%)
5	0 (0%)	0 (0%)	0 (0%)
6	0 (0%)	0 (0%)	0 (0%)
7	7 (70%)	17 (70.8%)	5 (50%)
(3) Bristol stool form scale
	n = 10	n = 26	n = 10	0.243
1	0 (0%)	1 (100%)	0 (0%)
2	0 (0%)	1 (3.8%)	0 (0%)
3	1 (10%)	2 (7.7%)	3 (30%)
4	4 (40%)	17 (65.4%)	4 (40%)
5	3 (30%)	4 (15.4%)	2 (20%)
6	2 (20%)	1 (3.8%)	1 (10%)
7	0 (0%)	0 (0%)	0 (0%)
(4) Sense of incomplete rectal evacuation
	n = 10	n = 25	n = 10	0.697
Presence	1 (10%)	1 (4%)	0 (0%)
(5) Development or worsening of strain in passing bowel movements
	n = 10	n = 25	n = 10	0.49
Presence	2 (20%)	2 (8%)	0 (0%)

(1) (2) (3) p-Values by Kruskal–Wallis test, (4) (5) p-values by Fisher’s exact test.

Results of before-and-after Comparison in Each Group

Figure 1 shows the individual plots of the measured data before and after the introduction of oxycodone.

Fig. 1. Pre- and Post-comparison of Five Items Regarding Constipation and Defecation Status in Each Group

(1) Support Team Assessment Schedule Japanese edition (STAS-J): (A) n = 13 (B) n = 28 (C) n = 10, ** p < 0.01, Wilcoxon signed-rank sum test. (2) Frequency of defecation (times/week): (A) n = 10 (B) n = 24 (C) n = 10, ** p < 0.01, Wilcoxon signed-rank sum test. (3) Bristol stool form scale: (A) n = 10 (B) n = 26 (C) n = 10, ** p < 0.01, Wilcoxon signed-rank sum test. (4) Sense of incomplete rectal evacuation: (A) n = 10 (B) n = 25 (C) n = 10, McNemar test. (5) Development or worsening of the strain to pass bowel movements: (A) n = 10, (B) n = 25, (C) n = 10, * p < 0.05, McNemar test.

(1) STAS-J

After the introduction of oxycodone tablets, the STAS-J score increased in 18 patients in Group B, and there was a significant worsening of the STAS-J score (p < 0.001).

(2) Frequency of defecation (times/week)

In Group B, 11 patients reported a decrease in the frequency of defecation; 10 of them reported passing stools fewer than 4 times per week, while the frequency had been daily earlier. Reduction in the frequency of defecation was significant (p = 0.0032).

(3) Stool characteristics (Bristol stool form scale)

In Group B, 11 patients showed a decrease in the scores on the Bristol stool form scale after the introduction of oxycodone tablets. Ten of them had normal stools, with Bristol stool form scale score of 4 and 5 before the introduction of oxycodone tablets, which worsened after the introduction of oxycodone tablets. There was a significant decrease in the scores in Group B (p = 0.0014).

(4) Sense of incomplete rectal evacuation

There was no significant change in the sense of incomplete rectal evacuation after the introduction of oxycodone tablets in all groups

(5) Development or worsening of straining to pass bowel movements

In Group B, nine patients experienced development or worsening of straining to pass bowel movements after the introduction of oxycodone tablets and there was a significant difference in Group B (p = 0.0269).

Factors Influencing the Prophylactic Effects of Naldemedine on OIC

Analysis was performed on 19 patients: 13 in group A (including 1 with worsening STAS-J) and 28 in group B (including 18 with worsening STAS-J). Table 3 shows the results of the logistic regression analysis to determine the factors influencing the efficacy of naldemedine in preventing OIC. Before the analysis, ROC curves were generated for “age” and “body weight,” and the cut-off values obtained were 53-year-old (area under the curve (AUC) = 0.621, 95% confidence interval (CI) 0.446–0.796) and 51.8 kg (AUC = 0.730, 95% CI 0.571–0.888), respectively.

Table 3. Logistic Regression Analysis for Factors Affecting Effectiveness in Preventing OIC of Naldemedine

Factors that attenuate the effect	Univariate analysis		Multivariate analysis
	OR (95% CI)	p-Value	OR (95% CI)	p-Value
Sex (female)	0.786 (0.22–2.77)	0.707
≥53-Year-old	3.940 (0.37–41.50)	0.254
≥51.8 kg	0.152 (0.04–0.62)	0.009**	0.603 (1.66–49.50)	0.011*
Regular laxatives*** (yes)	21.600 (2.44–191.00)	0.006**	29.00 (2.73–308.0)	0.005**
Anti-cancer agent (yes)	1.010 (0.27–3.78)	0.987
CYP3A4 inhibitor (yes)	0.405 (0.03–4.85)	0.475
P-glycoprotein inhibitors (Yes)	< 0.001 (0.00- inf)	0.994

* p < 0.05. ** p < 0.01. *** Regular laxatives before the introduction of oxycodone tablets.

Univariate analysis showed that “body weight ≥51.8 kg” and “regular laxatives use before the introduction of oxycodone” were the statistically significant factors related to the preventive effect of naldemedine on OIC. Based on these results, multivariate analysis was conducted, and “body weight ≥51.8 kg” was still identified as the factor that significantly decreasing the preventive effect of naldemedine on OIC, and “regular laxatives use before the introduction of oxycodone” was still as the factor that increasing the preventive of naldemedine on OIC.

DISCUSSION

In this study, we showed the poor prophylactic effect of naldemedine on OIC, along with the factors influencing the prophylactic effect of naldemedine on OIC.

In Group B patients who started naldemedine for the prevention of OIC at the time of introduction of oxycodone tablets, there was a significant worsening after the introduction of oxycodone tablets of the STAS-J score, which was evaluated by medical personnel, as well as the frequency of defecation, Bristol stool form scale, and development or worsening of straining to pass bowel movements, which are patient-reported outcomes (PROs). These results suggest that naldemedine alone does not prevent OIC induced by oxycodone.

In the subsequent analysis to determine the factors affecting the efficacy of naldemedine in preventing OIC, it was found that the efficacy of naldemedine in preventing OIC may be weakened by the following two factors: body weight of ≥51.8 kg and no regular laxative intake before the introduction of oxycodone tablets. Similarly, in examining the efficacy of naldemedine in the poor Performance Status group, the authors noted that a body weight of 55 kg or more may have contributed to the reduced efficacy of naldemedine.¹⁹⁾ Lubiprostone, another peripheral μ-opioid receptor antagonists (PAMORA), was reported to have a higher incidence of diarrhea and nausea side effects in cancer patients, especially in those with a lower body mass index (BMI).²⁰⁾ A domestic phase III study of naldemedine also suggested that the maximum drug concentration (C_max) of naldemedine was higher in patients who weighed <50 kg than that in patients who weighed ≥50 kg.²¹⁾ It is unclear whether the effect of naldemedine is C_max-dependent, and the dosage in the package insert does not set the dose according to body weight. It is possible that the required dose of naldemedine for the prevention of OIC may differ according to the body weight.

The guidelines of the Japanese Society for Palliative Medicine state that laxatives should be administered prophylactically at the same time as opioid administration, and if laxatives do not improve constipation, PAMORA should be administered. In addition, overseas guidelines state that PAMORA should be started only when laxatives do not adequately improve constipation.²²⁾ Considering cost-effectiveness and these guidelines, regular oral laxatives should always be taken at the time of induction of opioid analgesics to prevent OIC.

Recently, a randomized study of naldemedine and magnesium oxide (1500 mg/d) for preventing OIC reported that naldemedine significantly improved the QOL of patients.²³⁾ Further studies on the preventive effect of naldemedine on OIC are required.

In this study, we were unable to obtain detailed information on the factors that affect bowel movements, such as dietary intake and physical activity, since this was a retrospective analysis of medical records. Moreover, it was limited to outpatients, making it difficult to confirm the status of medications. These points should be included in future surveys.

Acknowledgments

We gratefully acknowledge Professors Yoshitaka Yano and Chikako Matsumura for their technical assistance.

Conflict of Interest

The authors declare no conflict of interests.

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