A Retrospective Study of the Effects of Oncology Pharmacist Participation in Treatment on Therapeutic Outcomes and Medical Costs

Abstract

Specialist oncology pharmacists are being trained in Japan to assist cancer treatment teams. These specialized pharmacists address patients’ physical and mental problems in pharmacist-managed cancer care clinics, actively participate in formulating treatment policies, and are beneficial in offering qualitative improvements to patient services and team medical care. However, the effect of outpatient treatment by oncology pharmacists on therapeutic outcomes and medical costs is still unknown. A retroactive comparative analysis of the treatment details and clinical course was conducted among three groups of patients: patients who underwent adjuvant chemotherapy managed by a gynecologic oncologist only (S arm), patients managed by a non-oncologist (general practice gynecologist) only (NS arm), and patients managed by both a non-oncologist and a specialist oncology pharmacist (NS+Ph arm). The medical cost per course was significantly lower for patients in the NS+Ph arm than for those in the other two arms. Surprisingly, the outpatient treatment rate in the NS+Ph arm was overwhelmingly high. The involvement of an oncology pharmacist did not make a significant difference in therapeutic outcomes such as recurrence rate and survival. The participation of oncology pharmacists in the management of cancer patients undergoing chemotherapy enables safe outpatient treatment and also reduces medical costs.

The development of drug therapies for cancer has resulted in improved therapeutic outcomes; these drugs play an important role in cancer treatment. However, unfortunately, cancer drugs always cause side effects, including hematological adverse events such as neutropenia and thrombocytopenia and non-hematological adverse events such as nausea, vomiting, and skin disorders. Such side effects not only diminish a patient’s quality of life but may also make it difficult for the patient to continue treatment; dose adjustment, decisions on implementation, and supportive care all become important. In recent years, a policy designed to encourage outpatient treatment of cancer patients was introduced in Japan. However, satisfactory management of treatment in the outpatient setting, where there are few points of contact with patients, has been difficult, and structuring an efficient medical system is important. We established the collaborative drug therapy management (CDTM) care framework in 2008 as a method for managing joint care provided to cancer patients by physicians and specialist oncology pharmacists who address the physicians’ requests.¹⁾ In the CDTM workflow, specialist oncology pharmacists examine cancer patients at a pharmacist-managed cancer care clinic before they are seen by their attending physician, and offer proposals to the physician regarding chemotherapy management. Specialist oncology pharmacists play a major role in cancer drug therapy management, and a very high proportion of their proposals are ultimately adopted. According to the results of a study involving 167 cancer chemotherapy patients treated under the CDTM framework between May 2008 and September 2013, proposals made to physicians by specialist oncology pharmacists were implemented with the following frequencies: proposals concerning supportive drug therapies: 96% (1421/1478), proposals concerning postponing the administration of chemotherapy: 96% (146/152), proposals concerning adjustments to anticancer drug dosages: 90% (79/88). As we reported previously, this multidisciplinary approach by physicians and oncology pharmacists reduces physicians’ workloads, effectively enhances the quality of medical care, improves risk management, and is received very well by patients.^1,2) Several studies on the effectiveness of pharmacist’s activities in the field of cancer chemotherapy have been reported in Japan.^1–8) However, no study has yet addressed the effect of collaboration between oncology pharmacists and physicians on therapeutic outcomes and medical costs in Japan.⁹⁾

In this study, we compared patients undergoing chemotherapy for cancer who were managed by physicians alone with those managed in collaboration with oncology pharmacists. Specifically, we investigated the effects of such collaboration on therapeutic outcomes and medical costs.

MATERIALS AND METHODS

Study Design

This was an observational study to investigate the efficacy and safety of collaborative management between physicians and oncology pharmacists of the treatment of patients undergoing adjuvant chemotherapy after radical surgery for ovarian cancer. The study complied with Good Clinical Practice guidelines and the Helsinki Declaration, and it was approved by the Kurashiki Medical Center Ethics Committee (No. 42/2008).

The study subjects were patients who started treatment between April 2009 and March 2014, and their outcomes were investigated retrospectively after the completion of follow-up in March 2016. As follows, we configurated three groups whose care was managed 1) by an oncologist board-certified by the Japan Society of Gynecologic Oncology (the specialist (S) arm), 2) by a non-board-certified oncologist (the non-specialist (NS) arm), 3) collaboratively by a non-board-certified oncologist and an oncology pharmacist (the non-specialist+pharmacist (NS+Ph) arm). We compared NS+Ph arm (the study group) with S and NS arms (the conventional treatment groups).

Whether the physician in charge of treatment was a specialist or a non-specialist was decided at random, and whether non-specialist physicians collaborated with a specialist oncology pharmacist was dependent on the preference of the non-specialist. Particularly, patients who have the typical features such as strong anxiety, lack of understanding, and decrease in liver or kidney function were divided into the NS+Ph arm. As such, this study design prevented any intentional arrangement of the number of patients in each group or the makeup of the patients’ backgrounds (Fig. 1).

Fig. 1. Method for Allocating Patients into Groups

The head of the department of gynecology randomly appointed the physician who would attend to the patient following surgery. Gynecologic oncologists treated patients without requesting assistance from a specialist oncology pharmacist in the form of a joint medical examination. A non-oncologist (general practice gynecologist) consulted with a specialist oncology pharmacist when necessary while considering factors such as the patient’s background and selected treatment method. Because this was a retroactive study, it was not possible to adjust the number of patients in each group or the makeup of the patients’ backgrounds.

Patient Population

The study subjects were patients who underwent radical surgery for ovarian cancer at the Kurashiki Medical Center during a 5-year period between April 2009 and March 2014, who received a histological diagnosis of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, who had undergone optimal surgery with a remaining tumor diameter ≤1 cm, and who were scheduled to undergo adjuvant chemotherapy. No distinction was made among the chemotherapy regimens used. Patients who met any of the following criteria after initiating treatment were excluded from the analysis: (1) unable to continue chemotherapy due to development of postoperative complications or a non-cancerous disorder during the chemotherapy period, (2) follow-up for less than 2 years, or (3) treatment with bevacizumab in addition to chemotherapy. Bevacizumab is a very expensive drug that has been demonstrated to prolong progression-free survival significantly when added to chemotherapy regimens to treat ovarian cancer, which would have an enormous impact on the endpoint of this study.^10,11)

Pharmaceutical Intervention

In the NS+Ph arm, the oncology pharmacist conducted the following intervention. (1) consideration of the regimen according to patients’ backgrounds, (2) guidance to patients before chemotherapy starts, (3) continuous medical interview at a pharmacist-managed cancer care clinic during the chemotherapy period, (4) proposal to physicians concerning chemotherapy management (Fig. 2).

Fig. 2. Pharmaceutical Interventions in the NS+Ph Arm

In the NS+Ph arm, the oncology pharmacist conducted the above intervention. They evaluated the tolerability to alcohol, frequency of attending the hospital, how to visit the hospital, etc. to determine the optimal regimen for each patient. From decision of regimen to management during the treatment period, the oncology pharmacist work extensively. ddTC: dose dense paclitaxel and carboplatin therapy, TC: paclitaxel and carboplatin therapy, DC: docetaxel and carboplatin therapy.

Statistical Analysis

The primary endpoint was the medical cost per chemotherapy cycle. To eliminate surgery-related bias, this was calculated by subtracting the medical costs of surgery and postoperative complications from the total medical costs incurred from the date of initial examination (for the concerned disease) until the completion of adjuvant chemotherapy, and dividing the result by the number of cycles implemented (Fig. 3). If a patient had undergone both surgery and chemotherapy as an inpatient, the cost of hospitalization from 2 days prior to surgery until 2 weeks after surgery was subtracted from the total costs containing surgical costs, and the remainder was considered the medical cost of chemotherapy. The date of completion of adjuvant chemotherapy was defined as 3 weeks after the start of the final cycle.

Fig. 3. Formula for Calculating the Medical Cost per Chemotherapy Cycle

The medical cost per chemotherapy cycle was calculated by subtracting the medical costs of surgery and postoperative complications from the total medical cost incurred during the treatment and dividing the result by the number of cycles implemented.

The secondary endpoints were the 2-year relapse-free survival (2-year RFS), relative dose intensity (RDI), and the outpatient treatment rate. Two-year RFS was monitored for 2 years after the date of the start of treatment, with a diagnosis of relapse or death from any cause regarded as events. The RDI was calculated as the ratio of the actual weekly dose administered compared with the planned weekly dose. The outpatient treatment rate was calculated as the proportion of all chemotherapy cycles that were implemented in outpatient clinics. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (ver. 4.0).

Quantitative data on the baseline characteristics of patients in the three arms were compared using one-way ANOVA, and qualitative data were compared using χ² tests. Comparisons of quantitative data between two groups were performed using the Mann–Whitney U-test for non-parametric data and Student’s t-test or Welch’s t-test for parametric data. Comparisons of qualitative data between two groups were made using the χ² test or Fisher’s exact test. Multiple regression analysis was used to analyze the factors affecting the medical cost per cycle and the outpatient treatment rate. For qualitative independent variables, two values were entered as dummy variables. SPSS software (ver. 23; Japan IBM, Tokyo, Japan) was used for statistical analysis. p values <0.05 were considered to indicate statistical significance.

RESULTS

Patient Characteristics

In total, 74 patients were enrolled during the study period, of whom 3 were excluded because of bevacizumab use, leaving 71 patients analyzed (Fig. 4). The S arm included 21 patients, the NS arm 26, and the NS+Ph arm 24. With the exception of the regimen used, there were no differences in the baseline characteristics of the patients among the three arms (Table 1).

Fig. 4. Patient Flow Chart

Patients who underwent additional treatment with bevacizumab after the start of chemotherapy were excluded from the study (one patient from the NS arm, two from the NS+PS arm).

Table 1. Baseline Patient Characteristics

		S	NS	NS+Ph	p-Value
		n=21	n=26	n=24
Age, years mean±S.D.		57.3±10.1	55.3±14.3	54.8±8.7	NSa)
BSA, m2 mean±S.D.		1.50±0.12	1.50±0.12	1.49±0.10	NSa)
Stage, n (%)	I	11 (52.4)	9 (34.6)	5 (20.8)
	II	3 (14.3)	5 (18.5)	9 (38.5)	NSb)
	III	7 (33.3)	12 (46.2)	10 (42.3)
Histology, n (%)	Serous adenoca.	10 (47.6)	12 (46.2)	10 (42.3)
	Clear cell adenoca.	3 (14.3)	5 (18.5)	6 (25.0)
	Endometrioid adenoca.	4 (19.0)	4 (14.8)	4 (16.7)	NSb)
	Mucinous adenoca.	2 (9.5)	4 (14.8)	2 (7.7)
	Others	2 (9.5)	1 (3.7)	2 (7.7)
Chemotherapy, n (%)	PTX+CBDCA (TC)	20 (95.2)	22 (85.2)	12 (50.0)
	DOC+CBDCA (DC)	(0)	4 (14.8)	(0)	p<0.01b)
	dose dense TC (ddTC)	1 (4.8)	(0)	12 (50.0)

BSA: Body surface area, adenoca. PTX: paclitaxel, DOC: docetaxel, CBDCA: carboplatin, NS: not significant. a) One-way ANOVA, b) Chi squared test.

Treatment Administration

The outpatient treatment rate was significantly higher in the NS+Ph arm (79.2%) compared with the S arm (29.4%) and the NS arm (12.1%; p<0.001 vs. both the S and NS arms). There was no significant difference among any of the arms in terms of the treatment completion rate; two patients in the S arm and three in the NS arm refused to continue treatment, and only one patient in the NS+Ph arm discontinued treatment due to development of a drug allergy. Patients in the S and NS+Ph arms underwent at least the standard six cycles of chemotherapy, whereas those in the NS arm underwent only five cycles (p<0.05, vs. the NS arm). The RDI was highest in the NS+Ph arm, although not significantly different from those of the other two arms (Table 2).

Table 2. Comparison of Therapeutic Outcomes

		S	NS	NS+Ph	p-Value
		n=21	n=26	n=24	NS+Ph vs. S	NS+Ph vs. NS
No. of cycles		6.7±2.2	5.0±1.8	6.1±1.5	NSa)	p<0.05a)
Share of outpatient chemotherapy, %		29.4±39.1	12.1±25.0	79.2±27.2	p<0.001a)	p<0.001a)
Treatment completion rate, n (%)		19 (90.5)	23 (88.5)	23 (95.8)	NSb)	NSb)
RDI, %	Taxane	86.8±16.6	89.1±17.2	91.2±10.4	NSa)	NSb)
	CBDCA	79.5±16.0	84.6±18.2	85.6±13.9	NSa)	NSb)
2y RFS, n (%)		17 (81.0)	20 (76.9)	21 (87.5)	NSb)	NSb)
2y OS, n (%)		21 (100)	23 (88.5)	24 (100)	—	NSb)

RDI: relative dose intensity; 2y RFS: 2-year relapse free survival; 2y OS: 2-year overall survival; NS: not significant. a) Mann–Whitney’s U-test, b) Fisher’s exact test.

Efficacy

There was no significant difference in the 2-year RFS between the NS+Ph arm and the S or NS arm, although the rate was highest in the NS+Ph arm. There was no significant difference in the 2-year overall survival among the three arms (Table 2).

Safety

Although the rate of Grade 3 or higher neutropenia was similar among the arms, a significant difference in the rate of Grade 3 or higher thrombocytopenia between the NS+Ph and NS arms was observed. Grade 3 pyrogenic neutropenia was observed in four cases in the NS arm only. No significant difference was observed in the amount of preventative antibiotics or G-CSF administered per case, but the number of medications administered as supportive therapy was 15.8 in the NS+Ph arm, 11.6 in the S arm, and 11.9 in the NS arm (p<0.01, vs. both the S and NS arms; Table 3).

Table 3. Comparison of Hematological Toxicity and Supportive Care Drugs

		S	NS	NS+Ph	p-Value
		n=21	n=26	n=24	NS+Ph vs. S	NS+Ph vs. NS
Neutropenia, n (%)	Grade 3	20 (95.2)	20 (76.9)	19 (79.2)	NSa)	NSb)
	Grade 4	9 (42.9)	12 (46.2)	9 (37.5)	NSb)	NSb)
Thrombocytopenia, n (%)	Grade 3	3 (14.3)	0 (0)	5 (20.8)	NSa)	p<0.05a)
	Grade 4	0 (0)	0 (0)	1 (4.0)	NSa)	NSb)
Febrile neutropenia, n (%)	Grade 3	0 (0)	4 (15.4)	0 (0)	—	NSb)
Use of G-CSF, n		0.7±1.3	5.2±8.1	2.3±4.0	NSc)	NSc)
Use of antibiotic prophylaxis, days		3.7±4.4	5.2±7.0	8.7±9.5	NSc)	NSc)
Drugs for supportive care, n		11.6±6.0	11.9±3.6	15.8±6.0	p<0.01c)	p<0.01d)

Adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0. G-CSF: granulocyte-colony stimulating factor; NS: not significant. a) Fisher’s exact test, b) Chi squared test, c) Mann–Whitney’s U-test, d) Welch’s t-test.

Cost Analysis

The mean medical cost per cycle was lowest for patients in the NS+Ph arm at ¥296330; this was significantly lower than ¥364890 for those in the S arm and ¥432570 for those in the NS arm (p<0.05 vs. the S arm and p<0.001 vs. the NS arm). The drug cost of anti-cancer drugs was significantly higher in the NS+Ph arm compared with the other two arms (p<0.01 vs. the S arm and p<0.05 vs. the NS arm). The cost of supportive care drugs was significantly different between the NS+Ph and S arms (p<0.01; Fig. 5).

Fig. 5. Comparison of Medical Costs

Comparison of the costs required to administer one cycle of chemotherapy. A) Average medical costs per cycle; B) Drug costs (chemotherapy); C) Drug costs (supportive care). A) includes the drug costs, laboratory test costs, outpatient examination costs, and hospital admission costs of B and C. a) Welch’s t-test, b) Student’s t-test. * p<0.05, ** p<0.01, *** p<0.001. NS, not significant.

Multiple Regression Analysis

Three factors were identified that significantly contributed to an increase in medical cost per cycle: the cost of anti-cancer drugs, patient age, and the cost of supportive care drugs. Two factors were identified that contributed to a decrease in cost: the outpatient treatment rate and average RDI (ARDI). The effect was greatest for the outpatient treatment rate, followed by the cost of anti-cancer drugs, ARDI, age, and cost of supportive care drugs (Table 4). Factors that significantly increased the outpatient treatment rate were collaboration with oncology pharmacists, ARDI, and the number of drugs used for supportive care, in that order (Table 5).

Table 4. Multiple Regression Analysis Using Medical Cost per Chemotherapy Cycle as the Dependent Variable

	Unstandardized coefficients B	Standardized coefficients Beta	t	Sig.	95% confidence interval for B		VIF
					Lower bound	Upper bound
Age	233.230	0.225	2.835	0.006	68.921	397.539	1.378
Share of outpatient chemotherapy	−21159.636	−0.753	−9.999	<0.001	−25386.129	−16933.143	1.242
ARDI	−27897.488	−0.357	−4.956	<0.001	−39139.084	−16655.893	1.137
Drug costs (chemotherapy)	2.686	0.459	5.562	<0.001	1.722	3.651	1.494
Drug costs (supportive care)	1.768	0.157	2.282	0.026	0.221	3.315	1.04
(Constant)	18975.611		1.831	0.072	−1720.376	39671.598
R square			0.703
Adjusted R square			0.680
Goodness of model fit			p<0.001

ARDI: average relative dose intensity.

Table 5. Multiple Regression Analysis Using the Outpatient Treatment Rate as the Dependent Variable

	Unstandardized coefficients B	Standardized coefficients Beta	t	Sig.	95% confidence interval for B		VIF
					Lower bound	Upper bound
Age	0.004	0.107	1.266	0.21	−0.002	0.010	1.047
Cooperation with Oncology Pharmacist	0.510	0.581	6.467	<0.001	0.353	0.668	1.182
ARDI	0.531	0.191	2.231	0.029	0.056	1.006	1.076
Drugs for supportive care	0.015	0.193	2.125	0.037	0.001	0.028	1.208
Use of G-CSF	−0.015	−0.205	−2.399	0.019	−0.027	−0.003	1.071
(Constant)	−0.600		−1.922	0.059	−1.224	0.023
R square			0.557
Adjusted R square			0.523
Goodness of model fit			p<0.001

ARDI: Average relative dose intensity; G-CSF: granulocyte-colony stimulating factor. Collaboration with oncology pharmacists was inputted as dummy variables, with yes=1 and no=0.

DISCUSSION

This study was designed to provide a multifaceted evaluation of the effect of collaborative management of cancer chemotherapy between physicians and oncology pharmacists on therapeutic outcomes and medical costs. We assumed that there would be evidence of superiority in the ability to provide cancer chemotherapy between specialist oncologists with specialized cancer treatment knowledge and non-specialists lacking this knowledge, and we compared the three arms to investigate the effect of collaboration between a non-specialist physician and an oncology pharmacist on the ability to provide treatment. We found that the treatment of patients in the NS+Ph arm, who were managed in collaboration with oncology pharmacists, followed a clearly different pattern from those of patients in the NS and S arms. The medical cost per chemotherapy cycle, which was the primary endpoint of this study, was lower in the group that collaborated with oncology pharmacists.

Multiple regression analysis showed that the cost of anti-cancer drugs, patient age, and the cost of supportive care drugs were factors that increased the medical cost per cycle, whereas the outpatient treatment rate had a major effect on reducing this cost. The cost of anti-cancer drugs was significantly more expensive for patients in the NS+Ph arm than in the other two arms, but the far higher outpatient treatment rate in the NS+Ph arm resulted in a significantly cheaper medical cost per cycle. The anti-cancer drugs used in the NS+Ph arm were more expensive, because the regimen used was dose-dense paclitaxel and carboplatin (ddTC) chemotherapy in >50% of cases. The paclitaxel dose per cycle in ddTC chemotherapy is 240 mg/m² (3 weeks consecutive administration at 80 mg/m²), whereas in regular paclitaxel+carboplatin (TC) therapy, the regimen used by most patients in the other two arms, paclitaxel was administered in a single dose of 180 mg/m². There was no difference among the three arms in body surface area or RDI, and thus, the difference in cost was attributed to the cost of the ‘extra’ 60 mg/m² paclitaxel.

Ward et al. analyzed the medical costs for 478 cancer patients who underwent chemotherapy in Australia and found that hospitalization costs accounted for 40% of the total cost, and the cost of anti-cancer drugs accounted for 36%.¹²⁾ Wani et al. analyzed the medical costs for 275 cancer patients who underwent inpatient chemotherapy in India and found that drug costs accounted for 46% of the total cost, and staff costs accounted for 49%.¹³⁾ Several recent comparative studies of inpatient and outpatient chemotherapy found no difference in safety between the two types of chemotherapy, but outpatient treatment reduced medical costs, by approximately 15–20%, and increased patient satisfaction.^14–16) Previous studies in other countries also found that the extra cost of hospital admission exceeds the costs of anti-cancer drugs and other expenses, and treating patients as outpatients reduces the total cost, consistent with our analysis.

The outpatient treatment rate, one of the secondary endpoints, was significantly greater in the NS+Ph arm than in the other two arms, with 79% of treatment administered in outpatient clinics. Multiple regression analysis, using outpatient treatment rate as a dependent variable, found that collaboration with oncology pharmacists was the most important factor contributing to the increased outpatient treatment rate. Unlike inpatient treatment, in outpatient treatment, the patient observation time is limited, and therapies cannot be administered safely without the provision of an efficient and highly accurate treatment system. It is difficult for physicians alone to assess large volumes of data accurately and manage treatment in accordance with complex criteria. However, an interdisciplinary approach to outpatient care provided by both physicians and pharmacists becomes possible when specialist oncology pharmacists conduct detailed patient evaluations and advise physicians on dosage feasibility, dosage amounts, prescription planning, and supportive therapies. In our facility, whether chemotherapy is administered in hospitalization depends on the patient’s intention. Particularly, in the case of having strong anxiety or side effects symptoms in patients, they tend to wish to be treated inpatient. In the NS+Ph arm, oncology pharmacists explained the treatment in detail to patients, for example, possible side effects and symptom management techniques. Oncology pharmacists explained to patients that if patients were provided with appropriate supportive care they would be able to receive chemotherapy safely in outpatient. Therefore, there were many patients who started treatment in outpatient or transferred from inpatient treatment to outpatient treatment in the NS+Ph arm. In our previous research, we determined that collaboration between physicians and specialist pharmacists is effective in reducing workload, increasing the quality of care, and enhancing risk management activities.²⁾ Because the NS+Ph arm was able to benefit from these advantages, we believe that outpatient treatment of these patients can be managed by the confidence of both the physician and the patient.

To enable patients to undergo outpatient treatment comfortably and without any sense of unease, it is vital to prevent serious adverse events, to provide appropriate treatment for side effects, and to implement measures to prevent side effects from becoming serious. Due to measures taken by oncology pharmacists to optimize supportive therapy, patients in the NS+Ph arm were administered an average of four more supportive therapy drugs per patient than were those in the other two arms. In a previous study, we found that patient evaluation by oncology pharmacists was valuable in providing patients with information to help alleviate both physical and mental discomfort and encouragement to continue treatment.²⁾ No patient in the NS+Ph arm refused to continue treatment, but two patients in the S arm and three in the NS arm refused to continue, and the number of cycles of chemotherapy administered differed significantly between the NS and NS+Ph arms. Our results suggest that the involvement of oncology pharmacists in treatment, including the withdrawal or dose reduction of anti-cancer drugs, management of supportive care, and management of multiple aspects of parent care, was effective in implementing planned therapeutic regimens.

In the present study, we should consider two limitations at least. First, this was a retrospective observational study in a single facility; second, the results obtained were only for postoperative adjuvant chemotherapy of ovarian cancer. Therefore, we had to consider carefully in interpreting the results. Because the subjects of this study were patients with a residual tumor diameter <1 cm whose prognosis was good, it seemed unlikely that differences would emerge in measures of therapeutic outcomes such as relapse and survival rates. However, considering that the 2-year progression-free survival rate of subjects given TC therapy in the JGOG3016 study conducted under the same conditions (residual tumor diameter <1 cm) was 69%,¹⁷⁾ all three groups achieved favorable therapeutic results. We intend to extend the follow-up period to 5 years and to perform another investigation of the therapeutic outcomes at that point by comparing the 5-year relapse-free survival and 5-year overall survival.

Acknowledgments

We thank the Department of Gynecology, Kurashiki Medical Center, for permitting the joint treatment management of the patients in this study. This work was supported in part by the Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan Grants-in-Aid for Scientific Research (B) 15H04649.

Conflict of Interest

The authors declare no conflict of interest.

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