Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients.

OBJECTIVES: This retrospective study examined how a pharmacist-involved education program in a multidisciplinary team (PEMT) for oral mucositis (OM) affected head-and-neck cancer (HNC) patients receiving concurrent chemoradiotherapy (CCRT).
MATERIALS AND METHODS: Total samples data of 53 patients during the stipulated timeframe were retrospectively collected from electronic medical records from February 2017 to January 2019. We compared the presence/absence of OM (OM: yes/no) between patients with and without PEMT (PEMT: yes/no) as the primary endpoint and OM severity as the secondary endpoint. The following information was surveyed: age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose, switch to tape), and length of hospital day (LOD). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set.
RESULTS: The group managed by PEMT had significantly lower weight loss and a significantly lower incidence of local anesthetic and opioid use and switch to tape compared with the group not managed by PEMT (p<0.05). The two groups showed no significant difference in OM (yes/no) or OM severity. The PEMT group had significantly shorter LOD at 57 (53-64) days compared with the non-PEMT group at 63.5 (57-68) days (p<0.05).
CONCLUSIONS: Our results showed that PEMT did not improve OM (yes/no) or OM severity in HNC patients undergoing CCRT. However, the PEMT group had a lower incidence of grades 3 and 4 OM than the non-PEMT group, although not significantly. In addition, PEMT contributed to oral pain relief and the lowering of the risk for OM by reduction in weight loss.

Introduction

Oral mucositis (OM) has been described as the most painful aspect of chemotherapy [1]. Due to increased pain attributed to OM, the ingested amount of food is decreased, motivation with respect to treatment is reduced, and treatment-related deaths can occur, all of which warrant a change in the therapeutic approach [2]. The rate of OM has been reported to be 91% and 66% in patients with grades (Grs) 3 and 4 OM, respectively [3], receiving concurrent chemoradiotherapy (CCRT) for head and neck cancer (HNC).

The Multinational Association of Supportive Care in Cancer and European Society for Medical Oncology guidelines [4, 5] report that moisturizing agents are protective and stimulate brittle mucosa, and mouth cleaning can reduce the risk of mucosal infection by bacteria. Furthermore, the provision of oral care by dentists and dental hygienists has been reported to be highly effective in the treatment of OM, reducing its severity, shortening the length of hospital day (LOD), and reducing the dosage of morphine when it is required [6-9]. Patient education programs are also an important aspect of oral care [10]. Indeed, reports of randomized studies indicate that OM decreases as a result of educational interventions for patients with acute myeloblastic leukemia [11]. A multidisciplinary medical team approach has been shown to be protective against OM in patients. Such approach supports treatment and evaluations by dentists, professional oral care delivered by dental hygienists, and daily care and mental health follow-ups provided by nurses. In contrast, few reports describe the contributions made by pharmacists in a medical care team. In our hospital, pharmacists have been providing patient education on oral care since February 2018 with the goal of increasing adherence to mouth washing and moisturizing. These pharmacists were trained via an oral care program offered by dentists. In this study, we examined how a pharmacist-involved education program in a multidisciplinary team (PEMT) for OM affected HNC patients receiving concurrent chemoradiotherapy (CCRT).

Materials and methods

Subjects

This study was performed with the approval of the Research Ethics Niigata University Hospital (approval number 2018–0201). All data were fully anonymized, so the Research Ethics Niigata University Hospital waived the requirement for informed consent. The subjects were patients who were undergoing CCRT from February 2017 to January 2019. All patients received the first cycle of chemotherapy. Pharmacist was educated by a dentist in January 2018. Therefore, the surveillance period was chosen to compare the year prior to January 2018, when no education was received, and the year after January 2018, when education was received. All patients received CCRT on a regimen of cisplatin 80 mg/m2 on days 1, 22, and 43 during the aforementioned time period.

A retrospective survey of electronic medical records was conducted with the cooperation of the Medical Information Department of Niigata University Hospital. The patient data collected included age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose), switch to fentanyl tape, and LOD. All patients who underwent CCRT during the investigation period were surveyed as a countermeasure against selection bias. Investigators were not involved CCRT as a countermeasure against medical surveillance bias. Presence/absence of OM and grade evaluator are not all author.

Definitions of terms

Weight loss was defined as the difference in body weight before the initiation of CCRT (0 Gy) and after the delivery of all fractions (70 Gy). Hematological values were the median of four points (0, 20, 40, and 60 Gy). The presence or absence of OM and its severity were evaluated using an oral radiology criterion based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The opioid dose used was determined from the oral morphine conversion ratio of the Japanese Society for Palliative Medicine as follows: oral morphine: oral oxycodone: transdermal fentanyl = (30:20:1) [12]. Patients who have already used opioids before the target period are not included summary of data for patients receiving opioids. The LOD was the period from the CCRT start date to discharge from the hospital.

Mouthwash type

There were four types of mouthwash used: sodium azulene sulfonate hydrate (SASH) preparation, SASH + sodium bicarbonate (NaHCO3) + lidocaine hydrochloride viscous, steroidal anti-inflammatory agent, and the Japanese traditional drug Hangeshashinto. The moisturizer used was dimethylisopropylazulene ointment.

Pharmacist-delivered education program in the multidisciplinary team

Dentists provided an oral care program of a total duration of 240 minutes which was designed to train pharmacists in a didactic manner using a 64-slide PowerPoint presentation. The program delivered an overview of oral care (oral care need, OM mechanism, and OM-related adverse events), management (pain management, dental care, and general care), and oral assessment (graded by points using photographs of patients).

The pharmacists made medication instruction manual and explained in person to the patients at least once a week using a medication instruction manual (mechanism of drug, usage, and side effects). Listed below is a summary of the oral care program (Fig 1).

Fig 1

Education program by pharmacist’s involvement in the multidisciplinary team.

Need to continue using a mouthwash and a moisturizer

The pharmacist explained to the patient as follows:

If you do not use a mouthwash, your mouth cannot be kept clean.

If you do not moisturize, the moisture will decrease in the lining inside your mouth.

From the above, OM is likely to occur and to become more severe once it occurs.

Frequency of use of at least 6 times a day

The pharmacist explained to the patient as follows:

Make it a habit to use a mouthwash and moisturizer at least 6 times a day: when you wake up, after breakfast, after lunch, around 15:00, after dinner, and before going to bed. This regimen helps to maintain the cleanliness of the oral cavity and the amount of intraoral moisture.

Moisturizer after mouth washing

The pharmacist explained to the patient as follows:

If you use a moisturizer first, the effect of the mouthwash may be weakened.

Proper storage of mouthwash (in darkness)

The pharmacist explained to the patient as follows:

The mouthwash used was sodium azulene sulfonate hydrate (SASH). If SASH is placed in a bright place, the effect of SASH may be weakened.

Statistical analysis

Patient background characteristics were summarized by group (PEMT: yes/no). The two groups were compared using Fisher’s exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set. JMP® 14.2 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis. It is an exploratory study, and there were no similar reports in the past, so sample size could not be calculated. Therefore, from the viewpoint of feasibility, we investigated two-year survey period and conducted a retrospective survey.

Results

Background

Of the 53 patients enrolled in this study, 23 patients received PEMT and 30 patients did not. The combination of SASH + sodium bicarbonate (NaHCO3) + lidocaine hydrochloride viscous was used by 0% of the patients who received PEMT versus 30% (9 patients; p<0.01 Table 1) of those who did not.

Table 1

Background characteristics by patient groups.

	Received PEMT
	Yes	No	p
	(n = 23)	(n = 30)
Age	64 (56–77)	64 (59–69.8)	0.47b
Gender (male:female)	21:2	29:1	0.81c
Steroid use(%)	1 (4.4%)	0	0.89c
Immunosuppressant use	0	0	-
Hematological values
Albumin (g/dL)a	3.6(3.5–3.8)	3.6(3.4–3.9)	0.91b
WBC count (/μL)a	4570 (3655–5705)	4740 (4198.8–5377.5)	0.73b
Neutrophils (/μL)a	3345 (2565–4050)	3550 (3097.5–3947.5)	0.51b
Platelets (/μL)a	18.1 (16.2–25.5)	19.5 (16.4–23.1)	0.88b
eGFR (mL/min/1.73m2)a	80.1 (69.2–86.2)	80.1 (70.7–88.0)	0.50b
Serum Cr (mg/dL)a	0.8 (0.7–0.8)	0.75 (0.7–0.9)	0.66b
CRP (mg/dL)a	0.2 (0.1–0.4)	0.3 (0.1–0.7)	0.30b
Cancer grade (%)
1	3 (13.0%)	2 (6.9%)	0.46c
2	5 (21.7%)	11 (36.7%)
3	6 (26.1%)	10 (34.5%)
4	9 (39.1%)	7 (24.1%)
Primary cancer site
Epipharynx	2	5	0.85b
Oropharynx	5	7
Hypopharynx	9	9
Salivary gland	2	3
Nasopharynx	1	0
Maxillary sinus	1	2
Larynx	3	3
Tongue	0	1
Type (%)
Sodium azulene sulfonate hydrate preparation	23 (100)	29 (96.7)	0.89c
Dimethylisopropylazulene ointment	23 (100)	29 (96.7)	0.89c
Sodium azulene sulfonate hydrate + sodium	0	9 (30)	0.01c
bicarbonate + lidocaine hydrochloride viscos
Steroidal anti-inflammatory agent	0	3 (10)	0.34c
Japanese traditional drug Hangeshashinto	0	3 (10)	0.34c
Dosage
Sodium azulene sulfonate hydrate preparation (mL)a	45 (25–80)	62.5 (39–83)	0.16b
Dimethylisopropylazulene ointment (g) a	120 (60–180)	120 (60–185)	0.76b

PEMT = pharmacist-involved education program in a multidisciplinary team.

eGFR = estimated glomerular filtration rate, Cr = creatinine, CRP = C-reactive protein, RT = radiotherapy.

a Data are the median (interquartile range(IQR)) unless otherwise indicated.

b Mann-Whitney U test.

c Fisher’s exact test.

Weight loss

Weight loss was lower in the group that received PEMT (p<0.05; Table 2).

Table 2

Weight loss.

	Received PEMT
	Yes	No	p
	(n = 23)	(n = 30)
Weight loss (kg)a	3.1 (1.3–4.9)	4.3 (2.6–5.8)	0.048a

PEMT = pharmacist-involved education program in a multidisciplinary team.

a Data are the median (interquartile range(IQR)) unless otherwise indicated.

Opioids

Opioids were used by 65.2% of patients (15 cases) who received PEMT and by 92% (23 cases) of those who did not; although the difference between groups was not significant (Table 3). Days until the start of opioid use were 19 (17–21.5) days in the PEMT group and 18 (15–21.5) days in the non-PEMT group, resulting in no significant difference between groups. The median opioid dose was significantly different between groups; 1102.5 (0–1736.3) mg in the PEMT group and 1860 (1050–2850) mg in the non-PEMT group (p<0.01). Oral oxycodone was switched to fentanyl tape in a significantly lower percentage of patients in the PEMT group (22.7%; 5 cases) than non-PEMT group (64%; 16 cases) (Table 3).

Table 3

Summary of data for patients receiving opioids.

	Received PEMT
	Yesa	Nob	p
	(n = 22)	(n = 25)
Opioid use (%)	15 (65.2)	23 (92)	0.09c
Days until opioid use median(IQR)	19(17–21.5)	18 (15–21.5)	0.20d
Opioid dose (mg) median (IQR)	1102.5 (0–1736.3)	1860 (1050–2850)	0.01d
Switching to fentanyl tape (%)	5 (22.7)	16 (64)	0.01c

PEMT = pharmacist-involved education program in a multidisciplinary team.

a One patient excluded before concurrent chemoradiotherapy (CCRT).

b Five patients excluded before CCRT.

a and b: Because patient(s) was/were on opioids before CCRT.

c Fisher’s exact test.

d Mann-Whitney U test.

※Oral morphine: oral oxycodone: transdermal fentanyl = (30:20:1).

Severity of OM

The severity of OM by CTCAE grade is depicted for the PEMT group and non-PEMT group (PEMT group: Gr 0, 26.1% of patients [6 cases]; Gr 1, 13.0% [3 cases]; Gr 2, 52.2% [12 cases]; Gr 3, 8.7% [2 cases]; and Gr 4, 0% [0 cases]; non-PEMT group: Gr 0, 13.3% [4 cases]; Gr 1, 6.7% [2 cases]; Gr 2, 63.3% [19 cases]; Gr 3, 13.3% [4 cases]; and Gr 4, 3.3% [1 case]). There was no significant difference between the groups (Fig 2).

Fig 2

Severity of oral mucositis by CTCAE grade.

CTCAE = Common terminology criteria for adverse events. a Fisher’s exact test.

Length of hospital days

The PEMT group had significantly fewer days of LOD at 57 (53–64) days compared with the non-PEMT group at 63.5 (57–68) days (p<0.05; Fig 3).

Fig 3

Length of hospital days.

Discussion

Oral care has been reported to reduce the risk of OM or minimize its effects. For instance, oral care reduces the severity of OM, shortens the LOD, and reduces the use of morphine in patients treated with chemotherapy [6-9]. Dentists, dental hygienists, and nurses are actively engaged in oral care at many healthcare facilities. The rate of OM has been reported to be 91% in patients with HNC receiving CCRT, and the incidence of Gr 3 and Gr 4 OM—which can determine the need to interrupt or discontinue chemotherapy—has been reported to be 66% [3]. Systematic oral care programs among patients with HNC receiving CCRT are unable to reduce the rate of severe OM but may reduce the infection risk and indirectly improve treatment compliance [13]. In particular, patient education about oral care has been regarded as an important process, and reduction of OM severity has been reported [11]. In addition, randomised controlled study reported that mouth wash and education program promote better physical and quality of life in CCRT [14, 15]. Mouthwash provides a moist environment for the oral mucosa and decreases pain, improves xerostomia and promotes oral comfort [16, 17]. Therefore, it is very important to continue mouthwash properly.

Generally, pharmacists are professionals who are well positioned to explain to patients information about the pharmacological effects of chemotherapy, possible side effects, the timing of side effects, and appropriate drugs for counteracting some of the side effects that may develop. In addition, pharmacists who receive professional oral-care training may further benefit patients. In type 2 diabetes patients, glycated hemoglobin or HbA1c has been shown to be significantly reduced when their pharmacists are highly knowledgeable about diabetes and help them to better manage their condition [18]. Therefore, it may be useful to involve a pharmacist to increase patient adherence to OM management. Patients can benefit from having an oral care team of dentists, dental hygienists, and nurses explain to them how to use a mouthwash and moisturizer. The addition of pharmacists to a medical team provides further support to patients because pharmacists can also explain the necessity of a mouthwash and oral moisturizer to patients. The patient education efforts by pharmacists in this study specifically focused on the frequency of product use and methods of use which were considered to further improve patient adherence to oral care. Our findings showed that PEMT for OM positively affected patients with HNC receiving CCRT.

The background of the patients assessed in our study revealed that weight loss was significantly less among patients who received PEMT compared with those who did not. A body mass index (BMI) less than 22 kg/m2 has been reported to be a risk factor for moderate-to-severe OM [19]. It was thought that the reduction of weight loss achieved as a consequence of PEMT could limit the risk for OM.

Lidocaine is often used to alleviate pain due to OM. Based on our study results, the pain due to OM was observed to be comparatively less severe among the group of patients that received PEMT. This result was supported by the significantly lower percentage of patients in this group requiring opioids.

In our hospital, opioid was started by oral administration of oxycodone and was switched to fentanyl tape when oral pain made it difficult for the patient to swallow. Switching to fentanyl tape was significantly lower among those patients who received PEMT versus those who did not, possibly because those procedures reduced their oral pain. Enforcement of correct mouthwash and moisturizer use by pharmacists enables the maximal therapeutic advantages to the patients.

There was no difference in the presence or absence of OM and its severity between the PEMT and non-PEMT groups. However, there was a lower incidence of Gr 3 and Gr 4 OM in the PEMT group, although not significantly. For this reason, PEMT was thought to have reduced the adverse events which required judgment on whether CCRT should be interrupted (Fig 2).

LOD was significantly shorter in the PEMT group than the non-PEMT group. PEMT had a significant effect on reduction of weight loss, use of lidocaine viscous, opioid dose, and rate of switch to fentanyl tape. However, we did not perform multivariate analysis because there were not enough events for this analysis.

This study has several limitations. First, the retrospective study may introduce unavoidable bias. Various factors are involved in the pathology of OM, such as oral environment, patient background, and management system of the hospital. The second limitation of our study was the inconsistency in the exact product usage among patients. The usage was challenging to investigate. For example, some cases were required to use a high dose at one time by the prescribing physician, and other cases were already using a high dose prior to hospitalization. Another limitation was that the patients were not surveyed with respect to compliance in this study. Patients with PEMT were asked to verbally confirm that the mouthwash and oral moisturizer were used at least 6 times daily. Each time this regimen was not followed, the pharmacist explained again the need for mouthwash and oral moisturizers. The accuracy of future investigations will likely be improved by the exclusion of the aforementioned OM risk factors from all cases, critical observation of OM cases, and addressing the need for further prospective studies.

Conclusion

Our results showed that PEMT did not improve OM (yes/no) or OM severity in HNC patients undergoing CCRT. However, we found lower incidence of Gr 3 and Gr 4 OM in the group that received PEMT, although not significantly. In addition, PEMT contributed to oral pain relief and lowered the risk for OM by reduction in weight loss.

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11 Jun 2021

PONE-D-21-15398

Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients

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Reviewer #1: The paper documented the clinical outcomes of a pharmacist-involved education intervention among patients with head and neck cancer receiving concurrent chemoradiotherapy.

Major issues:

- There is potential of selection bias with a retrospective study design. For example, what are the selection criteria for a patient to be enrolled in the intervention compared to those without? The authors need to specify the efforts to reduce this bias. Although baseline characteristics of the two groups showed no statistical significance, but how were the number of study subjects determined and chosen? By inclusion of all and so-happened both groups were equal? Unless it is shown that selection bias is adequately addressed, the results and conclusion of the study may be invalid.

- An in-depth discussion of how a pharmacist helped in improving the clinical outcomes is required. Any documented increase in adherence to the prescribed regimen? It is suggested that more references to previous literatures should be included, especially in the field of oral care to substantiate the authors’ claims.

Minor issues:

- Duplicate keywords. Suggest ‘patient education’ to replace ‘education program’, ‘education’ and ‘advanced dental education’

- Please include statistical analysis in the abstract. Why 53 patients? Total samples during the stipulated timeframe?

- Please include study setting in the abstract

- p-value should not be capitalized

- Table 1: please double check the gender ratio under non-PEMT

- Table 1: weight loss should be an outcome rather than baseline characteristic

- Table 2: total sample was 53 but reduced to 47 in table 2?

- line 2 under introduction: amount

- Please provide the full name of the statistical software under methodology

- What are the criteria for PEMT compared to those without? If without PEMT, does it mean just without pharmacist (other healthcare professionals are available) or without a multidisciplinary team?

- If this was not the patients’ first cycle of chemotherapy, what was the history of OM occurrence between both comparison groups?

- 5th paragraph of discussion: how had the involvement of a pharmacist reduced pain?

Reviewer #2: Notes:

• The number of subjects (53) enrolled was in the result section,not the method section. The 53 subjects were not bad for drawing a conclusion, but a larger sample would be better for future research.

• *A personal preference for the conclusion to be more precise without acronyms (stand-alone)

• For Figure 2:

o The title should have no acronym. (Note: the “MO” better to be written in full). However, It was written on the legend page (page 13), but it was not on the single page of figure 2. Thus, if the final version has the full title, as in the legend, then no issues.

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Reviewer #1: Yes: Huey Miin Cheah

Reviewer #2: Yes: Aliah Aldahash

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30 Jun 2021

The paper documented the clinical outcomes of a pharmacist-involved education intervention among patients with head and neck cancer receiving concurrent chemoradiotherapy.

Major issues:

- There is potential of selection bias with a retrospective study design. For example, what are the selection criteria for a patient to be enrolled in the intervention compared to those without? The authors need to specify the efforts to reduce this bias. Although baseline characteristics of the two groups showed no statistical significance, but how were the number of study subjects determined and chosen? By inclusion of all and so-happened both groups were equal? Unless it is shown that selection bias is adequately addressed, the results and conclusion of the study may be invalid.

→Thank you very much for your suggestion. Pharmacist was educated by a dentist in January 2018. Therefore, the surveillance period was chosen to compare the year prior to January 2018, when no education was received, and the year after January 2018, when education was received.

We considered that the following as a method to reduce selection bias.

・All patients who underwent CCRT during the investigation period were surveyed as a countermeasure against selection bias.

・Investigators were not involved CCRT as a countermeasure against medical surveillance bias.

・ Presence/absence of oral mucositis and grade evaluator are not all author.

It is an exploratory study, and there were no similar reports in the past, so sample size could not be calculated. Therefore, from the viewpoint of feasibility, we investigated two-year survey period and conducted a retrospective survey. With the publication of this paper, it will be possible to calculate the sample size in the future, so I would like to determine patient information in more detail and randomized controlled trials. Thank you for your wonderful suggestions.

We modified the manuscript as follows:

P5L6

This study was performed with the approval of the Research Ethics Niigata university Hospital (approval number 2018-0201). The subjects were patients who were undergoing CCRT from February 2017 to January 2019. All patients received a first cycle of chemotherapy. Pharmacist was educated by a dentist in January 2018. Therefore, the surveillance period was chosen to compare the year prior to January 2018, when no education was received, and the year after January 2018, when education was received. All patients received CCRT on a regimen of cisplatin 80 mg/m2 on days 1, 22, and 43 during the aforementioned time period.

A retrospective survey of electronic medical records was conducted with the cooperation of the Medical Information Department of Niigata university Hospital. The patient data collected included age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose), switch to fentanyl tape, and LOD. All patients who underwent CCRT during the investigation period were surveyed as a countermeasure against selection bias. Investigators were not involved CCRT as a countermeasure against medical surveillance bias. Presence/absence of OM and grade evaluator are not all author.

P8L5

Patient background characteristics were summarized by group (PEMT: yes/no). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set. JMP® 14.2 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis. It is an exploratory study, and there were no similar reports in the past, so sample size could not be calculated. Therefore, from the viewpoint of feasibility, we investigated two-year survey period and conducted a retrospective survey.

- An in-depth discussion of how a pharmacist helped in improving the clinical outcomes is required. Any documented increase in adherence to the prescribed regimen? It is suggested that more references to previous literatures should be included, especially in the field of oral care to substantiate the authors’ claims.

- →Thank you very much for your suggestion. This study was retrospective study, so there was no document. Therefore, we investigated increase in adherence by the amount of mouthwash and moisturizer used, but could not follow the detailed information and could not show the statistical difference. However, as the pharmacist explained, we always checked on a face-to-face basis once a week that moisturizing was performed after moisturizer and proper storage of mouthwash (in darkness) was followed. In the future, We would like to proceed with more detailed prospective research.

We added 4references to previous literatures. Please check again.

P12L14

In addition, randomised controlled study reported that mouth wash and education program promote better physical and quality of life in CCRT［14,15］. Mouthwash provides a moist environment for the oral mucosa and decreases pain, improves xerostomia and promotes oral comfort［16,17］. Therefore, it is very important to continue mouthwash properly.

Minor issues:

- Duplicate keywords. Suggest ‘patient education’ to replace ‘education program’, ‘education’ and ‘advanced dental education’

→Thank you for your suggestion. We corrected it.

P5L14　Patient education

- Please include statistical analysis in the abstract. Why 53 patients? Total samples during the stipulated timeframe?

→Thank you for your suggestion. We include statistical analysis in the abstract.

As you pointed out, there were 53 people during the stipulated timeframe.

We corrected it.

P2L7

Total samples data of 53 patients during the stipulated timeframe were retrospectively collected from electronic medical records from February 2017 to January 2019. We compared the presence/absence of OM (OM: yes/no) between patients with and without PEMT (PEMT: yes/no) as the primary endpoint and OM severity as the secondary endpoint.

The following information was surveyed: age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose, switch to tape), and length of hospital day (LOD). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set.

- Please include study setting in the abstract

→Thank you for your suggestion. We include study setting in the abstract. Same as the above correction.

- p-value should not be capitalized

→We corrected it.

- Table 1: please double check the gender ratio under non-PEMT

→Thank you very much for your suggestion. We corrected it. Please check again.

- Table 1: weight loss should be an outcome rather than baseline characteristic

→Thank you very much for your suggestion. We added Table.

Table 2. Weight loss

- Table 2: total sample was 53 but reduced to 47 in table 2?

→Thank you very much for your suggestion. Because patients who have already used opioids before the target period are not included summary of data for patients receiving opioids. Very sorry for the lack of explanation. We added manuscript.

P6L6

The opioid dose used was determined from the oral morphine conversion ratio of the Japanese Society for Palliative Medicine as follows: oral morphine: oral oxycodone: transdermal fentanyl = (30:20:1) ［12］. Patients who have already used opioids before the target period are not included summary of data for patients receiving opioids. The LOD was the period from the CCRT start date to discharge from the hospital.

- line 2 under introduction: amount

→Thank you very much for your suggestion. We corrected it. Please check again.

P4L3

Oral mucositis (OM) has been described as the most painful aspect of chemotherapy［1］. Due to increased pain attributed to OM, the ingested amount of food is decreased, motivation with respect to treatment is reduced, and treatment-related deaths can occur, all of which warrant a change in the therapeutic approach［2］.

- Please provide the full name of the statistical software under methodology

→Thank you for your suggestion. We corrected JMP® 14.2 (SAS Institute Inc., Cary, NC, USA).

P8L5

Patient background characteristics were summarized by group (PEMT: yes/no). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set. JMP® 14.2 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis.

- What are the criteria for PEMT compared to those without? If without PEMT, does it mean just without pharmacist (other healthcare professionals are available) or without a multidisciplinary team?

→Thank you very much for your suggestion. Pharmacist was educated by a dentist in January 2018. Therefore, the surveillance period was chosen to compare the year prior to January 2018, when no education was received, and the year after January 2018, when education was received. →Same as the above correction.

If without PEMT, it mean that pharmacist did not educate CCRT patient (other healthcare professionals are available).

- If this was not the patients’ first cycle of chemotherapy, what was the history of OM occurrence between both comparison groups?

→Thank you for your suggestion. All patients received a first cycle of chemotherapy. We added manuscript.

P5L6

This study was performed with the approval of the Research Ethics Niigata university Hospital (approval number 2018-0201). The subjects were patients who were undergoing CCRT from February 2017 to January 2019. All patients received a first cycle of chemotherapy.

- 5th paragraph of discussion: how had the involvement of a pharmacist reduced pain?

→Thank you for your suggestion. The involvement of a pharmacist reduced lidocaine viscous, opioid doses, and the rate of fentanyl tape switching due to mouth pain. We considered that this result was attributed to the correct use of mouthwash and moisturizer to reduce the severity of OM.

P14L5

PEMT had a significant effect on reduction of weight loss, use of lidocaine viscous, opioid dose, and rate of switch to fentanyl tape.

Other

We corrected the manuscript according to the PLOS ONE guidelines. Please check again.

About the supplementary information, we did not see any need for it.

We would like to appreciate it if you could tell us what information you need.

Submitted filename: Response to Reviewers.docx

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22 Jul 2021

PONE-D-21-15398R1

Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients

PLOS ONE

Dear Dr. Yoshida,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 05 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Vijayaprakash Suppiah, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you very much for the efforts in the latest revision. The article is now more convincing and reads better.

Just a few minor suggestions as below:

1. Please double check the affiliation superscripts on the title page. What’s the difference between:

a. ¶: These authors contributed equally to this work.

b. &: These authors also contributed equally to this work.

2. Please ensure p-value is not capitalised in the main text and the figures

3. Please standardize to use either Figure or Fig.

4. Materials and methods> Subjects>

a. Please capitalise ‘University Hospital’

b. ‘the’ first cycle of chemotherapy

c. >Definition of terms: please either define RT or use CCRT

5. Results> Opioids> line 2 should be (Table 3)

6. There are differences between values in Table 3 and in the result paragraph. Please double check.

7. Definition of RT is not needed in Table 1 since the term isn’t there.

8. Please remove the unnecessary ‘ ) ’ after a superscript annotation in all tables

9. Maybe can consider to the delete the intepretation of whisker plot?

a. Fig 3 Length of hospital days. a Data are shown in a box and whisker plot. The ends of the box represent the upper and lower quartiles and the median is depicted by the horizontal line within the box.

Reviewer #2: The research is original, it has not been published nor the same data and analysis used elsewhere. However, the statistical analysis in the methodology was clarified. Also, the authors provide approval from their local area where the study was conducted.

In terms of the previous feedback, the authors have addressed the comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Aliah Aldahash

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: reviewer comments.docx

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28 Jul 2021

Thank you very much for the efforts in the latest revision. The article is now more convincing and reads better.

Just a few minor suggestions as below:

Thank you very much for carefully checking our paper. We were able to correct it to a better manuscript.

1. Please double check the affiliation superscripts on the title page. What’s the difference between:

a. ¶: These authors contributed equally to this work.

b. &: These authors also contributed equally to this work.

→Thank you very much for your suggestion. According to PLOS ONE's style requirements, we marked ¶ for the firstly contributed equally to this work and & for the secondly contributed equally to this work.

P1L21

¶: These authors contributed firstly equally to this work.

&: These authors also contributed secondly equally to this work.

2. Please ensure p-value is not capitalised in the main text and the figures

→Thank you very much for your suggestion. We corrected it.

P8L19

Of the 53 patients enrolled in this study, 23 patients received PEMT and 30 patients did not. The combination of SASH + sodium bicarbonate (NaHCO3) + lidocaine hydrochloride viscous was used by 0% of the patients who received PEMT versus 30% (9 patients; p<0.01 Table 1) of those who did not.

3. Please standardize to use either Figure or Fig.

→Thank you very much for your suggestion. We standardize to use Fig.

Fig1. Pharmacist-involved education program in the multidisciplinary team

4. Materials and methods> Subjects>

a. Please capitalise ‘University Hospital’

b. ‘the’ first cycle of chemotherapy

c. >Definition of terms: please either define RT or use CCRT

→Thank you very much for your suggestion. We corrected it.

P5L6

This study was performed with the approval of the Research Ethics Niigata University Hospital (approval number 2018-0201). All data were fully anonymized, so the Research Ethics Niigata University Hospital waived the requirement for informed consent.

P5L17

A retrospective survey of electronic medical records was conducted with the cooperation of the Medical Information Department of Niigata University Hospital.

P5L9

All patients received the first cycle of chemotherapy. Pharmacist was educated by a dentist in January 2018.

P6L5

Weight loss was defined as the difference in body weight before the initiation of CCRT (0 Gy) and after the delivery of all fractions (70 Gy).

5. Results> Opioids> line 2 should be (Table 3)

→Thank you very much for your suggestion. We corrected it.

P10L5

Opioids were used by 65.2% of patients (15 cases) who received PEMT and by 92.0% (23 cases) of those who did not; although the difference between groups was not significant (Table 3).

6. There are differences between values in Table 3 and in the result paragraph. Please double check.

→Thank you very much for your suggestion. We corrected it.

P10L9

The median opioid dose was significantly different between groups; 1102.5 (0–1736.5) mg in the PEMT group and 1860.5 (1050.5–2850.0) mg in the non-PEMT group (p<0.01).

7. Definition of RT is not needed in Table 1 since the term isn’t there.

→Thank you very much for your suggestion. We deleted RT.

8. Please remove the unnecessary ‘ ) ’ after a superscript annotation in all tables

→Thank you very much for your suggestion. We deleted its, please check again.

9. Maybe can consider to the delete the intepretation of whisker plot?

a. Fig 3 Length of hospital days. a Data are shown in a box and whisker plot. The ends of the box represent the upper and lower quartiles and the median is depicted by the horizontal line within the box.

→Thank you very much for your suggestion. We deleted it.

P12L1

Fig 3 Length of hospital days.

Other

We corrected references.

P16L1

1. Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ. Patient reports of complications of bone marrow transplantation. Support Care Cancer. 2000; 8: 33–39.

2. Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007; 109: 820–831.

3. Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys. 2007; 68: 1110–1120.

4. Peterson DE, Boers-Doets CB, Bensadoun RJ, Herrstedt J, ESMO Guidelines Committee. Management of oral and gastrointestinal mucosal injury: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015; 5: 139–151.

5. Elad S, Cheng KKF, Lalla RV, Yarom N, Hong C, Logan RM, et al. Mucositis Guidelines Leadership Group of the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO)(2020) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2020; 126: 4423–4431.

6. Saito H, Watanabe Y, Sato K, Ikawa H, Yoshida Y, Katakura A, et al. Effects of professional oral health care on reducing the risk of chemotherapy-induced oral mucositis. Support Care Cancer. 2014; 22: 2935–2940.

7. Kubota K, Kobayashi W, Sasaki H, Nakagawa H, Kon T, Mimura M, et al. Professional oral health care reduces oral mucositis pain in patients treated by superselective intra-arterial chemotherapy concurrent with radiotherapy for oral cancer. Support Care Cancer. 2015; 23: 3323–3329.

8. Legert KG, Remberger M, Ringden O, Heimdahl A, Dahllof G. Reduced intensity conditioning and oral care measures prevent oral mucositis and reduces days of hospitalization in allogeneic stem cell transplantation recipients. Support Care Cancer. 2014; 22: 2133–2140.

9. Soga Y, Sugiura Y, Takahashi K, Nishimoto H, Maeda Y, Tanimoto M, et al. Progress of oral care and reduction of oral mucositis--a pilot study in a hematopoietic stem cell transplantation ward. Support Care Cancer. 2010; 19: 303–307.

10. The European Oral Care in Cancer Group (EOCC). Oral care guidance 2018. Japanese Association of Supportive Care in Cancer Web site. http://jascc.jp/wp/wp-content/uploads/2018/01/guidance_20180115.pdf. Accessed February 20, 2020.

11. Leppla L, Geest SD, Fierz K, Deschler-Baier B, Koller A. An oral care self-management support protocol (OrCaSS) to reduce oral mucositis in hospitalized patients with acute myeloid leukemia and allogeneic hematopoietic stem cell transplantation: a randomized controlled pilot study. Support Care Cancer. 2016; 24: 773–782.

12. Japanese Society for Palliative Medicine. Japanese Society for Palliative Medicine Guidelines 2010. Japanese Society for Palliative Medicine Web site. www.jspm.ne.jp/guidelines/pain/2010/chapter02/02 04 01 05.php. Accessed February 20, 2020.

13. Yokota T, Tachibana H, Konishi T, Yurikusa T, Hamauchi S, Sakai K, et al. Multicenter phase II study of an oral care program for patients with head and neck cancer receiving chemoradiotherapy. Support Care Cancer. 2016; 24: 3029–3036.

14. Yüce UÖ, Yurtsever S. Effect of Education About Oral Mucositis Given to the Cancer Patients Having Chemotherapy on Life Quality. J Cancer Educ. 2019; 34: 35-40.

15. B-S Huang, S-C Wu, C-Y Lin, K-H Fan, J T-C Chang, S-C Chen. The effectiveness of a saline mouth rinse regimen and education programme on radiation-induced oral mucositis and quality of life in oral cavity cancer patients: A randomised controlled trial. Eur J Cancer Care (Engl). 2018; 27: e12819.

16. Dorothy M Keefe, Mark M Schubert, Linda S Elting, Stephen T Sonis, Joel B Epstein, Judith E Raber-Durlacher et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007; 109: 820-831.

17. Edward B Rubenstein, Douglas E Peterson, Mark Schubert, Dorothy Keefe, Deborah McGuire, Joel Epstein. Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer. 2004; 100: 2026-2046.

18. Okada H, Onda, Shoji, Kotani K, Nakayama T, Nakagawa Y, Sakane N. Effects of lifestyle intervention performed by community pharmacists on glycemic control in patients with type 2 diabetes: the community pharmacists assist (Compass) project, a pragmatic cluster randomized trial. Pharmacol Pharmacy. 2016; 7: 124–132.

19. Saito N, Imai Y, Muto T, Sairenchi T. Low body mass index as a risk factor of moderate to severe oral mucositis in oral cancer patients with radiotherapy. Support Care Cancer. 2012; 20: 3373–3377.

Submitted filename: Response to Reviewers.docx

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25 Aug 2021

PONE-D-21-15398R2

Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients

PLOS ONE

Dear Dr. Yoshida,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Oct 09 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Rohit Kunnath Menon

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Table 2 and Table 3 > please delete the ‘)’ behind a superscript

Page 10 and Table 3, Opioids> consider to delete the trailing zeros, 19 and 18

Table 3> Maybe need to provide a brief reason for the exclusion at footnote a and b (eg because patient(s) was/were on opioids before CCRT)

The figures in Table 3 and result paragraph ‘Opioids’ are still different. 1860.5 in paragraph but 1860.0 in Table 3. 1736.5 in paragraph but 1736.3 in Table 3. Consider to remove all trailing zeros (eg 15, instead of 15.0)

Please standardize references to use small caps for all the first alphabets of each word in the journal article/report title.

Discussion> Switching to fentanyl tape was significantly lower among those patients who received PEMT versus those who did not, possibly because those procedures reduced their oral pain.> Consider to elaborate this (eg. Enforcement of correct mouthwash and moisturizer use by pharmacists enables the maximal therapeutic advantages to the patients)

Reviewer #2: The research is original, it has not been published nor the same data and analysis used elsewhere. The methodology and the statistical analysis were clarified. Also, the authors provide approval from their local area where the study was conducted.

In terms of the previous feedback, the authors have addressed the comments.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Cheah Huey Miin

Reviewer #2: Yes: Aliah Aldahash

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

29 Aug 2021

Reviewer #1: Table 2 and Table 3 > please delete the ‘)’ behind a superscript

→Thank you very much for your suggestion. We deleted its, please check again.

Page 10 and Table 3, Opioids> consider to delete the trailing zeros, 19 and 18

→Thank you very much for your suggestion. We deleted its, please check again.

P10

Opioids were used by 65.2% of patients (15 cases) who received PEMT and by 92% (23 cases) of those who did not; although the difference between groups was not significant (Table 3). Days until the start of opioid use were 19 (17–21.5) days in the PEMT group and 18 (15–21.5) days in the non-PEMT group, resulting in no significant difference between groups. The median opioid dose was significantly different between groups; 1102.5 (0–1736.3) mg in the PEMT group and 1860 (1050–2850) mg in the non-PEMT group (p<0.01). Oral oxycodone was switched to fentanyl tape in a significantly lower percentage of patients in the PEMT group (22.7%; 5 cases) than non-PEMT group (64.0%; 16 cases) (Table 3).

Table 3> Maybe need to provide a brief reason for the exclusion at footnote a and b (eg because patient(s) was/were on opioids before CCRT)

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The figures in Table 3 and result paragraph ‘Opioids’ are still different. 1860.5 in paragraph but 1860.0 in Table 3. 1736.5 in paragraph but 1736.3 in Table 3. Consider to remove all trailing zeros (eg 15, instead of 15.0)

→Thank you very much for checking carefully. We corrected its, please check again. Same as the above correction.

Please standardize references to use small caps for all the first alphabets of each word in the journal article/report title.

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1. Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ. Patient reports of complications of bone marrow transplantation. Support Care Cancer. 2000; 8: 33–39.

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Discussion> Switching to fentanyl tape was significantly lower among those patients who received PEMT versus those who did not, possibly because those procedures reduced their oral pain.> Consider to elaborate this (eg. Enforcement of correct mouthwash and moisturizer use by pharmacists enables the maximal therapeutic advantages to the patients)

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P13L23

In our hospital, opioid was started by oral administration of oxycodone and was switched to fentanyl tape when oral pain made it difficult for the patient to swallow. Switching to fentanyl tape was significantly lower among those patients who received PEMT versus those who did not, possibly because those procedures reduced their oral pain. Enforcement of correct mouthwash and moisturizer use by pharmacists enables the maximal therapeutic advantages to the patients.

Reviewer #2: The research is original, it has not been published nor the same data and analysis used elsewhere. The methodology and the statistical analysis were clarified. Also, the authors provide approval from their local area where the study was conducted.

In terms of the previous feedback, the authors have addressed the comments.

Submitted filename: R3resonse to Reviewers.docx

Click here for additional data file.

2 Nov 2021

Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients

PONE-D-21-15398R3

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10 Nov 2021

PONE-D-21-15398R3

Pharmacist involved education program in a multidisciplinary team for oral mucositis: its impact in head-and-neck cancer patients

Dear Dr. Yoshida:

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