Effect of a supersaturated calcium-phosphate rinse on oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT): a systematic review and meta- analysis

doi:10.21203/rs.3.rs-2707857/v1

Download PDF

Research Article

Effect of a supersaturated calcium-phosphate rinse on oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT): a systematic review and meta- analysis

https://doi.org/10.21203/rs.3.rs-2707857/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Oral mucositis (OM) is a common complication of hematopoietic stem cell transplantation (HSCT). OM is very painful, influences nutritional intake and impairs patients’ quality of life (QoL). Although several studies have investigated the potential of supersaturated calcium-phosphate rinse (SCPR) in reducing the incidence, duration and severity of OM in patients undergoing HSCT, conclusive results have not yet been found. Therefore, the aim of this systematic review and meta-analysis is to comprehensively evaluate whether SCPR is effective in reducing the incidence, duration and severity of HSCT-induced OM.

Methods

Five electronic databases were searched: PubMed, EMBASE, the Cochrane Library, CINAHL and Google Scholar up to August 2021. Both randomized controlled trials (RCTs) and non-randomized studies of interventions (NRISs) were included. Two reviewers independently screened titles, abstracts and full texts for study inclusion, and extracted data from the included studies. We used the RoB 2 and ROBINS-I to critically appraise the included studies, and GRADE to assess the quality of evidence.

Results

Out of 1008 publications, 8 RCTs and 3 NRSIs with in total 830 participants, were included. Meta-analyses showed that SCPR did not decrease the incidence of OM: 3 studies (RR, 0.93; 95% CI, 0.80–1.08), moderate severe OM: 2 studies (RR, 1.16; 95% CI, 0.85–1.59) and severe OM: 2 studies (RR, 0.66; 95% CI, 0.27–1.64). Meta-analysis was not possible for the duration of OM due to heterogeneity between the studies.The overall quality of evidence was moderate for the incidence of OM and low for the duration and severity of OM.

Conclusions

Based on the available evidence, SCPR does not seem effective in reducing the incidence, duration and severity of OM in patients undergoing HSCT. Further large-scale studies with more rigorous methodology are required to enhance the quality of evidence.

Supersaturated calcium phosphate rinse

Oral mucositis

Stem cell transplantation

Chemotherapy

Meta-analysis

Oral mucositis (OM) is an inflammation of the mucosa and is characterized by edema, erythema, bleeding, pseudomembranes and ulcerations [1, 2]. Oral ulcerations can be very painful and can negatively affect a person’s daily life. It affects all functions of the mouth: drinking, eating, speaking and oral care. Previous studies have shown that patients with OM also have an increased risk of mood disorders, anxiety and depression [3, 4].

The oral mucosa is particularly vulnerable to toxicity from chemotherapy and/or radiotherapy [5, 6]. Research among oncology patients has shown that OM may lead to a need for opioid analgesics and/or enteral or parenteral nutrition [7]. In addition, OM causes negative consequences such as delaying the treatment, extending hospital stays and increasing costs [7–9].

Many patients undergoing hematopoietic stem cell transplantation (HSCT) develop OM as a result of direct cytotoxic effects of high-dose chemotherapy and/or total body irradiation (TBI), with an estimated incidence ranging from 76–99% [10, 11]. Due to pain, intake difficulties and an increased risk of systemic infection, patients may be less motivated to continue with HSCT [3, 8].

Currently, three strategies are recommended to prevent or treat OM in patients with hematologic malignancies receiving high-dose chemotherapy and radiotherapy: palifermin, cryotherapy and low-level laser therapy [12–14]. Palifermin, a human keratinocyte growth factor is an effective, but expensive option [15]. Cryotherapy, the application of ice chips to the buccal mucosa during the administration of chemotherapeutic agents, is an easy applicable treatment, but causes side effects such as headache, tooth sensitivity and numbness of the mouth [16]. Low-level laser therapy is effective too, but requires the utilization of specialized equipment, trained personnel, involvement of a multidisciplinary team, and requires manipulation of the oral cavity that may be painful [17].

Recently, the use of a supersaturated calcium-phosphate rinse (SCPR) has become popular [18]. SCPR is designed to moisten, lubricate and clean the mucosa and replace important minerals, such as calcium and phosphate, involved in restoring and maintaining mucosal integrity, and may be helpful in the prevention and treatment of OM [18]. When mixed, the calcium solution and the phosphate solution form a stable supersaturated solution with a composition similar to that of natural saliva. Calcium ions have an anti-inflammatory function, decrease prostaglandin production and promote tissue regeneration. Phosphate ions can protect against infections and maintain an appropriate pH level. High concentration of calcium and phosphate reduces inflammation and activates mucosal healing and epithelial proliferation [19].

In contrast to the other strategies, SCPR is considered an easily applicable and cost-effective method with no side effects in clinical settings. In 2003, promising results were published from a prospective randomized study showing that an oral solution of supersaturated calcium-phosphate (Caphosol®) reduced the frequency, intensity and duration of OM [20]. Since then, several randomized controlled trials (RCTs) and controlled clinical trials investigating the effect of SCPR on HSCT-induced OM have been published. However, the results show mixed results. For example, some studies demonstrate benefits of SCPR in reducing OM in patients undergoing HSCT [21, 22], but Treister et al. found that SCPR did not reduce the incidence of mucositis [18]. So the efficacy of SCPR to prevent or treat HSCT-induced OM remains controversial.

Therefore, the aim of this systematic review and meta-analysis is to comprehensively evaluate whether SCPR is effective in reducing the incidence, duration and severity of HSCT-induced OM.

The present systematic review was executed according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines [23, 24]. The protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) platform (CRD42022333796).

Inclusion criteria

We used the following criteria for inclusion in the review: (1) studies that report on adults and children at any age, sex and ethnicity, with OM induced by HSCT (allogeneic or autologous); (2) studies with patients undergoing HSCT for any indication, including malignant and non-malignant conditions; (3) studies using SCPR from the first day of HSCT up to 30 days after HSCT; (4) studies that report on incidence, duration and severity of HSCT-induced OM, as well as pain relief, side effects and quality of life (QoL); (5) randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs), such as cohort studies and case-control studies.

Exclusion Criteria

Exclusion criteria were: (1) studies measuring the effect of SCPR on OM in patients with head and neck cancer; (2) studies reporting the effect of SCPR without a clearly defined control group; (3) cross-sectional studies, case studies, pilot studies, animal studies, editorials and reviews.

Definition Of Outcomes

The incidence of OM was defined as the number of all patients with OM in each group (score 0 vs ≥ 1). The duration of OM was defined as mean days with OM. The severity of OM was evaluated by the grade of OM which was scored according to World Health Organization (WHO) Oral Toxicity Scale [25] or other OM grading scales. We were interested in different grades of severity, and evaluated moderate versus severe OM (grade 1–2 vs. 3–4). Pain relief was assessed by the incidence of pain, mean pain score or the number of days with pain (as reported in the publication). SCPR-related side effects were included if they were described. We included QoL, when it was assessed by means of a validated scale in the individual studies.

Search Strategy

The systematic search was conducted by a clinical librarian (FE) at the Amsterdam University Medical Centre and commissioned by JV and MV. The following databases were searched: PubMed, EMBASE, Cochrane Library, CINAHL and Google Scholar from inception to August 2021. All search strategies, are published in the supplementary data (Table S1). In addition, the reference lists of all included studies were hand searched.

Study Selection

Two reviewers (JV, MV) independently screened titles and abstracts for study inclusion. When more information was needed, the full-text was obtained. If there were any disagreements, a third reviewer (JM) was included in the discussion to reach consensus. If researchers had used identical study populations within two studies, we excluded the study with the lowest methodological quality. The selection was supported by Rayyan reference management software [26].

Data Extraction

Two reviewers (JV, MV) performed the data extraction independently, using a data extraction sheet based on the Cochrane Handbook for Systematic Reviews [23]. We contacted the authors by email for additional information when needed. The following data was extracted: author, year of publication, country, study design, sample size, cancer type, details of HSCT, details of intervention and control regimes, duration, OM grading scales and outcomes of interest.

Risk Of Bias Assessment

Risk of bias was assessed independently by two reviewers (JV, MV) using the Collaboration's Risk of Bias Tool for Randomized Controlled Trials (RoB 2) and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) [27, 28]. All criteria were scored as high risk, moderate risk, low risk or some concerns. Disagreement was resolved through discussion, with involvement of JM as third reviewer when necessary.

Data analysis

The data were analyzed by RevMan (Review Manager 5.4) statistical software [29]. We report the risk ratio (RR) with the 95% confidence interval (95% CI) for (pooled) dichotomous outcomes, and the standardized mean difference (SMD) with the 95% CI for continuous outcomes. The SMD was used when different OM grading scales were used in the included studies. We calculated means and standard deviations (SD) when necessary from medians and range according to Hozo et al. and Wan et al. [30, 31]. Chi-square (Chi²) test and I-square (I²) index were used for testing heterogeneity [32, 33]. When p < 0.05 and I² > 50%, the Random Effects Model (REM) was used. In case of p > 0.05 and < I² 50%, the Fixed Effects Model (FEM) was used for the meta-analysis. When I² was > 75%, no meta-analysis was performed, but a descriptive analysis was provided. The sources of heterogeneity were explored through subgroup analyses when I² was > 75%. We planned subgroup analyses based on different ages (adults versus children), type of disease (malignant versus non-malignant) and type of HSCT (autologous versus allogeneic). A sensitivity analysis was carried out by excluding studies at high risk of bias to assess the robustness of the meta-analysis. Also, we performed a sensitivity analysis to explore the differences between the effect estimates of RCTs and NRSIs.

Publication bias and small study effects were assessed using funnel plot asymmetry testing and Egger’s test, respectively. When the number of included studies for an individual outcome was less than 10, the funnel plot was not drawn [34].

GRADE

The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to rate the quality of evidence [35]. Two reviewers (JV, MV) graded the evidence independently using ‘GRADE profiler’. We planned to include the primary outcomes in the 'Summary of findings' table.

Study selection

The database searches gave a total number of 1008 studies. There were 274 duplicate studies. After the title and abstract screening, 720 studies were excluded, and 14 studies met the inclusion criteria. After studying full text, 3 more studies were excluded. Two studies could not be included because of an unclear control group [22, 36]. Wasko-Grabowska et al. had used identical populations in two studies, and we excluded the study with the lowest methodological quality and least number of patients [37]. The final number of studies that could be included was 11. The process of study selection is visualized in Fig. 1.

Description Of Studies

The 11 included studies were published between 2003 and 2020. There were 8 RCTs [18, 20, 21, 39–43] and 3 NRSIs [38, 44, 45]. One RCT was designed as a cross-over study with two cycles of 7 days [41]. Of the 3 NRSIs, 2 were designed as cohort studies [38, 44] and 1 as a non-randomized controlled trial [45].

The studies included a total of 837 participants, with a range of 29–220. Six of the included studies recruited only adult patients [20, 21, 38, 42, 43], 1 study included both adults and children [44], and 4 studies included pediatric patients only [18, 39–41]. The haematological cancer type for which patients were being treated was leukemia in 8 studies [20, 21, 38, 40, 42–45], lymphoma in 5 studies [20, 38, 42, 43, 45], multiple myeloma in 5 studies [20, 38, 42, 43, 45], and solid tumors in 3 studies [18, 39, 41].

All of the 11 studies provided a clear description of the intervention including the dose and method of administration for the SCPR and control groups. All studies used SCPR in two 15 ml ampules to prevent and treat HSCT-induced OM in the intervention groups. However, the control regimes in the studies differed: NaCl 0.9% [18, 39, 41], palifermin [38], chlorhexidine-chlorobutanol (Eludril®) [44], NaF 0.01% rinse [20], chlorhexidine gluconate + benzydamine hydrochloride (Andorex®) [45], black mulberry syrup [45], topical mouth solutions [21], filtered water [42], calcium-phosphate in two 225 ml bottles (Fomukal®) [43] and an oral hygiene protocol with or without an extra-soft toothbrush [40].

Seven studies reported an incidence of OM [18, 38, 40–42, 44, 45], 7 reported the duration of OM [18, 20, 21, 38, 39, 42, 43], and 5 reported the severity of OM [18, 38, 42, 44, 45]. The severity of OM was reported as the incidence of moderate and severe OM. The used grading scales for OM were World Health Organization (WHO) Oral Toxicity Scale [18, 21, 38, 40–45], National Cancer Institute Common Toxicity Criteria Grading Scale (NCI-CTCAE) [39] and the National Institute of Dental and Craniofacial Research (NIDCR) [20]. Detailed information is shown in Table 1.

Table 1

Characteristics of included studies
References	Country	Study design	Sample size	Eligibility criteria (cancer type, HSCT/type of treatment)	Groups	Total (n)	Age (mean/sd)	Gender male : female	Intervention	Control	Duration	Scale(s)	Outcomes
Treister 2017 [18]	USA	RCT, double-blinded	220	Malignant conditions and non-malignant conditions; Allogeneic & autologous: Conditioning with TBI or melphalan	Int. Contr.	110 110	13.1 (2.8) 13.3 (2.9) Median/range: 13.7 (4.0-20.9) 13.7 (4.1–21.9)	62 : 48 56 : 54	SCPR*/Caphosol®, four times daily	NaCl 0.9%, four times daily	20 days**	WHO	-Incidence, duration and severity of OM (WHO: 0–4) -Adverse events
Raphael 2014 [37]	The Netherlands	RCT, double-blinded	29	Hematologic malignancies, solid tumors, benign hematologic diseases; Autologous: Chemotherapy, chemo + TBI	Int. Contr.	15 14	11.3 (3.9) 9.9 (4.7)	10 : 5 9 : 5	SCPR*/Caphosol®, four times daily	NaCl 0.9%, four times daily	26 days Important: grade of OM > 1 at start; 5 in SCPR group and 9 in contr. group	NCI-CTCAE	-Duration of OM (grade: 1–5) -Duration of pain and peak level of pain
Mubaraki 2020 [38]	Saudi Arabia	RCT	45	Aplastic anemia, Acute Lymphoblastic leukemia, Acute myeloblastic leukemia, Fanconi anemia, Sickle cell disease, Thalassemia; Allogeneic: Busulfan, Fludarabine, Cytosine, Antithymocyte globulin, Cyclophosphamide, Methotrexate	Int. Contr. 1 Contr. 2	15 15 15	The mean age of the population was 7.7 (3.12)	The sample comprised 20 males and 25 females	SCPR, four times daily + oral hygiene protocol	Control 1: Oral hygiene protocol = 0.12% CHX + 3% sodium bicarbonate + nystatin 5000 U/mL Control 2: Teethbrushing with an extra-soft toothbrush, twice a day + oral hygiene protocol	28 days**	WHO	-Incidence of OM (WHO > 0)
Bourdelin 2015 [42]	France	Cohort study (prospective)	91	Acute myeloid leukemia, Myelodysplastic syndrome; Allogeneic: Fludarabine, Melphalan, Busulfan IV, Cyclophosphamide	Int. Contr.	42 49	40 (?) 41 (?) The mean age of the population was 40.7 (10)	25 : 17 28 : 21	SCPR*/Caphosol®, four times daily	Chlorhexidine-chlorobutanol (Eludril®), four times daily	32 days**	WHO	-Incidence and severity of OM (WHO: 0–4)
Papas 2003 [20]	USA	RCT, double-blinded	95	Acute lymphocytic leukemia Acute myelogenous leukemia Chronic myelogenous leukemia Hodgkin’s disease Non-Hodgkin’s lymphoma Multiple myeloma Myelodysplastic syndrome Breast cancer Ovarian cancer; Allogeneic & autologous (separately analyzed): TBI, Melphalan, Cytoxan, VP16-BUC, EPA/Carboplatinum	Int. Contr.	50 45	43 (12.5) 42 (13.0)	24 : 26 25 : 20	SCPR/Caphosol®, four times daily Important: prior to HSCT, 4 topical fluoride treatments of 1% fluoride gel (2.24% NaF)*	NaF 0.01% rinse, four times daily Prior to HSCT, 4 topical treatments with a placebo gel	23 days	NIDCR	-Duration of OM (NIDCR: 0–5)* -Duration of pain and peak level of pain (0-100 VAS)
Harman 2019 [43]	Turkey	Non-randomized controlled trial	90	Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, Lymphoma; Allogeneic & autologous: Busulfan cyclophosphamide, BEAM, TBI, Cyclophosphamide, Melphalan, Busulfan-Fuldarabin	Int. Contr. 1 Contr. 2	30 28 25	Unable to calculate mean or median, due to different age groups (18–32, 33–47, 48–63, 64–79)	17 : 11 16 : 14 12 : 13	SCPR*, four times daily	Control 1: CHX + benzydamine hydrochloride solution (Andorex®), four times daily Control 2: Black mulberry syrup, four times daily	21 days**	WHO	Incidence and severity of OM (WHO: 0–4)
Immonen 2020 [39]	Finland	RCT, double blinded, cross-over trial	45	Hematological malignancy, solid tumor, CNS tumor; Allogeneic & autologous: High-dose methotrexate Other chemotherapy: anthracycline (doxorubicin, daunorubicin, idarubicin, mitoxantrone) or cisplatin	Group 1 Group 2	24 21	7.2 (3.1) 8.6 (3.5) Median/range: 6.0 (2.1–14.7) 7.2 (3.1–17.1)	11 : 13 14 : 7	Group 1: SCPR*/Caphosol® → Saline (NaCl 0.9%) Four times daily	Group 2: Saline (NaCl 0.9%) → SCPR*/Caphosol® Four times daily	14 days** (Two 7-day cycles)	WHO	-Incidence of OM (WHO: 0–4) -Duration of pain
Wasko -Grabowska 2012 [36]	Poland	Cohort study (retrospective)	64	Acute myeloid leukemia Acute lymphoblastic leukemia Chronic myeloid leukemia Hodgkin’s lymphoma non-Hodgkin’s lymphoma Myelodysplastic syndrome Multiple myeloma; Allogeneic & autologous: Etoposide, TBI, Busulphan, Cyclophosphamide, Fludarabine Melphalan, Alemtuzumab, BEAM, TreoMel, Rituximab	Int. Contr.	44 20	37.63 (13.6) 44.05 (12.7)	Unclear	SCPR*, four times daily	Palifermin/Kepivance®, 3 days before and after conditioning therapy (6x total) Some patients used opoids	Beginning of the first day of the preparatory regime until discharge Unclear how many days	WHO	-Incidence, duration and severity of OM (WHO: 0–4)
Markiewicz 2012 [21]	Poland	RCT, non-blinded	40	Acute myeloblastic leukemia Acute lymphoblastic leukemia Chronic myelogenous leukemia Paroxysmal nocturnal hemoglobinuria Other (osteomyelfibrosis, myelodysplastic syndrome, severe aplastic anemia); Allogeneic: Busulfan, Cyclophosphamide, TBI, Treosulfan, Fludarabine, Treosulfan	Int. Contr.	20 20	38 (9.5) 36 (9.2)	13 : 7 11 : 9	SCPR*, four times daily	Topical mouth Solutions, four times daily + customary care Solutions made with salvia leaf extract, povidone-iodine and fluconazole [fluconazole (50 mg), glycerin (50 mg), vitamin A (10 g), and vitamin E (10 g) with or without benzocaine (2.5 g)]	21 days**	WHO	-Duration of OM (WHO: 0–4) -Peak mean pain (0–10 VAS)
Kröner 2016 [40]	Switzerland	RCT, non-blinded	72	Leukemia Lymphoma Multiple Myeloma Myelodysplastic Syndrome; Allogeneic: Fludarabine - Busulfan Cyclophosphamide - TBI Cyclophosphamide - Busulfan Cylophosphamide – Fludarabine Cyclophosphamide	Int. Contr.	36 36	48.2 (12.5) 47.3 (12.8)	19 : 17 23 : 13	SCPR*/Caphosol®, four times daily	Filtered water, four times daily	20–30 days	WHO	-Incidence, severity and duration of OM (WHO: 0–4) -Duration of pain and peak mean pain (0–10 NRS)
Markiewicz 2020 [41]	Poland	RCT, non-blinded	46	Acute myeloblastic leukemia Acute lymphoblastic leukemia Chronic myelomonocytic leukemia Myelodysplastic syndrome Myelofibrosis Hodgkin lymphoma Other (chronic myelogenous leukemia, chronic lymphocytic leukemia, severe aplastic anemia, multiple myeloma); Allogeneic: Busulfan, TBI, Treosulfan Other: rituximab, fludarabine, bendamustine	Int. Contr.	23 23	47 (10) 48 (12.2)	13 : 10 9 : 14	SCPR*/Caphosol®, four times daily	Fomukal® **, four times daily Important: officially the intervention in this study*	29 days	WHO	-Duration of OM (WHO: 0–4) -Peak mean pain (0–10 VAS)
HSCT, hematopoietic stem cell transplantation; SD, standard deviation; TBI, Total Body Irradiation; SCPR, supersaturated calcium-phosphate rinse; NaCl, sodium chloride; WHO, World Health Organization; OM, Oral Mucositis; NCI-CTCAE, National Cancer Institute Common Toxicity Criteria Grading Scale; CHX, chlorhexidine gluconate; NaF, sodium fluoride; NIDCR, National Institute of Dental and Craniofacial Research; BEAM, Carmustine, Etoposid, Ara-C, Melfalan; VAS, Visual Analog Scale; NRS, Numeric Rating Scale.
*SCPR or Caphosol® was supplied as two separately packaged aqueous solutions, a 15 ml phosphate solution and a 15 ml calcium solution, that were mixed to form a pH neutral supersaturated solution at the time of use.
**First day of conditioning.
***Fomukal® and Caphosol® each consist of two aqueous solutions (a phosphate solution and calcium solution). Combining both solutions in equal volumes prior to use forms a supersaturated solution with both calcium and phosphate ions. Fomukal® solutions are separately packaged in two 225 ml bottles, Caphosol® in two 15 ml plastic ampules. Fomukal® and Caphosol® active chemical components are identical.

Risk Of Bias In Included Studies

Four RCTs had a high overall risk of bias [21, 40, 42, 43]. These studies were judged to be at high risk in de domain ‘randomization process’, due to inadequate randomization, failure to ensure allocation concealment and imbalanced patient characteristics. One RCT was also judged to be at high risk in the domain ‘deviations from intended interventions’ [42]. In this study, 17% of patients in the SCPR group and 8% of patients in the control group discontinued their treatments because of dry mouth or deterioration of condition. SCPR patients who continued rinsing with filtered water, were analyzed in a different group, which may have affected the outcome. The overall risk of bias of the NRSIs was moderate for all studies [38, 44, 45]. Overviews of the risk of bias are presented in Figs. 2 and 3.

Incidence of OM

The incidence of OM was analyzed in 7 studies, involving 528 patients [18, 38, 40–42, 44, 45]. All studies showed no significant differences in the incidence of OM between the SCPR group and control groups (Table S2). After exploration of the heterogeneity, we included 3 RCTs in the meta-analysis [18, 40, 42]. The results showed that the incidence of OM was not statistically significant between the SCPR and control groups (RR, 0.93; 95% CI, 0.80–1.08) (Fig. 4a).

Duration of OM

The duration of OM was analyzed in 7 studies, involving 513 patients [18, 20, 21, 38, 39, 42, 43]. We did not pool data due to a significant heterogeneity (I² = 97%, p < 0.00001) (Fig. 4b). The included studies showed mixed results (Table S3). Two studies reported significant differences in the duration of OM in days for the SCPR group [20, 21], while 3 studies found non-significant differences between groups [18, 39, 42]. The remaining 2 trials showed a significant reduction in the duration of OM for the control group [38, 42].

Severity of OM

The severity of OM was analyzed in 5 studies, involving 483 patients [18, 38, 42, 44, 45]. These studies reported the incidence of moderate OM (grade 1–2) and the incidence of severe OM (grade 3–4).

All studies [18, 38, 44, 45] showed no significant differences in the incidence of moderate OM between the SCPR and control groups (Table S4). We included 2 RCTs for meta-analysis [18, 40]. The meta-analysis suggested that the incidence of moderate OM is not statistically significant between the SCPR and control groups (RR, 1.16; 95% CI, 0.85–1.59) (Fig. 4c).

No significant differences in the incidence of severe OM were found in all studies [18, 38, 42, 44, 45] (Table S4). Meta-analysis of 2 RCTs [18, 42] also suggested that the incidence of severe OM was not statistically significant between the SCPR and control groups (RR, 0.66; 95% CI, 0.27–1.64) (Fig. 4d).

Effect on Pain Relief

The impact of SCPR on pain relief was reported by 5 studies involving 417 patients [20, 21, 39, 42, 43]. Two studies reported a statistically significant improvement of pain on a VAS scale. Papas et al. found a significant reduction in days of pain and peak level of pain in the SCPR group (p < 0.001) [20]. In another study, the group treated with SCPR showed a statistically significant reduction in peak level of pain (p = 0.005) [21]. The remaining 3 studies reported no statistically significant differences in peak level of pain and duration of pain between the SCPR and control groups [39, 42, 43].

QoL and side effects

None of the studies assessed the QoL, and side effects were not observed or reported.

Subgroup analysis

To explore the heterogeneity, we conducted a subgroup analysis based on different ages and type of HSCT for the duration of OM as I² was > 75%. No interaction was seen between different ages or type of HSCT and the effect of SCPR (Fig. S1 and S2). The high heterogeneity remains unexplained.

Sensitivity analyses

We conducted sensitivity analyses to examine whether risk of bias and study design would affect the results of our meta-analyses. We excluded the RCTs with a high risk of bias for the incidence and severity of OM, but found no significant change in the results (Fig. S3). Exploration of the differences between the RCTs and NRSIs showed similar effect estimates for the incidence and severity of OM (Fig. S4).

Publication Bias

The accumulated number of eligible studies for each outcome of interest was less than 10. We therefore did not draw a funnel plot to check potential publication bias.

GRADE

In this systematic review, study limitations were mainly reflected by risk of bias, which we judged to be high for all primary outcomes. We downgraded the quality of evidence on every primary outcome due to risk of bias. Inconsistency of results is reflected by heterogeneity between studies. We downgraded the quality of evidence on the outcomes duration of OM and severity (incidence of severe OM) because of substantial heterogeneity. Imprecision of results is often seen in a situation where the point estimator indicates a likely beneficial or harmful effect while the confidence interval is wide and exceeds the null-effect line. This problem is caused by limited data available for an outcome or because there are few studies that have examined the outcome. In this systematic review, we downgraded the quality of evidence on the outcome severity (incidence of moderate OM) for imprecision, because the small number of studies reported a small number of events.

In summary, the overall quality of evidence for the use of SCPR in patients with HSCT-induced OM was moderate for the incidence of OM and low for the duration of OM and severity of OM. More details are provided in the ‘Summary of findings’ table (Table S5).

This systematic review and meta-analysis evaluates the effects of SCPR for OM in patients undergoing HSCT. Our results, based on 11 studies, suggest that SCPR is not effective in reducing the incidence, duration and severity of HSCT-induced OM. Additionally, SCPR does not seem to contribute to pain relief. None of the studies assessed the secondary outcome QoL, and side effects were not observed or reported.

Of all the included studies, the conclusion of 8 trials [18, 38–42, 44, 45] were consistent with our meta-analysis, while the results of the other 3 studies [20, 21, 43] were contradictory. Markiewicz et al. (2012) showed a significant reduction in the duration of OM in the SCPR group [21]. But this study has limitations, such as the lack of blinding. Iodine solutions (red/orange color) contrast dramatically with the SCPR (colorless), making it difficult to disguise the differences. Furthermore, the SCPR has to be mixed and requires opening a blue ampule with phosphate and a clear ampule with calcium immediately before administration. Another study performed by Markiewicz et al. (2020), compared SCPR with Fomukal® and found a significant reduction of OM in the Fomukal® group [43]. It should be noted that in this study, patients in the intervention group were assigned to receive a calcium and phosphate solution in two 225 ml bottles (Fomukal®), but patients in the control group were assigned to take two 15 ml bottles (Caphosol®). But besides the fact that this study used a higher dose of SCPR, lack of blinding may also have influenced the results.

Six RCTs compared SCPR with different control regimes on the duration of HSCT-induced OM, but the heterogeneity hampered a meta-analysis. There may be several explanation for this heterogeneity, such as differences in patient characteristics, study design, controls, follow-up, oral treatment protocols, HSCT regimes and OM grading scales. Surprisingly, we found less heterogeneity between the studies on the outcomes incidence and severity. After conducting subgroup analysis for the duration of OM, based on different ages and type of HSCT, the high heterogeneity remains unexplained. The study by Papas et al. possibly accounted for a fraction of the heterogeneity, because the authors reported and analyzed the data on autologous HSCT and allogeneic HSCT separately [20]. Furthermore, the SCPR group received, prior to HSCT, four topical fluoride treatments of 1% fluoride gel. This procedure resulted in a cleaner tooth surface with fewer areas of bacterial growth, which possibly decreased the risk of infection [46]. This may have led to the significant effect between the SCPR group and NaF 0.01% control group.

A few clinical studies established the effects of SCPR in preventing and treating OM in patients treated with high-dose chemotherapy and/or radiotherapy for head and neck cancers [47–50]. Kiprian et al. found a beneficial effect of SCPR in reducing the severity of OM, xerostomia, and dysphagia in patients irradiated for head and neck tumors [47]. An explanation could be that the frequency of application was increased up to 10 times a day depending on the severity of symptoms associated with OM while in our included studies, SCPR rinses were performed four times a day. Furthermore, the lack of blinding may also have influenced the outcomes. Nevertheless, the finding of our meta-analysis showed that SCPR did not decrease the incidence and severity of HSCT-induced OM, which was consistent with the result obtained in three clinical studies for radiation induced OM [48–50]. Lambrecht et al. reported that the addition of SCPR to standard care did not improve the incidence, duration and severity of OM during and early after (chemo)radiation [48]. The conclusions of Wong et al. and Stokman et al. were also consistent with our findings [49, 50]. They found no significant differences between the SCPR and control groups on the incidence, duration and severity of OM during (chemo)radiation in patients with head and neck cancer.

We acknowledge several limitations to our study. First, not all databases were explored, although the main medical electronic databases were included. Secondly, due to the limited number of studies available for each meta-analysis, we did not construct funnel plots, and thus cannot exclude the possibility of publication bias. Finally, in our analysis, we recalculated median scores and ranges into mean scores and standard deviations to determine a pooled estimate. Though legitimized [30, 31], this could have influenced the outcomes.

Because the overall findings from this systematic review suggest that SCPR is not beneficial in reducing the incidence, duration, severity and pain of OM, further research is needed. Up to date no single strategy and agent has been found to be superior or considered the treatment of first choice. It is, therefore, necessary to investigate the value of other alternative methods for the prevention and treatment of HSCT-induced OM. Recently, the alternative aqueous mouthwash solution of high dosage supersaturated calcium-phosphate, Fomukal®, has become available. Markiewicz et al. and Kiprian et al. found a significant reduction in mean severity and duration of OM in the Fomukal® group [43, 51]. Studies to evaluate the role of Fomukal® in preventing and reducing OM are warranted. We suggest a large-scale study with a high dosage of SCPR (Fomukal®) compared to uniform control regime to explore the potential benefit of SCPR in HSCT-induced OM. In addition, outcomes from patients’ perspective, such as QoL, should be designed in future SCPR studies, and we recommend a consistent OM grading. Finally, future research should require greater attention to critical methodological issues, including adequate sample size, randomization and blinding.

Based on the available evidence, SCPR does not seem effective in reducing the incidence, duration and severity of OM in patients undergoing HSCT. Heterogeneity among studies and the fact that there are no studies with low risk of bias are both limitations. However, further large-scale studies with more rigorous methodology are required to enhance the quality of evidence.

Acknowledgements

Not applicable.

Author contribution

Conceptualization: JV and JM. Formal analysis: JV, MV and JM. Writing-review and editing: JV and JM. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Availability of data and materials

All data generated and analyzed during this study are included in this manuscript and its supplementary information files.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Harris DJ. Cancer treatment‐induced mucositis pain: Strategies for assessment and management. Therapeutics and Clinical Risk Management. 2006;2:3:251–258.
Sonis ST. Pathobiology of oral mucositis: novel insights and opportunities. Review. J Support Oncol. 2007;5:3–11.
Lalla RV, Bowen J, Barasch A et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;20:1453– 1461.
Cheng KK. Oral mucositis: a phenomenological study of pediatric patients´ and their parents´ perspectives and experiences. Support Care Cancer. 2009;17:7:829-837.
Bellm LA, Epstein JB, Rose‐Ped A, Martin P, Fuchs HJ. Patient reports of complications of bone marrow transplantation. Supportive Care in Cancer 2000;8:1:33–39.
Vera‐Llonch M, Oster G, Ford CM, Lu J, Sonis S. Oral mucositis and outcomes of allogeneic hematopoietic stem‐cell transplantation in patients with hematologic malignancies. Supportive Care in Cancer. 2007;15:5:491–496.
Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer. 2003;98:1531-1539.
Keefe DMK. Mucositis management in patients with cancer. Supportive Cancer Therapy. 2006;3:154–157.
Sonis ST, Oster G, Fuchs H. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol. 2001;19:2201-2205.
Cinausero M, Aprile G, Ermacora P, Basile D, Vitale MG, Fanotto V, et al. New frontiers in the pathobiology and treatment of cancer regimen-related mucosal injury. Front Pharmacol. 2017;8:354.
Dodd MJ, Miaskowski C, Dibble SL, Paul SM, MacPhail L, Greenspan D, et al. Factors influencing oral mucositis in patients receiving chemotherapy. Cancer Practice 2000;8:6:291–297.
Riley P, Glenny A, Worthington HV, Littlewood A, Fernandez Mauleffinch LM, Clarkson JE, et al. Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors. Cochrane Database Syst Rev. 20017;11:11:CD011990.
Riley P, Glenny A, Worthington HV, Littlewood A, Clarkson JE, McCabe MG. Interventions for preventing oral mucositis in patients with cancer receiving treatment: oral cryotherapy. Cochrane Database Syst Rev. 2015;12:CD011552.
Peng J, Shi Y, Wang J, Wang F, Dan H, Xu H, Zeng X. Low-level laser therapy in the prevention and treatment of oral mucositis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020;130:4:387-397.
Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007;109:820–831.
Kadakia KC, Rozell SA, Butala AA, Loprinzi CL. Supportive cryotherapy: A review from head to toe. J. Pain Symptom Manag. 2014;47:1100–1115.
Oberoi S, Zamperlini-Netto G, Beyene J, Treister, NS, Sung, L. Effect of prophylactic low level laser therapy on oral mucositis: a systematic review and meta-analysis. PLoS One. 2014;9:9:e107418.
Treister N, Nieder M, Baggott C, Olson E, Chen L, Dang H, et al. Caphosol for prevention of oral mucositis in pediatric myeloablative haematopoietic cell transplantation. Br J Cancer. 2017;116:1:21-27.
Murdock JL, Reeves DJ. Chemotherapy-induced oral mucositis management: a retrospective analysis of MuGard, Caphosol, and standard supportive care measures. J Oncol Pharm Pract. 2020;26:521-528.
Papas AS, Clark RE, Martuscelli G, O’Loughlin KT, Johansen E, Miller KB. A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;31:8:705-12.
Markiewicz M, Dzierzak-Mietla M, Frankiewicz A, Zielinska P, Koclega A, Kruszelnicka M, et al. Treating oral mucositis with a supersaturated calcium phosphate rinse: comparison with control in patients undergoing allogeneic hematopoietic stem cell transplantation. Support Care Cancer. 2012;20:9:2223-9.
Waśko-Grabowska A, Rzepecki P, Oborska S, Barzał J, Gawroński K, Młot B, et al. Efficiency of supersaturated calcium phosphate mouth rinse treatment in patients receiving high-dose melphalan or BEAM prior to autologous blood stem cell transplantation: a single-center experience. Transplant Proc. 2011;43:8:3111-3.
Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. http://www.handbook.cochrane.org. (2011, accessed 10 October 2021).
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Syst Rev. 2021;10:1:89.
World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva: World Health Organization. 1979.
Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan - a web and mobile app for systematic reviews. Syst Rev. 2016;5:210.
Sterne JAC, Savovi´c J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials. BMJ. 2019;28:366:l4898.
Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;12:355:i4919.
The Cochrane Collaboration. Review Manager (RevMan). Version 5.4. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration. 2014.
Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:1:1-13.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:7414:557–560.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.
Palma Perez M, Delgado Rodriguez M. Practical considerations on detection of publication bias. Gac Sanit. 2006;3:10–6.
Schünemann H, Brożek J, Guyatt G, Oxman A. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. https://gdt. gradepro.org/app/handbook/ handbook.html. (2013, accessed 13 May 2022).
Bhatt N, Naithani R, Gupta SK. Supersaturated Calcium Phosphate Rinse in Prevention and Treatment of Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplant. Exp Clin Transplant. 2017;15:5:567-570.
Wasko-Grabowska A, Rzepecki PK. A supersaturated calcium phosphate solution-New hope for old problem. Single centre experience. Bone Marrow Transplantation. 2015;1:426-427.
Wasko-Grabowska A, Rzepecki PK, Oborska S, Barzal J, Mlot B, Gawronski K, et al. A supersaturated calcium phosphate solution seems to effectively prevent and treat oral mucositis in haematopoietic stem cell transplanted cancer patients - single centre experience. J BUON. 2012;17:2:363-8.
Raphael MF, den Boer AM, Kollen WJW, Mekelenkamp H, Abbink FCH, Kaspers GJL et al. Caphosol, a therapeutic option in case of cancer therapy-induced oral mucositis in children. Support Care Cancer. 2014;22:1:3-6.
Mubaraki S, Pani SH, Alseraihy A, Abed H, Alkhayal Z. The efficacy of two different oral hygiene regimens on the incidence and severity of oral mucositis in pediatric patients receiving hematopoietic stem cell transplantation: A prospective interventional study. Spec Care Dentist 2020;40:6:566-573.
Immonen E, Aine L, Nikkilä A, Parikka M, Grönroos M, Vepsäläinen K, et al. Randomized controlled and double-blinded study of Caphosol versus saline oral rinses in pediatric patients with cancer. Pediatr Blood Cancer. 2020;67:10:e28520.
Kröner A, Aerts E, Schanz U, Spirig R. Caphosol® versus State-of-the-Art Mouth Care in Patients with Allogeneic Stem Cell Transplantation: A Randomized Controlled Trial. J Nurs Care. 2016;5:4.
Markiewicz M, Dzierżak-Mietła M, Gaj M, Warzybok K, Burdacki A, Mizia S. Similar effectiveness of Fomukal and Caphosol in oral mucositis treatment after allogeneic hematopoietic stem cell transplantation. Postepy Hig Med Dosw. 2020;74:541-547.
Bourdelin M, Daguindau E, Larosa F, Legrand F, Nerich V, Deconinck E, et al. Mucositis after allogeneic stem cell transplantation: Risk factors, clinical consequences and prophylaxis. Pathologie Biologie. 2015;63:106-110.
Harman M, Ovayolu N, Ovayolu O. The effect of three different solutions on preventing oral mucositis in cancer patients undergoing stem cell transplantation: a non-randomized controlled trial: A Turkish study - NON-RANDOMISED TRIAL. Journal of the Pakistan Medical Association. 2019;69:6:811-816.
Yeung C. Fluoride prevents caries among adults of all ages. Evid Based Dent. 2007;8:3:72-3.
Kiprian D, Jarzabski A, Kawecki A. Evaluation of efficacy of Caphosol in prevention and alleviation of acute side effects in patients treated with radiotherapy for head and neck cancers. Contemp Oncol (Pozn). 2016;20:5:389-393.
Lambrecht M, Mercier C, Geussens Y, Nuyts S. The effect of a supersaturated calcium phosphate mouth rinse on the development of oral mucositis in head and neck cancer patients treated with (chemo)radiation: a single-center, randomized, prospective study of a calcium phosphate mouth rinse + standard of care versus standard of care. Support Care Cancer. 2013;21:10:2663-70.
Wong KH, Kuciejewska A, Sharabiani MTA, Ng-Cheng-Hin B, Hoy S, Hurley T, et al. A randomized controlled trial of Caphosol mouthwash in management of radiation-induced mucositis in head and neck cancer. Radiother Oncol. 2017;122:207–11.
Stokman MA, Burlage FR, Spijkervet FKL. The effect of a calcium phosphate mouth rinse on (chemo) radiation induced oral mucositis in head and neck cancer patients: a prospective study. Int J Dent Hyg. 2012;10:3:175-80.
Kiprian D, Rolski W, Michalski W. Evaluation the efficacy of Fomukal for treatment of oral mucositis induced by radiation therapy in head and neck cancer patients. Support Care Cancer. 2018;26:150–151.

No competing interests reported.

Additionalfile1TableS1JAdeVries.docx
Additional file 1: Table S1. Literature search-strategy.
Additionalfile2TableS2JAdeVries.docx
Additional file 2: Table S2. Studies evaluated the effect of SCPR on the incidence of OM compared to control groups.
Additionalfile3TableS3JAdeVries.docx
Additional file 3: Table S3. Studies evaluated the effect of SCPR on the duration (days) of OM compared to control groups.
Additionalfile4TableS4JAdeVries.docx
Additional file 4: Table S4. Studies evaluated the effect of SCPR on the severity of OM compared to control groups.
Additionalfile5TableS5JAdeVries.docx
Additional file 5: Table S5. Summary of findings (GRADE) and level of evidence for meta-analysis.
Additionalfile6SupplementaryfiguresJAdeVries.docx
Additional file 6: Supplementary figures.

Download PDF

Version 1

posted

You are reading this latest preprint version

Effect of a supersaturated calcium-phosphate rinse on oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT): a systematic review and meta- analysis

Status:

Version 1

Abstract

Figures

Introduction

Methods

Inclusion criteria

Exclusion Criteria

Definition Of Outcomes

Search Strategy

Study Selection

Data Extraction

Risk Of Bias Assessment

Data analysis

GRADE

Results

Study selection

Description Of Studies

Risk Of Bias In Included Studies

Incidence of OM

Duration of OM

Severity of OM

Effect on Pain Relief

QoL and side effects

Subgroup analysis

Sensitivity analyses

Publication Bias

GRADE

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1