Calcium Phosphate Mouth Rinse

Calcium Phosphate Mouth Rinse

PEP Topic 
Mucositis
Description 

Oral rinses containing calcium and phosphate have been studied in patients with cancer for effects on oral mucositis.

Effectiveness Not Established

Research Evidence Summaries

Lambrecht, M., Mercier, C., Geussens, Y., & Nuyts, S. (2013). 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. Supportive Care in Cancer, 21, 2663–2670.

doi: 10.1007/s00520-013-1829-0
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Study Purpose:

To investigate whether the addition of a neutral, supersaturated, calcium phosphate (CP) mouth rinse benefits the severity and duration of acute mucositis in patients with head and neck cancer treated with (chemo)radiation

Intervention Characteristics/Basic Study Process:

Patients in group A were instructed to use caphosol mouth rinse twice daily with 15 ml solution for one minute plus standard care. Patients in group B were instructed to use standard care consisting of gargling with 15 ml of “magic mouth wash” (hydrocortisone, lidocaine, nystatin, propylene glycol, sodium carboxymethylcellulose, aqua admixture) up to six times per day, swallowing one time out of two. Two experienced physicians conducted visual inspection of the oral cavity and visualized oropharyns weekly until two to seven weeks after completion or until mucositis grade 1 or 0.

Sample Characteristics:

  • N = 58
  • MALES: 84.4%, FEMALES: 15.5%
  • Patients had all histological subtypes of head and neck cancer.
  • Patients were receiving curative radiation (intensity-modulated radiation therapy of 60–72 Gy over six to seven weeks), primary or postoperative oral mucosa or part of oral mucosa in radiation field, concurrent chemotherapy consisting of 100mg/m2 cisplatin at weeks one and four, and induction chemotherapy with docetaxel, cisplatin, fluorouracil, or epidermal growth factor receptor monoclonal antibody.
  • Patients were excluded from the study if they had received prior head and neck cancer radiation therapy.

Setting:

  • Single site
  • Outpatient radiotherapy department at the University Hospital of Leuven, Belgium

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Study Design:

  • Single center
  • Prospective randomized controlled (no placebo) study

Measurement Instruments/Methods:

  • The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 3 (NCI CTCAE 3.0)
  • Oral pain was scored with a visual analog scale.

Results:

No significant differences were found in grade, time of onset, or duration of peak mucositis between groups. Fewer patients in the study arm experienced grade 3 or higher mucositis (59% versus 71%). Mean time to development  of mucositis was 28.6 days in the study group versus 28.7 days in the control group (p = .96). Duration of mucositis was 22.7 days in the study group versus 24.6 days in the control group (p = .62). No significant reduction in the need for analgesics was found.

Conclusions:

An oral solution of neutral CP mouth rinse does not reduce frequency, duration, or severity of oral mucositis or pain in patients treated with (chemo)radiation for head and neck cancer. No evidence supports its standard use.

Limitations:

  • Small sample (< 100)
  • Key sample group differences that could influence results
  • Other limitations include the heterogeneity of the patient population and treatment sample and no assessment of patient characteristics that could influence mucositis (poor oral health, alteration salivary production, alcohol use, or existing mucosal damage).

Nursing Implications:

Mucosal damage continues to be an important and debilitating side effect that warrants continued research.

Markiewicz, M., Dzierzak-Mietla, M., Frankiewicz, A., Zielinska, P., Koclega, A., Kruszelnicka, M., & Kyrcz-Krzemien, S. (2012). Treating oral mucositis with a supersaturated calcium phosphate rinse: comparison with control in patients undergoing allogeneic hematopoietic stem cell transplantation. Supportive Care in Cancer, 20, 2223–2229.

doi: 10.1007/s00520-012-1489-5
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Study Purpose:

To evaluate the efficacy of supersaturated calcium phosphate rinse (SCPR) with customary care (topical mouth solutions) on measures of severity and consequent interventions and complications  

Intervention Characteristics/Basic Study Process:

In the treatment group, patients rinsed their mouths four times daily with the SCPR. In the control group, patients received customary topical mouth care with the extract of salvia leaves (twice daily), providone-iodine mouth solution (1% water solution of iodide with polyvinylpyrrolidone) once daily, and fluconazole mouth solution (50 mg fluconazole, 50 mg glycerine, 10 g vitamin A, and 10 g vitamin E with or without 2.5 g benzociaine) twice daily.

The SCPR treatment was administered from the first day of conditioning until patients reached the absolute neutrophil count of greater or equal to 0.2 g/l (a value that was considered an indication of the beginning of neutrophil recovery). Patients self-assessed the level of pain in the mouth and pharynx using a 0–10 visual analog scale (VAS) and measured swallowing problems using a 0–5 VAS.

The same experienced hematologist performed a physical examination of the oral cavity each day throughout the study, ranking cases according to the World Health Organization (WHO) scale for grading oral toxic effects of cancer treatment.

Sample Characteristics:

  • The study reported on a sample of 40 patients. The SCPR group mean age was 38, with a range of 19–57 years. The control group mean age was 26, with a range of 20–57 years.
  • The SCPR group had 13 males and 7 females, and the control group had 11 males and 9 females.
  • The SCPR group had 8 patients with acute myelogenous leukemia (AML), 5 with acute lymphocytic leukemia (ALL), 2 with chronic myelogenous leukemia (CML), 3 with paroxysmal nocturnal hemoglobinuria (PNH), and 2 with other cancers (osteomyelfibrosis, myelodysplastic syndrome, severe aplastic anemia).
  • The control group consisted of 12 patients with AML, 5 patients with ALL, 1 patient with PNH, and 2 patients with other (see above).
  • In the SCPR group, 9 patients were receiving busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg), 5 patients were receiving total body irradiation (TBI) of 12 Gy and 120 mg/kg cyclophosphamide, and 6 were receiving treosulfan (42 g/m2) and fludarabine (150 mg/m2).
  • In the control group, 9 patients were receiving busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg), 5 were receiving TBI (12 Gy) and 120 mg/kg cyclophosphamide, 4 were receiving treosulfan (42 g/m2) and fludarabine (150 mg/m2), 1 was receiving treosulfan (20 g/m2) and cyclophosphamide (160 mg/kg) and 1 was receiving cyclophosphamide (200 mg/kg). 
  • In the SCPR group, 5 patients were receiving transplants from sibling donors and 15 from unrelated donors. In the control group, 4 were receiving transplants from sibling donors and 16 from unrelated donors.

Setting:

This was a single-site study conducted in an inpatient setting. The study was conducted at the Department of Hematology and Bone Marrow Transplantation at the Medical University of Silesia in Katowice, Poland, in 2009.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • This study has clinical applicability for end of life and palliative care.

Study Design:

This was a prospective randomized, non-blinded, controlled trial with 40 consecutive patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Half of the patients received treatment with the supersaturated rinse, and the remaining half received customary care with topical mouth solutions. Patients enrolled in this study underwent transplantation in the Medical University of Silesia in Katowice, Poland, in 2009.

Measurement Instruments/Methods:

The World Health Organization scale (WHO) was used to measure severity of mucositis. Duration was recorded in days. Peak mean pain in mouth was recorded using a 0–10 visual analog scale (VAS). Peak mean swallowing problems were recorded using a 0–5 VAS. Days to absolute neutrophil count of more than 0.5 g/L and days to platelets of more than 20 g/L were recorded.  

Interventions and complications were measured in terms of duration of analgesics used (days), duration of total parenteral nutrition (TPN) (days), use of granulocyte colony-stimulating factor (G-CSF), incidence of acute graft-versus-host disease (aGVHD), degree of aGVHD, and incidence of infectious complications.

Results:

  • Compared with the control group, the SCPR mouth rinse group demonstrated significantly lower means measures of oral toxicity, peak mouth pain, and disease course duration.
  • WHO oral toxicity scores were statistically lower in the SCPR group (p = 0.02) compared to the control group.
  • Disease course for the SCPR group was statistically shorter (p = 0.02) and peak mouth pain was statistically lower in the SCPR group (p = 0.005).
  • Days of analgesic needs were shorter for the SCPR group (p = 0.047).
  • The need for patients needing TPN in the SCPR group was lower (p = 0.02), and the mean days of TPN was lower in the SCPR group (p = 0.009).

Conclusions:

The findings in this prospective randomized, controlled study confirm findings in a 1992 report of a double-blind, prospective, randomized, controlled trial of 95 patients undergoing HSCT. In that trial, SCPR produced statistically significantly lower measures of pain duration, disease course duration, use of analgesics (morphine), and duration of time to absolute neutrophil recovery than did a fluoride rinse, demonstrating the SCPR regimen has a significant positive effect on oral mucositis associated with chemotherapy and radiotherapy.

Limitations:

  • The sample size was small with fewer than 100 patients.
  • The iodine solution (red) contrasted dramatically in color with the SCPR solution (colorless), thus making it difficult to disguise the difference and, therefore, making the study unblinded.
  • The red color of the iodine solution may have obscured assessment of the oral cavity.
  • It may be able to generalize these results to other settings because the control group treatment is not necessarily widely accepted as the standard of care for the prevention and treatment of mucositis. 

Nursing Implications:

These results warrant confirmation in controlled, multicenter, randomized trials. The use of a supersaturated calcium phosphate rinse holds promise for the prevention and early resolution of oral mucositis and appears to have no significant side effects when used four times daily in patients receiving stem cell transplant.

Raphael, M.F., den Boer, A.M., Kollen, W.J., Mekelenkamp, H., Abbink, F.C., Kaspers, G.J., . . . Tissing, W.J. (2014). Caphosol, a therapeutic option in case of cancer therapy-induced oral mucositis in children?: Results from a prospective multicenter double blind randomized controlled trial. Supportive Care in Cancer, 22, 3–6.

doi: 10.1007/s00520-013-2015-0
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Study Purpose:

To evaluate if Caphosol™ is effective to treat oral mucositis (OM) in pediatric patients who received chemotherapy or hematopoietic stem cell transplant (HSCT)

Intervention Characteristics/Basic Study Process:

A sample of 33 patients between 4–18 years old was assigned to Caphosol or placebo. All patients received standard local supportive care, in addition to Caphosol study or 0.9% sodium chloride (NaCl) placebo mouth rinse. All patients were instructed to use the study mouthwash four times daily during their OM period. Primary study outcome was defined as the number of days with OM greater than grade 1. Secondary outcomes were pain and analgesic use.

Sample Characteristics:

  • N = 29
  • AGE RANGE: 4–18 years
  • MALES: 66%, FEMALES: 34%
  • KEY DISEASE CHARACTERISTICS: Patients had been diagnosed with hematologic malignancies, solid tumor, and benign hematologic disorders and were receiving chemotherapy or HSCT.

Setting:

  • SITE: Multi-site
  • SETTING TYPE: Inpatient
  • LOCATION: Four university hospitals in the Netherlands

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment
  • APPLICATIONS: Pediatrics

Study Design:

  • Double-blinded, placebo-controlled trial

Measurement Instruments/Methods:

  • The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 mucositis scoring system was used to evaluate mucositis.
    • Days of mucositis greater than grade 1 and peak level of mucositis
    • Days of pain and peak of level pain
    • Days of analgesic use, morphine use, peak dose (mg/kg)
    • Need for tube feeding and number of days
    • Need for parenteral feeding and number of days
    • Blood cultures taken

Results:

Chi-square or t-test was used for analysis. The number of days with mucositis greater than grade 1 did not differ significantly between the two study groups (p = 0.154). No significant differences were found between Caphosol and placebo for all the outcome measures except days of pain and tube feeding requirement. Placebo was associated with significantly fewer days of pain (p = 0.035) . The need for tube feeding was significantly higher in the Caphosol group.

Conclusions:

Therapeutic use of Caphosol was not beneficial in the treatment of pediatric patients with cancer therapy-induced OM.

Limitations:

  • Small sample (< 30)
  • Risk of bias (sample characteristics)
  • Key sample group differences could influence results.
  • Findings not generalizable
  • High grades of mucositis were found at the start of the study with 64.3 % of the placebo group versus 33.3 % of the patients with Caphosol having greater than grade 1 mucositis at the start of the study (p = 0.143). The placebo group also showed a trend of shorter mucositis duration, which may suggest that mucositis was more advanced at baseline and resolved earlier. This, in turn, may have contributed to the finding that the placebo group had fewer days with mucositis greater than grade 1.
  • A problem was seen with a power calculation, and many analyses failed to demonstrate significant results. This study has significant risk for type II errors. In addition, this study included various types of cancer and cancer treatments, which may have contributed to the lack of significance in findings.

Nursing Implications:

Although this study was a double-blind, randomized, controlled trial, the significantly small sample size was problematic. The authors concluded that Caphosol was not effective in practice; however, it is not conclusive because of the significantly high risk for type II errors. A study with a larger sample size is required to assess the efficacy of Caphosol.

Stokman, M. A., Burlage, F.R., & Spijkervet, F.K. (2012). The effect of a calcium phosphate mouth rinse on (chemo) radiation induced oral mucositis in head and neck cancer patients: A prospective study. International Journal of Dental Hygiene, 10(3), 175–180.

doi: 10.1111/j.1601-5037.2012.00574.x
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Study Purpose:

To determine the effect of a calcium phosphate (CP) mouth rinse on oral mucositis

Intervention Characteristics/Basic Study Process:

Consecutive patients were asked if they were willing to use the CP mouth rinse. Those who were willing were assigned to the CP group, and those who refused served as controls and followed the standard oral care program.  Standard care with mouth rinsing with a salt and baking soda solution at least 8 times per day. The CP rinse was used twice per day. All patients received daily oral cleansing with a normal saline pressure spray and fluoride gel applications every other day to the teeth. The study period was 6 weeks. Outcomes were compared between groups and compared with historical controls.

Sample Characteristics:

  • The study reported on a sample of 36 patients, with a mean age of 60.3 years.
  • The sample was 64% male and 46% female.
  • All patients had head and neck cancer.
  • Some patients had radiation with intensity-modulated radiation therapy (IMRT), while others had 3D conformal radiation therapy (CRT).
  • Significant differences existed between groups in use of conventional or accelerated fractionation of radiation and use and history of smoking.

Setting:

The study was conducted at a single outpatient site in the Netherlands.

Phase of Care and Clinical Applications:

Patients were undergoing the active antitumor treatment phase of care.

Study Design:

This was a prospective, non-random comparison study.

Measurement Instruments/Methods:

  • The World Health Organization (WHO) mucositis grading scale was used.
  • The Oral Mucositis Daily Questionnaire was used.
  • Oral pain was evaluated using a visual analog scale (VAS).
  • Body weight was recorded.
  • Use of nasogastric feeding was recorded.

Results:

No significant differences were found between groups in any of the outcome measures. Patients in the CP group had more severe mucositis scores at most weeks, but the difference was not statistically significant.

Conclusions:

CP mouth rinsing had no effect on frequency, severity, or duration of oral mucositis in this group of patients.

Limitations:

  • The sample size was small with fewer than 100 patients.
  • Baseline sample and group differences of importance existed.
  • Risk of bias exists because no control group, blinding, or random assignment was used.
  • A risk of bias exists because of the population and sample group differences including use of IMRT and smoking behavior.
  • No information was provided about use of analgesics or patient compliance with oral care.

Nursing Implications:

This study did not show any benefit in the use of CP mouth rinses for the prevention and management of mucositis in patients receiving radiation therapy for head and neck cancer.

Systematic Review/Meta-Analysis

McGuire, D.B., Fulton, J.S., Park, J., Brown, C.G., Correa, M.E.P., Eilers, J., . . . Lalla, R.V. (2013). Systematic review of basic oral care for the management of oral mucositis in cancer patients. Supportive Care in Cancer, 21, 3165–3177.

doi: 10.1007/s00520-013-1942-0
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Purpose:

STUDY PURPOSE: To systematically review oral care interventions for the prevention and treatment of oral mucositis (OM) in patients undergoing cancer treatment

TYPE OF STUDY: Systematic review

Search Strategy:

DATABASES USED: Ovid MEDLINE

KEYWORDS: mucositis, stomatitis, cancer, oral care, oral care protocol, dental care, dental cleaning, oral decontamination, oral hygiene, saline, sodium bicarbonate, baking soda, chlorhexidine, magic/miracle mouthwash, calcium phosphate

INCLUSION CRITERIA: Primary research article, reflects a variety of research designs, rested the effects of intervention on severity of OM or mucositis-related symptoms

EXCLUSION CRITERIA: Review articles, clinical case reports, literature reviews, non-research articles

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 129

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Hadorn et al. criteria was used to assess the flaws in the selected publications, and levels of evidence were rated using the Somerfield schema.

Sample Characteristics:

FINAL NUMBER STUDIES INCLUDED = 52

SAMPLE RANGE ACROSS STUDIES, TOTAL PATIENTS INCLUDED IN REVIEW: Not stated

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Results:

The guidelines are as follows.

  • Oral care protocols: Oral care was suggested for the prevention of OM in adult and pediatric populations for all types of cancer therapies. No population-specific guidelines were recommended.
  • Dental care (by a professional): No guidelines were recommended for dental care in the prevention of OM.
  • Normal saline: No guidelines were recommended for normal saline for the prevention or treatment of OM.
  • Sodium bicarbonate rinse: No guidelines were recommended for sodium bicarbonate for the prevention or treatment of OM.
  • Chlorhexidine: No guidelines were recommended for chlorhexidine for the prevention or treatment of OM in patients receiving standard chemotherapy or hematopoietic stem cell transplantation. Guidelines suggest that chlorhexidine not be used to prevent OM in patients with head and neck cancer treated with radiotherapy.
  • Mixed medication mouthwash: No guidelines were recommended for mixed medication mouthwash for the prevention or treatment of OM.
  • Calcium phosphate: No guidelines were recommended for calcium phosphate for the prevention or treatment of OM.

Conclusions:

Oral care protocols are recommended to patients for the prevention and treatment of OM. Chlorhexidine is not recommended for patients with head and neck cancer who receive radiotherapy treatment.

Limitations:

Evidence for interventions to prevent and treat OM are limited, making guideline recommendations difficult.

Nursing Implications:

Nurses should teach patients appropriate oral care to help prevent OM.

Quinn, B. (2013). Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: A review of current data. European Journal of Cancer Care, 22, 564–579. 

doi: 10.1111/ecc.12073
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Purpose:

To summarize the literature on calcium phosphate oral rinse for the prevention and treatment of oral mucositis (OM)

Search Strategy:

DATABASES USED: PubMed, Google Scholar, Stanford HighWire, and Cochrane Library
 
KEYWORDS: Caphosol®, supersaturated calcium phosphate, mucositis, stomatitis, chemotherapy, stem cell transplantation, and radiotherapy
 
INCLUSION CRITERIA: Published in English between January 2003 and April 2012, evaluated Caphosol for the prevention or treatment of OM in patients with cancer
 
EXCLUSION CRITERIA: Did not include an evaluation of Caphosol for the prevention and treatment of OM in patients with cancer, did not directly measure OM, unclear regarding the contribution of Caphosol in oral care protocols, did not report the incidence or severity of OM, were described as experimental and did not allow interpretation of the results  

Literature Evaluated:

A total of 83 references were retrieved. These included two full-length, peer-reviewed articles and 28 published abstracts or conference presentations. The articles included 17 studies with 30 or more patients in which Caphosol was compared with a control treatment. The exclusion criteria were applied to exclude studies.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = 30
  • TOTAL PATIENTS INCLUDED IN REVIEW = 1,392, of which 890 patients received Caphosol
  • SAMPLE RANGE ACROSS STUDIES: Across 19 studies of patients undergoing hematopoietic stem cell transplant, 5–154; across 11 studies of patients with head and neck cancers, 11–218
  • KEY SAMPLE CHARACTERISTICS: Studies measured grade and duration of OM, pain assessment and medication, total parenteral nutrition, patient satisfaction, treatment compliance, oral infection rates, duration of hospitalization, polyethylene glycol use, and swallowing. Most of the studies were from single centers and involved free Caphosol provided to the hospital. Observational studies were included. The abstracts and conference proceedings did not consistently provide details about standard treatments and study design.  

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment
  • CLINICAL APPLICABILITY: Pediatrics

Results:

Caphosol was found to reduce OM grade, duration, or both in 24 out of 30 studies. Caphosol was associated with a reduction in OM-associated pain in 14 of 17 studies with more than 30 patients and 6 studies with fewer than 30 subjects. Data regarding nutrition, patient compliance, and length of hospitalization were conflicting, but the majority demonstrated a benefit with Caphosol. Two studies reported potential cost savings with the use of Caphosol. Three studies with 30 patients and three single-center studies with controls of standard mouth care and MuGard® did not find significant differences in OM grade or duration. Two studies of more than 30 patients did not demonstrate a benefit associated with OM-related pain. One study did not find a significant difference in nausea or dysphasia for Caphosol-treated patients. Three studies failed to demonstrate any differences in length of stay.

Conclusions:

The majority of the studies included in the review reported some benefit from Caphosol use. The data demonstrate the opportunity to further study the role of supersaturated calcium phosphate oral rinse in the prevention and treatment of OM.

Limitations:

  • The studies were heterogeneous in their design, so data could not be pooled or consolidated.  
  • The review was funded by EUSA Pharma.  
  • Porterhouse Medical Ltd provided medical writing services and was funded by EUSA Pharma.  
  • Only two full-length, peer-reviewed articles were included in this review.  
  • At least 12 of the 30 studies included in the review were observational or retrospective studies.  
  • The definition of standard oral care was not well defined in all of the studies, so determining the role of Caphosol in the improvements documented is difficult.

Nursing Implications:

The effects from OM remain a significant challenge for patients receiving cancer treatment. Nursing involvement in prospective, randomized, blinded studies could provide the best practice data needed to recommend treatments for OM. The limitations for the studies included in this review are significant and do not provide rigorous scientific support for the use of Caphosol.


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