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Volume: 15 Issue: 5 October 2017

FULL TEXT

ARTICLE
Supersaturated Calcium Phosphate Rinse in Prevention and Treatment of Mucositis in Patients Undergoing Hematopoietic Stem Cell Transplant

Objectives: Mucositis is a common morbidity in patients undergoing bone marrow transplant. Various agents have been used to prevent and treat it with variable success. Here, we assessed the efficacy of supersaturated calcium phosphate rinses in pre­vention and treatment of oral mucositis in patients undergoing hematopoietic stem cell transplant.

Materials and Methods: In this retrospective study, we evaluated the records of 80 patients who underwent hematopoietic stem cell transplant and received supersaturated calcium phosphate rinses for pre­vention of mucositis from April 2012 to January 2016. The World Health Organization scale was used to grade mucositis. Various parameters assessed included grade of mucositis, duration of mucositis, peak mucositis day, duration of pain, peak pain day, duration of total parenteral nutrition, neutrophil engraftment (defined as absolute neutrophil count ≥ 500/µL), mean dose of fentanyl used, incidences of infections, and type of transplant. Supersaturated calcium phosphate rinses at 4 times/day were started for prevention of mucositis as soon as a patient was admitted. All patients also received betadine mouth gargles for oral hygiene.

Results: Our study group included 42 autologous and 38 allogeneic hematopoietic stem cell transplant patients. Grade 1, 2, 3, and 4 mucositis levels were seen in 1, 19, 26, and 31 patients. We found no differences between our study group and historical control regarding parameters studied. Grade of mucositis was statistically significant (P < .01) when autologous transplant for myeloma was compared with auto­logous transplant for other diagnoses.

Conclusions: Supersaturated calcium phosphate rinses were ineffective in the management of mucositis associated with autologous and allogeneic bone marrow transplant.


Key words : Bone marrow transplantation, Mucositis, Supersaturated calcium phosphate rinse

Introduction

Oral mucositis is a debilitating toxicity of hema­topoietic stem cell transplant (HSCT).1 Significant oral mucositis occurs in about 75% of patients undergoing HSCT and causes severe pain and debilitating toxicity, despite current oral hygiene regimens.2 High-dose chemotherapy administered before HSCT leads to direct cytotoxic effects on the oral epithelium, causing injury or disruption of the mucosal barrier.3 This augments risk of infections and hence lengthens the hospital stay, decreases patient’s quality of life, and increases costs and the complications associated with HSCT.4

There are several strategies to reduce burden of mucositis in bone marrow transplant patients. Cryotherapy,5 recombinant keratinocyte growth factor,6 and low-dose laser therapy1 have been used to prevent and treat oral mucositis. There are few studies on the usefulness of supersaturated calcium phosphate rinse (SCPR) in the literature.3,5,7,8 Another recent study did not find any benefit of SCPR.9 There are conflicting data on the usefulness of this agent, and, so far, there are no published data available from India. Therefore, we performed a retrospective analysis of use of SCPR in our patients.

Materials and Methods

This was a retrospective or hospital record-based study, conducted at the Max Superspeciality Hospital, New Delhi, India. The study was approved by the Hospital Ethics Committee. We evaluated the records of 80 patients who underwent HSCT and received SCPR for prevention of mucositis from April 2012 to January 2016. The World Health Organization scale was used to grade mucositis.10 Various parameters assessed included grade of mucositis, duration of mucositis, peak mucositis day, duration of pain, peak pain day, duration of total parenteral nutrition, neutrophil engraftment (defined as absolute neutrophil count ≥ 500/μL), mean dose of fentanyl used, incidences of infections, and type of transplant. There was no control group; therefore, comparisons were done versus a historical control arm. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21, IBM Corporation, Armonk, NY, USA). Statistically significant values were represented by 2-tailed P values, with values < .05 accepted as statistically significant.

Results

Data were available for 42 autologous and 38 allogeneic HSCT patients. Supersaturated calcium phosphate rinses 4 times/day were started for prevention of mucositis as soon as a patient was admitted. All patients also received betadine mouth gargles for oral hygiene. Demographic details (age, sex, and weight), diagnosis, conditioning regimens, analgesics used, and infections are depicted in Table 1. Grade 1, 2, 3, and 4 mucositis levels were seen in 1, 19, 26, and 31 patients. Grade of mucositis was not available for 3 patients.

Figure 1 shows that no significant differences were found between our study group and the historical control, except duration of hos­pitalization after bone marrow transplant (P < .01). As shown in Table 2, we observed no significant differences, except days to reach absolute neutrophil count (P = .01) and days after bone marrow transplant (P = .02), when we compared data between our HSCT patients and the HSCT historical control group. There was no difference in any of the parameters between our allogeneic HSCT patients and historical controls. Grade of mucositis (P < .01) was found to be statistically significant when we compared the autologous myeloma versus the autologous other diagnostic groups (Figure 2). Overall, SCPR rinses were ineffective.

Discussion

Supersaturated calcium phosphate rinses have high concentration of calcium and phosphate ions. It is hypothesized that these highly concentrated ions exert their beneficial effect by diffusing into the intercellular spaces in the epithelium of mucosa and permeating the mucosal lesions in mucositis. The calcium ions play a significant role in inflammatory processes and tissue repair.11 Phosphate ions play an important biochemical role by promoting intra­cellular signaling and regulating the voltage potential inside the cell, which in turn helps to repair and protect the damaged mucosal surfaces.3

Papas and associates demonstrated that SCPR treatment was well-tolerated and that it significantly reduced the number of days of mucositis, peak level of mucositis, days requiring morphine, dose of morphine, and days to reach absolute neutrophil count in patients receiving HSCT.3 There was no difference between autologous and allogeneic HSCT patients. Another study concluded the effectiveness of SCPR in the treatment of mucositis in HSCT patients.7,8 However, SCPRs have not been universally effective. A recent study found no difference in mucositis-related parameters whether SCPR was used or not used.9

We compared our results with a historical control arm study; this study had assessed the effectiveness of recombinant human keratinocyte growth factor in prevention of oral mucositis.6 Results from the study showed significant reductions in the incidence, duration of oral mucositis, duration of analgesics used, total parenteral nutrition used, hospitalization, and engraftment in the palifermin versus control group. However, the combination of multiple interventions in patients receiving Caphosol (EUSA Pharma, Hemel Hempstead, UK) and the use of an active agent (fluoride rinse) in the control group made it difficult to demonstrate that the benefit was due to Caphosol.

In our study, we found a greater incidence of oral mucositis in the myeloma patients in our study group versus other indications for autologous stem cell transplant. Another study documented higher incidences in lymphoma patients conditioned with the BEAM (carmustine + etoposide + cytarabine + melphalan) regimen.12

The degree and extent of oral mucositis appear to depend on some demographic factors, such as age, sex, and weight.12 Studies have shown incidences in older age groups (> 50 years old)13 and in younger age groups (< 20 years old). Wildes and associates showed that frequency of comorbidities, neutrophil engraftment, platelet engraftment, CD34-positive cell doses, and frequency of other grade 3/4 toxicities were similar in patients more than 60 years and less than 60 years old. Development of grade 3/4 mucositis and days to platelet count > 50,000 mm3 were longer for older age groups than younger ones.12

Mucositis often leads to viral, bacterial, and fungal infections. In our study, bacterial (83%), viral (10.5%), and fungal (5.2%) infections were seen, with gram-negative infections higher than gram-positive infections. Escherichia coli were recorded as the predominant gram-negative organism in both groups of autologous and allogeneic transplant patients. Allogeneic HSCT patients had higher incidence of gram-negative infections than auto­logous HSCT patients. In a study by Shah and associates, major infections were bacterial infections in allogeneic and in autologous patients.14 Similarly, higher incidences of gram-negative infections were documented by another Indian study.15

Our study results are not similar to some other studies.2,8 Major reasons could be the smaller sample size in other studies and different definition and grading of mucositis in these studies. Our patients received only SCPR and betadine mouth gargles. Others studies have used various agents along with SCPR, including fluoride rinses, palifermin, and cryotherapy. It is therefore difficult to pinpoint efficacy to 1 particular agent. A major limitation of our study is the absence of a control group.

Based on the results presented here, we have now stopped using SCPR in our patients. This study has resulted in financial savings of 15 600 Indian rupees (233 US dollars) per patient due to stopping the 4 times/day mouth rinse.

Conclusions

Supersaturated calcium phosphate rinses were ineffective in the management of mucositis associated with autologous and allogeneic bone marrow transplant.


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Volume : 15
Issue : 5
Pages : 567 - 570
DOI : 10.6002/ect.2016.0180


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From the 1Delhi Institute of Pharmaceutical Science and Research Delhi University; the 2Division of Hematology and Bone Marrow Transplantation, Max Superspeciality Hospital; and the 3CR Department, Delhi Institute of Pharmaceutical Science and Research, Delhi University, Government of NCT of Delhi, India
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare. We thank Dr. Mansi Sachdev for her help in data collection.
Corresponding author: Rahul Naithani, Hematology & Bone Marrow Transplantation, Max Superspeciality Hospital, Delhi, India
Phone: +91 11 4303 3333
E-mail: dr_rahul6@hotmail.com