Effectiveness Not Established

Folinic Acid

for Mucositis

Folinic acid is a form of vitamin B that has vitamin activity like folic acid. It is a coenzyme in many metabolic reactions. Systemic and local administration of folinic acid have been examined in patients with cancer for prevention of oral mucositis.

Research Evidence Summaries

Sugita, J., Matsushita, T., Kashiwazaki, H., Kosugi, M., Takahashi, S., Wakasa, K., … Imamura, M. (2011). Efficacy of folinic acid in preventing oral mucositis in allogeneic hematopoietic stem cell transplant patients receiving MTX as prophylaxis for GVHD. Bone Marrow Transplantation, 47, 258–264.

Study Purpose

To assess the efficacy of folinic acid administration post-methotrexate treatment for graft-versus-host disease (GVHD) prophyllaxis on the incidence of oral mucositis and acute GVHD

Intervention Characteristics/Basic Study Process

A retrospective analysis of 118 consecutive patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) and received methotrexate (MTX) for GVHD prophylaxis between March 2006 and December 2009. Systemic folinic acid (given at the same dose as used for methotrexate administration on additional days of treatment) and folinic acid mouthwash (13% folinic acid 4 times per day on days 1–7) were given according to physician discretion.

Sample Characteristics

  • The sample consisted of 118 patients with an age range of 17–68 years.
  • The sample was 52% male and 48% female.
  • Patient diagnoses were acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), adult t-cell leukemia/lymphoma (ATLL), multiple myeloma (MM), AA amyloidosis, and mycosis fungoides (MF) undergoing HSCT.


The study was conducted at a single site in the Stem Cell Transplant Center of Hokkaido University Hospital in Japan.

Phase of Care and Clinical Applications

Patients were underoing the active treatment phase of care.

Study Design

The study was a retrospective analysis of 118 consecutive patients between March 2006 and December 2009.

Measurement Instruments/Methods

The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used.


The incidence of oral mucositis (p = 0.00063) and severe oral mucositis (grade 3 or 4) was significantly lower in patients who received systemic folinic acid than in those that did not (p = 0.0005). Oral mucositis occurred in 77.1% of patients, and grade 3-4 mucositits occurred in 31.4%. No significant difference was found in the incidence of acute GVHD on day 100 post-transplant between the systemic folinic acid and non-folinic groups. Oral mucositis did not correlate with the development of severe GVHD, and no significant differences were found in the incidence of relapse between the two groups. Multivariate analysis showed that the odds of developing severe oral mucositis was significantly associated with a longer duration of severe neutropenia (> 21 days) (OR 4.78, p = 0.0019) and systemic folinic acid administration (OR 0.13, p = 0.014).


Folinic acid administration reduced the incidence of severe oral mucositis. The strongest association with the development of severe oral mucositis was longer duration of severe neutropenia.


  • No appropriate control group was included.
  • Use of systemic folinic acid was random, based on physician preference.
  • Use of folinic acid mouthwash was also random (approximately 50%), and it was not known if it was used with the systemic or not.

Nursing Implications

Further randomized controlled studies are needed to assess the efficacy of systemic folinic acid plus or minus folinic acid mouthwash. Further studies are also needed to clarify the cost effectiveness of this treatment regimen. Findings suggest that prolonged severe neutropenia is an important factor in the development of severe oral mucositis.