Palifermin (Kepivance)

Number: 0851

Policy

Aetna considers palifermin (Kepivance) medically necessary for the prevention and treatment of severe oral mucositis in members with hematologic malignancies receiving myelotoxic therapy and requiring hematopoietic cell transplantation, using preparative regimens predicted to result in World Health Organization (WHO) grade 3 or 4 oral mucositis (see Appendix) in the majority of persons.

Aetna considers continuation of palifermin (Kepivance) medically necessary for members with oral mucositis meeting initial selection criteria who have experienced benefit from therapy.

Aetna considers palifermin experimental and investigational for the following indications: (not an all-inclusive list):

  • Inhibition of graft-versus-host disease in persons undergoing hematopoietic stem cell transplantation
  • Mitigation of dysphagia in persons with lung cancer treated with concurrent chemoradiotherapy
  • Prevention and treatment of high-dose methotrexate (HDMTX) induced oral mucositis in member not undergoing or planning a hematopoietic stem cell transplantation
  • Prevention of dry mouth and salivary gland dysfunction following radiotherapy
  • Treatment of acute graft-versus-host disease following hematopoietic stem cell transplantation
  • Treatment of alimentary/gastrointestinal mucositis
  • Treatment of caustic esophageal burns
  • Treatment of chemotherapy induced oral mucositis in children who are not undergoing a hematopoietic stem cell transplant.

Dosing Recommendations

  • Kepivance (palifermin) is available for injection as 6.25 mg lyophilized powder in single-dose vials for intravenous use.
  • The recommended dose of Kepivance is 60 mcg/kg/day, administered as an intravenous bolus injection for 3 consecutive days before and 3 consecutive days after myelotoxic therapy for a total of 6 doses.

    • Administer the first 3 doses prior to myelotoxic therapy with the third dose 24 to 48 hours before myelotoxic therapy.
    • Administer the last 3 doses after myelotoxic therapy is complete with the first of these doses on the day of hematopoietic stem cell infusion after the infusion is completed, and at least 7 days after the most recent administration of Kepivance.

Source: Swedish Orphan Biovitrum, 2020

Background

U.S. Food and Drug Administration (FDA)-Approved Indications:

  • Kepivance is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of autologous hematopoietic stem cell support. Kepivance is indicated as supportive care for preparative regimens predicted to result in ≥ WHO Grade 3 mucositis in the majority of patients (Swedish Orphan Biovitrum, 2020).

    • Limitations of use:

      • The safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies
      • Kepivance is not effective in decreasing the incidence of severe mucositis in patients with hematologic malignancies receiving myelotoxic therapy in the setting of allogenic hematopoietic stem cell support.
      • Kepivance is not recommended for use with melphalan 200 mg/m2 as a conditioning regimen (Swedish Orphan Biovitrum, 2020).

Effective oral hygiene, appropriate analgesia, oral cryotherapy, infection management and parenteral nutrition are considered to be standard of care for oral mucositis.

Guidelines from the European Society for Medical Oncology (Peterson et al, 2011) stated that palifermin is recommended in a dose of 60 ug/kg/day for 3 days before conditioning treatment and for 3 days post-transplant for the prevention of oral mucositis in patients with hematological malignancies receiving high-dose chemotherapy (HDC) and total body irradiation (TBI) with autologous stem cell transplantation.

Guidelines from the American Society for Clinical Oncology (ASCO, 2008) stated that palifermin is recommended for use in patients undergoing autologous stem-cell transplantation for a hematologic malignancy with a TBI conditioning regimen to decrease the incidence of severe mucositis.  The ASCO guidelines stated that there are insufficient data to recommend the routine use of palifermin for patients undergoing autologous stem-cell transplantation for a hematologic malignancy where the conditioning regimen is chemotherapy only.  The ASCO guidelines also stated that palifermin may be considered for use in patients undergoing myeloablative allogeneic hematopoietic stem-cell transplantation with a TBI-based conditioning regimen; there are insufficient data to recommend its use in myeloablative conditioning regimens consisting of chemotherapy alone in this setting.  The ASCO guidelines stated that palifermin should be administered intravenously at 60 ug/kg daily for 3 days preceding the start of the conditioning regimen and 60 ug/kg daily for 3 days beginning on the day of stem-cell infusion; it should not be administered within 24 hours of the initiation of the conditioning regimen.

ASCO guidelines stated that there are insufficient data to recommend the use of palifermin in the non–stem-cell transplantation setting, or for use in the treatment of solid tumors.

Bradstock et al (2014) noted that gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukemia (AML) and contributes substantially to treatment-related mortality.  In a placebo-controlled randomized trial, these investigators evaluated the effectiveness of palifermin (given intravenously at 60 μg/kg per/day for 3 days before and after chemotherapy) for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide.  Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study end-point) between the 2 treatment arms (3 in palifermin arm (4 %), 8 in placebo arm (10 %; p = 0.21); however, when considering the severity of oral mucositis (WHO grade 0 to 4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (p = 0.0007, test for trend).  There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21 % versus 44 % in placebo arm; p = 0.003), mainly due to a reduction in severe diarrhea (8 % palifermin, 26 % placebo; p = 0.01).  The authors concluded that palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy.

The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO)s clinical practice guidelines on "The management of mucositis secondary to cancer therapy" (Lalla et al, 2014) recommended that palifermin be used to prevent oral mucositis (at a dose of 60 µg/kg per day for 3 days prior to conditioning treatment and for 3 days after transplant) in patients receiving HDC and TBI, followed by autologous stem cell transplantation, for a hematological malignancy.

Experimental Indications

Vadhan-Raj et al (2013) noted that mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment.  It can have a negative impact on both QOL and health economics.  Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parenteral nutrition, suboptimal delivery of anti-neoplastic treatment, and morbidity and mortality.  Palifermin is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing HSCT.  Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high-risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer.  The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient-reported outcome in multiple studies.  The clinical response to palifermin appears to be related in part to epithelial proliferation and mucosal thickening.  Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft-versus-host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT.  Palifermin is generally well-tolerated with mild-to-moderate skin and oral adverse events.  The authors concluded that future studies may expand the use of palifermin into other areas that would benefit from its cyto-protective and regenerative effects.

Saber and colleagues (2016) stated that clinical trials evaluating palifermin have enrolled few pediatric patients, precluding safety analyses in large groups of children. These researchers compared hematopoietic cell transplantation (HCT) outcomes among pediatric patients who did or did not receive palifermin as a preventive treatment for oral mucositis.  Pediatric patients and controls, matched for HCT and donor type, disease, disease status, and age, were selected from the Center for International Blood and Marrow Transplant Research database and a 1:3 matched cohort analysis was performed.  Stratified Cox proportional hazards models were built and propensity score adjustments were used to compare overall survival (OS) and disease-free survival (DFS) outcomes between palifermin-treated and untreated patients; 3 controls were identified for 90 % of palifermin recipients.  The remaining cases were matched with 2 (8 %) controls or 1 (2 %) control, for a total of 210 palifermin-treated patients matched with 606 controls.  Median follow-up was 31 months in cases and 36 months in controls; 57 % of patients underwent allogeneic HCT, mostly for acute leukemia, and 43 % underwent autologous HCT, mostly for solid tumors.  In univariate analyses, 2-year OS and DFS rates after allogeneic HCT (58 % versus 66 %, p = 0.109; 49 % versus 60 %, p = 0.06) and after autologous HCT (73 % versus 77 %, p = 0.474; 60 % versus 64 %, p = 0.637) were similar between palifermin-treated patients and matched controls.  In multivariate analysis, palifermin treatment did not significantly increase the risk of mortality (relative risk [RR], 1.20; 95 % confidence interval [CI]: 0.87 to 1.66) or of relapse (RR, 1.12; 95 % CI: 0.78 to 1.62) compared with matched controls.  No significant differences in rates of acute or chronic graft-versus-host disease (GVHD) were observed between palifermin-treated patients and matched controls.  Among pediatric patients undergoing HCT, OS, DFS, neutrophil recovery, and GVHD rates were similar between palifermin-treated patients and matched controls.

Alimentary/Gastrointestinal Mucositis

Herbers et al (2014) reported that the matched-control study failed to show a clinical relevant impact of palifermin on intestinal mucositis, although there was a reduced inflammatory response and less febrile neutropenia among patients who had no bacteremia.

Wardill et al (2014) stated that chemotherapy-induced alimentary (gastrointestinal) mucositis is an extremely common condition that is caused by a breakdown of the mucosal barrier.  It occurs in between 40 to 100 % of cancer patients depending on the treatment regimen.  Symptoms typically include pain from oral ulceration, vomiting and diarrhea.  Alimentary mucositis often necessitates chemotherapy reductions or treatment breaks, overall potentially compromising survival outcomes.  Consequently, alimentary mucositis creates a burden not only on patients' quality of life (QOL) but also on healthcare costs.  Despite this, currently, there is no clinically effective localized/pharmacological therapy intervention strategy to prevent alimentary mucositis.  Over recent years, a number of novel pharmacotherapy agents have been trialed in various pre-clinical and clinical settings.  These researchers provided an overview of emerging pharmacotherapies for the treatment of alimentary mucositis following chemotherapy with particular emphasis on studies published in the last 2 years.  A PubMed literature search was conducted to identify eligible articles published before November 30, 2013 and each article was reviewed by all authors.  All articles were written in English.  The authors concluded that currently, there is no clinically effective localized therapeutic intervention strategy to prevent the condition.  New emerging areas of research have recently been proposed to play key roles in the development of alimentary mucositis and these areas may provide researchers and clinicians with new research directions.  Hopefully this will continue, and evidence-based informed guidelines can be produced to improve clinical practice management of this condition.

Caustic Esophageal Burns

Numanoglu et al (2014) noted that current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory.  These researchers investigated the effectiveness of palifermin for the prevention of stricture development following esophageal caustic injuries in a rat model.  A total of 32 female Wistar albino rats were divided into 4 groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups.  An experimental corrosive esophageal burn model was established in the B, S and S/P groups.  Weight gain was recorded and histopathological evaluation was performed for each group.  Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed.  In addition, statistically significant differences in weight gain were observed between the S/P group and the B group.  Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group.  In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group.  Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group.  The stenosis indexes in the C and S groups were significantly lower compared with the B group.  In addition, the stenosis index in the S/P group was significantly lower compared with the S group.  The authors concluded that the present study was the first to investigate the effect of palifermin on corrosive esophageal burns.  The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats.

Prevention and Treatment of Oral Mucositis from High-Dose Methotrexate (HDMTX)

Schmidt et al (2008) stated that oral mucositis is a frequent problem after high-dose methotrexate (HD-MTX), impairing patient's quality of life, leading to higher rates of infections and delaying subsequent chemotherapy. This report describes the effect of palifermin in patients treated within the GMALL-B-ALL 2002 protocol containing HD-MTX who developed a severe mucositis in cycle A1/B1. Ten patients, all with World Health Organization grades III-IV oral mucositis in cycles A1/B1, obtained palifermin with subsequent similar or identical cycles to reduce mucositis. Thus, patients serve as their own control for efficacy of palifermin. All 10 patients developed grades III-IV mucositis in cycles A1/B1 without palifermin, whereas only two of 10 developed grades III-IV mucositis in corresponding cycles A2/B2 with palifermin. Only four of 10 patients showed infections in the cycles with palifermin compared with 10 of 10 patients without palifermin. The duration of mucositits in patients who acquired a higher grade mucositis despite treatment with palifermin could be reduced from 12.9 days (median) without to 11 days with palifermin. The amount of i.v. opioid analgetics could be significantly reduced. The authors concluded that palifermin might reduce the incidence, severeness and duration of oral mucositis in HD-MTX-based chemotherapy and may influence clinical sequelae such as infection and quality of life.

Howard et al. (2016) stated high-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. The authors state that palifermin, a recombinant human keratinocyte growth factor that stimulates growth of epithelial cells, reduces the incidence of mucositis after HDMTX. However, even though interventions to prevent and treat mucositis have recently been reviewed, none is considered standard practice in patients receiving HDMTX.

Prevention of Dry Mouth and Salivary Gland Dysfunction Following Radiotherapy

In a Cochrane review, Riley and colleagues (2017) evaluated the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction.  Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to September 14, 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched September 14, 2016); MEDLINE Ovid (1946 to September 14, 2016); Embase Ovid (1980 to September 14, 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to September 14, 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to September 14, 2016); Zetoc Conference Proceedings (1993 to September 14, 2016); and OpenGrey (1997 to September 14, 2016).  These investigators searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials.  No restrictions were placed on the language or date of publication when searching the electronic databases.  These researchers included randomized controlled trials (RCTs), irrespective of their language of publication or publication status.  Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region.  Participants could be out-patients or in-patients.  They included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention.  Comparisons of radiation techniques were excluded.  The authors used standard methodological procedures expected by Cochrane.  They included 39 studies that randomized 3,520 participants; the number of participants analyzed varied by outcome and time-point.  The studies were ordered into 14 separate comparisons with meta-analysis only being possible in 3 of those.  These researchers found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (RR 0.35, 95 % CI: 0.19 to 0.67; p = 0.001, 3 studies, 119 participants), and up to 3 months after radiotherapy (RR 0.66, 95 % CI: 0.48 to 0.92; p = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95 % CI: 0.40 to 1.23; p = 0.21, 7 studies, 682 participants).  These investigators found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95 % CI: 0.09 to 0.55; p = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95 % CI: 1.13 to 1.86; p = 0.004, 1 study, 175 participants).  However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates.  There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures.  There was some very low-quality evidence of a small benefit for amifostine in terms of QOL (10-point scale) at 12 months after radiotherapy (MD 0.70, 95 % CI: 0.20 to 1.20; p = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to 3months post-radiotherapy.  A further study showed no evidence of a difference at 6, 12, 18 and 24 months post-radiotherapy.  There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95 % CI: 2.87 to 8.38; p < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95 % CI: 2.84 to 29.83; p = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95 % CI: 1.81 to 3.74; p < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95 % CI: 1.40 to 40.39; p = 0.02, 3 studies, 524 participants).  These investigators found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and QOL.  There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95 % CI: 1.43 to 6.22; p = 0.004, 5 studies, 389 participants).  These researchers found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.  There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, anti-septic mouth-rinse, anti-microbial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin).  The authors concluded that there was some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (3 months post-radiotherapy).  However, it is less clear whether or not this effect is sustained to 12 months post-radiotherapy.  The benefits of amifostine should be weighed against its high cost and side effects.  There was insufficient evidence to show that any other intervention is beneficial.

Treatment of Oral Mucositis in Non-Hematopoietic Stem Cell Transplant Children Receiving Chemotherapy

Liu and colleagues (2017) stated that palifermin has been proven to decrease the frequency of severe oral mucositis in adult patients with sarcoma and metastatic colorectal cancer receiving chemotherapy.  The impact of palifermin on the incidence of mucositis in non- HSCT pediatric population receiving chemotherapy has never been reported to-date.  This was a retrospective analysis of pediatric patients who received palifermin as secondary prophylaxis to prevent chemotherapy-induced mucositis at Memorial Sloan Kettering Cancer Center from January 1, 2008 to 2014.  Data from electronic medical records on days to mucositis resolution, use of opioids, use of total parenteral nutrition, duration of hospitalization, and antibiotics were collected and presented.  A total of 18 patients received palifermin for secondary prophylaxis after developing mucositis from the prior chemotherapy cycle.  Mucositis did not reoccur in the subsequent cycle for 13 of the 18 patients.  The majority of patients who received palifermin prophylaxis had decreased opioids and antibiotics use and decreased duration of hospitalization; 6 of the 7 patients previously requiring total parenteral nutrition due to mucositis had decreased supplemental nutritional needs following the use of palifermin.  The authors concluded that palifermin may provide benefit as secondary prophylaxis in pediatric patients to prevent chemotherapy-induced mucositis.  These preliminary findings need to be validated by well-designed studies.

Treatment of Acute Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation

In a meta-analysis, Mozaffari and colleagues (2017) evaluated the efficacy of palifermin after HSCT on the incidence and severity of oral mucositis (OM) or acute graft-versus-host disease (aGVHD) in hematologic malignancy patients in RCTs.  These investigators compared the efficacy of palifermin on adverse events (AEs), OM and aGVHD compared with placebo; they searched databases of PubMed/Medline, Web of Science and Cochrane Library for RCTs based on a number of criteria.  There was no difference observed in the incidence of OM and aGVHD between 2 groups.  The subgroup analysis didn't show significant differences in 2 groups for aGVHD grade 2 to 4 (odds ratio [OR] = 1.54, 95 % CI: 0.70 to 3.39, p = 0.28), aGVHD grade 3 to 4 (OR = 0.97, 95 % CI: 0.48 to 1.94, p = 0.92), OM grade 2 to 4 (OR = 0.76, 95 % CI: 0.42 to 1.38, p = 0.37) and OM grade 3 to 4 (OR = 0.54, 95 % CI: 0.25 to 1.15, p = 0.11], but erythema as an AE in palifermin group was higher than placebo group (OR = 1.86, 95 % CI: 1.10 to 3.15, p = 0.02].  The authors concluded that this meta-analysis of 6 clinical trials found no statistically significant difference in OM and aGVHD grades in patients receiving 60 μg/kg/day dose of palifermin compared with those receiving a placebo. However, oral mucosal erythema was more prevalent among patients receiving palifermin than patients receiving a placebo.

Appendix

Table: WHO Classification of Oral Mucositis
Grade 0 No oral mucositis
Grade 1 Soreness =/1 erythema
Grade 2 Erythema and ulcers
Grade 3 Extensive erythema, ulcers and inability to swallow solid food
Grade 4 Mucositis that prevents any form of alimentation, including swallowing liquids

Routine Oral Hygiene Care After Cancer Therapy

  • Toothbrushing (Note: Electric and ultrasonic toothbrushes are acceptable if the patient is capable of using them without causing trauma.)

  • Soft Nylon-Bristled Brush (2 to 3 rows)

    • Brush 2 to 3 times daily with Bass sulcular scrub method
    • Rinse frequently
    • Foam toothbrushes:

      • Use only when use of a regular toothbrush is not feasible
      • Use with anti-microbial rinses when routine brushing and flossing are not possible
      • Brush teeth 2 to 3 times a day
      • Rinse frequently
         
  • Dentifrice:

      • Patient preference as tolerated

        • (Note: Non-mint-flavored products are typically better tolerated than mint-flavored products when oral mucositis or oral graft-versus-host disease [GVHD] is present).

    • Fluoride recommended
    • Use 0.9 % saline or water if toothpaste causes irritation
       
  • Flossing:

    • Once daily
    • Atraumatic technique with modifications as needed
       
  • Bland Rinses:

      • Varieties:

        • 0.9 % saline
        • Sodium bicarbonate solution
        • 0.9 % saline plus sodium bicarbonate solution 

    • Use 8 to 12 oz of rinse, hold a mouthful, and expectorate until total volume is used; repeat every 2 to 4 hours or as needed to ameliorate discomfort.

  • Fluoride:

    • 1.1 % neutral sodium fluoride gel
    • 0.4 % stannous fluoride gel
    • Brush on gel for 2 to 3 minutes
    • Expectorate and rinse mouth gently
    • Apply once a day
       
  • Topical Anti-Microbial Rinses:

    • 0.12 % to 0.2 % chlorhexidine oral rinse for management of acute gingival lesions
    • Povidone iodine oral rinse
    • Rinse, hold 1 to 2 minutes, expectorate
    • Repeat 2 to 4 times a day depending on severity of periodontal disease  

Source: National Cancer Institute, 2016

Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy

  • Minimize denture use during first 3 to 4 weeks post-transplant

    • Wear dentures only when eating
    • Discontinue use at all other times
       
  • Clean twice a day with a soft brush and rinse well
  • Soak in anti-microbial solutions when not being worn
  • Perform routine oral mucosal care procedures 3 to 4 times a day with the oral appliances out of the mouth
  • Leave appliances out of mouth when sleeping and during periods of significant mouth soreness
  • Dentures may be used to hold medications needed for oral care (e.g., anti-fungals).
  • Discontinue use of removable appliances until oral mucositis has healed
  • Remove orthodontic appliances (e.g., brackets, wires, retainers) before conditioning. 
Source: National Cancer Institute, 2016

Mucositis Management

Bland Rinses

  • 0.9 % saline solution
  • Sodium bicarbonate solution
  • 0.9 % saline/sodium bicarbonate solution

Topical Anesthetics

  • Lidocaine: viscous, ointments, sprays
  • Benzocaine: sprays, gels
  • 0.5 % or 1.0 % dyclonine hydrochloride (HCl)
  • Diphenhydramine solution

Mucosal Coating Agents

  • Amphojel
  • Kaopectate
  • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin)
  • Gelclair (approved by the U.S. FDA as a device)

Analgesics

  • Benzydamine HCl topical rinse (not approved in the United States)
  • Opioid drugs: oral, intravenous (IV) (e.g., bolus, continuous infusion, patient-controlled analgesia [PCA]), patches, transmucosal.

Growth factor (keratinocyte growth factor-1):

  • Palifermin (approved by the FDA in December 2004 to decrease the incidence and duration of severe oral mucositis in patients undergoing high-dose chemotherapy with or without radiation therapy followed by bone marrow transplant for hematologic cancers).
Source: National Cancer Institute, 2016

Summary of Clinical Practice Guidelines for Care of Patients with Oral Mucositis

Basic Oral Care and Good Clinical Practices

  1. The panel suggests multi-disciplinary development and evaluation of oral care protocols, and patient and staff education in the use of such protocols to reduce the severity of oral mucositis from chemotherapy and/or radiation therapy (Level III evidence, grade B suggestion).  As part of the protocols, the panel suggests the use of a soft toothbrush that is replaced on a regular basis.  Elements of good clinical practice should include the use of validated tools to regularly assess oral pain and oral cavity health.  The inclusion of dental professionals is vital throughout the treatment and follow-up phases.

  2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT (Level 1 evidence, grade A recommendation).  Regular oral pain assessment using validated instruments for self-reporting is essential.

Radiotherapy: Prevention

  1. The panel recommends the use of midline radiation blocks and 3-dimensional radiation treatment to reduce mucosal injury.  (Level 2 evidence, grade B recommendation)

  2. The panel recommends benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy.  (Level I evidence, grade A recommendation)

  3. The panel recommends that chlorhexidine not be used to prevent oral mucositis in patients with solid tumors of the head and neck who are undergoing radiotherapy.  (Level II evidence, grade B recommendation)

  4. The panel recommends that anti-microbial lozenges not be used for the prevention of radiation-induced oral mucositis.  (Level II evidence, grade B recommendation)

Radiotherapy: Treatment

  1. The panel recommends that sucralfate not be used for the treatment of radiation-induced oral mucositis.  (Level II evidence, grade A recommendation)

Standard-Dose Chemotherapy Prevention

  1. The panel recommends that patients receiving bolus 5-fluorouracil (5-FU) chemotherapy undergo 30 minutes of oral cryotherapy to prevent oral mucositis.  (Level II evidence, grade A recommendation)

  2. The panel suggests the use of 20 to 30 minutes of oral cryotherapy to decrease mucositis in patients treated with bolus doses of edatrexate.  (Level IV evidence, grade B suggestion)

  3. The panel recommends that acyclovir and its analogues not be used routinely to prevent mucositis.  (Level II evidence, grade B recommendation)

Standard-Dose Chemotherapy: Treatment

  1. The panel suggests that chlorhexidine not be used to treat established oral mucositis.  (Level III evidence, grade C recommendation)

High-Dose Chemotherapy With or Without Total Body Irradiation Plus HCST: Prevention

  1. In patients with hematologic malignancies who are receiving HDC and TBI with autologous stem cell transplantation, the panel recommends the use of keratinocyte growth factor-1 (palifermin) in a dose of 60 micrograms/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplantation for the prevention of oral mucositis.  (Level 1 evidence, grade A recommendation)

  2. The panel suggests the use of cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan.  (Level II evidence, grade A recommendation)

  3. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT.  (Level II evidence, grade B recommendation) 

  4. The panel suggests that granulocyte macrophage colony-stimulating factor (GM-CSF) mouthwashes not be used for the prevention of oral mucositis in patients undergoing HSCT.  (Level II evidence, grade C recommendation)

  5. The panel suggests the use of low-level laser therapy (LLLT) to reduce the incidence of oral mucositis and its associated pain in patients receiving HDC or chemoradiotherapy before HSCT if the treatment center is able to support the necessary technology and training, because LLLT requires expensive equipment and specialized training.  Because of inter-operator variability, clinical trials are difficult to conduct, and their results are difficult to compare; nevertheless, the panel is encouraged by the accumulating evidence in support of LLLT.  (Level II evidence, grade B recommendation)

Key: HSCT: hematopoietic stem cell transplantation; 5-FU: 5-fluorouracil; TBI: total-body irradiation; LLLT: low-level laser therapy.

Source: Lalla et al., 2014

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

Other CPT codes related to the CPB :

38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241     autologous transplantation
38242     HPC boost

HCPCS codes covered if selection criteria are met:

J2425 Injection, palifermin, 50 micrograms

Other HCPCS codes related to the CPB:

J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg

ICD-10 codes covered if selection criteria are met:

C81.00 - C88.9 Malignant neoplasm of lymphatic and hematopoietic tissue [in members with hematologic malignancies undergoing high-dose chemotherapy requiring hematopoietic cell transplantation, using preparative regimens predicted to result in WHO grade 3 or 4 oral mucositis]
K12.31 Oral mucositis (ulcerative) due to antineoplastic therapy

ICD-10 codes not covered for indications listed in the CPB:

D89.810 Acute graft-versus-host disease
K11.9 Disease of salivary gland, unspecified [following radiotherapy]
R68.2 Dry mouth, unspecified [following radiotherapy]
T66.xxxA - T66xxxS Radiation sickness, unspecified [following radiotherapy]

The above policy is based on the following references:

  1. American Society of Clinical Oncology 2008 clinical practice guideline update summary: Use of chemotherapy and radiation therapy protectants. JOP. 2008;4(6):277-279.
  2. Amgen, Inc. Kepivance (palifermin) for injection, for intravenous use. Prescribing Information. Thousand Oaks, CA: Amgen; January 2010.
  3. Bradstock KF, Link E, Collins M, et al; Australasian Leukaemia and Lymphoma Group. A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia. Br J Haematol. 2014;167(5):618-625.
  4. Chaveli-Lopez B, Bagan-Sebastian JV. Treatment of oral mucositis due to chemotherapy. J Clin Exp Dent. 2016;8(2):e201-e209.
  5. Herbers AH, van der Velden WJ, de Haan AF, et al. Impact of palifermin on intestinal mucositis of HSCT recipients after BEAM. Bone Marrow Transplant. 2014;49(1):8-10.
  6. Howard SC, McCormick J, Pui CH, et al. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist. 2016;21(12):1471-1482.
  7. Lalla RV, Bowen J, Barasch A, et al; Mucositis Guidelines Leadership Group of the MASCC/ISOO [trunc]. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120(10):1453-1461.
  8. Liu D, Seyboth B, Mathew S, et al. Retrospective evaluation of palifermin use in nonhematopoietic stem cell transplant pediatric patients. J Pediatr Hematol Oncol. 2017 y;39(4):e177-e182. 
  9. Mozaffari HR, Payandeh M, Ramezani M, et al. Efficacy of palifermin on oral mucositis and acute GVHD after hematopoietic stem cell transplantation (HSCT) in hematology malignancy patients: A meta-analysis of trials. Contemp Oncol (Pozn). 2017;21(4):299-305.
  10. National Cancer Institute (NCI), Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ®): Health Professional Version. Bethesda, MD: NCI; updated December 16, 2016. 
  11. Numanoglu KV, Tatli D, Bektas S, Er E. Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns. Exp Ther Med. 2014;8(4):1087-1091.
  12. Peterson DE, Bensadoun R-J, Roila F. Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22 (Suppl 6): vi78-vi84.
  13. Riley P, Glenny AM, Hua F, Worthington HV. Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy. Cochrane Database Syst Rev. 2017;7:CD012744.
  14. Saber W, Zhang MJ, Steinert P, et al. The impact of palifermin use on hematopoietic cell transplant outcomes in children. Biol Blood Marrow Transplant. 2016;22(8):1460-1466.
  15. Schmidt E, Thoennissen NH, Rudat A, et al. Use of palifermin for the prevention of high-dose methotrexate-induced oral mucositis. Ann Oncol. 2008;19(9):1644-9.
  16. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351(25):2590-2598.
  17. Swedish Orphan Biovitrum. Kepivance (palifermin) for injection, for intravenous use. Prescribing Information. Stockholm, Sweden: Swedish Orphan Biovitrum; revised July 2016.
  18. Swedish Orphan Biovitrum. Kepivance (palifermin) for injection, for intravenous use. Prescribing Information. Stockholm, Sweden: Swedish Orphan Biovitrum; revised April 2020.
  19. Vadhan-Raj S, Goldberg JD, Perales MA, et al. Clinical applications of palifermin: Amelioration of oral mucositis and other potential indications. J Cell Mol Med. 2013;17(11):1371-1384.
  20. Wardill HR, Bowen JM, Gibson RJ. New pharmacotherapy options for chemotherapy-induced alimentary mucositis. Expert Opin Biol Ther. 2014;14(3):347-354