Palifermin with High-Dose Chemotherapy and/or Hematopoietic Cell Transplantation

To evaluate the evidence supporting the use of palifermin for its approved indication in patients undergoing hematopoietic stem cell transplantation (HSCT) for hematologic maligancies, and for other populations at risk of oral mucositis

• Databases searched were MEDLINEand PubMed. Also, meeting abstracts for American Society of Clinical Oncology (ASCO) and American Society for Therapeutic Radiology and Oncology (ASTRO) were searched using the keywords mucositis and palifermin.
• Search keywords were oral mucositis, palifermin, and keratinocyte growth factor (KGF).
• Studies were included if they involved only human clinical trials.
• Studies were excluded if they were reviews or preclinical studies.

A total of 100 papers and four abstracts were retrieved. Full papers were used. Studies with level 2 or higher clinical evidence, studies that were not randomized clinical trials (RCTs), case reports, and economic evidence also were used.

• A total of 12 papers and three abstracts were included in the final review.
• The review did not discuss the samples.
• Patients had hematologic malignancies and planned to receive conditioning regimen for an autologous or allogenic HSCT, cycled chemotherapy for the treatment of solid tumors, or radiation therapy with concomitant chemotherapy for the treatment of cancers of the head and neck.

The evidence review supported palefermin use in the amelioration of oral mucositis. Palifermin was associated with a reduced need for opioid analgesics, reduced risk of febrile neutropenia, reduced need for total parenteral nutrition (TPN), improved patient‐reported function, and reduced hospital stay. In addition, palifermin was associated with a decrease in the costs of mucositis-associated complications in autologus HSCT recepients. It must be noted that the this was not a decrease in costs associated with mucositis‐associated complications, but a decrease in costs because of the lower incidence of adverse outcomes in patients treated with palifermin.

Palefermin is effective in the treatment of mucositis and the need to receive mucotoxic conditioning regimens in preparation for HSCT.

RCTs are needed to investigate the benefits of palifermin in patients who are not diagnosed with head and neck cancer, as the risk of significant mucositis is unpredictable in these patients. Also, concerns exist that palifermin has the potential to stimulate primary or secondary tumor growth.

Databases searched were MEDLINE, EMBASE, and CINAHL (1966–2004). 

Search keywords were [neoplasms] AND [(mucositis OR stomatitis)] AND [limit to (clinical trial OR randomized-controlled trials)]. 

Studies were included in the review if they were

• Published in English.
• Were aimed at the prevention of mucositis in patients undergoing head and neck radiation, chemotherapy, or chemoradiation.

The search yielded 109 publications. Of these, five were not aimed at prevention, 13 were nonrandomized, and 29 did not contain data in a comprehensive form. Seventeen articles stood alone in terms of intervention, and 45 articles included meta-analyses. Studies with zero or infinite odds ratios were omitted because variances could not be calculated with accuracy. Sample sizes ranged from 14–502.

Patients with various cancer diagnoses receiving chemotherapy, radiation therapy, or combination chemoradiotherapy.

Of the 27 interventions identified for the prevention of oral mucositis, meta-analysis could be performed on eight. Four interventions showed a preventive effect on the development or severity of oral mucositis: PTA (polymyxin E, tobramycine, and amphotericin B) lozenges or paste, systemic administration of granulocyte macrophage–colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), oral cooling, and amifostine.

Of 14 studies (each on a different intervention type), nine showed some positive results; however, methodological flaws (e.g., small sample sizes, lack of double-blind or placebo-controlled designs) prevented those studies from demonstrating effectiveness. One study of benzydamine (Epstein et al., 2001) showed an improved ulcer-free rate and decreased incidence of ulcer and erythema.

Palifermin demonstrated positive results for the prevention of mucositis in patients with hematologic malignancies undergoing autologous stem cell transplantation.

A systematic review of the English medical literature was performed. Only clinical trials were included in the first search, January 1966–May 2002. In the June 2002–May 2005 review, clinical and preclinical trials were included.

In the 2002 review, 35 studies were identified. In the 2005 review, 14 preclinical and 9 clinical studies were identified. Studies reporting on cytokines or growth factors for the amelioration of chemotherapy- and radiation-induced mucositis throughout the entire alimentary canal were included.

Based on the review, guidelines recommend palifermin at a dose of 60 mg/kg per day for three days prior to conditioning for hematologic malignancies receiving high-dose chemotherapy and total body irradiation (TBI) with autologous stem cell transplantation (SCT). Preliminary results indicated effectiveness for repifermin. Trials are in process for velafermin.

Two randomized studies of granulocyte colony-stimulating factor (G-CSF) showed reduction in mucositis incidence. Two cohort studies demonstrated reduced severity of mucositis. One study did not show any positive results for mucositis. Another showed that use of growth factors was not a significant determinant of oral mucositis. Two studies failed to demonstrate improvement with G-CSF in the radiation setting. Studies demonstrate conflicting results. No recommendation can be made at this time.

One cohort study with granulocyte macrophage colony-stimulating factor (GM-CSF) showed reduction in severity and duration of oral mucositis. Another study showed no effect on radiation-induced oral mucositis. Two studies showed some positive effects for radiation-induced mucositis. Studies demonstrated conflicting results. No recommendation can be made at this time. Two studies with GM-CSF mouthwash demonstrated no positive effects. The Multinational Association of Supportive Care in Cancer guideline has been updated to suggest that GM-CSF mouthwash not be used for the prevention of mucositis in the transplant setting.

For other agents, evidence was insufficient or toxicities too severe to recommend use.

To evaluate efficacy of palifermin versus placebo for prevention of oral mucositis (OM), as well as burden of patients with multiple myeloma (MM) who receive autologous stem cell transplant (SCT)

This randomized study compared three groups: (1) placebo, (2) palifermin on days -6, -5, -4, 0, 1, and 2 (pre-/post-SCT), and (3) palifermin on days 0, 1, and 2 (post-SCT). The palifermin dose was 60 µg/kg per day IV. Patients were assessed daily for OM from day 2 until day 32 or discharge.

• The study reported on 257 patients with MM.
• Median age was 57 years old with a range of 32–69 years.
• The placebo group sample was 58% male and 42% female; the group 2 sample was 55% male and 45% female; and the group 3 sample was 54% male and 46% female.
• All patients were receiving autologous SCT and high-dose melphalan.

This was a multisite, inpatient study conducted in the Netherlands.

• Patients were undergoing the active antitumor treatment phase of care. 
• This study has clinical applicability for elder care.

This was a randomized, placebo-controlled, parallel-group study.

• The World Health Organization (WHO) scale for OM, the Oral Mucocitis Daily Questionnaire, and the Quality of Life Utility Scale were used.
• Investigators recorded the use of opioids, non-opioids, days of severe OM, incidence of infections, time to absolute monocyte count (AMC) recovery, and adverse events.

• No statistically significant differences were found in maximum OM severity. Severe OM occurred in 37% of patients in the placebo group, 38% in the pre-/post-group (group 2), and 24% in the pre- group (group 3).
• No significant differences were observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in group 2 versus the placebo group (51% versus 26%).
• No significant differences were found across groups in incidence of ulcerative OM or duration of OM. Those on palifermin pre-transplant had significantly lower incidence of opioid analgesic use compared to placebo (p = 0.03).

Palifermin was unable to reduce OM or OM-related patient burden in patients with MM undergoing transplant.

• A risk of bias exists because no blinding was done.
• Unintended interventions or applicable interventions that could have influenced results were not described.
• Findings are not generalizable.
• The authors indicated that the short period of intervention time or timing of giving palifermin may have had a suboptimal effect with palifermin. The authors also suggested that hyperkeratosis may have been misinterpreted for mucositis, despite observer training in assessment.

Short term of use of palifermin for auto-SCT in patients with MM undergoing transplant was not effective in reducing OM. The fact that authors suggest that hyperkeratosis may have been incorrectly interpreted as OM suggests that correct assessment can be an issue in evaluating this symptom. Findings suggest that the specific timing of use of this agent may be critical. In using palifermin, nurses need to be aware of the appropriate timing in concert with timing of antineoplastic treatment and treatment effects.

To assess the effectiveness of palifermin in preventing mucositis in children with acute lymphocytic leukemia (ALL) undergoing chemotherapy

A clinical trial of 90 children with ALL who were randomized to receive chlorhexidine or palifermin. One group received 60 mcg/kg palifermin as an IV bolus once daily three days before and three days after chemotherapy. The other group received chlorhexidine mouthwash administered once daily three days before and three days after chemotherapy.

• N = 90   
• AGE = 5–18 years
• MALES: 44, FEMALES: 46
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: ALL 
• OTHER KEY SAMPLE CHARACTERISTICS: Induction chemotherapy protocol consisted of standard risk B-precursor ALL (COG)/dexamethasone, vincristine, L-asparaginase, intrathecal (MTN + Ara C + hydrocortisone). The intensification protocol was dexamethasone, vincristine, L-asparaginase/dexamethasone, cyclophosphamide/6-thioguanine + cytarabine + intrathecal MTX.

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Tehran, Iran

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics, palliative care 

Randomized, controlled trial

The World Health Organization (WHO) Oral Toxicity Scale was used for grading mucositis. The data were analyzed with two-way ANOVA.

The group that used the palifermin had a decreased incidence and severity of chemotherapy-induced mucositis.

Palifermin reduced oral mucositis in children with ALL.

• Small sample (< 100)
• Risk of bias (no blinding)

In this study, palifermin has reduced the severity of mucositis in children with ALL who received induction and intensification chemotherapy.

Palifermin was administered at 60 mcg/kg per day for three consecutive days before the initiation of conditioning therapy and again after graft infusion.

A group of 30 patients who had been treated with palifermin and undergone allogeneic hematopoietic stem-cell transplantation (HSCT) were retrospectively compared to a control group of 30 consecutive untreated patients receiving myeloablative conditioning.

• Median age of patients was 38 years old, with a range was 18–59 years.
• Patients had the following diagnoses.
  • Acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) (n = 40)
  • Acute lymphocytic leukemia (ALL) (n = 14)
  • Chronic myelogenous leukemia (CML) (n = 5)
  • Chronic myelomonocytic (CMML) (n = 1)
• Patients received allogeneic HSCT after CY/TBI or chemotherapy solely.
• No growth factors were given.

The study was conducted from May 2005 to December 2006 in Austria and Germany.

The study was conducted within a compassionate use program.

The World Health Organization (WHO) Oral Toxicity Scale was used.

• Incidence of grade 2–4 WHO oral toxicity was 60% in the palifermin group and 86% in the control group (p = 0.04).
• Grade 3–4 oral toxicity was present in 37% of the palifermin group and 53% of the control group (p = 0.19).
• Mean duration of oral mucositis (OM) was 6 versus 12 days (p = 0.003) in favor of palifermin. 
• Severity of OM was significantly reduced in the study group at 1.73 versus 2.47 (p = 0.03).
• Palifermin was associated with significantly decreased use of opioids. The median cumulative dose  was 150 versus 378 morphine equivalents (p = 0.04). However, the difference in median time of use was not significant at 6 versus 7 (p = NS).
• Total parenteral nutrition (TPN) use was lower in the palifermin group at 26 versus 15 days (p = 0.002). 
• No significant difference was found in incidence and duration of febrile neutropenia, with the palifermin group at 4 days versus 3 days in the control group (p = NS).
• Hematopoietic recovery was not influenced.
• No significant difference was found in graft-versus-host disease (GVHD).

• The authors declared no funding or financial support by company.
• An historical control group was used.
• The sample size was small.
• No discussion of added costs was included.

To evaluate the efficacy of palifermin, an N-terminal truncated version of endogenous keratinocyte growth factor, in the control of oral mucositis during antiblastic therapy for pediatric patients with acute lymphoblastic leukemia

Twenty patients received palifermin and other 20 patients didn’t. The palifermin group received a 60 mg/kg IV bolus per day for three consecutive days before and three consecutive days after transplant (a total of six doses). All patients were evaluated for 30 days.

• N = 40  
• MEDIAN AGE = 11 years
• MALES: 52%, FEMALES: 48%
• KEY DISEASE CHARACTERISTICS: Acute lymphoblastic leukemia
• OTHER KEY SAMPLE CHARACTERISTICS: Pediatric, allogeneic stem cell transplant

• SITE: Single-site    
• SETTING TYPE: Inpatient

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

Case-controlled study

• World Health Organization (WHO) grading scale
• Average duration of episode of oral mucositis, duration of use of total parenteral nutrition, infection rate, 100-day survival rate

This study demonstrated a statistically significant reduction in the duration of parenteral nutrition (p = .002), duration of mucositis (p = .003), and the average grade of mucositis (p = .03). Other measures were not significant. The statistical analysis showed that the drug decreased the severity of mucositis.

These data suggest that palifermin could be a valid therapeutic adjuvant to improve quality of life for pediatric patients with leukemia.

• Small sample (< 100)
• Risk of bias (no random assignment)

Palifermin decreased the duration of oral mucositis in pediatric patients being treated for leukemia. Nurses should be aware that this intervention may compliment other interventions to reduce oral mucositis in this population.

To evaluate the efficacy and safety of palifermin in the reduction of oral mucositis (OM) associated with definitive chemoradiotherapy for locally advanced head and neck cancer (HNC)

• Patients were randomized to receive 180 mcg/kg palifermin or a matching IV placebo (consisting of sterile water, 4% mannitol, 2% sucrose, 10 mmol/L histadine, 0.010% polysorbate-20, pH 6.5, and no preservatives). Palifermin or placebo was administered as a bolus injection over 30–60 seconds in eight weekly doses, starting three days before initiation of radiation therapy (RT) and then once weekly after the week’s last RT treatment.
• Medications for mucositis and mouthwash solutions containing chlorhexidine, hydrogen peroxide, or diphenhydramine were not allowed.
• Hematopoietic growth factors were allowed only to manage severe anemia or myleosuppresion.

• The study reported on 188 patients with a mean age of 55.
• The study arm sample was 84% male and 16% female; the control arm was 85% male and 15% female.
• Patients were newly diagnosed with unresected stage III–IVB squamous cell carcinoma of the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx: no evidence of a secondary malignancy; and planned RT dose of more than 50 Gy to different subsites of the inspected oral cavity and oropahrynx.

The study was conducted in a multi-institutional setting.

Patients were undergoing the active treatment phase of care.

This was a randomized, placebo-controlled study.

• The World Health Organization (WHO) Oral Toxicity Scale was used for grading OM.
• Investigators were all trained uniformly, and the same investigators were asked to assess individual patients serially.    
• Patients reported mouth and throat soreness (MTS) scores with the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer.
• Researchers recorded duration of severe OM, time to onset of severe OM, incidence of greater than or equal to 2 xerostomia at month 4, average MTS scores, opioid analgesic use, incidence of RT breaks of at least five consecutive fractions, and incidence of chemotherapy delays.

The incidence of severe OM was significantly lower in patients receiving palifermin than those receiving placebo (54% versus 69%). In the palifermin arm, the median time to severe OM was delayed, median duration of severe OM was shortened, and the incidence of xerostomia at grade 2 or more was lower, favoring palifermin; however, the differences were not significant after multiplicity adjustment.

Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms.

Adverse events were similar between arms. The most common study drug related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between the treatment arms.

There was no mention as to whether the study was blinded to the researchers.

Oral mucositis is a severe complication of treatment for head and neck cancer, and effective treatment strategies are still needed. Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemotherapy remains unclear. Effective treatment strategies to manage OM associated with high-dose chemoradiotherapy still are needed.

To study the efficacy of palifermin for prophylaxis of OM in pediatric patients undergoing hematopoetic cell transplant (HCT)

Patients were randomly assigned to receive either IV palifermin 60 mcg/kg per day starting three days prior to transplant conditioning chemotherapy or placebo. All patients received basic oral hygiene and invasive nutrition as needed. All other aspects of care were essentially the same between groups. OM was assessed daily from 7 days prior to transplantation to 28 days after transplantation. Assessment was conducted by the same clinician.

• N = 54
• MEDIAN AGE = 11 years
• AGE RANGE = 7–16 years
• MALES: 48%, FEMALES: 52%
• KEY DISEASE CHARACTERISTICS: All had lymphoblastic leukemia and were undergoing HCT.

• SITE: Single site  
• SETTING TYPE: Inpatient  
• LOCATION: Italy

• PHASE OF CARE: Active antitumor treatment

• Placebo-controlled randomized controlled trial

• Oral Mucositis Daily Questionnaire (OMDQ)
• World Health Organization (WHO) Oral Mucositis Toxicity Scale

Significantly fewer patients in the palifermin group developed grade 2 (p = 0.038) and grade 4 (p = 0.006) mucositis compared to the placebo group. Grade 4 was seen in 11% of patients in the palifermin group and 59% of patients in the control group. Fewer patients in the palifermin group had any grade mucositis, but not all differences in grades were statistically significant. The duration of grade 3 and 4 OM in patients in the palifermin group was three days compared to eight days in the control group (p < 0.001). The only adverse reactions reported were rashes and altered taste, lasting for 48–72 hours. The cumulative morphine daily dose per body weight was lower in the palifermin group (p = 0.04).

Palifermin was shown to effectively reduce the severity, prevalence, and duration of OM among pediatric patients undergoing HCT and was not associated with any significant adverse effects.

• Small sample (< 100)
• Risk of bias (no blinding)

Palifermin was shown to be beneficial to pediatric patients undergoing HCT for primary prophylaxis for OM. OM is one of the most painful and debilitating effects of high-dose myeloablative chemotherapy. Nurses can advocate for the consideration of palifermin in these patients. Additional research in support of these findings is warranted, and research regarding the potential role of palifermin in other types of chemotherapy regimens associated with OM is needed.

To assess the effect of palifermin on mucositis and infection risk according to conditioning regimen used, and to evaluate the effect of palifermin on fibrinogen levels

This is a retrospective study of patients who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-SCT) because of hematologic malignancies. The authors evaluated the differences between a cohort of patients who received prophylaxis with palifermin and a matched control group of patients who did not receive this agent, and assessed the effect of palifermin on infection risk according to the conditioning regimen used, comparing BEAM, BU-CY, THIO-CY, and HD-PAM conditioning regimens.

• N = 120 (40 with palifermen, 80 in control)  
• MEDIAN AGE = 47 years in palifermin group and 50 years in control group
• MALES: 65% in palifermin group, 55% in control; FEMALES: 35% in palifermin group, 45% in control group
• KEY DISEASE CHARACTERISTICS: Diagnosis of MM in 57.5% of both groups; lymphoma diagnosis in 22.5% of palifermin group and 31.2% of control group; other diagnoses in 20% of palifermin group and 11.3% in control group
• OTHER KEY SAMPLE CHARACTERISTICS: Pretreatment with less than two lines of therapy prior to SCT in 19% of palifermin group and 29% of control group; HD-PAM in 65% of palifermin group and 57.5% in control group; BEAM/BUS in 35% of palifermin group and 42.5% of control group

• SITE: Single site    
• SETTING TYPE: Inpatient  
• LOCATION: Italian transplantation center

• PHASE OF CARE: Active antitumor treatment

Total of 120 patients who underwent SCT from 2000–2009 who either received palifermin prophylaxis or did not receive palifermin (control group)

Weekly blood cultures, serum galactomannan assay, and skin and oral culture swabs were used in afebrile patients. Standard febrile workup was used including blood and urine cultures, chest radiography (CXR), and a CT of the thorax within 72 hours of the onset of fever. Any infection arising during the first 30 days was evaluated. Fever of unknown origin (FUO), pneumonia, febrile gram-positive bacteremia, and CVC-related infections were all evaluated. Mucositis was assessed for all patients using daily inspection and grading according to daily mucositis scoring using Eastern Cooperative Oncology Group (ECOG) Common Terminology Criteria for Adverse Events (CTCAE) criteria. Gastrointestinal (GI) toxicity was deemed as severe if there were five or more stools per day.

Palifermin reduced rates of severe mucositis when evaluation was conducted taking into account conditioning type. There was a significant reduction in the severe mucositis rate in the BEAM/BUS group, whereas there was no significant reduction in the HD-PAM group. Palifermin had no effect on GI toxicity. FUO was significantly reduced in palifermin treated group. A reduction in severe infections (p = 0.06) existed in the BEAM/BUS group. A highly significant reduction in gram-positive infections existed in the BEAM/BUS group but not in HD-PAM group. Rate of patients with fevers was decreased in the palifermin group, but not significantly. A reduction in serum fibrinogen peak levels during the aplastic phase was observed with palifermin in the BEAM/BUS group but not in HD-PAM group.

Palifermin reduced FUO and severe infections unrelated to gram-positive bacteria with a more evident effect after conditioning based on BEAM/BUS. Severe mucositis was also reduced in the BEAM/BUS group but not in the HD-PAM group. The reduction in fibrinogen level substantiates the beneficial effect and may suggest a reduction in risk of mortality.

• Risk of bias (no blinding)
• Retrospective study

Nurses should monitor fever, mucositis, and onset of infection; educate patients on infection prevention and use of medications; and advocate for use of palifermin in high-risk populations, including the elderly, those receiving BEAM/BUS therapy, or heavily pretreated patients.

To assess the use of palifermin in the prevention of oral mucositis (OM) and acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT)

IV palifermin was administered at 60 mcg/kg for three consecutive days before and after conditioning therapy. These patients were compared to a retrospective control group.

• The study reported on a total of 106 patients, with 53 in the palifermin group and 53 in the control group.
• All patients received autologous or allogeneic transplantation with hematologic and nonhematologic diseases and had a Karnofsky score of 80 or higher.
• The palifermin group received transplantations between June 2005 and March 2006; the control group received transplantations between December 2000 and December 2005.
• Protocols were not indicated for either group.

This was a multicenter study conducted in Poland.

This was a retrospective control trial.

• The World Health Organization (WHO) Oral Toxicity Scale was used.
• Researchers recorded mucositis onset and incidence, use of analgesics, duration of total parenteral nutrition (TPN), incidence of febrile neutropenia, severe infections, and incidence of acute GVHD.

Incidence of all grades of mucositis was lower in the palifermin group (p < 0.001). Incidence of grades 3–4 was 13% in the palifermin group and 43% in the control group (p < 0.001). Mean duration was significantly lower (p < 0.001). No statistically significant differences in the onset of OM, duration of TPN, opioid use, incidence of febrile neutropenia, or severe infection were observed. No statistical significance in acute GVHD measures were observed, although the authors suggested that a decrease in acute GVHD may occur. Additional studies are necessary.

Adverse events (e.g., rash, pruritis, erythema, generalized edema, taste alteration, mouth or tongue thickness and discoloration, proteinuria) were mild in 15 patients, moderate in 15 patients, and severe but not life-threatening in 4 patients. No events caused discontinuation of palifermin.

• This was a retrospective trial.
• Expense was not addressed.
• The study used an IV formulation of palifermin.
• Ensuring all treatments were equal is not possible because of the study’s historical nature.

To evaluate possible differences between the severity and duration of oral mucositis (OM) and other clinical end points previously found to be associated with OM in patients who received palifermin compared to those who did not

A retrospective chart review of 99 consecutive patients who received an allogeneic hematopoietic stem cell transplantation (AHSCT) with palifermin from December 2006 to December 2009 was conducted, and 30 patients who received AHSCT from January to December 2005 served as control group (this group was treated before palifermin became standard of practice). Palifermin was administered for three consecutive days with the third dose 24 hours before the initiation of fractionated total body irradiation and three additional doses after the completion of the conditioning regimen (days 0–2). All patients received a comprehensive oral care regimen, and oral assessments were conducted every three days by a certified respiratory therapist.

• N = 129  
• AGE RANGE = 18–59.2 years
• MALES: 51%, FEMALES: 49%
• KEY DISEASE CHARACTERISTICS: Hematologic malignancies (acute lymphoblastic leukemia and acute myeloid leukemia)
• OTHER KEY SAMPLE CHARACTERISTICS: Conditioned with fractionated total body irradiation and etoposide

• SITE: Single site    
• SETTING TYPE: Not specified    
• LOCATION: Cancer center

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care  

• Retrospective chart review

• National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v2.0
• OM grades 1 and 2 were categorized as mild, and grades 3 and 4 were categorized as severe.

OM developed in 95% of patients in the palifermin group and all 30 patients in the control group. Severe OM developed in 34% of the palifermin group and 80% of the control group (p < 0.0001) with the median duration of OM 13 days with palifermin and 18 days with the control. The median duration of sever OM was not found to be different between groups. The median duration patient-controlled analgesia use was shorter in the palifermin group as was the use of opioids. No significant difference in the duration of total parenteral nutrition use was found.

Palifermin reduced the incidence of severe OM and the overall duration of OM in this study. This supported the use of palifermin.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (sample characteristics)

This study supported palifermin use in this population. However, additional studies providing evidence on quality of life and patient-reported outcomes are needed.

IV palifermin 60 mcg/kg per day was given for three consecutive days before chemotherapy cycle A2 or B2 and then for three consecutive days after chemotherapy. All patients received granulocyte colony-stimulating factor (G-CSF). Prophylactic treatment consisted of a number of agents, including tetracaine, chamomile, oral hygiene, and amphotericin B suspensions. Authors used previous studies as historical controls.

This study used a retrospective series of 10 patients with B cell acute lymphocytic leukemia (ALL) or aggressive B cell lymphoma. Patients had World Health Organization (WHO) Oral Mucositis grades of 3 or 4 during cycle A1 or B1 of high-dose methotrexate (HDMTX).

Patients were selected retrospectively from September 2004 to March 2007.

• WHO mucositis grading was obtained daily.
• Opioid use was recorded.

• Sixteen episodes of grade 4 and one episode of grade 3 mucositis were observed without palifermin.
• One episode of grade 4, four episodes of grade 3, and four episodes of grade 2 mucositis were observed with palifermin (p < 0.05).
• IV opioids were reduced from 2,403 mg to 640 mg morphine (p < 0.05).
• Duration of higher grade mucositis was reduced slightly from 12.9 days to 11 days (not significant).

• The sample size was very small.
• Historical controls were used.
• Other prophylactic measures may have had effects.
• No discussion of cost was provided.

To evaluate the safety and efficacy of single-dose palifermin in reducing oral mucositis incidence in patients with hematologic malignancies undergoing peripheral blood progenitor cell transplant receiving total-body irradiation and high-dose chemotherapy 

Patients were randomized to receive 60 mcg/kg palifermin once daily for three days before the start of fractionated total-body irradiation (TBI) (Arm A), 180 mcg/kg once only on day -1 (Arm B), day -2 (Arm C), or day -3 (Arm D) before starting fractionated TBI and stratified by etoposide use and number of days of TBI.  All patients received 60 mcg/kg for three days post-transplantation.

The study reported on 47 patients receiving high-dose chemotherapy with an age range of 18–74 years. Patients had multiple cancer diagnoses.

The World Health Organization (WHO) Oral Toxicity Scale was used.

• All arms had similar adverse effects.
• Overall incidence of severe mucositis was 61% with a mean of 4.3 days.
  • Arm A: 82% (70% actual)
  • Arm B: 60% (73% actual)
  • Arm C: 31% (38% actual)
  • Arm D: 75% (67% actual)

• The four study arm sample sizes were small.
• The total sample was small with only 47 patients total.
• The authors collapsed Arms B, C, and D for severe mucositis.
• A large percentage (n = 20) of patients had significant protocol deviations.
• The study was stopped early; participant accrual was difficult.
• The report did not include a discussion of costs.

IV palifermin (recombinant human keratinocyte growth factor) 60 mg/kg was given for three consecutive days immediately before a conditioning regimen (total body irradiation [TBI] plus high-dose [HD] chemo). Additional doses administered on days 0, 1, and 2.

• The study reported on 212 patients with a median age of 48.5 years and an age range of 18–69 years.
• Patients were stratified according to the center and type of cancer; 106 were given palifermin and 106 received placebo.
• All patients had hematologic cancers and were receiving autologous stem cell transplant (SCT).

The study was conducted in a multisite setting.

This was a placebo-controlled, double-blind, phase 3, randomized trial.

• The World Health Organization (WHO) oral toxicity scale was used.
• The Radiation Therapy Oncology Group (RTOG) acute radiation-morbidity scoring criteria for mucous membranes was used.
• The Western Consortium for Cancer Nursing Research (WCCNR) revised staging system for oral mucositis was used.
• Use of analgesia and total parenteral nutrition (TPN) was recorded.
• Duration of mucositis was recorded.
• Incidence of mucositis was recorded.
• Mucositis was evaluated for 28 days.

• Fewer patients in the palifermin group had WHO grades 3 or 4 (63%) than in the control group (98%) (p < 0.001).
• Fewer patients in the palifermin group had WHO grades 4 (20%) than in the control group (62%) (p < 0.001).
• Patients in the palifermin group had a lower median duration of mucositis at 6 days versus 9 days in the control group (p < 0.001).
• Fewer patient in the palifermin group reported soreness of mouth and throat (29%) than in the control group (46.8%) (p < 0.001).
• Patients in the palifermin group reported lower use of opioids (212 mg morphine equivalents) compared to the control group (535 mg morphine equivalents) (p < 0.001).
• Incidence of TPN was lower in the palifermin group (31%) than the control group (55%) (p < 0.001).
• Adverse events were rash, pruritus, erythema, mouth and tongue disorders, and taste alteration.

Patients in the palifermin group experienced statistically significant decreases in incidence and duration of mucositis.

• One or more of the study researchers had a relationship with AMGEN, which manufactures palifermin.
• The study only looked at a hemotologic autologous SCT population.
• The trial only studied the IV formulation.
• Palifermin costs may be a limitation.

To review the role of palifermin and other current and potential treatments for chemotherapy-induced mucositis in the context of pathobiology in hematologic malignancies

Database searched was MEDLINE. Abstracts and published proceedings reporting the role of palifermin in the management of mucositis were reviewed. 

Search keywords were MeSH headings for chemotherapy, cyclophosphamide, etoposide, GI mucositis, GVHD, hematology, hematological malignancies, hematopoeietic stem cell transplantation, hemorrhagic  cystitis, HSCT, keratinocyte growth factor, KGF, leukemia, lymphoma, melphalan, methotrexate, mucositis, multiple myeloma, oncohematology, oral mucositis, pain, palifermin, radiation, radiotherapy, soreness, and total parenteral nutrition.

Palifermin in standard and high dose chemotherapy

• Only case reports and one small study were included.  It was concluded that insufficient evidence exists to support palifermin use in patients without transplantation.

Palifermin in autologous stem cell transplantation

• One study in 212 patients showed that among those who developed grade 3 or 4 mucositis, the duration was shorter in those who received palifermin (p < 0.001).
• No randomized controlled trials and only a few additional small studies and case series were included.
• Insufficient evidence was found to make any recommendation regarding palifermin in these cases.

Palfiermin in graft-versus-host disease

• Two studies using palifermin were cited, but no appraisal of findings was provided. It was noted that palifermin is used in this setting, and the biological rationale and brief findings in animal models are stated.

Other interventions for management of mucositis

• Findings from meta analyses indicate that, while some interventions have some benefit, the strength of the evidence was variable, and findings in one meta-analysis reported that no single intervention was capable of completely preventing oral mucositis.
• A number of cytokines and growth factors other than palifermin were indicated that have been or are currently being investigated to treat or prevent mucositis. The mechanism of potential activity and effects seen were provided.
• Other agents outlined included chlorhexidine, povidone iodine, pilocarpine, histamine gel, benzydamine oral rinse, amifostine, systemic glutamine, nonsteroidal anti-inflammatory drugs, and oral doxepin. Evidence was deemed insufficient to determine the efficacy and role of these agents.

Control of oral mucositis pain and provision of supportive therapy and regular assessment are critical management components.

This article provided information about various approaches in the management and prevention of oral mucositis in patients with hematologic malignancies and outlined the biologic mechanism of action and observed effects from review of the literature. However, it provided little information about the actual strength of evidence and is based on a limited literature search. No clear description of rationale for article inclusion was included.

The authors concluded that evidence supports the use of palifermin, but the article stated elsewhere that evidence in this area is insufficient in some patient groups, and only one nonrandomized study is cited where the duration of high-grade mucositis was shorter in patients who received palifermin, suggesting a biased view of the role of palifermin.

This article can provide useful information regarding the mechanism of action of various treatments, but it is not helpful in determining relative effectiveness of various interventions.

To summarize the evidence around the use of radiotherapy, standard-dose chemotherapy, and high-dose chemotherapy with or without total body irradiation plus hematopoietic stem cell transplantation (HSCT) for the management of mucositis

• Databases searched were the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO).
• Evidence was evaluated based on the American Society of Clinical Oncology (ASCO) Levels of Evidence (I-V) and Grades of Recommendation (A-D). Statements without grading were considered justified standard clinical practice by the expert authors and the European Society for Medical Oncology (ESMO) faculty.

• Institutions should develop oral care protocols based on clinical practice and interdisciplinary involvement. Staff and patient education are essential. Basic oral care should include saline mouth rinses 4–6 times per day and use of a soft toothbrush replaced on a regular basis. 
• Patient-controlled analgesic (PCA) with morphine is recommended for the treatment of pain in patients with oral mucositis undergoing HSCT.
• Regular oral pain assessment and topical anesthetics can provide short-term pain relief. 
• Chlorhexidine rinses are not recommended to treat established mucositis but may be an option to enhance treatment of oral infection.
• Benzydamine oral rinse is recommended for prevention of mucositis in patients with head and neck cancer receiving radiotherapy.
• For prevention of mucositis in patients receiving standard-dose chemotherapy,
  • Oral cryotherapy for 30 minutes is recommended in patients receiving fluorouracil (5-FU).
  • Keratinocyte growth factor-1 (palifermin) 40 mcg/kg per day for three days may be useful in patients receiving bolus 5-FU plus leucovorin.
• For prevention of mucositis in patients receiving high-dose chemotherapy with or without total body irradiation plus HSCT, the following are recommended.
  • Palifermin 60 mcg/kg per day for three days prior to transplant and three days post-transplant
  • Cryotherapy in high-dose melphalan
  • Low-level laser therapy (LLLT) before HSCT

The primary author was the principal investigator on the National Institutes of Health (NIH) R13 Conference Grant that provided partial support for the symposium “Oral Complications of Emerging Cancer Therapies,” 14-15 April 2009, Bethesda, MD, USA. Production of a Journal of the National Cancer Institute (JNCI) Monograph for conference publications was supported by an unrestricted educational grant form Biovirum, which owned palifermin at the time of the publication. Peterson also is a member of the Scientific Advisory Board and a paid consultant for the GI Co., Inc, which is responsible for the development of recombinant intestinal trefoil factor, for which the phase II study is cited in the references.

The mucositis guidelines reported contain few changes from the previous two versions of the ESMO Clinical Practice Guidelines. With the 2009 MASCC/ISCO Mucositis Study Group in June 2009, it was decided that no new guidelines were warranted based on the current published literature. Progress has been made in the understanding of molecular basis of mucositis. Evidence-based, cancer-specific identification of risk factors and management of mucositis depend on clinical research so that approval of new drugs and devices will be possible.

To review the literature and define clinical practice guidelines for use of cytokines and growth factor agents for the prevention or treatment of oral mucositis from chemotherapy or radiation therapy in patients with various types of cancer receiving radiation, chemotherapy, or hemapoietic stem cell transplant (HSCT)

In this evidence-based guideline, two independent reviewers scored level of evidence by Somerfield and Hadorn criteria. Following panel consensus, findings were integrated into guidelines.

Databases searched were Ovid, MEDLINE, and hand searching.

Search keywords included all types of cytokines and growth factors.

Inclusion and exclusion criteria were not specified.

Patients were undergoing the active antitumor treatment phase of care.

Out of 1,718 papers that were initially retrieved, 64 studies were included in the systematic review.

Palifermin 60 mcg/kg/day for three days prior to conditioning and three days post-transplantation was recommended in patients receiving HSCT. No guideline was possible for palifermin use in other patient types. For granulocyte colony-stimulating factor (G-CSF), no guideline was possible. No guidelines were possible for granulocyte macrophage colony-stimulating factor (GM-CSF) mouthwash, topical transforming growth factor beta, mil-derived growth factor, epidermal growth factor, interleukin-II, ALT 104, or recombinant human intestinal trefoil factor.

Very limited research has been done in children. Guidelines do not specify if recommendations are for adults and children. Most studies had relatively low levels of evidence. Sample sizes were not reported.

Use of palifermin for mucositis prevention in HSCT recipients was recommended.