Palifermin for Patients Receiving Chemotherapy and Radiation for Head and Neck Cancer

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.

To determine if palifermin reduces severe oral mucositis (OM), defined as grade 3 or 4 on the World Health Organization (WHO) Oral Mucositis Grading Scale, in patients undergoing postoperative radiochemotherapy for locally advanced head and neck cancer

• This study had three arms. In arm 1, patients received 120 ug/kg palifermin per week during radiochemotherapy (at least seven doses). In arm 2, patients received 120 ug/kg palifermin per week for four doses, then placebo throughout the remainder of radiochemotherpy. In arm 3, patients received placebo throughout radiochemotherapy.
• Radiation therapy consisted of conventional or three-dimensional radiation planning for standard fractionation (5 X 2 Gy per week), for a total dose 60 Gy to 66 Gy. Chemotherapy consisted of 100 mg/m² cisplatin on days 1 and 22. Palifermin was administered once, three days prior to starting radiochemotherapy, followed by six once-weekly doses. 
• Local supportive care of normal saline rinses, topical anesthetics, feeding tube, and hematopoietic growth factors were allowed. Anti-inflammatory, antifungal, or antibiotic mouthwash solutions were not permitted.

• The study reported on 186 patients with a mean age of 56.5 years.
• The sample was 82% male and 18% female.
• Patients were resected for pathohistologically documented, high-risk Stage II to IVB squamous cell cancer of the oral cavity, oropharynx, hypopharynx, or larynx and were expected to receive at least 50 Gy to at least two of the main areas of the oral or oropharyngeal mucosa.
• Patients had European Cooperative Oncology Group (ECOG) performance status of 0–2, no history of pancreatitis or acute pancreatitis within the last year, and no prior radiation to the head and neck region or prior to chemotherapy.

This was a multisite study conducted in Australia, Canada, France, Germany, Italy, Spain, and United Kingdom.

Patients were undergoing the active treatment phase of care.

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

• The WHO oral toxicity scale was used.
• Trained evaluators conducted twice weekly assessments (at least 3±1 days apart throughout radiochemotherapy) until resolution of OM to WHO grade 2 or lower or until week 15.
• If OM was not resolved by week 15, weekly assessments were continued until OM reached grade 0 or 1 or until week 24.
• Evaluations immediately analyzed for data quality and accuracy by Clinical Assistance Programs.

• The four-arm palifermin arm was halted because of slow enrollment. Results for the 38 patients on this arm were analyzed separately and matched for the first 38 patients enrolled in the placebo arm.
• Palifermin at 120 ug/kg reduced severe OM in patients with head and neck cancer undergoing concomitant postoperative radiochemotherapy.
• Severe OM was observed in 47 (51%) in the palifermin arm and 63 (67%) in the placebo arm (p = 0.027). The median durations of severe OM were 4.5 days in the palifermin arm and 22.0 days in the placebo arm (p = 0.037). The median times to develop severe OM were 45 or 21 days (p = 0.022) in the palifermin and placeblo arms, respectively.

Palifermin administered prior to initiation of and weekly during concurrent chemotherapy-radiation therapy reduced OM incidence. The study also examined secondary endpoints (i.e., duration and onset, xerostomia, mouth and throat soreness (MTS) score) as well as radiation treatment breaks and chemotherapy delays. Patients receiving palifermin did not experience fewer breaks or lower average MTS  even though these patients did receive fewer opiod analgesics.

This study was supported by Amgen, which manufactures paliferrmin.

Treatment-related OM is debilitating for patients with head and neck cancer undergoing concurrent chemotherapy-radiation therapy. This can significantly impact patient comfort, nutritional status, and response to therapy. Further research is needed to identify effective therapies to better protect the oral mucosa.

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.