Palifermin for General Oncology Patients

• STUDY PURPOSE: To assess the effects of cytokines and growth factors for preventing oral mucositis in patients with cancer who are receiving treatment.
• TYPE OF STUDY: Systematic review

• DATABASES USED: Cochrane Oral Health’s information specialist searched the following databases: Cochrane Oral Health’s Trials Register (searched May 2017); the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 4) in the Cochrane Library (searched May 2017); MEDLINE Ovid (1946 to May 2017); Embase Ovid (December 2015 to May 2017); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to May 2017); and CANCERLIT PubMed (1950 to May 2017). The U.S. National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. 
• YEARS INCLUDED: Through May 2017 
• INCLUSION CRITERIA: RCTs
• EXCLUSION CRITERIA:Not a RCT or unclear; stomatitis incidence reported in adverse events table; unclear if mucositis was oral or gastrointestinal; study stopped early with very few participants enrolled; oral mucositis not mentioned and unknown if measured; some participants had oral mucositis at baseline; crossover study with no reporting of first-period data; results reported by cycle assuming independence; survival/cure was primary outcome with mucositis (unclear if oral or gastrointestinal) as a toxicity

• TOTAL REFERENCES RETRIEVED: 3,145
• EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two review authors independently screened the results of electronic searches, extracted data, and assessed risk of bias. For dichotomous outcomes, they reported risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, they reported mean differences (MD) and 95% CIs. They pooled similar studies in random-effects meta-analyses. 

• FINAL NUMBER STUDIES INCLUDED: 35 (published from 1993 to 2017) 
• TOTAL PATIENTS INCLUDED IN REVIEW: 3,102 
• SAMPLE RANGE ACROSS STUDIES: Fourteen studies enrolled participants with hematological cancers. Eighteen studies enrolled participants with solid cancers: head and neck, colorectal, breast, and sarcoma. The remaining three studies enrolled a mixture of participants with solid cancers and participants with hematological cancers, two of which were 80%-90% solid, and the other study only 3% solid.
• KEY SAMPLE CHARACTERISTICS: All patients being treated for cancer, aged 1 to 87 years old

PHASE OF CARE: Active anti-tumor treatment

• There might be a reduction in the risk of moderate to severe oral mucositis in adults receiving bone marrow/stem cell transplantation after conditioning therapy for hematological cancers (RR = 0.89, 95% CI [0.8, 0.99]; 6 studies; 852 participants; low-quality evidence).
• A possible reduction in the risk of severe oral mucositis in bone marrow/stem cell transplantation after conditioning therapy for hematological cancers, but there is also some possibility of an increase in risk (RR = 0.85, 95% CI [0.65, 1.11]; 6 studies; 852 participants; low-quality evidence).  
• Probably a reduction in the risk of moderate to severe oral mucositis in adults receiving radiotherapy to the head and neck with cisplatin or fluorouracil (RR = 0.91, 95% CI [0.83, 1]; 3 studies; 471 participants; moderate-quality evidence). 
• Likely that there is a reduction in the risk of severe oral mucositis in adults receiving radiotherapy to the head and neck (RR = 0.79, 95% CI [0.69, 0.9]; 3 studies; 471 participants; high-quality evidence)
• Likely that there is a reduction in the risk of moderate to severe oral mucositis in adults receiving chemotherapy alone for mixed solid and hematologic cancers (RR = 0.56, 95% CI [0.45, 0.7]; 4 studies; 344 participants; moderate-quality evidence)
• Might be a reduction in the risk of severe oral mucositis in this population (RR = 0.3, 95% CI [0.14, 0.65]; 3 studies; 263 participants; low-quality evidence)

Although authors concluded that KGF is beneficial in the prevention of oral mucositis in adults who are receiving (a) radiotherapy to the head and neck with cisplatin or fluorouracil, or (b) chemotherapy alone for mixed solid and hematologic cancers, the results are not conclusive. Could conclude likely effective but not established

• Low sample sizes
• 13 studies (37%) were at low overall risk of bias
• 12 studies (34%) were at unclear overall risk of bias.
• 10 studies (29%) were at high overall risk of bias

The analysis showed inconsistent effect of KGF (keratinocyte growth factor). Because of the concern of cost and benefit, this is not strong evidence enough to recommend.

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.

Palifermin was administered at 40 mcg/kg IV for three consecutive days before each of two chemotherapy cycles with fluorouracil (5-FU) or leucovorin (LV).

The study reported on patients with metastatic colorectal cancer receiving 5-FU or LV. The group receiving palifermin had 28 patients, and the group receiving placebo had 36 patients.

This was a phase I and II randomized double-blind, placebo-controlled study.

• The World Health Organization (WHO) Oral Toxicity scale was used.
• Patients were assessed on days 1, 4, 8,12, 15, and at the end of both cycles on day 28.
• Patients also were assessed with the Oral Mucositis Daily Questionnaire, which consists of 10 questions on overall health, mouth and throat soreness, and diarrhea.
• Incidence and severity of mucositis and diarrhea were recorded.

• Statistically significant differences in grade 2 or higher mucositis were observed during the first cycle (p = 0.002).
• Lower incidence of mucositis was observed during the second cycle (still statistically significant for palifermin group) (p = 0.003).
• Fewer patients receiving palifermin required a chemotherapy dose reduction of 10% or more.
• Disease outcomes were similar for the two groups; the authors concluded that palifermin had no effect on the disease in this clinical setting.

• A researcher had relationships with Amgen.
• The study involved the IV formulation.
• Expense was not addressed.
• Palifermin currently is not U.S. Food and Drug Administration (FDA) approved for nonhematologic malignancies.

To evaluate the efficacy and safety of palifermin given as a single dose before each cycle in patients receiving doxorubicin-based multicycle chemotherapy

Patients were randomly assigned in a 2:1 ratio to receive palifermin or placebo.

• The study reported on 48 patients with an age range of 15–65 years.
• The sample was 53% male and 47% female.
• All patients had sarcoma with Karnofsky performance status greater than or equal to 80% and adequate bone marrow, renal, and hepatic function.

This study was conducted at a single-site at the University of Texas M.D. Anderson Cancer Center.

Patients were undergoing the active treatment phase of care.

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

• The World Health Organization (WHO) oral toxicity scale was used.
• Common Terminology Criteria for Adverse Events were used.
• A patient-reported outcome questionnaire was used; no data was provided about the reliability or validity of this instrument.
• A daily record symptom record diary was used; no data was provided about the reliability or validity of this instrument but it was referenced.
• Optical imaging studies and oral punch biopsies were performed prior to and 48–72 hours after the first dose of study drug to evaluate biologic effects of treatment on mucosa.

Palifermin significantly reduced the incidence of moderate to severe (grade 2 or higher) mucositis (44% versus 88%; p <0.001) and severe mucositis (13% versus 51%; p < 0.002).

A single dose of palifermin before each cycle reduced the incidence and severity of mucositis. It also demonstrated effectiveness as secondary prophylaxis in a few patients with severe mucositis.

• The sample size was small with fewer than 100 patients.
• A perceived unblinding of the treatment may have occurred because of notable differences between the biologic effects of palifermin and placebo.
• The study only looked at treatment of one disease.
• The follow-up period was short.

Mucositis and the pain it causes can significantly impact patients with cancer during treatment. Further research is needed to establish the alleviation of pain and the improved ability to drink, eat, and talk. If the mucosal lining is maintained, it would be important to establish if there are fewer infections, use of total parenteral nutrition (TPN) to maintain nutrition, and use of opiod patient-controlled analgesia (PCA) for pain control.

To determine if administration of palifermin during autologous hematopoietic stem cell transplantation (AHSCT) in children will lower incidence of oral mucositis and shorter duration of hospitalization

Patients received palifermin 60 µg/kg/day IV for the three consecutive days prior to myeloablative conditioning and for the three consecutive days after the end of chemotherapy. All patients received six total doses. Treating physicians were responsible for the decision to administer palifermin. Data were collected using electronic and paper medical charts.

• N = 58  
• AGE RANGE = 6.85–7.96 years
• MALES: 58.3%, FEMALES: 39.2%
• KEY DISEASE CHARACTERISTICS: Brain tumor, solid tumor, lymphoma
• OTHER KEY SAMPLE CHARACTERISTICS: Prior radiation, conditioning regimens (e.g., carboplatin, thiotepa, etoposide)

• SITE: Single site    
• SETTING TYPE: Inpatient    
• LOCATION: NewYork-Presbyterian Morgan Stanley Children’s Hospital

• APPLICATIONS: Pediatrics

• Retrospective analysis

• World Health Organization (WHO) grading for mucositis

No statistical difference in grades III-IV mucositis (p = 1.0), lower incidence in grades III–IV (p = 0.047) in patients receiving solid tumor regimen, and no difference in length of hospitalization

Palifermin administration did not result in a statistically significant decrease in incidence and grade of oral mucositis, nor did it result in shorter hospitalization.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: Retrospective analysis

High doses of chemotherapy prior to AHSCT causes significant morbidity due to oral mucositis. A larger study is needed to confirm findings of lower incidence of grades III and IV mucositis in the solid tumor regimens.

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.