Originally published as JCO Early Release 10.1200/JCO.2005.02.8340 on January 3 2006

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Palifermin Reduces Patient-Reported Mouth and Throat Soreness and Improves Patient Functioning in the Hematopoietic Stem-Cell Transplantation Setting

Patrick J. Stiff, Christos Emmanouilides, William I. Bensinger, Teresa Gentile, Bruce Blazar, Thomas C. Shea, John Lu, John Isitt, Alessandra Cesano, Ricardo Spielberger

From the Cardinal Bernardin Cancer Center, Maywood, IL; University of California, Los Angeles; Amgen Inc, Thousand Oaks; City of Hope National Cancer Center, Duarte, CA; Fred Hutchison Research Cancer Center, Seattle, WA; State University of New York Upstate Medical University, Syracuse, NY; University of Minnesota, Minneapolis, MN; and University of North Carolina, Chapel Hill, NC

Address reprint requests to Patrick J. Stiff, MD, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S First Avenue, Bldg 112, Rm 240, Maywood, IL 60153; email: pstiff{at}lumc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose To describe patient-reported outcomes of mouth and throat soreness (MTS) and related sequelae on daily activities from a phase III study of palifermin in the autologous hematopoietic stem-cell transplantation (HSCT) setting and to compare patient self-evaluations with clinicians' assessments of oral mucositis using objective scales.

Patients and Methods Patients (n = 212) received palifermin (60 µg/kg/d) or placebo for 3 days before total-body irradiation (12 Gy), etoposide 60 mg/kg, and cyclophosphamide 100 mg/kg, and 3 days after HSCT. Patients completed a daily questionnaire (Oral Mucositis Daily Questionnaire [OMDQ]) evaluating MTS severity and its effects on daily functional activities. Patients' self-assessment data were compared with clinicians' assessments of oral mucositis using the objective scales.

Results Palifermin reduced the incidence and duration of severe oral mucositis, as assessed by both clinicians and patients. Comparisons between patient and clinician assessments demonstrated that the average daily scores between mucositis grade and subjective (MTS) instruments were similar, although patients reported MTS onset, peak, and resolution earlier (1 to 3 days) than clinicians' assessments. Patients receiving palifermin reported statistically significant improvements (P < .001) in daily functioning activities (swallowing, drinking, eating, talking, sleeping) and required significantly less narcotic opioids (P < .001); improvement in the patient's overall physical and functional well-being was also reported. This was confirmed by the results of the Functional Assessment of Cancer Treatment questionnaire.

Conclusion These results support the clinical benefit of palifermin in the HSCT setting, providing evidence that a patient's self-assessment instrument (OMDQ) may serve as an alternative tool to assess oral mucositis severity in clinical trials.

	INTRODUCTION

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Oral mucositis (OM) is one of the most debilitating adverse effects suffered by cancer patients undergoing high-dose myelotoxic chemoradiotherapy. This complication results from cytotoxic injury to the epithelial lining of the mucosa, including the oral, oropharyngeal, and GI tracts.¹ The severity of OM varies from erythema and edema accompanied by mild soreness to full mucosal thickness ulcerations penetrating into the submucosa, often resulting in severe pain (requiring narcotic analgesia) and impaired swallowing, prolonged hospitalization, and increased risks for infections and potentially life-threatening sequelae.^2,3 Between 40% to 80% of cancer patients undergoing intensive treatment regimens requiring hematopoietic stem-cell transplantation (HSCT) suffer the debilitating effects of OM during their cancer therapy.^4-7

The clinical consequences of OM are multifaceted. From the patients' perspective, this is the most serious, painful, and detrimental condition leading to significant decreases in their daily functioning and quality of life because of the difficulty or inability to eat, drink, swallow, or speak.⁸ The consequences of this complication often necessitate the use of narcotic analgesics for pain control and/or some form of parenteral nutrition to allow hydration and caloric intake.⁸ From the clinicians' point of view, severe OM may increase the patients' risk for life-threatening infections and may prolong hospitalization.^9-12 The severity of this condition in the transplantation setting has been associated with increased mortality.^13,14

The most common interventions for management of OM include good oral hygiene to minimize the risk of infections, pain medication, and parenteral nutrition, if needed.^15,16 Experimental therapies under investigation include amifostine, sucralfate, glutamine, and granulocyte-macrophage colony-stimulating factor mouthwash.^17-22 Until recently, there have been no approved medications to reduce the incidence and/or duration of OM.^23-25

Palifermin is a truncated, recombinant form of human keratinocyte growth factor that has been approved in the United States to decrease the incidence and duration of severe OM in patients with hematologic malignancies receiving myelotoxic therapy requiring HSCT support. The safety and efficacy of palifermin have not been established in patients with nonhematologic malignancies. Discovered in 1989, keratinocyte growth factor is a 28-kd member of the fibroblast growth factor family with epithelial cell proliferative properties.²⁶ Preclinical trials demonstrated the protective abilities of palifermin in preserving the integrity of the epithelial lining in animals undergoing chemoradiotherapy followed by HSCT.^27,28

We conducted a placebo-controlled, double-blind, phase III trial that demonstrated the efficacy of palifermin in reducing the incidence and duration of OM in the HSCT setting.²⁹ Sixty-three percent of patients receiving palifermin treatment developed severe OM (WHO toxicity grade 3 or 4), compared with 98% of patients receiving placebo. In addition, the incidence of the highest grade (WHO grade 4) of OM was reduced from 62% in patients receiving placebo to 20% in patients receiving palifermin (P < .001). Three clinical grading scales (WHO, Radiation Therapy Oncology Group [RTOG], and Western Consortium for Cancer Nursing Research [WCCNR]) were used to assess the signs, symptoms, and severity of OM in the phase III study.²⁹ In addition, a patient self-reported daily questionnaire was used to measure the severity of mouth pain as perceived by patients and its impact on daily functional activities (drinking, eating, swallowing, talking, and sleeping). Patients were asked to complete the questionnaire, the Oral Mucositis Daily Questionnaire (OMDQ), every day from the day before the start of the conditioning regimen (day –12) up to 28 days after transplantation for a maximum of 41 days. In this report, we describe the methods and results of the analysis of the patient self-reported data as collected in this study using the OMDQ instrument, compared with previously reported subjective measures.

	PATIENTS AND METHODS

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This study was a placebo-controlled, double blind, phase III trial conducted in North America. Complete details of the study design have been reported previously.²⁹ Briefly, patients were randomly assigned in a 1:1 ratio to receive palifermin (60 µg/kg/d) or placebo intravenously for 3 consecutive days before the conditioning regimen (total-body irradiation, etoposide, and cyclophosphamide) and 3 consecutive days after HSCT (Fig 1). Total-body irradiation was delivered in 6, 8, or 10 fractions during 3 or 4 days (beginning on day –8) for a total dose of 12 Gy. Chemotherapy included intravenous etoposide 60 mg/kg on the day after the final radiation treatment and one dose of cyclophosphamide 100 mg/kg 2 days before transplantation.³⁰

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study design and treatment schedule. Conditioning regimen: fractionated total-body irradiation (TBI; 12 Gy total dose in 6, 8, or 10 fractions during 3 to 4 days) plus etoposide (VP-16; one dose of 60 mg/kg intravenously [IV] during 4 hours) plus cyclophosphamide (Cy; one dose of 100 mg/kg IV during 1 hour). Treatment group A, palifermin (K) 60 µg/kg/d IV bolus; treatment group B, placebo (P). Filgrastim (G) 5 µg/kg once daily starting on day 0 after hematopoietic stem-cell transplantation (HSCT) and continuing until day 21 or engraftment.

Oral Mucositis, Patient Reported Outcomes, and Quality-of-Life Assessment Instruments
Clinical assessment of OM was performed using the WHO oral toxicity scale as the primary assessment scale.^29,34 Patients were rated on objective and subjective signs and symptoms as follows: grade 0, no mucositis; grade 1, soreness with or without erythema, no ulceration; grade 2, erythema and ulcers, patients can swallow solid diet; grade 3, extensive erythema and ulcers, patients cannot swallow solid diet; and grade 4, mucositis to the extent that alimentation is not possible. Observers assessed patients on a daily basis beginning at 8 days before transplantation and continuing through day 28 post-transplantation (or until resolution of mucositis).

Patient self-reported mouth and throat soreness (MTS) and the resulting limitations on daily functional activities were obtained from the OMDQ (Fig 2). This evaluative instrument is composed of 10 questions: overall health (question 1), severity of MTS (questions 2 and 4), functional limitations due to MTS (questions 3a to 3e), and severity of diarrhea (questions 5 and 6). Questions 2, 3a to 3e, and 5 are scored on a Likert-like 5-point scale, with 0 = least symptom or limitation (no soreness, not limited, or no diarrhea, respectively), and 4 = worst symptom or limitation (extreme soreness, unable to do, or severe diarrhea, respectively). Questions 1, 4, and 6 were scored on a 0 to 10 scale. For question 1 (overall health), a higher score indicated better overall health status. For question 4 (overall MTS) and question 6 (overall diarrhea), a higher score indicated a worsening in symptom severity.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Oral mucositis daily questionnaire.

Although the OMDQ was designed specifically to measure the impact of OM on patients' pain and daily functioning, a generic cancer quality-of-life questionnaire, the Functional Assessment of Cancer Treatment (FACT), was also used to assess the impact of OM on patients' general well-being. The FACT contains four domains (physical well-being, functional well-being, emotional well-being, and social/family well-being). The FACT includes 27 questions and has been validated repeatedly in studies of cancer patients.^38-40 A higher domain score indicates better well-being or quality of life. In this study, it was administered on day –12 (before the start of the conditioning regimen), day-1 (the day before transplantation), and days 7, 10, 14, and 28 after HSCT.

Analysis of Patient-Reported Outcomes End Points, and Statistical Methods
In addition to the MTS score (question 2 in OMDQ), which was a secondary end point in the protocol, the statistical analysis plan also included an analysis of the following prespecified patient-reported outcomes end points: the resulting limitation of MTS on daily functioning including swallowing, drinking, eating, talking, and sleeping (questions 3a to 3e of OMDQ), and the FACT physical well-being domain score. Results from other patient-reported outcomes variables (questions 1, 4, 5, and 6 from OMDQ and functional well-being, social/family well-being, and emotional well-being from FACT) were summarized descriptively.

In the primary analysis, area under the curve (AUC) was calculated over the duration of study (from day –12 to day 28) for all patient-reported outcomes end points. The criteria for a valid AUC calculation for MTS and MTS-related limitation end points were one assessment before transplantation (from day –12 to day –1); three assessments within 14 days post-transplantation (day 0 to day 14); and one assessment between day 15 to end of study (day 28). The criteria for a valid AUC calculation for the FACT physical well-being end point were one assessment before transplantation (from day –12 to day –1); two assessments within 14 days post-transplantation (day 0 to day 14); and one assessment between day 15 to end of study (day 28). For each nonmissing assessment between starting (day –12) and ending (day 28) days, the trapezoidal area was calculated as

The AUC for the entire study duration was the sum of all of these trapezoidal areas.^41,42 For the MTS-related end points, a lower AUC score indicated improvement. For the FACT end point, a higher AUC score indicated improvement.

For patients who met the AUC calculation criteria, the missing assessment for the starting (day –12) or ending (day 28) day was imputed with the nearest nonmissing assessment. For patients who did not meet the calculation criteria, their AUC value was imputed as follows: if they completed the clinical study, the AUC was imputed using the grand mean AUC value irrespective of treatment assignment among patients with the same type of hematologic disease; if they withdrew from or died during the study, the AUC was imputed with the worst AUC value among patients with the same type of hematologic disease.

Patient compliance in completing the OMDQ was assessed by calculating the percentage of patients completing the questionnaire on each study day (from day –12 to day 28). In addition, the percentage of patients completing at least 80% of all scheduled assessments was also calculated. All compliance rates were calculated by treatment group, as well as for the overall patient sample.

The OMDQ has a skip pattern. Patients who responded with a zero (no MTS) in question 2 were instructed to skip questions 3 and 4 and answer question 5. The compliance rate calculations included imputed values of zero for questions 3 and 4 for patients who responded with a zero to question 2 and answered question 5. The same methodology was applied for question 6.

Analysis of all prespecified patient-reported outcomes end points followed a sequential testing order after the primary end point was determined to be statistically significant. The difference in mean AUC MTS score between treatment groups was analyzed first, using the generalized Cochran-Mantel-Haenszel test and a nominal significance level of .05. After the difference was determined to be statistically significant, testing was conducted on the AUC MTS limitation scores, including limitations on swallowing, drinking, eating, talking, and sleeping. The testing on the difference in AUC patient well-being domain score was conducted last.

To test the robustness of the analysis results on the MTS and MTS-related limitation end points, a conservative imputation method was used for patients who did not meet the calculation criteria for their AUC score. First, the most favorable value, zero for MTS and MTS-related limitation end points (representing no soreness or no limitation) for all missing observations, was used to estimate missing values for patients who received placebo and the AUC was recalculated. Second, the least favorable value, 4 for MTS and MTS-related limitation (representing extreme soreness or unable to do or perform activity) for all missing observations, was used to estimate missing values for patients who received palifermin, and the AUC was recalculated.

The use of opioid analgesics was compared between the treatment groups using the generalized Cochran-Mantel-Haenszel method.

	RESULTS

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A total of 212 patients were enrolled and completed the study. Baseline characteristics for patients were similar across the treatment groups. The majority of patients were male ( 56%) and white ( 74%), with a median age of 49 years (range, 18 to 69 years). A majority of patients in both treatment groups had non-Hodgkin's lymphoma or Hodgkin's disease, had a Karnofsky performance status more than 90, and received prior chemotherapy. Complete baseline characteristics have been described previously by Spielberger et al.²⁹

Patient compliance in filling out the OMDQ was stable and consistently high during the course of the study. The mean daily compliance rate for completing the OMDQ during the entire study period was 84% in the placebo group and 89% in the palifermin group. For MTS, the main patient-reported outcomes end point, at least 78% of patients receiving placebo and 87% of patients receiving palifermin completed more than 80% of the 41 possible assessments. Similar compliance rates were seen for the MTS-related limitation and FACT physical well-being end points. The effect of compliance on the MTS AUC calculation showed that 89% of patients receiving placebo and 92% of patients receiving palifermin met the criteria for calculating the AUC for MTS score (ie, imputation not required). Similar rates were observed for the other patient-reported outcomes end points analyzed.

The curve outlines of patients' assessments of MTS and its resulting functional limitations were comparable to the clinicians' assessments of OM using the three different scales (WHO, RTOG, and WCCNR). However, the timing of the patient-reported MTS relative to the WHO clinical grade was different (Fig 3). Patients reported onset, peak, and resolution of oral pain/soreness earlier, by an average 1 to 3 days, than the respective changes observed by clinicians. For example, the mean MTS scores peaked on day 5, whereas the mean WHO score peaked on day 7. Thus, this patient-reported outcomes measure detected change in the severity of mucositis, based on the patients' experience, sooner compared with objective measurements, which rely on the clinicians' assessments.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Mouth and throat soreness (MTS) scores versus WHO mucositis grade scores. Vertical lines represent 95% CIs.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Mouth and throat soreness (MTS) scores (placebo v palifermin). Vertical lines represent 95% CIs.

View this table: [in this window] [in a new window]   Table 2. Duration of MTS and MTS-Related Limitations Two by Treatment Group

	DISCUSSION

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One of the major difficulties in the assessments of potential effective agents against OM has been the lack of a reliable, reproducible, easy-to-use, and accurate instrument to measure the severity of this complication. The differences in perception between patient and clinician on the impact of mucositis highlight this problem.^43-52 For patients, OM, even in its milder manifestations, is the most troublesome adverse effect of their chemotherapeutic/radiotherapeutic regimens.⁸ Meanwhile, clinicians tend to worry that severe mucositis increases the risks for infections and other complications.^9-12 An instrument that accurately measures both patient response and clinician observations remains elusive.

There are several commonly used scales for the clinical assessment of mucositis, each of which has its own limitations (ie, complexity, reproducibility, practicality). These include the Oral Mucositis Assessment Scale, WHO, RTOG, and WCCNR.^{14,34,50,53,54} With the exception of the WHO scale, these scales are mostly anatomically based and highly dependent on the training of clinicians to accurately and consistently assess the size and severity of ulcers and other associated symptoms in the patient's mouth and throat areas. Perceptions of mucositis may differ between the patient and physician. Assessment tools that rely only on the clinical observer's evaluation of the severity of the condition without consideration for the patient's perspective may lead to inadequate treatment of the symptoms and inaccurate conclusions about a therapeutic agent's effectiveness in the management of this condition. Furthermore, because these assessments are often made during examinations requiring clinic or hospital visits, the observations may not be sensitive enough to capture accurately the day-to-day changes in severity of OM and its accompanying consequences. Thus, the use of an instrument based on the patient's self-assessment in conjunction with the clinical scales can aid greatly in determining a more accurate assessment of the patient's condition.

The findings reported here demonstrate the clinical benefit of palifermin in this setting (ie, subjective benefit for patients) and the feasibility and reliability of the OMDQ to assess mucositis (ie, an alternative tool for assessments).

The major portion of this self-assessment tool was a 10-item, easy-to-administer questionnaire (OMDQ) administered on a daily basis for approximately 6 weeks. The questions inquired about symptoms of MTS and related functional limitations, overall health, and diarrhea. The results from the patient self-assessment tool demonstrated clearly that palifermin significantly and meaningfully reduced MTS and functional limitations related to its functions (drinking, eating, talking, and swallowing) related to MTS after intensive chemoradiotherapy and autologous HSCT, which in turn led to an improvement in patient overall physical and functional well-being, thus proving clinical benefit. The reduction in pain was paralleled by the decreased use of opioid analgesics (both incidence and dose). Thus, the subjective measure of MTS was validated by an internal objective measure of pain, which we believe strengthens the value of the daily questionnaire in accurately measuring OM.

With a compliance rate consistently more than 80%, the OMDQ proved to be a feasible assessment tool demonstrating that the patients' observations closely paralleled those of their caregivers who used clinical scales to assess mucositis incidence and severity. The WHO scale had the strongest correlation with the OMDQ, suggesting that it may be the best objective clinical measure. Interestingly, the OMDQ was able to detect changes in patients' MTS and its functional limitations sooner than the clinical scales (on average, 1 to 3 days earlier). These findings support the hypothesis by Sonis et al⁵⁵ that OM has a multifaceted mechanism of action where the early indications of the deterioration of the oral mucosa caused by cytotoxic insult may be felt by patients but may not have visible manifestations that are detectable by clinicians using the clinical scales.

In conclusion, these results demonstrate clearly that palifermin significantly and meaningfully reduced the impact of symptoms associated with severe OM. In addition, a patient's self-assessment instrument such as the OMDQ can be used successfully as a valid alternative to established assessment tools, particularly in clinical settings where daily evaluations of OM by clinicians are impractical (eg, the multicycle chemotherapy setting).

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Patrick J. Stiff Amgen Inc (A) Amgen Inc (B) Christos Emmanouilides Amgen Inc (B) William I. Bensinger Amgen Inc (A) Amgen Inc (A) Thomas C. Shea Amgen Inc (A); Biogen IDEC (A); PDL (A) Amgen Inc (B); Biogen IDEC (B); PDL (B) John Lu Amgen Inc (N/R) Amgen Inc (B) John Isitt Amgen Inc (N/R) Amgen Inc (B) Alessandra Cesano Amgen Inc (N/R) Amgen Inc (B) Ricardo Spielberger Amgen Inc (A)

	Author Contributions

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Conception and design: Patrick J. Stiff, Christos Emmanouilides, William I. Bensinger, Thomas C. Shea, John Lu, John Isitt, Ricardo Spielberger Administrative support: Bruce Blazar Provision of study materials or patients: Patrick J. Stiff, Christos Emmanouilides, William I. Bensinger, Theresa Gentile, Bruce Blazar, Thomas C. Shea, Ricardo Spielberger Collection and assembly of data: Patrick J. Stiff, William I. Bensinger, Theresa Gentile, Bruce Blazar, John Lu, Ricardo Spielberger Data analysis and interpretation: Patrick J. Stiff, William I. Bensinger, Bruce Blazar, John Lu, John Isitt, Alessandra Cesano, Ricardo Spielberger Manuscript writing: Patrick J. Stiff, William I. Bensinger, Bruce Blazar, Thomas C. Shea, John Lu, John Isitt, Alessandra Cesano Final approval of manuscript: Patrick J. Stiff, Christos Emmanouilides, William I. Bensinger, Theresa Gentile, Bruce Blazar, Thomas C. Shea, John Lu, John Isitt, Alessandra Cesano, Ricardo Spielberger

 

	ACKNOWLEDGMENTS

 
We thank M. Haim Erder, PhD, and Dieter Elhardt, PhD, for assistance with the conduct of the study; Stephen Sonis, DMD, DMSc, for advice regarding assessment of oral mucositis; Alan Rong, PhD, and Mon-gy Chen, MS, for statistical consultations. In addition, we thank the patients who participated in this study, their families, and all of the physicians, nurses, and study coordinators who cared for the patients.

	NOTES

 
published online ahead of print at www.jco.org on November 6, 2006.

Supported by Amgen Inc, Thousand Oaks, CA.

Presented as interim results at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003; 40th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 5-8, 2004; and the Annual Meeting of the American Society for Blood and Marrow Transplantation, Keystone, CO, February 10-14, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 27, 2005; accepted October 5, 2005.

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