Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers
Ricardo Spielberger, M.D., Patrick Stiff, M.D., William Bensinger, M.D., Teresa Gentile, M.D., Ph.D., Daniel Weisdorf, M.D., Tarun Kewalramani, M.D., Thomas Shea, M.D., Saul Yanovich, M.D., Keith Hansen, M.D., Stephen Noga, M.D., Ph.D., John McCarty, M.D., C. Frederick LeMaistre, M.D., Eric C. Sung, D.D.S., Bruce R. Blazar, M.D., Dieter Elhardt, Ph.D., Mon-Gy Chen, M.S., and Christos Emmanouilides, M.D.
Background Oral mucositis is a complication of intensive chemotherapyand radiotherapy with no effective treatment. We tested theability of palifermin (recombinant human keratinocyte growthfactor) to decrease oral mucosal injury induced by cytotoxictherapy.
Methods This double-blind study compared the effect of paliferminwith that of a placebo on the development of oral mucositisin 212 patients with hematologic cancers; 106 patients receivedpalifermin (60 µg per kilogram of body weight per day)and 106 received a placebo intravenously for three consecutivedays immediately before the initiation of conditioning therapy(fractionated total-body irradiation plus high-dose chemotherapy)and after autologous hematopoietic stem-cell transplantation.Oral mucositis was evaluated daily for 28 days after transplantation.
Results The incidence of oral mucositis of World Health Organization(WHO) grade 3 or 4 was 63 percent in the palifermin group and98 percent in the placebo group (P<0.001). Among patientswith this degree of mucositis, the median duration of mucositiswas 6 days (range, 1 to 22) in the palifermin group and 9 days(range, 1 to 27) in the placebo group. Among all patients, regardlessof the occurrence of mucositis, the median duration of oralmucositis of WHO grade 3 or 4 was 3 days (range, 0 to 22) inthe palifermin group and 9 days (range, 0 to 27) in the placebogroup (P<0.001). As compared with placebo, palifermin wasassociated with significant reductions in the incidence of grade4 oral mucositis (20 percent vs. 62 percent, P<0.001), patient-reportedsoreness of the mouth and throat (area-under-the-curve score,29.0 [range, 0 to 98] vs. 46.8 [range, 0 to 110]; P<0.001),the use of opioid analgesics (median, 212 mg of morphine equivalents[range, 0 to 9418] vs. 535 mg of morphine equivalents [range,0 to 9418], P<0.001), and the incidence of use of total parenteralnutrition (31 percent vs. 55 percent, P<0.001). Adverse events,mainly rash, pruritus, erythema, mouth and tongue disorders,and taste alteration, were mild to moderate in severity andwere transient.
Conclusions Palifermin reduced the duration and severity oforal mucositis after intensive chemotherapy and radiotherapyfor hematologic cancers.
High-dose chemotherapy and radiotherapy followed by hematopoieticstem-cell support is a well-established treatment for hematologiccancers. Oral mucositis develops and requires treatment in approximately70 to 80 percent of patients receiving radiation-based conditioningtreatments.1,2 The incidence and severity of oral mucositisvary with the conditioning regimen.
Oral mucositis results from injury to epithelial cells thatline the oral cavity. The damage causes changes ranging frommild atrophy to severe ulceration. Serious consequences includepain requiring opioid analgesia, potentially life-threateninginfections, inadequate nutrition requiring parenteral feeding,and prolonged hospitalization.1,2,3,4,5 Currently, no standardtherapy prevents or treats severe oral mucositis.6,7
Keratinocyte growth factor is a 28-kD, heparin-binding memberof the family of fibroblast growth factors that was originallyisolated from pulmonary fibroblasts as a protein (FGF-7) withkeratinocyte-stimulating activity. Palifermin (recombinant humankeratinocyte growth factor) is an N-terminal, truncated versionof endogenous keratinocyte growth factor with biologic activitysimilar to that of the native protein, but with increased stability.8In animal models of chemotherapy, radiotherapy, and hematopoieticstem-cell transplantation,9,10 palifermin protected severaltypes of epithelial tissues. A phase 1 trial indicated thatpalifermin at doses of up to 80 µg per kilogram of bodyweight per day for three consecutive days was not associatedwith major adverse events.11 We evaluated the efficacy and safetyof palifermin in reducing the duration and severity of oralmucositis and its sequelae (soreness of the mouth and throat,use of opioid analgesics and total parenteral nutrition, andinfections) in patients with hematologic cancers who were undergoingautologous hematopoietic stem-cell transplantation after receivingtotal-body irradiation and high-dose chemotherapy.
Methods
Patients
The institutional review board at each of the 13 study sitesapproved the study protocol; all patients gave written informedconsent before all study-related procedures. This study enrolledpatients who were at least 18 years of age, had a Karnofskyperformance-status score of at least 70, and were scheduledto undergo autologous stem-cell transplantation after receivinga conditioning regimen12,13,14,15 of fractionated total-bodyirradiation plus etoposide and cyclophosphamide for non-Hodgkin'slymphoma, Hodgkin's disease, acute myelogenous leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, or multiplemyeloma. Patients were to have at least 1.5x106 cryopreservedCD34+ cells per kilogram available for transplantation and adequatecardiac, pulmonary, renal, and hepatic function, as determinedby institutional guidelines.
Study Drug
Palifermin and its matching placebo were manufactured and packagedby Amgen. The placebo contained all the ingredients of the paliferminpreparation (i.e., 10 mM histidine [pH 6.5], 2 percent sucrose,4 percent mannitol, and 0.01 percent polysorbate 20) exceptpalifermin.
Study Design
In this placebo-controlled, double-blind, phase 3 trial, patientswere randomly assigned in a 1:1 ratio (stratified accordingto center and type of hematologic cancer) to receive palifermin(60 µg per kilogram per day) or placebo intravenouslyfor three consecutive days, starting three days before the initiationof total-body irradiation. After the conditioning regimen wasadministered, patients received three additional doses16 ofpalifermin or placebo on days 0, 1, and 2 after transplantation.Filgrastim (Neupogen, Amgen) (5 µg per kilogram per day)was administered to all patients daily from the day of transplantationuntil the neutrophil count recovered.
Conditioning therapy and supportive care were administered accordingto standard institutional practice. Total-body irradiation (total,1200 cGy) was delivered in 6, 8, or 10 fractions over a periodof three or four days, with at least six hours between fractions,before chemotherapy was administered. Chemotherapy includedintravenous etoposide (60 mg per kilogram) the day after thelast radiation fraction (four days before transplantation) andone dose of cyclophosphamide (100 mg per kilogram) two daysbefore transplantation. Patients received peripheral-blood hematopoieticstem cells collected after mobilization by means of either cytokinesor chemotherapy with or (for one patient) without cytokines.
Oral mucositis was assessed with the use of three scales: thefive-grade World Health Organization (WHO) oral-toxicity scale17(primary scale), the five-grade Radiation Therapy Oncology Group(RTOG) acute radiation–morbidity scoring criteria formucous membranes,18 and the four-grade Western Consortium forCancer Nursing Research (WCCNR) revised staging system for oralmucositis.19 At each center, Clinical Assistance Programs trainedevaluation-team members to assess and document oral mucositis.Each patient was assessed daily for oral mucositis beginning8 days before transplantation and continuing for 28 days aftertransplantation or until severe oral mucositis had resolved(i.e., returned to WHO grade 0, 1, or 2).
Data on patient-reported outcomes (soreness of the mouth andthroat and ability to participate in the activities of dailyliving) were collected with the use of a daily questionnaire.The functional and physical well-being domains of the FunctionalAssessment of Cancer Therapy general questionnaire20 were collecteddaily from 12 days before transplantation to 28 days after transplantation(total, 41 days).
Information concerning the use of parenteral or transdermalnarcotic analgesics was collected daily. Total parenteral nutritionwas given according to the standards of each study site.
Antibodies against palifermin were assayed by an electrochemiluminescence-basedimmunoassay (IGEN International). Any positive test was followedby retesting for neutralizing antibodies with a cell-based assay.Laboratory assessments included routine hematologic and bloodchemical tests and measurement of serum amylase and lipase concentrations.
The study was designed by Amgen and the principal investigators,who also recruited the patients and collected the data. Theinvestigators and Ms. Chen and Dr. Elhardt of Amgen analyzedthe data; all investigators had access to the data. The decisionto publish was made by the investigators and Amgen; no limitationswere imposed by the sponsor. The lead investigator wrote thearticle with editorial assistance from Amgen.
Efficacy and Safety End Points
Analyses of all efficacy and safety end points included allpatients who underwent randomization and received at least onedose of study medication. The prespecified primary end pointwas the duration of oral mucositis of WHO grade 3 (inabilityto swallow solid food) or 4 (no form of oral alimentation possible);the duration was considered to be zero days among patients whodid not have oral mucositis.
Other end points included the incidence of oral mucositis ofWHO grade 3 or 4, the duration of oral mucositis of WHO grade3 or 4 among patients with this adverse effect, the incidenceof WHO grade 4 oral mucositis, the duration of WHO grade 4 oralmucositis among patients with this adverse effect, the durationof oral mucositis of WHO grade 2 (moderate) or higher, the durationof oral mucositis of RTOG grade 3 or 4, the duration of lesionsof WCCNR grade 2 or 3, the area under the curve (AUC) for patient-reportedoutcomes of soreness of the mouth and throat and swallowinglimitations plotted against time, scores for the FunctionalAssessment of Cancer Therapy general questionnaire, and thetotal dose and duration of parenteral or transdermal opioidanalgesics. Additional exploratory end points included the incidenceof febrile neutropenia, the incidence of infections, and theincidence of the use of total parenteral nutrition.
Safety was assessed on the basis of the incidence of adverseevents, graded on a five-point scale (a score of 1 indicatesmild adverse effects, and a score of 5 fatal adverse effects);changes in clinical laboratory values; the occurrence of antibodiesagainst palifermin; and the rates of progression-free survivaland secondary cancers during follow-up.
Statistical Analysis
The planned sample size of 210 patients (105 per group) waschosen to provide the study with the statistical power to detecta minimal mean (±SD) difference between groups in theduration of severe oral mucositis of more than 3.0±6.6days, with the use of a t-test with 90 percent power and a two-sidedsignificance level of 5 percent. For the end points involvingthe duration of oral mucositis, missing data with two adjacentobserved assessments were assigned the poorer of the two adjacentvalues. For each patient whose oral mucositis had not resolvedby the end of the study we imputed the duration by assigningthe mean duration among all patients who had severe oral mucositisfor as long as or longer than the patient had it before thestudy ended. Treatment groups were compared by means of thegeneralized Cochran–Mantel–Haenszel method stratifiedaccording to study center.21 The test statistic was based onthe within-stratum standardized midranks. Secondary end pointswere evaluated in a prespecified order only after the primaryend point was determined to be statistically significant. Allstatistical tests were two-sided at the 0.05 level of significance.The Kaplan–Meier method22 was used to estimate the rateof progression-free survival.
Results
Patients
Between March 23, 2001, and October 23, 2002, 245 patients werescreened, 214 (107 per group) were randomly assigned to a treatmentgroup, and 212 (106 per group) received at least one dose ofpalifermin or placebo and were included in the safety and efficacyanalyses. The center that enrolled the most patients enrolled19 percent of them.
The baseline characteristics of the patients were similar inthe two groups (Table 1). Of the 212 patients, 88 (83 percent)in the palifermin group and 86 (81 percent) in the placebo grouphad a baseline Karnofsky performance-status score of at least90. All patients had received prior chemotherapy; 88 percentof those in the palifermin group and 92 percent of those inthe placebo group had received no prior radiotherapy. Radiotherapyschedules were similar in the two groups. A combination of chemotherapyand cytokines was used for CD34+ cell mobilization in 75 percentof patients in the palifermin group and 72 percent of patientsin the placebo group. Most patients (92 percent of those inthe palifermin group and 93 percent of those in the placebogroup) received acyclovir or a similar antiviral drug. Similarnumbers of patients in both groups completed the study: 103patients in the palifermin group (97 percent) and 102 patientsin the placebo group (96 percent).
Table 1. Baseline Characteristics of the Patients.
Efficacy
Oral mucositis of WHO grade 3 or 4 developed in 67 of 106 patientsin the palifermin group (63 percent) and 104 of 106 patientsin the placebo group (98 percent, P<0.001) (Table 2). Themedian duration of oral mucositis of grade 3 or 4 among patientswith this adverse effect was 6.0 days (range, 1 to 22) in thepalifermin group and 9.0 days (range, 1 to 27) in the placebogroup (P<0.001) (Table 2). The median duration of oral mucositisof WHO grade 3 or 4 among all patients was 3.0 days (range,0 to 22) in the palifermin group and 9.0 days (range, 0 to 27)in the placebo group (P<0.001) (Table 2). This result —the primary end point — was reproducible when the analysiswas performed according to center, type of hematologic cancer,or number of fractions of irradiation (Figure 1). A two-partstatistical model,23 which simultaneously considered the incidenceof oral mucositis of WHO grade 3 or 4 and the duration of oralmucositis of WHO grade 3 or 4 among patients with this adverseeffect, showed significant improvements in the palifermin group,as compared with the placebo group (P<0.001) (Table 2).
Figure 1. Mean Difference between the Placebo Group and the Palifermin Group in the Duration of Mucositis of WHO Grade 3 or 4, According to Center (Panel A), Type of Hematologic Cancer (Panel B), and Number of Fractions of Total-Body Irradiation (Panel C).
Values in parentheses are the mean differences in duration between the placebo group and the palifermin group (also indicated by the squares) and the numbers of patients. Horizontal bars represent 95 percent confidence intervals. The mean difference could not be calculated for center 39, which enrolled only one patient, who received palifermin; centers 35, 42, and 46 did not enroll any patients. The lower limit of the 95 percent confidence interval for the difference in duration exceeded 0 days for all centers except center 40 (six patients [four in the palifermin group and two in the placebo group]), for all hematologic cancers except leukemia (seven patients [two and five, respectively]), and for all three irradiation subgroups.
The incidence of oral mucositis of WHO grade 4 (Figure 2) wassignificantly lower among palifermin recipients than among placeborecipients (20 percent vs. 62 percent, P<0.001), and themedian duration of grade 4 oral mucositis was significantlyshorter among the 21 palifermin recipients than among the 66placebo recipients with this adverse effect (2.0 days [range,1 to 9] vs. 6.0 days [range, 1 to 37], P=0.004).
Figure 2. Incidence of Oral Mucositis in the Palifermin and Placebo Groups.
The severity of oral mucositis, as measured by the WHO assessment scale, is classified as follows: no oral mucositis (grade 0); soreness or erythema (grade 1); erythema and ulcers (grade 2); extensive erythema, ulcers, and inability to swallow solid food (grade 3); and mucositis that prevents any form of alimentation, including swallowing liquids (grade 4). No patient in the placebo group had grade 1 oral mucositis. The incidence of oral mucositis of WHO grade 3 or 4 was significantly lower in the palifermin group than in the placebo group (P<0.001), as was the incidence of grade 4 oral mucositis (P<0.001) and the incidence of oral mucositis of grade 2 or higher (P<0.01).
Approximately 3 percent of assessments for oral mucositis weremissing. In a sensitivity analysis that imputed missing oral-mucositisassessments by assigning the worst possible score for paliferminand the best possible score for placebo, the median durationof oral mucositis of grade 3 or 4 was still significantly shorterin the palifermin group than in the placebo group (3.0 days[range, 0 to 20] vs. 8.0 days [range, 0 to 27], P<0.001).
Similar results were seen for other measurements of oral mucositisamong all patients, including the median duration of oral mucositisof WHO grade 2 or higher (8.0 days [range, 0 to 28] in the palifermingroup and 14.3 days [range, 0 to 37] in the placebo group, P<0.001),the median duration of oral mucositis of RTOG grade 3 or 4 (0.0days [range, 0 to 24] and 6.0 days [range, 0 to 54], P<0.001),and the median duration of lesions of WCCNR grade 2 or 3 (1.0day [range, 0 to 36] and 7.0 days [range, 0 to 56], P<0.001).
In agreement with the measurement of oral mucositis, the medianscores for the soreness of the mouth and throat, measured bymeans of a Likert (categorical) scale, were significantly lowerin the palifermin group than the placebo group (AUC, 29.0 [range,0 to 98] vs. 46.8 [range, 0 to 110]; difference between groups,38 percent; P<0.001) (Table 2). By comparing daily mean scoresfor soreness of the mouth and throat with the WHO grade of oralmucositis, we found that the changes in the patient-reportedscores for soreness of the mouth and throat preceded the observer-reportedchanges in the grade of oral mucositis (Figure 3). Similar resultswere observed for the incidence and duration of swallowing limitations(Table 2) and other patient-reported sequelae related to sorenessof the mouth and throat (e.g., ability to drink, eat, talk,and sleep) (data not shown). Palifermin recipients had significantlyhigher scores for the physical and functional well-being domainsof the Functional Assessment of Cancer Therapy general questionnairethan did placebo recipients, also indicating greater improvement(Table 2).
Figure 3. Mean WHO Grade of Oral Mucositis (Panel A) and Scores for Soreness of the Mouth and Throat (Panel B) during the Study.
The WHO grades were determined by members of the evaluation team, and the scores for soreness of the mouth and throat were determined by the patients. For days –8 (before stem-cell transplantation), 0, 7, 14, 21, and 28, vertical lines represent 95 percent confidence intervals. Mouth soreness was graded on a four-point scale, with higher scores indicating greater soreness.
Palifermin recipients used less parenteral or transdermal opioidanalgesics for mucositis than did placebo recipients, as measuredby the median cumulative dose administered (212 mg of morphineequivalents [range, 0 to 9418] vs. 535 mg of morphine equivalents[range, 0 to 9418], P<0.001) and the median duration of administration(7.0 days [range, 0 to 28] vs. 11.0 days [range, 0 to 32], P<0.001).Palifermin recipients had a lower incidence of febrile neutropeniathan did placebo recipients (75 percent vs. 92 percent, P<0.001).Exploratory analysis revealed a trend toward a lower incidenceof blood-borne infections in the palifermin group than in theplacebo group (15 percent vs. 25 percent). The incidence ofthe use of total parenteral nutrition during the study was alsolower among palifermin recipients than among placebo recipients(31 percent vs. 55 percent, P<0.001).
Safety
The incidence, frequency, and severity of adverse events weresimilar in the two groups, and most were attributable to theunderlying cancer, cytotoxic chemotherapy, or total-body irradiation.Those that occurred with an incidence that was at least 5 percentagepoints higher in the palifermin group than in the placebo groupare listed in Table 3. Most of these adverse events were consistentwith the pharmacologic action of palifermin on skin and oralepithelium (e.g., rash, pruritus, erythema, paresthesia, mouthand tongue disorders, and taste alteration). All these eventswere mild to moderate in severity, transient (occurring approximatelythree days after the third dose of palifermin and lasting approximatelythree days), and not a cause for the discontinuation of studydrug.
Table 3. Adverse Events Occurring with an Incidence That Was at Least 5 Percentage Points Higher in the Palifermin Group Than in the Placebo Group.
Serious adverse events considered to be related to treatmentoccurred in one palifermin recipient (rash) and one placeborecipient (hypotension). Two patients died during the studyor within 30 days after the last dose of palifermin or placebo:one patient in the palifermin group died of veno-occlusive liverdisease, and one patient in the placebo group died of sepsis.Neither death was considered to be related to treatment.
Data collection on hematologic recovery after transplantationwas not prospectively specified; however, by day 12 after transplantation,most palifermin recipients (90 percent) and placebo recipients(93 percent) had absolute neutrophil counts of at least 500per cubic millimeter.
Transient, asymptomatic increases in serum amylase (primarilyof salivary origin) and lipase concentrations were observedin both groups, with the peak value for amylase occurring onthe last day of irradiation and the peak value for lipase occurringafter the third dose of study drug. The increases were higherin the palifermin group (median maximal increases from baseline,166.5 U of amylase per liter and 17.5 U of lipase per liter)than the placebo group (92.0 and 12.5 U per liter, respectively).No additional increase was observed for either enzyme, and concentrationsreturned to near-baseline values by the day of transplantation.
No clinically significant differences were observed betweengroups in other laboratory results. Increases from baselinein WHO toxicity grades of alanine aminotransferase, aspartateaminotransferase, bilirubin, alkaline phosphatase, and creatinineconcentrations — primarily one-grade increases —were observed in less than 35 percent of patients in each group.Antibodies against palifermin were not detectable in any patient.
As of November 2003, the median duration of follow-up was 12.6months in the palifermin group and 12.0 months in the placebogroup. The Kaplan–Meier estimate of the rate of progression-freesurvival at 12 months was 0.69 (95 percent confidence interval,0.60 to 0.78) in the palifermin group and 0.73 (95 percent confidenceinterval, 0.64 to 0.82) in the placebo group. In follow-up studiesto date, secondary cancers have been diagnosed in three patients:myelodysplastic syndrome in one patient in the palifermin groupand one patient in the placebo group and acute lymphoblasticleukemia in one patient in the palifermin group.
Discussion
This study provides evidence that palifermin can significantlyreduce, in a clinically meaningful way, the duration and incidenceof oral mucositis after intensive chemotherapy and radiotherapyand autologous hematopoietic stem-cell transplantation. Paliferminconsistently decreased the incidence and duration of severeoral mucositis and its clinical sequelae independently of themeasure used, the participating center, the type of underlyingdisease, and the number of radiation fractions used. The intensivetraining of study personnel on the assessment of oral mucositisenhanced the quality of the data, and the quantity of missingdata was minimal (approximately 3 percent), increasing confidencein the results. In addition, observer-reported assessments concurredwith patient-reported assessments of the soreness of the mouthand throat and related functions, including swallowing.
An important finding was that palifermin markedly reduced theincidence of oral mucositis of WHO grade 4 (20 percent, as comparedwith 62 percent in the placebo group; P<0.001), the mostdebilitating form of oral mucositis, in which oral alimentationis impossible. It is consistent with these findings that thepercentage of patients who received total parenteral nutrition,an intervention frequently required for severe oral mucositis,24,25and the amount and duration of use of parenteral opioid analgesicswere significantly lower among palifermin recipients than placeborecipients.
Our results are particularly compelling because of the severityand duration of oral mucositis typically seen in patients withhematologic cancers who undergo intensive treatment. Althoughantibiotics and topical palliative agents can help manage infectionsand pain resulting from mild-to-moderate oral mucositis, noneof the growth factors and cytokines unrelated to keratinocytegrowth factor tested to date have demonstrated a clear benefitin the setting of oral mucositis.7,26,27,28,29,30
Severe oral mucositis is associated with an increased risk ofblood-borne bacterial infections, which can be life-threatening.31,32Our exploratory analysis of blood-borne infections showed alower incidence among patients receiving palifermin than amongthose receiving placebo. If confirmed by future investigations,the ability of palifermin therapy to reduce the breakdown ofmucosal barriers could decrease the complications caused bysystemic infection. In turn, reducing the complications of oralmucositis could decrease the use of parenteral or transdermalopioid analgesics for mucositis and parenteral nutrition andreduce the length of hospitalization.
Palifermin is a growth factor. Keratinocyte growth-factor receptoris not known to be expressed in hematologic cancers33; nevertheless,the growth of second tumors that express this receptor is theoreticallypossible. Evaluation of this risk requires long-term follow-up,which is ongoing. At 12 months, the progression-free survivalrates for palifermin and placebo were nearly identical. In summary,60 µg of palifermin per kilogram per day was associatedwith reductions in the duration and severity of debilitatingoral mucositis and related sequelae of high-dose myelosuppressivetreatment with autologous hematopoietic stem-cell support.
Funded by Amgen.
Drs. Spielberger, Kewalramani, and Emmanouilides report havingreceived consulting and lecture fees from Amgen; Drs. Stiffand Blazar, consulting fees, lecture fees, and grant supportfrom Amgen; Dr. Bensinger, consulting fees and grant supportfrom Amgen; Dr. Shea, lecture fees and grant support from Amgen;and Dr. Noga, lecture fees from Amgen and Ortho Biotech. Dr.Elhardt and Ms. Chen are employees of Amgen and hold equityin Amgen.
We are indebted to Robert Heard, Ph.D., and Alessandra Cesano,M.D., for assistance with the conduct of the study; to StephenSonis, D.M.D., D.M.Sc., for advice regarding the assessmentof oral mucositis; to M. Haim Erder, Ph.D., and Jon Ford, Ph.D.,for evaluating patient-reported outcomes; to Alan Rong, Ph.D.,and John Isitt, Ph.D., for assistance with statistical analysis;to Kathy Jelaca-Maxwell, R.N., for assistance with safety evaluations;to Don Smith, Ph.D., for editorial assistance; and to the patientswho participated in this study, their families, and all thephysicians, nurses, and study coordinators who cared for thepatients.
Source Information
From the City of Hope National Medical Center, Duarte, Calif. (R.S.); Loyola University Medical Center, Maywood, Ill. (P.S.); the Fred Hutchinson Cancer Research Center, Seattle (W.B.); State University of New York Upstate Medical University, Syracuse (T.G.); the University of Minnesota, Minneapolis (D.W., B.R.B.); Memorial Sloan-Kettering Cancer Center, New York (T.K.); the University of North Carolina, Chapel Hill (T.S.); Georgetown University Cancer Center, Washington, D.C. (S.Y.); the Northwest Marrow Transplant Center, Portland, Oreg. (K.H.); Sinai Hospital of Baltimore, Baltimore (S.N.); the Medical College of Virginia, Richmond (J.M.); the Texas Transplant Institute, San Antonio (C.F.L.); the School of Dentistry (E.C.S.) and the Division of Hematology/Oncology (C.E.), University of California at Los Angeles, Los Angeles; and Amgen, Thousand Oaks, Calif. (D.E., M.-G.C.).
Address reprint requests to Dr. Spielberger at the City of Hope National Medical Center, Department of Hematology and Hematopoietic Cell Transplantation and Kaiser Permanente BMT Program, 1500 E. Duarte Rd., Duarte, CA 91010, or at rspielberger{at}coh.org.
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Palifermin and Chemotherapy-Induced Oral Mucositis
Awada A., Genot M.-T., Klastersky J., Köstler W. J., Hejna M., Zielinski C. C., Palmieri C., Vigushin D., Spielberger R., Stiff P., Bensinger W.
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N Engl J Med 2005;
352:1264-1265, Mar 24, 2005.
Correspondence
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