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Single-Dose Palifermin Prevents Severe Oral Mucositis During Multicycle Chemotherapy in Patients With Cancer: A Randomized Trial FREE

Saroj Vadhan-Raj, MD; Jonathan Trent, MD; Shreyaskumar Patel, MD; Xiao Zhou, MD, PhD; Marcella M. Johnson, MS; Dejka Araujo, MD; Joseph A. Ludwig, MD; Shana O'Roark, RN, APN; Ann M. Gillenwater, MD; Carlos Bueso-Ramos, MD, PhD; Adel K. El-Naggar, MD, PhD; and Robert S. Benjamin, MD
[+] Article and Author Information

From University of Texas M.D. Anderson Cancer Center, Houston, Texas.


Acknowledgment: The authors thank Wanda Toole for her assistance with data collection and Teofila Spear for preparation of the manuscript.

Grant Support: By Amgen.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0240.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Vadhan-Raj (e-mail, svadhanr@mdanderson.org).

Requests for Single Reprints: Saroj Vadhan-Raj, MD, Section of Cytokines and Supportive Oncology, Department of Sarcoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 450, Box 301402, Houston, TX 77230-1402; e-mail, svadhanr@mdanderson.org.

Current Author Addresses: Drs. Vadhan-Raj and Zhou and Ms. O'Roark: Section of Cytokines and Supportive Oncology, Department of Sarcoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 450, Box 301402, Houston, TX 77230-1402.

Drs. Trent, Patel, Araujo, Ludwig, and Benjamin: Department of Sarcoma Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 450, Box 301402, Houston, TX 77230-1402.

Ms. Johnson: Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1409, Houston, TX 77030.

Dr. Gillenwater: Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1445, Houston, TX 77030.

Dr. Bueso-Ramos: Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 72, Houston, TX 77030.

Dr. El-Naggar: Department of Pathology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX 77030.

Author Contributions: Conception and design: S. Vadhan-Raj, M.M. Johnson.

Analysis and interpretation of the data: S. Vadhan-Raj, J. Trent, X. Zhou, M.M. Johnson, C. Bueso-Ramos, A.K. El-Naggar, R.S. Benjamin.

Drafting of the article: S. Vadhan-Raj, J. Trent, S. Patel, J.A. Ludwig, A.K. El-Naggar.

Critical revision of the article for important intellectual content: S. Vadhan-Raj, S. Patel, X. Zhou, R.S. Benjamin.

Final approval of the article: S. Vadhan-Raj, J. Trent, S. Patel, X. Zhou, A.M. Gillenwater, A.K. El-Naggar, R.S. Benjamin.

Provision of study materials or patients: S. Vadhan-Raj, J. Trent, S. Patel, D. Araujo, J.A. Ludwig, A.M. Gillenwater, A.K. El-Naggar, R.S. Benjamin.

Statistical expertise: X. Zhou, M.M. Johnson.

Obtaining of funding: S. Vadhan-Raj.

Administrative, technical, or logistic support: S. Vadhan-Raj, R.S. Benjamin.

Collection and assembly of data: S. Vadhan-Raj, X. Zhou, S. O'Roark, A.M. Gillenwater, C. Bueso-Ramos, R.S. Benjamin.


Ann Intern Med. 2010;153(6):358-367. doi:10.7326/0003-4819-153-6-201009210-00003
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Background: Mucositis can be a serious complication of cancer treatment. Palifermin reduces mucositis when given in multiple doses to patients undergoing hematopoietic stem-cell transplantation.

Objective: To evaluate the efficacy of palifermin given as a single dose before each cycle in patients receiving multicycle chemotherapy.

Design: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00267046)

Setting: The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Patients: 48 patients with sarcoma were randomly assigned in a 2:1 ratio to receive palifermin or placebo. All patients received doxorubicin-based chemotherapy (90 mg per m2 of body surface area over 3 days, by infusion).

Intervention: Palifermin (180 µg per kg of body weight) or placebo was administered intravenously as a single dose 3 days before each chemotherapy cycle (maximum, 6 cycles). Patients who had severe mucositis received open-label palifermin in subsequent cycles.

Measurements: Oral assessment of mucositis by using World Health Organization (WHO) oral toxicity scale (grades 0 to 4), with moderate to severe mucositis (grades 2 to 4) as the main outcomes; patient-reported outcome questionnaire; and daily symptom record diary.

Results: A median of 6 blinded cycles (range, 1 to 6) were completed by the palifermin group and 2 (range, 1 to 6) by the placebo group. Compared with placebo, palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, −44 percentage points [95% CI, −71 to −16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, −38 percentage points [CI, −67 to −9 percentage points]). The main adverse effects were thickening of oral mucosa (72% in the palifermin group vs. 31% in the placebo group; P = 0.007) and altered taste. Seven of the 8 patients who had severe mucositis in the placebo group received open-label palifermin. None of these patients had severe mucositis in the subsequent cycles (a total of 17) with open-label palifermin.

Limitations: Study limitations include smaller sample size for the control group, inclusion of only patients with sarcoma, and perceived unblinding of the treatment because of notable differences between the biologic effects of palifermin and placebo.

Conclusion: A single dose of palifermin before each cycle reduced the incidence and severity of mucositis. The drug was generally well tolerated, but most patients experienced thickening of oral mucosa. Further investigation is needed to determine whether palifermin use will facilitate greater adherence to chemotherapy regimens by reducing mucositis.

Primary Funding Source: Amgen.

Editors' Notes
Context

  • Mucositis limits the dose and duration of chemotherapy with doxorubicin.

Contribution

  • This small, randomized, placebo-controlled trial of palifermin, a ketinocyte growth factor, in patients with sarcoma found that the severity and incidence of mucositis over multiple chemotherapy cycles were reduced compared with placebo. Adverse effects were mild.

Caution

  • This was a small, single-center study. Blinding might not have been maintained because of adverse effects of palifermin. Palifermin was compared with placebo, not an active treatment.

Implication

  • If confirmed in larger, more diverse patient groups, palifermin may reduce the extent to which mucositis impedes completion of a full course of chemotherapy.

—The Editors

Chemotherapy-induced mucositis can be very painful and debilitating and can lead to dose reduction and treatment delays, which can potentially compromise the treatment outcome and reduce the quality of life (13). Until recently, the attempts to prevent and manage severe mucositis have been limited to topical anesthetics, antimicrobials, oral rinses, ice, and opioid analgesics (410). None of these measures has been uniformly effective, and more effective therapies are needed.

Keratinocyte growth factor, a member of the fibroblast growth factor family, has potent epithelial cell proliferative activity and has induced epithelial thickening of the nonkeratinocyte layers of the oral mucosa and gastrointestinal tract in preclinical studies (1112). Palifermin, a recombinant human keratinocyte growth factor, has been shown to exhibit a protective role in murine models of chemoradiotherapy-induced mucositis (1215). In patients with hematologic cancer, a palifermin dosage of 60 µg per kg of body weight per day, administered as 3 doses before the preparative regimen and 3 doses after the stem-cell infusion, significantly reduced the incidence and duration of severe mucositis and was granted U.S. Food and Drug Administration approval for this setting (1618).

The clinical experience in patients undergoing multicycle chemotherapy is limited. In a phase 1 and 2 trial in patients with colorectal cancer who received 5-fluorouracil with leucovorin (1920), palifermin was safe at dosages up to 80 µg/kg per day for 3 days and significantly reduced the incidence of mucositis when administered at 40 µg/kg per day for 3 days before 2 chemotherapy cycles. In the clinical trials reported so far, palifermin was investigated for primary prevention of mucositis and was administered in multiple doses for 1 or 2 cycles only. One potential concern of administering multiple doses of palifermin up to the day before chemotherapy for the repeated cycles is that rapidly proliferating mucosal tissue may be more sensitized to chemotherapy-induced injury. A single dose administered a few days before chemotherapy may reduce this concern and may also be more convenient for the patient. In preclinical studies (15), a single dose of palifermin administered before mucosal insult is effective in decreasing mucositis. In addition, palifermin's effectiveness as secondary prophylaxis in patients who have already had severe mucositis is unknown.

On the basis of these observations, we designed our randomized study to evaluate the efficacy and safety of palifermin, administered as a single dose before each cycle, as primary prophylaxis in patients with sarcoma who received doxorubicin-based, multicycle chemotherapy, which causes clinically significant mucositis in more than 75% of patients (2122). Our study design allowed us to examine the effect of open-label palifermin in patients who already experienced severe mucositis in the blinded cycles. We also examined the effects of treatment on patient-reported outcome and the biologic basis for response.

Design Overview

This was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of palifermin for reducing the incidence and severity of oral mucositis in patients with sarcoma who received multicycle chemotherapy. Our additional objectives were to evaluate safety, pharmacokinetics and biomarkers (the subject of a separate report), and the biologic effects of palifermin on oral mucosa. The institutional review board approved this study, and all patients gave written informed consent before study entry.

Setting and Participants

Patients with sarcoma who planned to start chemotherapy at the University of Texas M.D. Anderson Cancer Center were eligible for our phase 2 study if they were aged 15 to 65 years and had a Karnofsky performance status greater than or equal to 80% and adequate bone marrow and renal and hepatic function. Patients with a history of pelvic radiation or clinically significant cardiac disease and those who had had surgery within the past 2 weeks were excluded. Patients with sarcoma were referred to our comprehensive cancer center from multiple sources.

Randomization and Interventions

Eligible patients were randomly assigned to receive either palifermin or placebo in a 2:1 ratio, which yielded 32 patients assigned to receive palifermin and 16 assigned to receive placebo. Two distinct computer-generated randomization lists were prepared by the University of Texas M.D. Anderson Cancer Center, Department of Biostatistics, one for the 20 patients who consented to pharmacokinetic sampling and the other for the 28 patients who did not. For the pharmacokinetics cohort, the treatment allocation ratio was 4 patients receiving palifermin to 1 receiving placebo, in blocks of 5; for the other cohort, the ratio was 4 patients receiving palifermin to 3 receiving placebo, in blocks of 14. No stratification was performed for either cohort of patients. The statistician provided both randomization lists to the pharmacy, so the patient and the clinical research team (who assessed outcomes) were blinded to the study treatment. At patient enrollment, the research team notified the pharmacy, which assigned the patient the next sequential slot and treatment from the appropriate randomization list on the basis of whether he or she had consented to pharmacokinetic sampling. The pharmacy provided the research team with the blinded study medication. Upon completion of the study, pharmacy provided the statistician with the 2 randomization lists, including individual patient treatment assignments, for analysis.

Patients were randomly assigned to receive palifermin, 180 µg/kg, or placebo intravenously as a single dose 3 days before chemotherapy in each cycle. Chemotherapy included doxorubicin (total dosage, 90 mg per m2 of body surface area) administered by continuous intravenous infusion over 72 hours and ifosfamide (total dosage, 10 g/m2), administered by 3-hour intravenous infusion for 4 days. All patients also received mesna with ifosfamide at standard dosages for uroprotection (23). Patients with osteosarcoma received the same doses of doxorubicin with cisplatin (120 mg/m2) intra-arterially. Pegfilgrastim was administered on the day after chemotherapy. The chemotherapy cycles (maximum, 6 cycles) were repeated every 3 weeks after recovery. All patients were instructed to rinse their mouth approximately 5 times per day with a salt and soda solution. However, use of specific prophylactic measures for mucositis, such as various commercially available or investigational mouthwash solutions or oral rinses, oprelvekin, granulocyte-macrophage colony-stimulating factor, l-glutamine, amifostine, or bioadherent oral gel, were not permitted. The appropriate standard supportive care measures for oral mucositis, including basic oral hygiene, analgesia, infection management, and parenteral nutrition, were provided when needed.

The World Health Organization (WHO) has established 4 grades of mucositis severity: no mucositis (grade 0); soreness and erythema (grade 1); erythema and ulcers, patient can swallow solid food (grade 2); ulcers with extensive erythema and inability to swallow solid food (grade 3); and mucositis so extensive that oral alimentation is not possible, including swallowing liquids (grade 4). Patients who had severe (grade 3 or 4) mucositis during blinded cycles received open-label palifermin at the same dosages in subsequent chemotherapy cycles. The dose of doxorubicin was reduced to 75 mg/m2 in patients with recurrent severe mucositis.

Amgen (Thousand Oaks, California) manufactured and provided both the palifermin and its matching placebo. The reconstituted palifermin solution contained palifermin, 5 mg/mL; mannitol, 4%; sucrose, 2%; histidine, 10 mM; Tween 20, 0.01%, at a pH of 6.5; and no preservatives. The placebo contained all of these ingredients except palifermin.

Outcomes and Follow-up

The primary end point of the study was the incidence of moderate to severe (grade 2 or higher) mucositis. The other end points were the incidence of severe (grade 3 or 4) mucositis, duration of oral mucositis, patient-reported outcomes, use of narcotic analgesics, weight loss, and dose reductions or delays in chemotherapy.

Complete history and physical examination, including weight, were recorded before each cycle. The research team assessed patients for oral mucositis in each cycle at baseline before chemotherapy; at days 10, 12, and 14 and more often if mucositis did not resolve to grade 1; and at the end of the cycle. Patients were monitored for toxicity as inpatients or outpatients during chemotherapy. Oral mucositis was assessed by using the WHO oral toxicity scale as a primary scale and the Common Terminology Criteria for Adverse Events. In addition, patients were asked to record a daily oral mucositis score based on their pain and ability to eat and drink (0 = none; 1 = mild pain or soreness; 2 = painful sores, can eat solid foods; 3 = painful sores, cannot eat solid foods, requires liquid diet; and 4 = severe painful sores, cannot eat or drink, requires tube or venous fluids) on daily symptom record diaries. Patient-reported outcome data were collected during oral assessment visits by using a questionnaire to evaluate oral and throat soreness and ability to participate in activities of daily living, including eating, drinking, talking, brushing teeth, sleeping, overall health, and quality of life (17). Patient blood counts were monitored twice weekly and daily during severe myelosuppression, and serum electrolytes, chemistry, and amylase and lipase levels were measured before each cycle. In addition, blood samples were drawn from consenting patients before and after the first dose of the study drug for pharmacokinetic and biomarker development (subject of a separate report). To evaluate the biologic effects of treatment on mucosa, noninvasive optical imaging studies and oral punch biopsies were performed in consenting patients before and 48 to 72 hours after the first dose of the study drug. The tissue sections were stained immunohistochemically for Ki-67 and cyclin E to evaluate both proliferative and cell cycle status (2425).

Statistical Analysis

We chose a sample size of 48 patients to allow the study to detect an absolute difference of 50 percentage points in grade 2 to 4 mucositis between patients who received placebo (76%) and those who received palifermin (26%), using a 2-group, continuity-corrected chi-square test with 88% power and a 2-sided significance level of 5%. With 32 patients receiving palifermin, this sample size provided a 28% chance of detecting an adverse event with a true incidence of 1% and a nearly 97% chance of detecting an adverse event with an incidence of 10%.

Mucositis incidence (grades 1 to 4) and patient disposition during the blinded cycles were summarized on an event chart for all enrolled patients (26). We calculated cumulative incidence of grade 2 or higher mucositis, with early withdrawal due to chemotoxicity or progression as competing risks, by using the methods of Fine and Gray (2728). Time to moderate to severe (grade 2 or higher) mucositis in the blinded cycles was calculated from the date when chemotherapy was initiated to the first date of grade 2 or higher mucositis or the date of last follow-up if a patient did not present with grade 2 or higher mucositis. For patients with multiple grade 2 or higher mucositis events, we used the date of the first such occurrence.

We used the cmprsk package (29) for the R computing language (R Foundation for Statistical Computing, Vienna, Austria) to conduct competing risk analyses for all blinded cycles. This allowed us to estimate the cumulative incidence, which was our focus because we sought to evaluate the treatment effects of palifermin on an adverse effect (mucositis) of chemotherapy. Similar methods were used to assess the cumulative incidence of grade 3 or 4 mucositis. Progression-free survival was assessed by using the Kaplan–Meier method. Comparisons of patient-reported outcomes and adverse events were examined during the first 2 blinded cycles. All continuous variables were analyzed by using the Wilcoxon rank-sum test, and all categorical variables were analyzed by using the chi-square test. All statistical analyses were conducted on the basis of each patient's original treatment assignment, and no subgroup analyses were performed. Analyses were carried out by using SAS, version 9.1.3 (SAS Institute, Cary, North Carolina); S-plus (Insightful, Seattle, Washington); and R. All tests were 2-sided with a significance level of 5%.

Role of the Funding Source

Amgen provided the palifermin and partial funding for the study. The collection, analysis, and the interpretation of the data and the decision to submit the manuscript for publication were under the control of the principal investigator.

Patients

Forty-nine patients were enrolled between December 2005 and February 2008, with the last follow-up in May 2008 (Figure 1). One patient withdrew and 48 patients were randomly assigned (32 to the palifermin group and 16 to the placebo group). Of these, 25 were men and 23 were women, with a median age of 45 years (range, 15 to 64 years) and a median Karnofsky performance status of 90 (range, 80 to 100). Patients in both groups were balanced with regard to both age and sex, and all patients had normal mucosa at baseline (Table 1). Seven patients had had previous radiotherapy to the tumor (excluding the head and neck area), and all were chemotherapy-naive, except for 2 patients in the palifermin group who had received 1 previous regimen. All patients were evaluable for toxicity and response to palifermin.

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Figure 1.
Study flow diagram.

* One patient returned home for further treatment.

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Table Jump PlaceholderTable 1.  Baseline Characteristics of Study Patients
Clinical Efficacy
Blinded Phase

The incidence and severity of mucositis were significantly reduced in the palifermin group compared with the placebo group (Table 2). Patients in the palifermin group had a lower cumulative incidence of grade 2 or higher mucositis (44% vs. 88%; P < 0.001; difference, −44 percentage points (95% CI, −71 to −16 percentage points]) and grade 3 or 4 mucositis (13% vs. 51%; P = 0.002; difference, −38 percentage points [CI, −67 to −9 percentage points]) (Figure 2). These patients also had a shorter duration of grade 2 or higher mucositis and grade 3 or 4 mucositis. The median duration of grade 2 or higher mucositis in the blinded cycles was 4.5 days (range, 1 to 15 days) versus 7.5 days (range, 2 to 16 days), and that of grade 3 or 4 mucositis was 3 days (range, 2 to 5 days) versus 6 days (range, 3 to 13 days) for the palifermin and placebo groups, respectively.

Table Jump PlaceholderTable 2.  Effect of Palifermin Versus Placebo on the Incidence, Severity, and Duration of Mucositis and Patient-Reported Outcomes in the Blinded Phase
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Figure 2.
Cumulative incidence of oral mucositis in the palifermin and placebo groups.

Incidence was measured according to the World Health Organization scale, determined by the oral assessment. Cumulative incidence of grade 2 or higher mucositis was significantly reduced (88% [95% CI, 52% to 97%] vs. 44% [CI, 24% to 62%]; P < 0.001 by the Fine and Gray {27, 28} method]) (top), as was that of grade 3 or 4 mucositis (51% [CI, 23% to 73%] vs. 13% [CI, 4% to 27%]; P = 0.002]) (bottom). C1D1 = cycle 1, day 1.

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The results from our objective oral assessment (WHO grading) correlated with the patients' subjective assessment (Appendix Figure), as reported in their daily diaries (weighted κ, 0.63 [CI, 0.47 to 0.79]; P < 0.001). Overall, both assessments indicate a significant reduction in grades 2 to 4 mucositis and an increase in grades 0 and 1 mucositis in the palifermin group compared with the placebo group during the blinded cycles.

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Appendix Figure.
Concordance between research team assessment and patient-reported grading.

Incidence of maximum grades of mucositis experienced by patients, as reported by the clinical research team using the World Health Organization assessment scale and by the patient-reported score in the daily symptom record diary. Circles are shown at the various World Health Organization grade–patient score pairs, with each circle's size based on the number of patients with that grading. The objective assessment of mucositis severity correlated significantly with the patient-reported severity (weighted κ, 0.63 [95% CI, 0.47 to 0.79]; P < 0.001).

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On the basis of patient-reported outcome during the first 2 blinded cycles, the median scores of mouth, throat, and rectal soreness were significantly lower in the palifermin group than in the placebo group (Table 2 and Appendix Table 1). In addition, scores for activities of daily living, such as swallowing, drinking, eating, talking, and brushing teeth, were significantly better in the palifermin group than in the placebo group. We limited our analysis of the patient-reported outcomes to the first 2 blinded cycles because few patients were receiving placebo during the later blinded cycles.

Table Jump PlaceholderAppendix Table 1.  Patient-Reported Outcomes in the First 2 Blinded Cycles

Grade 3 or 4 mucositis was significantly delayed in the palifermin group (Figure 3). The duration of the blinded treatment received was significantly longer (median, 6 vs. 2 cycles; P = 0.002) and the proportion of patients who completed 6 blinded cycles was significantly higher (63% vs. 31%; P = 0.041) in the palifermin group than in the placebo group (Table 2). Patients in the palifermin group used fewer opioid analgesics than those in the placebo group (morphine equivalent per cycle, 28 mg vs. 161 mg; P = 0.013) during the blinded phase. Patients who received palifermin may have had less weight reduction in the first 2 blinded cycles than those who received placebo; the average cumulative weight loss was 1.3 kg versus 2.2 kg (difference, 0.9 kg [CI, −5.1 to 3.3 kg]).

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Figure 3.
Interval event chart displaying time and events during the blinded cycles for all patients.

Patients are listed by patient accession number. Mucositis is indicated by circles, with increasing size by grade and solid circles for grade 3 or 4 mucositis. Different symbols are used to depict patients who were unblinded (received open-label palifermin) or who withdrew early because of chemotoxicity, disease progression, radiation, or surgery. Patients are grouped first by presentation of grade 3 or 4 mucositis and then by reason for discontinuation within each treatment group. C1D1 = cycle 1, day 1.

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Open-Label Phase

Eight of 16 patients (50%) in the placebo group had grade 3 or 4 mucositis. Of these, 7 received open-label palifermin in the subsequent cycles; 1 patient left the study because of disease progression. In the placebo cycle, the median duration of grade 3 or 4 mucositis was 6 days (range, 3 to 12 days) and the median duration of grade 2 or higher mucositis was 9 days (range, 6 to 12 days) for these patients. Each of the patients avoided severe mucositis in the next and subsequent cycles (a total of 17) at the same doses of chemotherapy with open-label palifermin. The reduction in mucositis was associated with improvement in mouth and throat soreness and less difficulty in swallowing, drinking, eating, and talking.

Biology of Response to Palifermin

Many patients who received palifermin sensed thickening of the oral mucosa and tongue. Photographs taken 3 days after palifermin therapy began showed pronounced leukoedema of the buccal mucosa and gingiva (Figure 4). To better understand the mechanism of response to palifermin, we performed a histopathologic analysis of mucosal biopsy samples obtained from the 8 consenting patients before and after the first dose of the study drug. Biopsies of the buccal mucosa showed increased epithelial hyperplasia and a marked increase in levels of the proliferative marker Ki-67 in 5 of the 7 patients from the palifermin group, which further supports that the increase in proliferation may be palifermin induced (Figure 5). Biopsy results before and after therapy from patients who received placebo did not differ. The expression of cyclin E, a putative G1 marker, was also increased in 6 of the 7 patients from the palifermin group.

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Figure 4.
Photographs of a patient who experienced sensation of thickness of tongue and oral mucosa after a single dose of palifermin administered on day −3.

Photographs taken 3 days after palifermin therapy began show pronounced leukoedema of the buccal mucosa (top) and gingiva (bottom).

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Figure 5.
Photomicrographs of buccal mucosa.

A. Before palifermin therapy. B. Increased epithelial thickness of the buccal mucosa 3 days after a single dose of palifermin. C. Scattered positive nuclear brown Ki-67 staining of the basal layer before palifermin therapy. D. Marked increase in nuclear brown Ki-67 staining of the basal layer after palifermin therapy. E. Few, scattered positive brown nuclear cyclin E staining, a putative G1 phase marker, before palifermin therapy. F. Increased positive brown nuclear cyclin E staining after palifermin therapy.

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Clinical Safety

We administered a total of 52 blinded cycles in the placebo group and 160 in the palifermin group. Treatment with palifermin was well tolerated. Table 3 shows the common adverse effects that occurred during the first 2 blinded cycles, which included symptoms of thickness of oral mucosa, tongue, and lips (Figure 4); altered taste; flushing; warm sensation; and increased saliva. These adverse effects were mild to moderate and transient in nature. Similar side effects were observed during later cycles (Appendix Table 2), but they did not worsen in severity. During the study, 3 patients (2 in the palifermin group and 1 in the placebo group) had transient elevations in serum amylase levels (maximum grade, 1 [1 to 1.5 × the upper limit of normal]). In addition, 2 patients in the palifermin group, who had had no increase in serum amylase levels during the study, had elevated levels during the off-study period; 1 patient had a grade 1 increase 2 months after the last dose of palifermin during the post-operative period, and 1 had a grade 4 increase 3 months after the last dose of palifermin during severe sepsis syndrome. These increases were not attributed to the study drug. Two patients, 1 from each group, had transient increases in lipase levels (maximum grade, 1).

Table Jump PlaceholderTable 3.  Common Adverse Events in the First 2 Blinded Cycles
Table Jump PlaceholderAppendix Table 2.  Possible Adverse Events of Palifermin in the Blinded Cycles

Patients in the palifermin group had less severe nausea (grade 3 or 4 nausea, 11% [17 of 159 cycles] vs. 25% [13 of 52 cycles]; difference, −14 percentage points [CI, −3 to −28 percentage points; P = 0.010) and constipation (all grades combined, 36% [57 of 159 cycles] vs. 52% [27 of 52 cycles]; difference, −16 percentage points [CI, −31 to −1 percentage points; P = 0.040]). The incidence of diarrhea did not differ between groups (27% vs. 25%; difference, 2 percentage points [CI, −13 to 14 percentage points]), nor did that of neutropenic fever (31% vs. 27%; difference, 4 percentage points [CI, −11 to 16 percentage points]). For the 41 patients with measurable disease, objective tumor response did not differ (63% vs. 43%; difference, 19 percentage points [CI, −11 to 47 percentage points]), nor did progression-free survival (21 months [interquartile range, 10 to not reached] vs. 17 months [interquartile range, 4 to not reached]) between the palifermin and placebo groups.

Oral mucositis is one of the most common and serious toxicities of cancer treatment, with profound clinical and economic implications. Until recently, treatment of oral mucositis in patients receiving multicycle chemotherapy represented a clinically significant unmet medical need. In our study, palifermin significantly reduced the incidence, severity, and duration of mucositis in patients who received up to 6 cycles of chemotherapy. The clinical benefits of reduction in mucositis were significant mitigation of mouth and throat soreness and improvement in ability to drink, eat, and talk. These salutary effects were achieved with a single dose of palifermin administered before each chemotherapy cycle, even in patients who previously had severe mucositis.

Mucositis is one of the dose-limiting toxicities of doxorubicin. Palifermin therapy reduced the estimated cumulative incidence of grade 2 or higher mucositis by one half (44% vs. 88%) and significantly reduced that of severe (grade 3 or 4) mucositis (13% vs. 51%). Palifermin also shortened the duration of painful mucositis (grades 2 to 4) more than placebo and delayed the time to first occurrence of mucositis. As a result, a greater proportion of patients who received palifermin completed 6 blinded cycles (63% vs. 31%). In addition, 7 of the 8 patients in the placebo group who had severe mucositis received palifermin in the open-label phase. All of these patients avoided the recurrence of severe mucositis in subsequent cycles, while receiving the same chemotherapy doses. However, because of the smaller sample size of our study and the uncontrolled aspect of the open-label phase, future larger trials should investigate the efficacy of secondary prophylaxis with palifermin for preventing mucositis in patients who have already had mucositis associated with different agents causing mucosal toxicity in the previous cycle.

Our study showed that palifermin may confer mucosal protection by inducing hypertrophy of the mucosal lining, as shown by increased epithelial hyperplasia and expression of the proliferative marker Ki-67 before the mucosal injury. One potential concern is that palifermin-induced proliferation before chemotherapy may render mucosa more sensitive to chemotherapy-induced damage. However, the expression of cyclin E, a putative G1 marker, also increased, which suggests that most of the mucosal cells were not in S phase or were not actively dividing just before chemotherapy (2425). Thus, the thickened mucosal surface before chemotherapy might serve as an increased tissue reservoir from which to draw on after chemotherapy.

Treatment with palifermin was well tolerated. The main adverse effects were thickness of oral mucosa, altered taste, flushing, warm sensation, film coating of mouth, and transient elevations in amylase and lipase levels in a few patients, as described elsewhere (1619). The palifermin group had less severe nausea, which may be related to less alimentary tract mucosal damage from chemotherapy in the first 48 hours. The reduced constipation in the palifermin group may be related to the decreased use of opioids resulting from reduced mucositis. Tumor response and progression-free survival did not differ, which suggests that palifermin had no detrimental effect on the underlying cancer therapy.

The differences in the safety and efficacy profiles of palifermin and placebo could be considered a limitation of our study because of the perceived unblinding of an individual patient's treatment. However, we used multiple measures of assessment, including validated tools for both safety and efficacy, and the patients were assessed at each cycle by both research and clinical teams, including those without direct knowledge of the protocol. Other limitations include the small sample size, with an inadequate number of patients to compare the groups beyond 2 cycles; a relatively short follow-up; and treatment of 1 disease type with a doxorubicin-based regimen. Because of the small sample size, evidence about adverse effects is limited; this needs to be assessed in larger patient populations.

In summary, we believe that our findings have important clinical implications. Our study indicates that a single dose of palifermin used as primary prophylaxis can prevent severe mucositis associated with multiple cycles of chemotherapy with agents causing mucosal toxicity. Our findings also suggest that palifermin used as secondary prophylaxis can prevent the recurrence of severe mucositis in high-risk patients with previous mucosal injury. The reduction in mucositis had several clinical benefits, including alleviation of mucosal pain; decreased use of narcotics; and improvements in the ability to drink, eat, and talk. However, these results cannot be interpreted as supporting the use of palifermin with other standard-dose chemotherapy or with regimens with a lower risk for mucositis. Future, larger studies should investigate the effect of palifermin treatment compared with standard care on other clinically significant end points, such as treatment outcome and health care cost, in patients who receive multicycle treatment with agents associated with dose-limiting mucositis.

Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M. et al.  Mucositis Study Section of the Multinational Association for Supportive Care in Cancer Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004; 100:1995-2025. PubMed
CrossRef
 
Scully C, Epstein J, Sonis S.  Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: part 1, pathogenesis and prophylaxis of mucositis. Head Neck. 2003; 25:1057-70. PubMed
 
Mead GM.  Management of oral mucositis associated with cancer chemotherapy. Lancet. 2002; 359:815-6. PubMed
 
Sorensen JB, Skovsgaard T, Bork E, Damstrup L, Ingeberg S.  Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies. Cancer. 2008; 112:1600-6. PubMed
 
Potting CM, Uitterhoeve R, OpReimer WS, VanAchterberg T.  The effectiveness of commonly used mouthwashes for the prevention of chemotherapy-induced oral mucositis: a systematic review. Eur J Cancer Care (Engl). 2006; 15:431-9. PubMed
 
Epstein JB, Klasser GD.  Emerging approaches for prophylaxis and management of oropharyngeal mucositis in cancer therapy. Expert Opin Emerg Drugs. 2006; 11:353-73. PubMed
 
Lalla RV, Peterson DE.  Treatment of mucositis, including new medications. Cancer J. 2006; 12:348-54. PubMed
 
Worthington HV, Clarkson JE, Eden OB.  Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2007; CD000978. PubMed
 
Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology.  Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007; 109:820-31. PubMed
 
Papas AS, Clark RE, Martuscelli G, O'Loughlin KT, Johansen E, Miller KB.  A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31:705-12. PubMed
 
Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA.  Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A. 1989; 86:802-6. PubMed
 
Farrell CL, Rex KL, Kaufman SA, Dipalma CR, Chen JN, Scully S. et al.  Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. Int J Radiat Biol. 1999; 75:609-20. PubMed
 
Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL. et al.  Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res. 1998; 58:933-9. PubMed
 
Borges L, Rex KL, Chen JN, Wei P, Kaufman S, Scully S. et al.  A protective role for keratinocyte growth factor in a murine model of chemotherapy and radiotherapy-induced mucositis. Int J Radiat Oncol Biol Phys. 2006; 66:254-62. PubMed
 
Dörr W, Heider K, Spekl K.  Reduction of oral mucositis by palifermin (rHuKGF): dose-effect of rHuKGF. Int J Radiat Biol. 2005; 81:557-65. PubMed
 
Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T. et al.  Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004; 351:2590-8. PubMed
 
Stiff PJ, Emmanouilides C, Bensinger WI, Gentile T, Blazar B, Shea TC. et al.  Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J Clin Oncol. 2006; 24:5186-93. PubMed
 
Stiff PJ, Erder H, Bensinger WI, Emmanouilides C, Gentile T, Isitt J. et al.  Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopoietic stem cell transplantation (HSCT). Bone Marrow Transplant. 2006; 37:393-401. PubMed
 
Meropol NJ, Somer RA, Gutheil J, Pelley RJ, Modiano MR, Rowinsky EK. et al.  Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol. 2003; 21:1452-8. PubMed
 
Rosen LS, Abdi E, Davis ID, Gutheil J, Schnell FM, Zalcberg J. et al.  Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol. 2006; 24:5194-200. PubMed
 
Vadhan-Raj S, Broxmeyer HE, Hittelman WN, Papadopoulos NE, Chawla SP, Fenoglio C. et al.  Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level. J Clin Oncol. 1992; 10:1266-77. PubMed
 
Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, et al. MRC BO06 and EORTC 80931 collaborators.  Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007; 99:112-28. PubMed
 
Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J. et al.  Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998; 21:317-21. PubMed
 
Bartek J, Lukas J.  Cell cycle. Order from destruction. Science. 2001; 294:66-7. PubMed
 
Neganova I, Lako M.  G1 to S phase cell cycle transition in somatic and embryonic stem cells. J Anat. 2008; 213:30-44. PubMed
 
Lee JJ, Hess KR, Dubin JA.  Extensions and applications of event charts. Am Stat. 2000; 54:63-70.
 
Gray RJ.  A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988; 16:1141-54.
 
Fine JP, Gray RJ.  A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999; 94:496-509.
 
Gray RJ.  cmprsk: subdistribution analysis of competing risks. R package version 2.1-5. 2004. Accessed athttp://biowww.dfci.harvard.edu/~grayon 26 July 2010.
 

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

* One patient returned home for further treatment.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Cumulative incidence of oral mucositis in the palifermin and placebo groups.

Incidence was measured according to the World Health Organization scale, determined by the oral assessment. Cumulative incidence of grade 2 or higher mucositis was significantly reduced (88% [95% CI, 52% to 97%] vs. 44% [CI, 24% to 62%]; P < 0.001 by the Fine and Gray {27, 28} method]) (top), as was that of grade 3 or 4 mucositis (51% [CI, 23% to 73%] vs. 13% [CI, 4% to 27%]; P = 0.002]) (bottom). C1D1 = cycle 1, day 1.

Grahic Jump Location
Grahic Jump Location
Appendix Figure.
Concordance between research team assessment and patient-reported grading.

Incidence of maximum grades of mucositis experienced by patients, as reported by the clinical research team using the World Health Organization assessment scale and by the patient-reported score in the daily symptom record diary. Circles are shown at the various World Health Organization grade–patient score pairs, with each circle's size based on the number of patients with that grading. The objective assessment of mucositis severity correlated significantly with the patient-reported severity (weighted κ, 0.63 [95% CI, 0.47 to 0.79]; P < 0.001).

Grahic Jump Location
Grahic Jump Location
Figure 3.
Interval event chart displaying time and events during the blinded cycles for all patients.

Patients are listed by patient accession number. Mucositis is indicated by circles, with increasing size by grade and solid circles for grade 3 or 4 mucositis. Different symbols are used to depict patients who were unblinded (received open-label palifermin) or who withdrew early because of chemotoxicity, disease progression, radiation, or surgery. Patients are grouped first by presentation of grade 3 or 4 mucositis and then by reason for discontinuation within each treatment group. C1D1 = cycle 1, day 1.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Photographs of a patient who experienced sensation of thickness of tongue and oral mucosa after a single dose of palifermin administered on day −3.

Photographs taken 3 days after palifermin therapy began show pronounced leukoedema of the buccal mucosa (top) and gingiva (bottom).

Grahic Jump Location
Grahic Jump Location
Figure 5.
Photomicrographs of buccal mucosa.

A. Before palifermin therapy. B. Increased epithelial thickness of the buccal mucosa 3 days after a single dose of palifermin. C. Scattered positive nuclear brown Ki-67 staining of the basal layer before palifermin therapy. D. Marked increase in nuclear brown Ki-67 staining of the basal layer after palifermin therapy. E. Few, scattered positive brown nuclear cyclin E staining, a putative G1 phase marker, before palifermin therapy. F. Increased positive brown nuclear cyclin E staining after palifermin therapy.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1.  Baseline Characteristics of Study Patients
Table Jump PlaceholderTable 2.  Effect of Palifermin Versus Placebo on the Incidence, Severity, and Duration of Mucositis and Patient-Reported Outcomes in the Blinded Phase
Table Jump PlaceholderAppendix Table 1.  Patient-Reported Outcomes in the First 2 Blinded Cycles
Table Jump PlaceholderTable 3.  Common Adverse Events in the First 2 Blinded Cycles
Table Jump PlaceholderAppendix Table 2.  Possible Adverse Events of Palifermin in the Blinded Cycles

References

Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M. et al.  Mucositis Study Section of the Multinational Association for Supportive Care in Cancer Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004; 100:1995-2025. PubMed
CrossRef
 
Scully C, Epstein J, Sonis S.  Oral mucositis: a challenging complication of radiotherapy, chemotherapy, and radiochemotherapy: part 1, pathogenesis and prophylaxis of mucositis. Head Neck. 2003; 25:1057-70. PubMed
 
Mead GM.  Management of oral mucositis associated with cancer chemotherapy. Lancet. 2002; 359:815-6. PubMed
 
Sorensen JB, Skovsgaard T, Bork E, Damstrup L, Ingeberg S.  Double-blind, placebo-controlled, randomized study of chlorhexidine prophylaxis for 5-fluorouracil-based chemotherapy-induced oral mucositis with nonblinded randomized comparison to oral cooling (cryotherapy) in gastrointestinal malignancies. Cancer. 2008; 112:1600-6. PubMed
 
Potting CM, Uitterhoeve R, OpReimer WS, VanAchterberg T.  The effectiveness of commonly used mouthwashes for the prevention of chemotherapy-induced oral mucositis: a systematic review. Eur J Cancer Care (Engl). 2006; 15:431-9. PubMed
 
Epstein JB, Klasser GD.  Emerging approaches for prophylaxis and management of oropharyngeal mucositis in cancer therapy. Expert Opin Emerg Drugs. 2006; 11:353-73. PubMed
 
Lalla RV, Peterson DE.  Treatment of mucositis, including new medications. Cancer J. 2006; 12:348-54. PubMed
 
Worthington HV, Clarkson JE, Eden OB.  Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2007; CD000978. PubMed
 
Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, et al. Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology.  Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007; 109:820-31. PubMed
 
Papas AS, Clark RE, Martuscelli G, O'Loughlin KT, Johansen E, Miller KB.  A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31:705-12. PubMed
 
Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA.  Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A. 1989; 86:802-6. PubMed
 
Farrell CL, Rex KL, Kaufman SA, Dipalma CR, Chen JN, Scully S. et al.  Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. Int J Radiat Biol. 1999; 75:609-20. PubMed
 
Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL. et al.  Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res. 1998; 58:933-9. PubMed
 
Borges L, Rex KL, Chen JN, Wei P, Kaufman S, Scully S. et al.  A protective role for keratinocyte growth factor in a murine model of chemotherapy and radiotherapy-induced mucositis. Int J Radiat Oncol Biol Phys. 2006; 66:254-62. PubMed
 
Dörr W, Heider K, Spekl K.  Reduction of oral mucositis by palifermin (rHuKGF): dose-effect of rHuKGF. Int J Radiat Biol. 2005; 81:557-65. PubMed
 
Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T. et al.  Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004; 351:2590-8. PubMed
 
Stiff PJ, Emmanouilides C, Bensinger WI, Gentile T, Blazar B, Shea TC. et al.  Palifermin reduces patient-reported mouth and throat soreness and improves patient functioning in the hematopoietic stem-cell transplantation setting. J Clin Oncol. 2006; 24:5186-93. PubMed
 
Stiff PJ, Erder H, Bensinger WI, Emmanouilides C, Gentile T, Isitt J. et al.  Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopoietic stem cell transplantation (HSCT). Bone Marrow Transplant. 2006; 37:393-401. PubMed
 
Meropol NJ, Somer RA, Gutheil J, Pelley RJ, Modiano MR, Rowinsky EK. et al.  Randomized phase I trial of recombinant human keratinocyte growth factor plus chemotherapy: potential role as mucosal protectant. J Clin Oncol. 2003; 21:1452-8. PubMed
 
Rosen LS, Abdi E, Davis ID, Gutheil J, Schnell FM, Zalcberg J. et al.  Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol. 2006; 24:5194-200. PubMed
 
Vadhan-Raj S, Broxmeyer HE, Hittelman WN, Papadopoulos NE, Chawla SP, Fenoglio C. et al.  Abrogating chemotherapy-induced myelosuppression by recombinant granulocyte-macrophage colony-stimulating factor in patients with sarcoma: protection at the progenitor cell level. J Clin Oncol. 1992; 10:1266-77. PubMed
 
Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, et al. MRC BO06 and EORTC 80931 collaborators.  Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst. 2007; 99:112-28. PubMed
 
Patel SR, Vadhan-Raj S, Burgess MA, Plager C, Papadopolous N, Jenkins J. et al.  Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol. 1998; 21:317-21. PubMed
 
Bartek J, Lukas J.  Cell cycle. Order from destruction. Science. 2001; 294:66-7. PubMed
 
Neganova I, Lako M.  G1 to S phase cell cycle transition in somatic and embryonic stem cells. J Anat. 2008; 213:30-44. PubMed
 
Lee JJ, Hess KR, Dubin JA.  Extensions and applications of event charts. Am Stat. 2000; 54:63-70.
 
Gray RJ.  A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988; 16:1141-54.
 
Fine JP, Gray RJ.  A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999; 94:496-509.
 
Gray RJ.  cmprsk: subdistribution analysis of competing risks. R package version 2.1-5. 2004. Accessed athttp://biowww.dfci.harvard.edu/~grayon 26 July 2010.
 

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Summary for Patients

Palifermin Can Prevent Severe Oral Mucositis During Chemotherapy

The summary below is from the full report titled “Single-Dose Palifermin Prevents Severe Oral Mucositis During Multicycle Chemotherapy in Patients With Cancer. A Randomized Trial.” It is in the 21 September 2010 issue of Annals of Internal Medicine (volume 153, pages 358-367). The authors are S. Vadhan-Raj, J. Trent, S. Patel, X. Zhou, M.M. Johnson, D. Araujo, J.A. Ludwig, S. O'Roark, A.M. Gillenwater, C. Bueso-Ramos, A.K. El-Naggar, and R.S. Benjamin.

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