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Phase II Study of Palifermin and Concurrent Chemoradiation in Head and Neck Squamous Cell Carcinoma

David M. Brizel, Barbara A. Murphy, David I. Rosenthal, Kishan J. Pandya, Stefan Glück, Herbert E. Brizel, Ruby F. Meredith, Dietmar Berger, Mon-Gy Chen, William Mendenhall

From the Departments of Radiation Oncology and Surgery, Duke University, Durham, NC; Department of Medical Oncology, Vanderbilt University, Nashville, TN; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA; Department of Medicine and Oncology, University of Rochester, Rochester, NY; Division of Hematology Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami; Department of Radiation Oncology, Memorial Hospital, Hollywood, FL; Department of Radiation Oncology, University of Florida, Gainesville, FL; Department of Radiation Oncology, University of Alabama, Birmingham, AL; and Clinical Development and Biostatistics, Amgen Inc, Thousand Oaks, CA

Corresponding author: David Brizel, MD, Duke University Medical Center, 05135 Morris Bld, Durham, NC 27710; e-mail: brizel{at}radonc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Acute mucositis is a dose-limiting toxicity of concurrent chemoradiotherapy regimens for locally advanced head and neck cancer. Palifermin (a recombinant human keratinocyte growth factor; N23-KGF) stimulates the proliferation and differentiation of mucosal epithelium to reduce mucositis in patients receiving intensive therapy for hematologic cancers. This study assessed the efficacy and safety of palifermin in patients receiving concurrent chemoradiotherapy for advanced head and neck squamous cell carcinoma.

Patients and Methods In a phase II trial, standard radiotherapy was delivered in daily 2-Gy fractions to 70 Gy, or hyperfractionated radiotherapy was delivered in 1.25-Gy fractions twice daily to 72 Gy, over 7 weeks. Chemotherapy included cisplatin 20 mg/m² for 4 days and continuous-infusion fluorouracil 1,000 mg/m²/d for 4 days on weeks 1 and 5 of irradiation. Patients were randomly assigned 2:1 to palifermin 60 µg/kg or placebo once weekly for 10 doses. A follow-up trial evaluated long-term survival.

Results Sixty-seven patients received palifermin and 32 received placebo. The median duration of grade 2 mucositis was 6.5 and 8.1 weeks in the palifermin and placebo groups, respectively (P = .157). Palifermin appeared to reduce mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy (n = 40) but not standard radiation therapy (n = 59). Adverse events were similar between treatment groups. Palifermin did not alter tumor response or survival.

Conclusion Ten once-weekly doses of palifermin at 60 µg/kg were well tolerated. Most patients completed treatment, but palifermin did not reduce the morbidity of concurrent chemotherapy and radiotherapy. Future studies should evaluate higher palifermin doses with longer and more standardized assessment of acute mucositis.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Mucositis develops early in the treatment of head and neck squamous cell carcinoma (HNSCC) and leads to odynophagia, dysphagia, infections, and treatment prolongation.^1-3 Many patients require intensive and sustained nutritional support including feeding tube placement.⁴ Concurrent chemotherapy exacerbates the incidence, severity, and duration of mucositis making this toxicity dose limiting.^5-7 No therapeutic strategies have consistently ameliorated treatment-induced mucositis in HNSCC.^8-14

Keratinocyte growth factor (KGF) is a fibroblast growth factor (FGF-7)^15,16 that stimulates cell proliferation, migration, differentiation, survival, and DNA repair, and induces detoxification of reactive oxygen species.^17,18 Recombinant human KGF (palifermin; N23-KGF) is approved for use in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support.¹⁹ Two studies of palifermin in HNSCC are reported herein. A randomized placebo-controlled study evaluated the safety and efficacy of palifermin treatment for mucositis, dysphagia, and xerostomia in patients with locally advanced HNSCC receiving chemoradiotherapy (CRT). A subsequent follow-up observational study included some of the participants in the randomized study and evaluated progression-free survival and overall survival because tumor protection is a potential risk of any cytoprotective strategy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
A multicenter, double-blind, randomized, placebo-controlled study was conducted at 22 centers, of which 18 in Australia, Canada, and the United States accrued patients (online-only Appendix). All study treatment and most study assessments occurred during an initial 12-week treatment and evaluation period. During a short-term follow-up period through week 20, evaluations of toxicity resolution and patient-reported outcomes were performed. The trial was conducted September 1999 to May 2001. Patients who completed the randomized study could choose to enroll in a separate long-term follow-up study that is ongoing; this report includes survival data through September 2006.

Study Population
Eligibility criteria. Adults with newly diagnosed stage III/IVa or IVb squamous carcinoma of the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx undergoing curative-intent CRT were eligible. Patients with unknown primary and extensive neck disease were also eligible. Other criteria included Karnofsky performance score 60, hemoglobin 10 g/dL; WBC count 3.5 x 10⁹/L or absolute neutrophil count 1.5 x 10⁹/L; platelet count 100 x 10⁹/L; serum bilirubin 1.5 mg/dL; and serum creatinine lower than 2.0 mg/dL (plus a 24-hour urinary creatinine clearance 50 mL/min in patients age 60 years).

Exclusion criteria. Patients were ineligible if they had prior head and neck radiation therapy, prior surgery for the primary tumor beyond biopsy, prior chemotherapy, or known allergy to Escherichia coli-derived products. Patients were excluded for participation in another investigational device/drug study within the prior 30 days, refusal to use adequate contraception during the study, or were pregnant or breast feeding.

The study was approved by institutional review boards for every site, and each patient gave written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and in compliance with guidelines and regulations from the US Food and Drug Administration, the Canadian Health Protection Branch, and the International Conference on Harmonisation Good Clinical Practice.

Treatment
Radiation therapy. Online-only Figure A1 summarizes treatment. Isocentric 4 to 6 MV photons were administered either as standard fractionation radiotherapy (SRT) and hyperfractionated radiotherapy (HRT). Each center declared which scheme would be used, and all patients at that center received the same schedule. Standard radiation therapy consisted of once daily 2-Gy fractions 5 days/week: total primary tumor dose of 70 Gy. Hyperfractionated radiation therapy was modified from a previously described regimen in which patients receiving radiation therapy with or without concurrent chemotherapy had very high rates of grade 3 mucositis⁶ and received 1.25 Gy twice daily (6-hour interfraction interval) to 37.5 Gy. A single 2-Gy fraction was then given followed by a planned 1-week treatment break. Twice-daily radiation therapy then resumed: total dose of 72 Gy/6.5 weeks. Adjuvant neck dissections were performed 6 to 8 weeks thereafter as clinically indicated in N2-N3 patients.

Conventional three field technique was utilized. Three-dimensional conformal treatment and intensity-modulated radiotherapy were not used. Field reductions at 39.5 to 40 Gy excluded the spinal cord. Involved posterior cervical nodes received electron boosts. Quality assurance was performed at the Radiation Therapy Quality Assurance Center (Tampa, FL) including an initial review of treatment fields and dose calculations during the first week of treatment. Two investigators (D.M.B., W.M.) performed a blinded review of all treatment fields after treatment completion.

Chemotherapy. Cisplatin (CDDP) 20 mg/m²/d was administered as an intravenous bolus injection and fluorouracil 1,000 mg/m²/d as a continuous infusion on the first 4 days of the first and fifth weeks of radiation therapy. Patients were thoroughly hydrated before daily CDDP administration.

Palifermin. Palifermin (Kepivance; Amgen Inc, Thousand Oaks, CA) 60 µg/kg or matching placebo was administered by intravenous bolus injection on Friday (study day 1) before the first week of CRT. Subsequent doses were administered for 7 consecutive weeks, on each Friday after completion of weekly radiation treatment. Two additional doses were given on weeks 8 and 9.

This trial was double blinded and placebo controlled with a 2:1 ratio of palifermin:placebo. Stratification parameters included tumor location (oral cavity, oropharynx/nasopharynx, and hypopharynx/larynx) and radiation therapy schedule. Investigators could prescribe supportive care other than pilocarpine, amifostine, other biologic response modifiers, institutional mouthwash formulations, oral comfort aids, and prophylactic antimicrobials. Saline mouthwash and/or topical lidocaine/xylocaine were permitted. Hematopoietic growth factors were permitted for clinically labeled indications.

Data Collection
During the first 12 weeks, a radiation oncologist performed a full head and neck examination at the end of each week, including ratings of mucositis, xerostomia, and dysphagia with version 2.0 of the National Cancer Institute Common Toxicity Criteria (CTC). During the first 7 weeks only (during radiation therapy), a research team member performed a limited oral cavity and swallowing assessment once weekly, at least 48 hours apart from the full examination, also using CTC. The Radiation Therapy Oncology Group (RTOG) late radiation morbidity scale was used to assess toxicities at weeks 14, 16, 18, and 20.

Adverse-event reports were collected throughout the study. Tumor measurements for locoregional control were done at baseline and week 12 by magnetic resonance imaging or computed tomography scan. Amylase and lipase concentrations were measured at baseline and weeks 1, 5, and 12. Clinical laboratory tests (chemistry and hematology) were performed at a central laboratory. Antipalifermin antibodies were measured by enzyme-linked immunosorbent assay at baseline and week 12.

Patients completing the randomized study and enrolling in the long-term follow-up study were assessed for overall survival and progression-free survival at 3, 6, 9, and 12 months, and then once annually. Survival assessments continued until death or loss to follow-up.

Statistical Considerations
The primary end point was duration of grade 2 oral mucositis during the first 12 weeks of treatment. Analyses were performed on all patients who received at least one dose of study medication. Statistical comparisons were performed with Cox proportional hazards regression with treatment, tumor site, and radiation therapy schedule in the models.

A sample size of 99 patients was sufficient to detect a difference of 30% in duration of grade 2 mucositis between treatment arms with 80% power if the mean duration in the placebo arm was 56 days, based on results of a previous phase I/II study.²⁰ A dropout rate of 10% would result in 87 patients completing the study.

Secondary efficacy end points included incidence, duration, time to onset, and cumulative radiation therapy dose at onset of mucositis, dysphagia, and xerostomia; incidence of nonscheduled treatment breaks; and incidence of supplemental feeding, narcotic analgesic use, and antibiotic use. Subgroup analyses were performed to assess the influence of radiation therapy schedule (SRT or HRT) on efficacy end points.

Safety end points included incidences of adverse events during weeks 1 to 20, tumor response rates at week 12, and Kaplan-Meier estimates with log-rank test for treatment comparison of progression-free and overall survival during long-term follow-up.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Study Population
Ninety-nine of 100 patients who were randomly assigned (67 palifermin, 32 placebo) received at least one dose of study treatment and were evaluated. Baseline demographic and clinical characteristics were similar between groups (Table 1). Figure 1 summarizes patient disposition. Three patients in the palifermin group and one in the placebo group discontinued study treatment with adverse events not considered related to study treatment. Treatment completion rates were comparable between the palifermin and placebo groups. The median number of study treatment doses was 10 in each group, with a mean of 8.4 doses of palifermin and 9.1 doses of placebo.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition.

Mucositis
Figure 2 shows duration of grade 2 mucositis and grade 3 mucositis. The primary efficacy end point, median duration of grade 2 mucositis, was shorter for palifermin than for placebo (6.5 and 8.1 weeks, respectively), but the difference was not statistically significant (P = .157). The proportion of patients that still had grade 2 mucositis at week 12 was 47% in the palifermin group and 42% in the placebo group. Most patients experienced at least one episode of grade 2 mucositis (Fig 3A). The palifermin and placebo groups were similar regarding median time to onset of grade 2 mucositis (2.6 and 2.7 weeks) and median radiation dose to onset of grade 2 mucositis (22.3 and 22.0 Gy).

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Duration of mucositis between week 1 and week 12. P values between the palifermin and placebo groups overall: grade 2 mucositis, P = .157; grade 3 mucositis, P = .177. P values not determined for retrospective subset analyses. SRT, standard fractionation radiotherapy; HRT, hyperfractionated radiotherapy.

View larger version (55K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Incidence during weeks 1 to 12 of (A) mucositis, (B) dysphagia, and (C; next page) xerostomia by National Cancer Institute Common Toxicity Criteria version 2 toxicity grade. Note: there were no reports of grade 3 xerostomia. SRT, standard fractionation radiotherapy; HRT, hyperfractionated radiotherapy.

A greater decrease in the incidence of mucositis with palifermin treatment was observed among HRT-treated patients than among SRT-treated patients (Fig 3A). In addition, duration of mucositis was shorter in the palifermin group than in the placebo group among HRT-treated patients, but not among SRT-treated patients (Fig 2).

Dysphagia
Most patients had grade 2 dysphagia (Fig 3B). Median values were similar between the palifermin and placebo groups for the time (2.6 and 2.7 weeks) and radiation dose (22.0 and 26.0 Gy) to onset of grade 2 dysphagia. Median duration of grade 2 dysphagia could not be determined because approximately two thirds of patients in each treatment group continued to have grade 2 dysphagia at week 12.

The majority of patients had grade 3 dysphagia (Fig 3B); no differences were observed between treatment groups for onset or duration of this parameter. Palifermin appeared to decrease the incidence of dysphagia among HRT-treated patients, but not among SRT-treated patients (Fig 3B).

Xerostomia
The incidence of grade 2 xerostomia was similar between the palifermin and placebo groups (Fig 3C). Time to onset, radiation dose to onset, and duration of grade 2 xerostomia were comparable between treatment groups. Palifermin appeared to decrease the incidence of xerostomia among HRT-treated patients, but not among SRT-treated patients (Fig 3C).

Other Efficacy End Points
Fewer patients required unscheduled radiation therapy breaks in the palifermin group than in the placebo group (28% and 45%, respectively). The incidence of unscheduled radiation therapy breaks exceeding 4 days was comparable between groups (11% and 12%, respectively). Most patients in the palifermin and placebo groups received narcotic analgesics (91% and 94%, respectively) and therapeutic antifungals/antibiotics (87% and 88%, respectively).

There were 44 patients (66%) in the palifermin group and 22 patients (69%) in the placebo group who received supplemental nutrition. Most of these patients—43 (64%) in the palifermin group and 20 (63%) in the placebo group—received supplementation nutrition by gastrostomy tubes, which were usually placed prophylactically before CRT.

Patients were evaluated for toxicity resolution during weeks 12 to 20 using the RTOG toxicity scale. No differences were detected with respect to mucous membranes, salivary glands, or other organs during this interval.

Safety
The type, incidence, and severity of adverse events were similar between treatment groups. Six deaths occurred during the 20-week study period, including four patients (6%) in the palifermin group (one of myocardial infarction, one of sepsis, one of stroke, and one of unknown causes) and two patients (6%) in the placebo group (both of respiratory insufficiency); none of the deaths were considered related to study treatment.

The most commonly reported adverse events are presented in Table 2. Neutropenia (granulocytopenia) and dyspnea occurred with a greater incidence ( 10% difference) in the palifermin group, and nausea and anxiety occurred with a greater incidence in the placebo group. Most adverse events were considered secondary to CRT or underlying malignant disease and not related to study treatment. Two patients receiving palifermin had serious adverse events related to study drug (one patient had increased sputum production; the other had dehydration, dysphagia, pain, abdominal pain, and pancreatitis and was subsequently determined to have schistosomiasis).

View this table: [in this window] [in a new window]   Table 2. Adverse Events With a 10% Incidence by Preferred Term

Survival
Combined survival data from the randomized trial and the follow-up trial are presented in Figure 4. Median follow-up was 44.8 months (range, 0.4 to 74.3) for all patients and 53.1 months (range, 0.4 to 74.3) for survivors. Differences in overall survival (Fig 4A) and progression-free survival (Fig 4B) were not statistically significant (P > .7) between the groups receiving palifermin and placebo through more than 5 years of follow-up. Of the 22 cases of disease progression through 5 years of follow-up, most (n = 17) involved locoregional progression.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Kaplan-Meier survival curves for long-term follow-up by treatment group as of September 27, 2006. (A) Overall survival; (B) progression-free survival. Note: curve for locoregional control could not be determined from the available data.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

A significant limitation of the trial design in retrospect was our assignment of a 12-week cutoff to the CTC scale for assessment of the primary end point of acute mucositis. Nearly 50% of patients in this trial still had grade 2 mucositis and dysphagia 12 weeks after the start of treatment. Censoring all patients with grade 2 mucositis at this juncture may have reduced the sensitivity to detect a difference in duration if one existed. Toxicity resolution during weeks 12 to 20 was also analyzed in this trial, but using a different scale (RTOG) that prevented direct combination with the results from weeks 1 to 12. Duration of acute mucositis is considerably greater after concurrent CRT than radiation alone, a fact not universally appreciated when this study was designed. Ongoing studies are more robustly designed to follow acute mucositis until its resolution.

Another study limitation was that mucositis grading was not standardized across the 18 study centers. Prospective mucositis assessment training of the investigators to decrease both interobserver and interinstitutional variability should have been performed.²¹ This practice is also now a standard component of ongoing trials.

Higher mucositis rates were reported in this study than in many other trials of CRT, probably because mucositis was the primary end point. Most CRT trials have assessed antitumor efficacy as the primary end point and suffer from underreporting bias with respect to toxicity end points.^22-24 In a phase I/II study of palifermin in head and neck cancer that also used mucositis as a primary study end point,²⁰ the rates of grade 3 mucositis were similarly high (71% and 72% in the placebo group and the combined palifermin groups, respectively).

Sample size calculations assumed a 10% dropout rate. However, 25% and 13% of patients in the palifermin and placebo groups, respectively, discontinued the study early, primarily due to investigator decision. Future trials should have larger study populations and larger drop-out allowances.

Most importantly, the dose of palifermin was probably too low. A dose of 3 x 60 µg/kg was administered in the pivotal transplant trial, before and after total-body irradiation (12 Gy at 1.2 Gy twice per day).²⁵ The duration of severe mucositis was 1 to 2 orders of magnitude less in both arms of the transplant trial compared with this study, which is consistent with the much larger mucosal doses of RT delivered to patients with HNSCC. It is possible that 60 µg/kg applied once weekly still provided marginal protection to the HRT patients in this trial because of the similarity in fractionation regimen to the transplant trial. Recent studies have reported significantly higher levels of mucosal proliferation from palifermin at 120 µg/kg and 180 µg/kg compared with 60 µg/kg.²⁶ Ongoing trials of palifermin during CRT for HNSCC use these higher doses.

Palifermin was well tolerated compared with placebo and the majority of subjects in the palifermin group received all 10 scheduled doses. In the follow-up survival study, palifermin did not compromise rates of overall or progression-free survival through more than 5 years. Maintenance of antitumor therapeutic efficacy is a critical component of any cytoprotective program. Although the follow-up trial was inadequately powered to definitively address this concern, the longer follow-up relative to other pharmacologic radioprotection trials^27-29 is a step in the right direction. In vitro study of human head and neck cancer cell lines has shown neither growth stimulation nor alteration in radiosensitivity from KGF exposures up to 2 days.³⁰ Larger trials will improve the understanding of the clinical relevance of tumor stimulation.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.

Employment or Leadership Position: Dietmar Berger, Amgen (C); Mon-Gy Chen, Amgen (C) Consultant or Advisory Role: David M. Brizel, Amgen (C); Barbara A. Murphy, Amgen (C); David I. Rosenthal, Amgen (C); Stefan Gluck, Abraxis (C), Genentech (C), Pfizer (C), Sanofi (C), Amgen (C), Eli Lilly (C), Novartis (C), Merck (C), AstraZeneca (C), GlaxoSmithKline (C) Stock Ownership: David M. Brizel, Amgen; Dietmar Berger, Amgen; Mon-Gy Chen, Amgen Honoraria: Barbara A. Murphy, Amgen; Stefan Gluck, Abraxis, Genentech, Pfizer, Sanofi, Amgen, Eli Lilly, Novartis, Merck, AstraZeneca, GlaxoSmithKline Research Funding: David M. Brizel, Amgen; Barbara A. Murphy, Amgen; Stefan Gluck, Lilly, Pfizer, Genentech, Abraxis, Novartis, AstraZeneca; Ruby F. Meredith, Amgen Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: David M. Brizel, Dietmar Berger, Mon-Gy Chen

Financial support: Dietmar Berger

Provision of study materials or patients: David M. Brizel, Barbara A. Murphy, David I. Rosenthal, Kishan J. Pandya, Stefan Gluck, Herbert E. Brizel, Ruby F. Meredith, William Mendenhall

Collection and assembly of data: David M. Brizel, David I. Rosenthal, Dietmar Berger

Data analysis and interpretation: David M. Brizel, Barbara A. Murphy, David I. Rosenthal, Stefan Gluck, Dietmar Berger, Mon-Gy Chen

Manuscript writing: David M. Brizel, David I. Rosenthal, Stefan Gluck, Dietmar Berger, Mon-Gy Chen

Final approval of manuscript: David M. Brizel, Barbara A. Murphy, David I. Rosenthal, Kishan J. Pandya, Stefan Gluck, Herbert E. Brizel, Ruby F. Meredith, Dietmar Berger, Mon-Gy Chen, William Mendenhall

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The following study investigators accrued patients (listed alphabetically):

David Brizel, Durham, NC; Herbert Brizel, Hollywood, FL; Tony Eng, San Antonio, TX; Stefan Gluck, Calgary, Alberta, Canada; Don Goffinet, Stanford, CA; John Holland, Portland, OR; Michael Jackson, Camperdown, Australia; Anne-Marie Maddox, Little Rock, AR; William M. Mendenhall, Gainesville, FL; Ruby F. Meredith, Birmingham, AL; Barbara A. Murphy, Nashville, TN; James Oleson, Tucson, AZ; Kishan Pandya, Rochester, NY; Michael Poulsen, Queensland, Australia; David I. Rosenthal, Philadelphia, PA; Scott Sailer, Chapel Hill, NC; Gary Schreiber, Evanston, IL; and Te Vuong, Montreal, Ontario.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Treatment schema. CTC, National Cancer Institute Common Toxicity Criteria; RTOG, Radiation Therapy Oncology Group.

	ACKNOWLEDGMENTS

 
We thank Jonathan N. Latham, Amgen Inc, for writing assistance and Alan Rong, Amgen Inc, for performing statistical analyses.

	NOTES

 
Supported by Amgen Inc.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted July 29, 2007; accepted February 8, 2008.

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