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A multinational, randomized phase iii trial of iseganan hcl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy
Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 3, pp. 674 – 681, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/S0630-3016(04)01627-4
CLINICAL INVESTIGATION
Head and Neck
A MULTINATIONAL, RANDOMIZED PHASE III TRIAL OF ISEGANAN HCL ORAL SOLUTION FOR REDUCING THE SEVERITY OF ORAL MUCOSITIS IN PATIENTS RECEIVING RADIOTHERAPY FOR HEAD-AND-NECK MALIGNANCY ANDY TROTTI, M.D.,* ADAM GARDEN, M.D.,† PADRAIG WARDE, M.B.,‡ PAUL SYMONDS, M.B.,§ COREY LANGER, M.D.,¶ REBECCA REDMAN, M.D.,㛳 THOMAS F. PAJAK, PH.D.,# TOMAS R. FLEMING, PH.D.,** MICHAEL HENKE, M.D.,†† JEAN BOURHIS, M.D.,‡‡ DAVID I. ROSENTHAL, M.D.,† ELIZABETH JUNOR, M.D.,§§ ANTHONY CMELAK, M.D.,¶¶ FINBARR SHEEHAN, M.B.,㛳㛳 JANIS PULLIAM, PH.D.,㛳 PATRICIA DEVITT-RISSE, PHARM. D.,㛳 HENRY FUCHS, M.D.,㛳 MARK CHAMBERS, D.M.D.,† BRIAN O’SULLIVAN, M.B.,† AND K. KIAN ANG, M.D., PH.D.† *Radiation Oncology Program, H. Lee Moffitt Cancer Center at the University of South Florida, Tampa, FL; †Department of Radiation Oncology, M. D. Anderson Cancer Center, Houston, TX; ‡Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada; §Department of Oncology, Leicester Royal Infirmary, Leicester, United Kingdom; ¶Department of Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, PA; 㛳IntraBiotics Pharmaceuticals, Inc., Palo Alto, CA; #American College of Radiology, Philadelphia, PA; **Department of Biostatistics, University of Washington, Seattle, WA; ††Abteilung Strahlenheilkunde, Radiologische Universitaetsklinik, Freiburg, Germany; ‡‡Service de Radiotherapie, Institute Gustave-Roussy, Villejuif, France; §§Beatson Oncology Centre, Glasgow, United Kingdom; ¶¶Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN; 㛳㛳Department of Radiation Oncology, Vancouver Cancer Center, British Columbia Cancer Center, Vancouver, Canada Purpose: Oral mucositis (OM) causes significant morbidity during the course of radiotherapy (RT) treatment of head-and-neck cancer. It is hypothesized that infection plays a role in the development of OM. We tested the efficacy of iseganan HCl (iseganan), a synthetic peptide with broad-spectrum antimicrobial activity, for preventing RT-associated OM. Methods: A multinational, randomized, double-blind, controlled trial was performed on patients receiving primary RT, primary chemoradiotherapy or postoperative RT. Patients were randomized to receive iseganan oral solution plus standard-of-care oral hygiene (SOC), placebo plus SOC, or SOC alone throughout the RT administration period. The severity of OM was assessed by NCI-CTC scoring and clinical symptoms by patient questionnaire. Results: A total of 545 patients were randomized to the study. Nine percent of the patients in both the iseganan and placebo groups did not develop ulcerative OM (Grades 2, 3, 4) (p ⴝ 0.998) whereas only 2% of the patients receiving SOC alone remained free of oral ulceration (p ⴝ 0.049). The maximum severity of mouth pain and difficulty swallowing did not differ in patients treated with iseganan or placebo. However, patients in both intervention groups reported less mouth pain and difficulty swallowing than did patients receiving SOC alone. Nausea was the only adverse event that occurred with >5% increased frequency in the iseganan group than in either the placebo or SOC groups (51% vs. 42% vs. 46%). Adverse events leading to study drug discontinuation and death did not differ significantly between groups. Conclusion: Iseganan oral solution was safe but did not reduce the risk for developing ulcerative OM relative to placebo. Intensified oral hygiene or the administration of the vehicle used to deliver study drug in this trial appears to have reduced the risk and severity of OM. Our results suggest that antimicrobial intervention may not meaningfully affect the pathogenesis of radiation-induced OM. © 2004 Elsevier Inc. Iseganan, Mucositis, Oral mucositis, Radiotherapy, Head and neck.
Langer, Kian Ang, Thomas Pajak, Thomas Fleming, Janis Pulliam, and Pat Devitt-Risse served as paid consultants to IntraBiotics Pharmaceuticals, Inc., for the design and conduct of the trial and interpretation of the results. Acknowledgments—The American College of Radiology and the Radiation Therapy Oncology Group (RTOG) provided access to RTOG institutions and advice in study design and interpretation. Received May 13, 2003. Accepted for publication Jul 14, 2003.
Reprint requests to: Andy Trotti, M.D., H. Lee Moffitt Cancer Center and Research Institute, Radiation Oncology Program, 12902 Magnolia Drive #3057, Tampa, FL 33612-9497. Tel: (813) 972-8424; Fax: (813) 979-7231; E-mail: [email protected] Sponsored by IntraBiotics Pharmaceuticals, Inc. Rebecca Redman and Henry Fuchs are employees of IntraBiotics Pharmaceuticals, Inc., and have equity ownership in the company. Andy Trotti, Adam Garden, Padraig Warde, Paul Symonds, Corey 674
Iseganan for prevention RT-associated mucositis
INTRODUCTION The treatment of head-and-neck cancer involving radiation or chemoradiotherapy generates significant toxicity (1–3). The foremost toxicity affecting quality of life during treatment has been identified as mucositis (4). Oral mucositis (OM) is characterized by erythema, ulceration, and pseudomembrane formation. This adverse effect can significantly complicate the treatment by causing pain, impaired oral intake, greater narcotic analgesic use, and prolonged hospitalization. In addition, severe OM may necessitate interrupting the radiotherapy (RT) treatment program, possibly affecting potential for cure. Currently, no therapy has been shown to directly affect the course of radiation-induced OM. Supportive care programs include application of topical anesthetics, administration of narcotics, and attention to oral hygiene. OM is believed to be initiated by the loss of mucosal stem cells from direct cellular effects of RT or chemotherapy treatment (5). This injury results in a breakdown of the mucosal integrity, subsequent inflammatory cascades, and eventual ulceration of the mucosal barrier. Endogenous oral flora are believed to play a role in exacerbating the inflammatory process and delaying healing. Several studies evaluating the oral topical administration of antimicrobial agents to patients at risk for OM have suggested a decrease in the severity of OM and improvements in other patient outcomes including less oral pain and difficulty swallowing (3, 6 – 8). In one study of 275 patients scheduled to receive RT for head-and-neck malignancy, patients were randomized to retain a lozenge containing polymyxin, tobramycin, and amphotericin (PTA) or a placebo lozenge in their mouth for 15 min four times daily (6). A greater proportion of patients randomized to receive the PTA lozenge did not develop OM than did patients randomized to placebo (24% vs. 11%, p ⫽ 0.011), and fewer patients randomized to receive PTA experienced severe OM (14% vs. 28%, p ⫽ 0.007). In addition, patients randomized to receive the PTA lozenge had less dysphagia (p ⫽ 0.006) and less weight loss (p ⫽ 0.009). This study also demonstrated that the severity of mucositis was directly related to the severity of pain with swallowing and dysphagia (3). Protegrins are naturally occurring peptides, initially isolated from porcine neutrophils, with broad-spectrum antimicrobial activity (9). The mechanism of action is by disruption of the microbial cellular membrane, causing cell lysis. Iseganan is a synthetic structural analog of naturally occurring Protegrin-1 (10, 11). Iseganan has rapid microbicidal activity in saliva, is microbicidal against a broad spectrum of endogenous oral flora including Gram-positive and Gram-negative bacteria and yeast, and can be applied topically to the oral cavity with no detectable systemic absorption (9 –12). Phase I studies in healthy volunteers and Phase II and III studies in patients receiving high-dose chemotherapy documented a reduction in oral colonization without the emergence of resistant pathogens. In addition, a Phase III placebo-controlled study in 323 patients receiving
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high-dose chemotherapy suggested that iseganan increased the proportion of patients who did not develop ulcerative OM (43% vs. 33%, p ⫽ 0.067) and decreased the amount of mouth pain and difficulty swallowing compared with placebo (8). Based on these previous studies, we conducted a Phase III randomized trial to test the safety and efficacy of iseganan oral solution in reducing the severity of OM in patients receiving RT for head-and-neck malignancies. METHODS This study was multinational, randomized, double blind, and placebo-controlled. Fifty-three institutions in the United States, Canada, and Europe (France, Germany, UK) participated. The study was approved by the institutional review boards at all sites. All patients gave written informed consent before study entry. Eligible patients were ⱖ18 years old and had a pathologically confirmed diagnosis of cancer involving the oral cavity, oropharynx, nasopharynx, larynx, hypopharynx, or major salivary gland. Patients were scheduled to receive a minimum of 60 Gy to no less than three protocol-specified anatomic sites, each involving a minimum 2-cm2 area of mucosa within the oral cavity and oropharynx. The intent was to deliver the entire course of RT over no longer than 8 weeks inclusive of any scheduled interruptions. All patients were required to be free of mucositis (National Cancer Institute-Common Toxicity Criteria [NCI-CTC] mucositis resulting from radiation Grade 0) at study entry and had to be able to perform an oral “swish” procedure. Allowable RT regimens included a minimum tumor bed dose of 60 Gy in the postoperative setting and 66.0 – 81.6 Gy for unresected disease. In addition to conventional RT (70.0 Gy in 7 weeks at 2.0 Gy per fraction), four different schedules of altered fractionation were allowed for unresected disease: hyperfractionation delivering 1.2 Gy per fraction twice a day to a total dose of 72.0 – 81.6 Gy, concomitant boost RT delivering 72 Gy over 6 weeks using twice-a-day treatment during the last 2.5 weeks, a Canadian accelerated regimen delivering 60 Gy in 25 fractions (2.4 Gy per fraction) over 5 weeks, and accelerated RT consisting of 1.6 Gy per fraction twice a day to a total dose of 64 Gy in 4 weeks. In addition, 3.5% of the patients received intensity-modulated RT. Conventional fractionation RT alone or conventional fractionation RT followed by hyperfractionated accelerated RT was used for patients receiving chemoradiotherapy. There was no restriction on the type or schedule of chemotherapy administered. All RT fields were reviewed at the quality of assurance center for the Radiation Therapy Oncology Group. Patients were randomized to receive 9 mg doses of iseganan, formulated as a 0.3% aqueous vehicle solution plus institute-specific standard-of-care (SOC) management of oral hygiene, or placebo (vehicle solution) plus SOC, or SOC alone in a 3:2:1 distribution. This distribution provided all patients with a 50% chance of receiving iseganan. Patients randomized to iseganan or placebo were treated in a
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Table 1. National Cancer Institute Common Toxicity Criteria, version 2.0 (National Cancer Institute-Common Toxocity Criteria, version 2.0) “Mucositis Due to Radiation” scale
Mucositis resulting from radiation
Grade 1
Grade 2
Grade 3
Grade 4
Erythema of the mucosa
Patchy pseudomembranous reaction (patches generally ⱕ1.5 cm in diameter and noncontiguous)
Confluent pseudomembranous reaction (contiguous patches generally ⬎1.5 cm in diameter)
Necrosis or deep ulceration; may include bleeding not induced by minor trauma or abrasion
double-blind fashion to ensure an unbiased assessment of the safety and efficacy of iseganan. The SOC group was included to demonstrate that observed benefits of iseganan stemmed from the activity of the antimicrobial agent and not amelioration of an irritating effect of the vehicle solution. Patients randomized to SOC alone were not treated in a blinded fashion and did not receive a protocol specified intervention. Randomization was stratified by geographic region (United States, Canada, Europe) and planned RT treatment regimen (conventional RT, altered fractionation RT, RT with concurrent chemotherapy). Study drug administration began within 3 days before and not more than 2 days after commencing RT and continued daily until the last day of RT administration. Patients, study personnel, and the sponsor were blinded as to whether an individual received iseganan or placebo. Iseganan oral solution was identical to placebo in odor and appearance. All study drug was packaged in identical multidose, white, opaque plastic bottles. Excipients in the vehicle solution were commonly used compendial substances including hydroxypropylmethyl cellulose, sweeteners, preservatives, and buffering agents. Patients randomized to receive study drug were instructed to self-administer study drug six times daily throughout the RT administration period. Topical anesthetic agents, Kaopectate, and antacids containing aluminum or magnesium were not allowed within 30 min before administration of each dose of study drug through 15 min after administration of each dose. Patients rinsed their mouths with water before administration of each dose of study drug. Study drug was swished in the mouth to cover all surface areas and gargled to ensure coverage of the oropharynx for 2 min and then swallowed. Patients who were unable to swallow were allowed to expectorate the study drug. Patients recorded each administration of study drug in a study diary. SOC oral hygiene was defined by each participating institution and kept consistent at each center during the study. In general, SOC consisted of oral rinsing with salt and baking soda solutions. In addition, patients were prescribed antifungal agents and other antimicrobial agents when needed, as determined by the treating physician. Study assessments were performed twice weekly during the RT administration period, as well as 4 and 8 weeks after the completion of RT. Mucositis severity was assessed by clinicians (physician or research nurse) trained before the study in the application of the NCI-CTC, version 2.0, scale
for “mucositis due to radiation” (Table 1). Mouth pain and difficulty swallowing were assessed by a patient questionnaire using an 11-point severity scale (0 ⫽ none, 10 ⫽ worst imaginable). In addition, saliva samples were obtained from all patients randomized to study drug before and 1 h after the first dose of study drug was administered on the first and last days of study drug administration, and 28 days after RT completion. All saliva samples were analyzed at a central laboratory for quantitative and qualitative microbiologic assessments. The study’s primary endpoint was the proportion of patients in the iseganan and placebo groups who did not develop ulcerative OM (Grades 0 –1), using the NCI-CTC radiation mucositis scale, throughout the RT administration period. A secondary endpoint was the peak severity of mucositis occurring during the RT administration period: no ulceration (NCI-CTC Grades 0 and 1) vs. patchy ulceration (NCI-CTC Grade 2) vs. confluent ulceration (NCI-CTC Grades 3 and 4). Additional secondary endpoints were peak severity of mouth pain and peak difficulty swallowing. The peak was defined as the highest score reported by each patient throughout the RT administration period. Average pain and difficulty swallowing were determined for each patient by summing all available scores during the RT administration period and dividing by the number of scores recorded. The efficacy of iseganan vs. SOC in preventing ulcerative OM also was evaluated. The study was designed to detect a clinically important reduction in the incidence of ulcerative OM in the iseganan and placebo groups. Based on a review of the literature including previous Radiation Therapy Oncology Group studies, baseline distributions of mucositis severity risk using conventional fractionation RT, altered fractionation RT, and chemoradiation were estimated. We assumed that approximately equal numbers of patients would be enrolled in each RT stratum. In addition, reductions in the different grades of OM were extrapolated from a Phase II study evaluating iseganan for prevention of OM in patients receiving stomatotoxic chemotherapy. With these estimates, the study had ⬎90% statistical power to detect an approximate 14% absolute increase in the proportion of patients that would not develop ulcerative OM in the iseganan group relative to placebo and approximately 78% statistical power to detect a similar increase in the iseganan group relative to SOC alone using an ␣ ⫽ 0.05 two-tailed Cochran Mantel
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Table 2. Baseline patient and tumor characteristics
Geographic region United States Canada Europe Age (years) % Male Race Caucasian Black Asian/Pacific Islander Hispanic Tumor location Oropharynx Oral cavity Hypopharynx Nasopharynx Larynx Salivary glands Other % postoperative Radiotherapy regimen Conventional Hyperfractionated Chemoradiotherapy
Iseganan⫹SOC (n ⫽ 253)
Placebo⫹SOC (n ⫽ 171)
SOC alone (n ⫽ 87)
53% 13% 34% 57 79%
53% 14% 33% 56 80%
52% 14% 34% 58 84%
88% 5% 4% 3%
94% 2% 3% 1%
92% 3% 1% 3%
46% 35% 11% 7% 5% 4% 10% 44%
43% 34% 11% 8% 7% 7% 15% 46%
55% 32% 8% 5% 7% 2% 8% 41%
42% 17% 41%
43% 16% 41%
40% 21% 40%
Abbreviation: SOC ⫽ institution-specific standard of care for oral hygiene.
Haenszel chi-square test for the nine subgroups defined by the two stratifying variables. RESULTS Between July 26, 2000, and December 6, 2001, 545 patients were randomized to the study, of which 511 patients were included in the analyses reported here: 253 patients were randomized to receive iseganan plus SOC, 171 to receive placebo plus SOC, and 87 to receive SOC alone. The first 27 patients randomized to the study (between July 26, 2000, and December 22, 2000) were potentially affected by an interactive voice randomization system error, and a decision was made before outcome results were available to exclude these patients from the efficacy analyses. In addition, 6 patients who were randomized to the blinded arms but never dispensed study drug and 1 patient randomized to the SOC-only arm and never completed a postbaseline assessment were also excluded from the analyses. Treatment groups were balanced with respect to patient demographics (age, gender, race), tumor location, macroscopic disease status (postoperative vs. unresected), and planned RT treatment regimen (Table 2). A total of 96 –97% of the scheduled oral assessments were performed in each of the three study groups. However, the percent of scheduled doses of study drug administered was lower in patients receiving iseganan (73%) than in those receiving placebo (80%) (p ⫽ 0.001) (Table 3).
No difference was seen between the iseganan and placebo groups for any study endpoint (Table 4). The proportion of patients who remained free of ulcerative OM and the peak severity of mucositis was similar between these two groups. In addition, there was no difference in mean peak mouth pain, mean peak difficulty swallowing, or mean percentage days of narcotic use. Patients randomized to iseganan and placebo experienced similar weight loss, feeding tube placement, and days of feeding tube use (data not displayed). Completion of planned RT and chemotherapy was similar between the iseganan and placebo groups. Statistically significant differences in outcomes were seen in patients randomized to iseganan compared with those randomized to SOC alone. A greater proportion of patients randomized to iseganan did not develop ulcerative OM (p ⫽ 0.049) and experienced less severe OM (p ⫽ 0.023) than patients randomized to SOC alone. Similarly, a smaller proportion of patients randomized to placebo developed ulcerative OM than patients randomized to SOC alone (p ⫽ 0.041). Thirty-four percent and 40% of the patients in the iseganan and placebo groups, respectively, did not develop confluent oral ulceration (NCI-CTC Grades 3 or 4) at any time during RT administration compared with 21% of the patients randomized to SOC alone. This difference represents a 16 –24% relative reduction in the most severe forms of mucositis. In addition, patients randomized to iseganan had less mean peak mouth pain, less mean peak difficulty swallowing, and fewer days of narcotic use than did patients randomized to SOC alone. Four percent of the patients in
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Table 3. Study conduct parameters Iseganan Placebo SOC (n ⫽ 253) (n ⫽ 171) (n ⫽ 87) Eligibility violations Completed oral assessments to end of radiotherapy % of scheduled oral assessments completed* Completed study drug administration to end of radiotherapy % of scheduled study drug doses taken*
0
1
0
95%
94%
97%
96%
97%
96%
73%
80%
NA
73%
80%
NA
p value
Iseganan vs placebo 0.001‡
Abbreviation: SOC ⫽ institution-specific standard of care for oral hygiene. * Percent reported is the mean of the individual patient percents. † Patients could have more than one reason for discontinuation. Percents are based on the total number of patients in the treatment group. ‡ Probability from Wilcoxon rank sum test.
the iseganan group, 3% in the placebo group, and 7% in the SOC only group received less than 95% their scheduled dose of RT (p ⫽ 0.28) (data not shown). Analysis of saliva samples collected from patients in the iseganan and placebo groups demonstrated that iseganan oral solution was microbicidal. In the group of patients randomized to receive iseganan, a reduction in mean total oral aerobic bacteria of 1.35 log10 colony forming units (CFU) per milliliter saliva (p ⬍ 0.0001) was demonstrated 1 h after administration of the first dose of study drug on the first day of therapy and a mean reduction of 0.71 log10 CFU/mL (p ⬍ 0.0001) was seen 1 h after administration of the first dose on the last day of therapy. In comparison, the placebo group demonstrated nonstatistically significant reductions of 0.01 log10 CFU/mL on the first day and 0.08 log10 CFU/mL on the last day of study drug administration. In both groups, there were statistically nonsignificant changes in mean total oral microbial burden between the first and last days of therapy (0.17 log10 CFU/mL reduction in the iseganan group and 0.07 log10 CFU/mL reduction in the placebo group). The quantity and type of microflora colonizing the oral cavity was similar in the two groups at follow-up—approximately 28 days after RT completion. Emerging resistance to iseganan was not observed. The proportion of patients experiencing adverse events (AEs) determined by the investigator to be related to study drug, AEs leading to study drug discontinuation, serious AEs, and deaths are summarized in Table 5. No serious AE of a specific organ class or preferred term occurred, with ⬎1% increased frequency in the iseganan group than both the placebo and SOC groups.
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Nausea was the AE most frequently attributed to study drug administration and the only AE that occurred with ⱖ5% increased frequency in the iseganan group than both the placebo and SOC groups. Fifty-one percent of the patients in the iseganan group, 42% in the placebo group, and 46% in the SOC group experienced nausea at some time during the study. A total of 84 –91% of the patients in each study group who experienced nausea had mild to moderately severe nausea. Two percent of the patients in the iseganan group, 3% in the placebo group, and 1% in the SOC group experienced nausea as a serious AE. A clinical diagnosis of oral candidiasis was reported as an AE in 18% of the patients in the iseganan group, 12% in the placebo group, and 15% in the SOC group at some time during the study. Candida spp. infections not specified as oral candidiasis were reported in 15%, 17%, and 29% of the patients in these groups, respectively. Mean time to Candida spp. infection was 29, 32, and 36 days in the iseganan, placebo, and SOC groups, respectively. Candidiasis resolved while taking study drug in 36% of the patients receiving iseganan and 33% of the patients receiving placebo. For all study groups, 98 –100% of the patients with candidiasis took an antimicrobial agent at some time during the study and 96 –100% took an antifungal agent. In the iseganan and placebo groups, oral candidiasis was not associated with oropharyngeal overgrowth of yeast, as determined by microbial analyses of saliva samples. DISCUSSION This is the largest randomized controlled trial of an antimicrobial intervention for prevention of OM reported to date. Despite measurable antibacterial and anticandidal activity in the oral cavity of patients participating in this trial, iseganan failed to reduce the rate of ulcerative OM, decrease the severity of mucositis, or attenuate its clinical sequelae when compared with placebo. However, it is of interest that patients randomized to receive iseganan or placebo had improved outcomes compared with patients randomized to SOC alone. These findings suggest that emphasis on oral rinsing or the vehicle solution used in this study may significantly reduce the incidence and severity of RT-induced ulcerative OM and its associated clinical outcomes. Although rigorous oral hygiene has been a tenet of supportive care during head-and-neck RT for many years, its true impact on OM has not been formally investigated. The results from this study suggest that attention to rigorous oral hygiene may have a significant impact on the development of OM and its clinical sequelae. In our study, patients randomized to receive study drug (iseganan or placebo) were encouraged to comply with a rigorous study specific oral hygiene regimen in addition to institution specific practices for oral hygiene care. Patients randomized to receive study drug were instructed to rinse their mouths before each study drug administration and then swish and gargle the study drug solution for 2 min six times daily throughout the period of RT administration. Study-specific techniques were
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Table 4. Study outcomes Iseganan (n ⫽ 253)
Placebo (n ⫽ 171)
SOC (n ⫽ 87)
p value
9%
9%
2%
9% 24% 66% 2.6
9% 30% 60% 2.5
2% 18% 79% 2.8
Ise vs. Pbo 0.998 Ise vs. SOC 0.049 Pbo vs. SOC 0.041 Ise vs. Pbo 0.160 Ise vs. SOC 0.023
1.5
1.4
1.6
5.8
5.7
7.0
Average mouth pain
2.8
2.7
3.2
Mean peak difficulty swallowing
6.2
6.2
7.5
Average difficulty swallowing
3.2
3.2
4.1
50%
50%
60%
Completion of planned RT and CT Dose of RT less than planned
9%
10%
17%
Dose RT longer than planned
50%
42%
49%
Dose CT less than planned
33%
33%
26%
Endpoint Mucositis No ulceration Peak severity of mucositis No ulcer (grades 0, 1) Patchy ulceration (grade 2) Confluent ulceration (grades 3, 4) Mean peak severity OM Average OM Patient reported mouth pain/difficulty swallowing Mean peak mouth pain
Mean % days narcotic use
Ise Ise Ise Ise
vs. vs. vs. vs.
Pbo 0.160 SOC 0.023 Pbo 0.613 SOC 0.076
Ise Ise Ise Ise Ise Ise Ise Ise Ise Ise
vs. vs. vs. vs. vs. vs. vs. vs. vs. vs.
Pbo 0.501 SOC 0.140 Pbo 0.986 SOC 0.036 Pbo 0.486 SOC ⬍0.001 Pbo 0.987 SOC ⬍0.001 Pbo 0.862 SOC 0.037
Ise Ise Ise Ise Ise Ise
vs. vs. vs. vs. vs. vs.
Pbo 0.921 SOC 0.042 Pbo 0.140 SOC 0.978 Pbo 0.964 SOC 0.478
Abbreviations: SOC ⫽ institution-specific standard of care for oral hygiene; Ise ⫽ iseganan; Pbo ⫽ placebo; OM ⫽ oral mucositis; RT ⫽ radiation therapy; CT ⫽ computed tomography.
developed to help remind patients to comply with study drug administration. In addition, patients randomized to receive iseganan or placebo maintained diaries of study drug administration that they reviewed with study staff at least twice weekly. However, patients randomized to SOC alone did not routinely receive these interventions. Therefore, it is possible that methods used to ensure compliance with study drug administration during the execution of this study may have inadvertently improved oral hygiene measures. Alternatively, it is possible that, after oral rinsing, the vehicle solution (placebo) used in this study provided a physical or chemical barrier that protected the mucosa from
further injury. These questions could be investigated further in both preclinical and clinical studies. Previous studies of oral, topically administered antimicrobial, or antiseptic agents have reported mixed success in reducing OM and its clinically relevant sequelae (6 – 8, 12–14). The variable efficacy of these agents may be due to differences in spectrum, speed, and duration of antimicrobial activity as well as possible inactivation by chemically charged molecules found in saliva and the oral cavity. It was hoped that iseganan’s broad-spectrum and rapid microbicidal activity in the presence of saliva would overcome the potential shortcomings of previously tested conventional
Table 5. Summary of adverse events Type of adverse event
Iseganan ⫹ SOC (n ⫽ 253)
Placebo ⫹ SOC (n ⫽ 171)
SOC alone (n ⫽ 26)
Related adverse events Adverse events leading to drug D/C Serious adverse events Deaths
21% 2% 26% 1%
5% 1% 20% 2%
NA NA 31% 2%
Abbreviations: D/C ⫽ discontinuation; SOC ⫽ institution-specific standard of care for oral hygiene.
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antimicrobial agents (11, 12). In addition, iseganan’s lack of systemic absorption after oral-topical administration, its unique mechanism of action that is unaffected by commonly encountered antimicrobial resistance mechanisms, and its low potential for engendering resistance were considered ideal characteristics for prolonged oral-topical administration as required for the indication of preventing OM (9, 11). It is possible that, despite measurable reductions in oral flora, iseganan could not penetrate the inflammatory pseudomembrane covering the wound or reduce the microbial burden at some undefined critical level within the submucosal tissues. The results of our study do not support the hypothesis that infection plays a major role in the pathogenesis of RTassociated OM or that oral topical administration of antimicrobial agents provides significant incremental benefit over frequent oral rinsing and conventional SOC treatment. If oral microflora do contribute to the development of RTassociated OM, attention to standard oral hygiene practices may be sufficient to remove topical debris and microorganisms within the oral cavity. In addition, other intervention strategies such as enhancement of mucosal stem cell regeneration or modulation of tissue injury, recovery, or inflammation may be worth pursuing. Results from our study indicate that iseganan oral solution is safe and well tolerated in patients with compromised oral mucosa while receiving RT for head-and-neck cancer. Investigations with iseganan in clinical settings where infection is a known and significant factor should continue. PG-015 PRINCIPAL INVESTIGATORS Hani Ashmalla, M.D., New York Methodist Hospital, Brooklyn, NY; Vilija Avizonis, M.D., Latter Day Saints Hospital, Salt Lake City, UT; Boris Bahoric, M.D., Nova Scotia Cancer Center, Halifax Nova Scotia, Canada; Etienne Bardet, M.D., Centre Rene Gauducheau, Saint-Herblain, France; Michael Beat, M.D., Brooke Army Medical Center, Fort Sam Houston TX; Jean Bourhis, M.D., Institute Gustave Roussy, Villejuif, France; Harmar Brereton, M.D., Radiation Medicine Associates of Scranton, Scranton, PA; Andrew Brown, M.D., Elliot Hospital, Manchester, NH; Roger Byhardt, M.D., Zablocki VA Medical Center, Milwaukee, WI; Giles Calais, M.D., Hoˆ pital Bretonneau Service Corad, Tours, France; Clifford Chao, M.D., Washington University, St. Louis, MO; Albert Clairmont, M.D., Atlanta Ear, Nose & Throat, Atlanta, GA; Anthony Cmelak, M.D., Vanderbilt-Ingram Cancer Center, Nashville, TN; Walter Curran, M.D., Jefferson Oncology Group, Philadelphia, PA; William Demas, M.D., Akron City Hospital,
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Akron, OH; Phillip Delvin, M.D., St. Anne’s Hospital, Fall River, MA; Samy El-Sayed, M.D., Ottawa Regional Cancer Center, Ottawa, Ontario, Canada; Joel Epstein, M.D., University of Washington, Seattle, WA; Adam Garden, M.D., MD Anderson Cancer Center, Houston, TX; Alex Hammond, M.D., University of Western Ontario, London, Ontario, Canada; Paul Harari, M.D., and Scott Tannehill, M.D., University of Wisconsin, Madison, WI; Michael Henke, M.D., Abteilung Strahlenheilkunde, Radiologische Universitaetsklinik, Freiburg, Germany; David Irwin, M.D., Alta Bates Comprehensive Cancer Center, Berkley, CA; Douglas Johnson, M.D., Florida Radiation Oncology Group, Jacksonville, FL; Guy Juilliard, M.D., UCLA Medical Center, Los Angeles, CA; Elizabeth Junor, M.D., Beatson Oncology Centre, Glasgow, Scotland, U.K.; Charles Kelley, M.D., Newcastle General Hospital, Newcastle upon Tyne, England, U.K.; Eric Lartigau, M.D., Service Unite de Radiotherapie Clinique Centre Oscar Lambret, Lille Cedex, France; Arnold Markoe, M.D., University of Miami, Miami, FL; Ruby Meredith, M.D., Ph.D., University of Alabama, Birmingham, AL; Charles Nichols, M.D., Gulf Coast Cancer Treatment Center, Panama City, FL; Matthew Parliament, M.D., University of Alberta, Edmonton, Alberta, Canada; Douglas Peterson, D.M.D., Ph.D., University of Connecticut Health Science Center, Farmington, CT; Pascal Pommier, M.D., Service de Radiotherapie Centre Leon Berard, Lyon, France; Adam Raben, M.D., Monmouth Medical Center, Long Branch, NJ; David Raben, M.D., University of Colorado, Aurora, CO; Murali Rajaraman, M.D., Nova Scotia Cancer Centre, Halifax, Nova Scotia, Canada; William Regine, M.D., University of Kentucky, Lexington, KY; David Rosenthal, M.D., University of Pennsylvania, Philadelphia, PA; Marvin Rotman, M.D., SUNY Health Science Center, Brooklyn, NY; Ulrich Schaefer, M.D., WWU Munster Strahlentherapie Radioonkologie, Munster, Germany; David Schwartz, M.D., Seattle VA/Puget Sound Health, Seattle, WA; Finbarr Sheehan, M.D., British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Eric Sherman, M.B., Fox Chase Cancer Center, Philadelphia, PA; Paul Song, M.D., INOVA-Fairfax Hospital, Falls Church, VA; John Suh, M.D., Cleveland Clinic Foundation, Cleveland, OH; Mohan Suntharalingam, M.D., University of Maryland, Baltimore, MD; Paul Symonds, M.B., Leicester Royal Infirmary, Leicester, England, U.K.; Andy Trotti, M.D., H. Lee Moffit Cancer Center, Tampa, FL; Renate Ulrich, M.D., Universitatsklinikum Charite, Berlin, Germany; Te Vuong, M.D., McGill University Hospital, Montreal, Quebec, Canada; and Padraig Warde, M.B., Princess Margaret Hospital, Toronto, Ontario, Canada.
REFERENCES 1. Trotti A. Toxicity in head and neck cancer: A review of trends and issues. Int J Radiat Oncol Biol Phys 2000;47:1–12. 2. Fu K, Pajak T, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare
hyperfractionation to two variants of accelerated fractionation for head and neck squamous carcinoma: First report of RTOG 90-03. Int J Radiat Oncol Biol Phys 2000;48:7– 16.
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3. Symonds P, Pulliam J, Redman R, et al. Endpoint evaluation of trials to reduce the severity of treatment induced oral mucositis [Abstract]. ASCO Proceedings 2002: 236a. 4. Rose-Ped A, Bellm L, Epstein J, et al. Complications of radiation therapy for head and neck cancer: The patient’s perspective. Cancer Nurs 2002;25:461–467. 5. Sonis ST. Mucositis as a biological process: A new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 1998;34:39–43. 6. Symonds RP, McIlroy P, Khorrami J, et al. The reduction of radiation oral mucositis by selective decontamination antibiotic pastilles: A placebo-controlled double blind trial. Br J Cancer 1996;74:312–317. 7. Okuno SH, Foote RL, Loprinzi CL, et al. A randomized trial of a nonabsorbable antibiotic lozenge given to alleviate radiation-induced mucositis. Cancer 1997;79:2193–2199. 8. Giles FJ, Miller CB, Hurd DD, et al. for the PROMPT-CT Trial Investigators. A phase III, randomized, double blind, placebo-controlled, multinational trial of iseganan for the prevention of oral mucositis in patients receiving stomatotoxic chemotherapy (PROMPT-CT Trial). Leuk Lymph. In Press. 9. Bellm L, Lehrer RI, Ganz T. Protegrins: New antibiotics of
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mammalian origin. Expert Opin Invest Drugs 2000;9:1731– 1742. Chen J, Falla TJ, Liu H, et al. Development of protegrins for the treatment and prevention of oral mucositis: Structureactivity relationships of synthetic protegrin analogues. Biopolymers 2000;55:88–98. Giles FJ, Redman R, Yazji S, et al. Iseganan HCl: A novel antimicrobial agent. Expert Opin Invest Drugs 2002;11:1161– 1170. Mosca Da, Hurst MA, So W, et al. IB-367, a protegrin peptide with in vitro and in vivo activities against the microflora associated with oral mucositis. Antimicrob Agents Chemother 2000;44:1803–1808. El-Sayed S, Nabid A, Shelley W, et al. Prophylaxis of radiation-associated mucositis in conventionally treated patients with head and neck cancer: A double blind, phase III, randomized, controlled trial evaluating the clinical efficacy of an antimicrobial lozenge using a validated mucositis scoring system. J Clin Oncol 2002;20:3956–3963. Foote R, Loprinzi C, Frank A, et al. Randomized trial of a chlorhexidine mouthwash for alleviation of radiation-induced mucositis. J Clin Oncol 1994;12:2630–2633.
doi:10.1016/S0630-3016(04)01627-4
CLINICAL INVESTIGATION
Head and Neck
A MULTINATIONAL, RANDOMIZED PHASE III TRIAL OF ISEGANAN HCL ORAL SOLUTION FOR REDUCING THE SEVERITY OF ORAL MUCOSITIS IN PATIENTS RECEIVING RADIOTHERAPY FOR HEAD-AND-NECK MALIGNANCY ANDY TROTTI, M.D.,* ADAM GARDEN, M.D.,† PADRAIG WARDE, M.B.,‡ PAUL SYMONDS, M.B.,§ COREY LANGER, M.D.,¶ REBECCA REDMAN, M.D.,㛳 THOMAS F. PAJAK, PH.D.,# TOMAS R. FLEMING, PH.D.,** MICHAEL HENKE, M.D.,†† JEAN BOURHIS, M.D.,‡‡ DAVID I. ROSENTHAL, M.D.,† ELIZABETH JUNOR, M.D.,§§ ANTHONY CMELAK, M.D.,¶¶ FINBARR SHEEHAN, M.B.,㛳㛳 JANIS PULLIAM, PH.D.,㛳 PATRICIA DEVITT-RISSE, PHARM. D.,㛳 HENRY FUCHS, M.D.,㛳 MARK CHAMBERS, D.M.D.,† BRIAN O’SULLIVAN, M.B.,† AND K. KIAN ANG, M.D., PH.D.† *Radiation Oncology Program, H. Lee Moffitt Cancer Center at the University of South Florida, Tampa, FL; †Department of Radiation Oncology, M. D. Anderson Cancer Center, Houston, TX; ‡Department of Radiation Oncology, Princess Margaret Hospital and University of Toronto, Toronto, Ontario, Canada; §Department of Oncology, Leicester Royal Infirmary, Leicester, United Kingdom; ¶Department of Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, PA; 㛳IntraBiotics Pharmaceuticals, Inc., Palo Alto, CA; #American College of Radiology, Philadelphia, PA; **Department of Biostatistics, University of Washington, Seattle, WA; ††Abteilung Strahlenheilkunde, Radiologische Universitaetsklinik, Freiburg, Germany; ‡‡Service de Radiotherapie, Institute Gustave-Roussy, Villejuif, France; §§Beatson Oncology Centre, Glasgow, United Kingdom; ¶¶Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN; 㛳㛳Department of Radiation Oncology, Vancouver Cancer Center, British Columbia Cancer Center, Vancouver, Canada Purpose: Oral mucositis (OM) causes significant morbidity during the course of radiotherapy (RT) treatment of head-and-neck cancer. It is hypothesized that infection plays a role in the development of OM. We tested the efficacy of iseganan HCl (iseganan), a synthetic peptide with broad-spectrum antimicrobial activity, for preventing RT-associated OM. Methods: A multinational, randomized, double-blind, controlled trial was performed on patients receiving primary RT, primary chemoradiotherapy or postoperative RT. Patients were randomized to receive iseganan oral solution plus standard-of-care oral hygiene (SOC), placebo plus SOC, or SOC alone throughout the RT administration period. The severity of OM was assessed by NCI-CTC scoring and clinical symptoms by patient questionnaire. Results: A total of 545 patients were randomized to the study. Nine percent of the patients in both the iseganan and placebo groups did not develop ulcerative OM (Grades 2, 3, 4) (p ⴝ 0.998) whereas only 2% of the patients receiving SOC alone remained free of oral ulceration (p ⴝ 0.049). The maximum severity of mouth pain and difficulty swallowing did not differ in patients treated with iseganan or placebo. However, patients in both intervention groups reported less mouth pain and difficulty swallowing than did patients receiving SOC alone. Nausea was the only adverse event that occurred with >5% increased frequency in the iseganan group than in either the placebo or SOC groups (51% vs. 42% vs. 46%). Adverse events leading to study drug discontinuation and death did not differ significantly between groups. Conclusion: Iseganan oral solution was safe but did not reduce the risk for developing ulcerative OM relative to placebo. Intensified oral hygiene or the administration of the vehicle used to deliver study drug in this trial appears to have reduced the risk and severity of OM. Our results suggest that antimicrobial intervention may not meaningfully affect the pathogenesis of radiation-induced OM. © 2004 Elsevier Inc. Iseganan, Mucositis, Oral mucositis, Radiotherapy, Head and neck.
Langer, Kian Ang, Thomas Pajak, Thomas Fleming, Janis Pulliam, and Pat Devitt-Risse served as paid consultants to IntraBiotics Pharmaceuticals, Inc., for the design and conduct of the trial and interpretation of the results. Acknowledgments—The American College of Radiology and the Radiation Therapy Oncology Group (RTOG) provided access to RTOG institutions and advice in study design and interpretation. Received May 13, 2003. Accepted for publication Jul 14, 2003.
Reprint requests to: Andy Trotti, M.D., H. Lee Moffitt Cancer Center and Research Institute, Radiation Oncology Program, 12902 Magnolia Drive #3057, Tampa, FL 33612-9497. Tel: (813) 972-8424; Fax: (813) 979-7231; E-mail: [email protected] Sponsored by IntraBiotics Pharmaceuticals, Inc. Rebecca Redman and Henry Fuchs are employees of IntraBiotics Pharmaceuticals, Inc., and have equity ownership in the company. Andy Trotti, Adam Garden, Padraig Warde, Paul Symonds, Corey 674
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INTRODUCTION The treatment of head-and-neck cancer involving radiation or chemoradiotherapy generates significant toxicity (1–3). The foremost toxicity affecting quality of life during treatment has been identified as mucositis (4). Oral mucositis (OM) is characterized by erythema, ulceration, and pseudomembrane formation. This adverse effect can significantly complicate the treatment by causing pain, impaired oral intake, greater narcotic analgesic use, and prolonged hospitalization. In addition, severe OM may necessitate interrupting the radiotherapy (RT) treatment program, possibly affecting potential for cure. Currently, no therapy has been shown to directly affect the course of radiation-induced OM. Supportive care programs include application of topical anesthetics, administration of narcotics, and attention to oral hygiene. OM is believed to be initiated by the loss of mucosal stem cells from direct cellular effects of RT or chemotherapy treatment (5). This injury results in a breakdown of the mucosal integrity, subsequent inflammatory cascades, and eventual ulceration of the mucosal barrier. Endogenous oral flora are believed to play a role in exacerbating the inflammatory process and delaying healing. Several studies evaluating the oral topical administration of antimicrobial agents to patients at risk for OM have suggested a decrease in the severity of OM and improvements in other patient outcomes including less oral pain and difficulty swallowing (3, 6 – 8). In one study of 275 patients scheduled to receive RT for head-and-neck malignancy, patients were randomized to retain a lozenge containing polymyxin, tobramycin, and amphotericin (PTA) or a placebo lozenge in their mouth for 15 min four times daily (6). A greater proportion of patients randomized to receive the PTA lozenge did not develop OM than did patients randomized to placebo (24% vs. 11%, p ⫽ 0.011), and fewer patients randomized to receive PTA experienced severe OM (14% vs. 28%, p ⫽ 0.007). In addition, patients randomized to receive the PTA lozenge had less dysphagia (p ⫽ 0.006) and less weight loss (p ⫽ 0.009). This study also demonstrated that the severity of mucositis was directly related to the severity of pain with swallowing and dysphagia (3). Protegrins are naturally occurring peptides, initially isolated from porcine neutrophils, with broad-spectrum antimicrobial activity (9). The mechanism of action is by disruption of the microbial cellular membrane, causing cell lysis. Iseganan is a synthetic structural analog of naturally occurring Protegrin-1 (10, 11). Iseganan has rapid microbicidal activity in saliva, is microbicidal against a broad spectrum of endogenous oral flora including Gram-positive and Gram-negative bacteria and yeast, and can be applied topically to the oral cavity with no detectable systemic absorption (9 –12). Phase I studies in healthy volunteers and Phase II and III studies in patients receiving high-dose chemotherapy documented a reduction in oral colonization without the emergence of resistant pathogens. In addition, a Phase III placebo-controlled study in 323 patients receiving
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high-dose chemotherapy suggested that iseganan increased the proportion of patients who did not develop ulcerative OM (43% vs. 33%, p ⫽ 0.067) and decreased the amount of mouth pain and difficulty swallowing compared with placebo (8). Based on these previous studies, we conducted a Phase III randomized trial to test the safety and efficacy of iseganan oral solution in reducing the severity of OM in patients receiving RT for head-and-neck malignancies. METHODS This study was multinational, randomized, double blind, and placebo-controlled. Fifty-three institutions in the United States, Canada, and Europe (France, Germany, UK) participated. The study was approved by the institutional review boards at all sites. All patients gave written informed consent before study entry. Eligible patients were ⱖ18 years old and had a pathologically confirmed diagnosis of cancer involving the oral cavity, oropharynx, nasopharynx, larynx, hypopharynx, or major salivary gland. Patients were scheduled to receive a minimum of 60 Gy to no less than three protocol-specified anatomic sites, each involving a minimum 2-cm2 area of mucosa within the oral cavity and oropharynx. The intent was to deliver the entire course of RT over no longer than 8 weeks inclusive of any scheduled interruptions. All patients were required to be free of mucositis (National Cancer Institute-Common Toxicity Criteria [NCI-CTC] mucositis resulting from radiation Grade 0) at study entry and had to be able to perform an oral “swish” procedure. Allowable RT regimens included a minimum tumor bed dose of 60 Gy in the postoperative setting and 66.0 – 81.6 Gy for unresected disease. In addition to conventional RT (70.0 Gy in 7 weeks at 2.0 Gy per fraction), four different schedules of altered fractionation were allowed for unresected disease: hyperfractionation delivering 1.2 Gy per fraction twice a day to a total dose of 72.0 – 81.6 Gy, concomitant boost RT delivering 72 Gy over 6 weeks using twice-a-day treatment during the last 2.5 weeks, a Canadian accelerated regimen delivering 60 Gy in 25 fractions (2.4 Gy per fraction) over 5 weeks, and accelerated RT consisting of 1.6 Gy per fraction twice a day to a total dose of 64 Gy in 4 weeks. In addition, 3.5% of the patients received intensity-modulated RT. Conventional fractionation RT alone or conventional fractionation RT followed by hyperfractionated accelerated RT was used for patients receiving chemoradiotherapy. There was no restriction on the type or schedule of chemotherapy administered. All RT fields were reviewed at the quality of assurance center for the Radiation Therapy Oncology Group. Patients were randomized to receive 9 mg doses of iseganan, formulated as a 0.3% aqueous vehicle solution plus institute-specific standard-of-care (SOC) management of oral hygiene, or placebo (vehicle solution) plus SOC, or SOC alone in a 3:2:1 distribution. This distribution provided all patients with a 50% chance of receiving iseganan. Patients randomized to iseganan or placebo were treated in a
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Table 1. National Cancer Institute Common Toxicity Criteria, version 2.0 (National Cancer Institute-Common Toxocity Criteria, version 2.0) “Mucositis Due to Radiation” scale
Mucositis resulting from radiation
Grade 1
Grade 2
Grade 3
Grade 4
Erythema of the mucosa
Patchy pseudomembranous reaction (patches generally ⱕ1.5 cm in diameter and noncontiguous)
Confluent pseudomembranous reaction (contiguous patches generally ⬎1.5 cm in diameter)
Necrosis or deep ulceration; may include bleeding not induced by minor trauma or abrasion
double-blind fashion to ensure an unbiased assessment of the safety and efficacy of iseganan. The SOC group was included to demonstrate that observed benefits of iseganan stemmed from the activity of the antimicrobial agent and not amelioration of an irritating effect of the vehicle solution. Patients randomized to SOC alone were not treated in a blinded fashion and did not receive a protocol specified intervention. Randomization was stratified by geographic region (United States, Canada, Europe) and planned RT treatment regimen (conventional RT, altered fractionation RT, RT with concurrent chemotherapy). Study drug administration began within 3 days before and not more than 2 days after commencing RT and continued daily until the last day of RT administration. Patients, study personnel, and the sponsor were blinded as to whether an individual received iseganan or placebo. Iseganan oral solution was identical to placebo in odor and appearance. All study drug was packaged in identical multidose, white, opaque plastic bottles. Excipients in the vehicle solution were commonly used compendial substances including hydroxypropylmethyl cellulose, sweeteners, preservatives, and buffering agents. Patients randomized to receive study drug were instructed to self-administer study drug six times daily throughout the RT administration period. Topical anesthetic agents, Kaopectate, and antacids containing aluminum or magnesium were not allowed within 30 min before administration of each dose of study drug through 15 min after administration of each dose. Patients rinsed their mouths with water before administration of each dose of study drug. Study drug was swished in the mouth to cover all surface areas and gargled to ensure coverage of the oropharynx for 2 min and then swallowed. Patients who were unable to swallow were allowed to expectorate the study drug. Patients recorded each administration of study drug in a study diary. SOC oral hygiene was defined by each participating institution and kept consistent at each center during the study. In general, SOC consisted of oral rinsing with salt and baking soda solutions. In addition, patients were prescribed antifungal agents and other antimicrobial agents when needed, as determined by the treating physician. Study assessments were performed twice weekly during the RT administration period, as well as 4 and 8 weeks after the completion of RT. Mucositis severity was assessed by clinicians (physician or research nurse) trained before the study in the application of the NCI-CTC, version 2.0, scale
for “mucositis due to radiation” (Table 1). Mouth pain and difficulty swallowing were assessed by a patient questionnaire using an 11-point severity scale (0 ⫽ none, 10 ⫽ worst imaginable). In addition, saliva samples were obtained from all patients randomized to study drug before and 1 h after the first dose of study drug was administered on the first and last days of study drug administration, and 28 days after RT completion. All saliva samples were analyzed at a central laboratory for quantitative and qualitative microbiologic assessments. The study’s primary endpoint was the proportion of patients in the iseganan and placebo groups who did not develop ulcerative OM (Grades 0 –1), using the NCI-CTC radiation mucositis scale, throughout the RT administration period. A secondary endpoint was the peak severity of mucositis occurring during the RT administration period: no ulceration (NCI-CTC Grades 0 and 1) vs. patchy ulceration (NCI-CTC Grade 2) vs. confluent ulceration (NCI-CTC Grades 3 and 4). Additional secondary endpoints were peak severity of mouth pain and peak difficulty swallowing. The peak was defined as the highest score reported by each patient throughout the RT administration period. Average pain and difficulty swallowing were determined for each patient by summing all available scores during the RT administration period and dividing by the number of scores recorded. The efficacy of iseganan vs. SOC in preventing ulcerative OM also was evaluated. The study was designed to detect a clinically important reduction in the incidence of ulcerative OM in the iseganan and placebo groups. Based on a review of the literature including previous Radiation Therapy Oncology Group studies, baseline distributions of mucositis severity risk using conventional fractionation RT, altered fractionation RT, and chemoradiation were estimated. We assumed that approximately equal numbers of patients would be enrolled in each RT stratum. In addition, reductions in the different grades of OM were extrapolated from a Phase II study evaluating iseganan for prevention of OM in patients receiving stomatotoxic chemotherapy. With these estimates, the study had ⬎90% statistical power to detect an approximate 14% absolute increase in the proportion of patients that would not develop ulcerative OM in the iseganan group relative to placebo and approximately 78% statistical power to detect a similar increase in the iseganan group relative to SOC alone using an ␣ ⫽ 0.05 two-tailed Cochran Mantel
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Table 2. Baseline patient and tumor characteristics
Geographic region United States Canada Europe Age (years) % Male Race Caucasian Black Asian/Pacific Islander Hispanic Tumor location Oropharynx Oral cavity Hypopharynx Nasopharynx Larynx Salivary glands Other % postoperative Radiotherapy regimen Conventional Hyperfractionated Chemoradiotherapy
Iseganan⫹SOC (n ⫽ 253)
Placebo⫹SOC (n ⫽ 171)
SOC alone (n ⫽ 87)
53% 13% 34% 57 79%
53% 14% 33% 56 80%
52% 14% 34% 58 84%
88% 5% 4% 3%
94% 2% 3% 1%
92% 3% 1% 3%
46% 35% 11% 7% 5% 4% 10% 44%
43% 34% 11% 8% 7% 7% 15% 46%
55% 32% 8% 5% 7% 2% 8% 41%
42% 17% 41%
43% 16% 41%
40% 21% 40%
Abbreviation: SOC ⫽ institution-specific standard of care for oral hygiene.
Haenszel chi-square test for the nine subgroups defined by the two stratifying variables. RESULTS Between July 26, 2000, and December 6, 2001, 545 patients were randomized to the study, of which 511 patients were included in the analyses reported here: 253 patients were randomized to receive iseganan plus SOC, 171 to receive placebo plus SOC, and 87 to receive SOC alone. The first 27 patients randomized to the study (between July 26, 2000, and December 22, 2000) were potentially affected by an interactive voice randomization system error, and a decision was made before outcome results were available to exclude these patients from the efficacy analyses. In addition, 6 patients who were randomized to the blinded arms but never dispensed study drug and 1 patient randomized to the SOC-only arm and never completed a postbaseline assessment were also excluded from the analyses. Treatment groups were balanced with respect to patient demographics (age, gender, race), tumor location, macroscopic disease status (postoperative vs. unresected), and planned RT treatment regimen (Table 2). A total of 96 –97% of the scheduled oral assessments were performed in each of the three study groups. However, the percent of scheduled doses of study drug administered was lower in patients receiving iseganan (73%) than in those receiving placebo (80%) (p ⫽ 0.001) (Table 3).
No difference was seen between the iseganan and placebo groups for any study endpoint (Table 4). The proportion of patients who remained free of ulcerative OM and the peak severity of mucositis was similar between these two groups. In addition, there was no difference in mean peak mouth pain, mean peak difficulty swallowing, or mean percentage days of narcotic use. Patients randomized to iseganan and placebo experienced similar weight loss, feeding tube placement, and days of feeding tube use (data not displayed). Completion of planned RT and chemotherapy was similar between the iseganan and placebo groups. Statistically significant differences in outcomes were seen in patients randomized to iseganan compared with those randomized to SOC alone. A greater proportion of patients randomized to iseganan did not develop ulcerative OM (p ⫽ 0.049) and experienced less severe OM (p ⫽ 0.023) than patients randomized to SOC alone. Similarly, a smaller proportion of patients randomized to placebo developed ulcerative OM than patients randomized to SOC alone (p ⫽ 0.041). Thirty-four percent and 40% of the patients in the iseganan and placebo groups, respectively, did not develop confluent oral ulceration (NCI-CTC Grades 3 or 4) at any time during RT administration compared with 21% of the patients randomized to SOC alone. This difference represents a 16 –24% relative reduction in the most severe forms of mucositis. In addition, patients randomized to iseganan had less mean peak mouth pain, less mean peak difficulty swallowing, and fewer days of narcotic use than did patients randomized to SOC alone. Four percent of the patients in
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Table 3. Study conduct parameters Iseganan Placebo SOC (n ⫽ 253) (n ⫽ 171) (n ⫽ 87) Eligibility violations Completed oral assessments to end of radiotherapy % of scheduled oral assessments completed* Completed study drug administration to end of radiotherapy % of scheduled study drug doses taken*
0
1
0
95%
94%
97%
96%
97%
96%
73%
80%
NA
73%
80%
NA
p value
Iseganan vs placebo 0.001‡
Abbreviation: SOC ⫽ institution-specific standard of care for oral hygiene. * Percent reported is the mean of the individual patient percents. † Patients could have more than one reason for discontinuation. Percents are based on the total number of patients in the treatment group. ‡ Probability from Wilcoxon rank sum test.
the iseganan group, 3% in the placebo group, and 7% in the SOC only group received less than 95% their scheduled dose of RT (p ⫽ 0.28) (data not shown). Analysis of saliva samples collected from patients in the iseganan and placebo groups demonstrated that iseganan oral solution was microbicidal. In the group of patients randomized to receive iseganan, a reduction in mean total oral aerobic bacteria of 1.35 log10 colony forming units (CFU) per milliliter saliva (p ⬍ 0.0001) was demonstrated 1 h after administration of the first dose of study drug on the first day of therapy and a mean reduction of 0.71 log10 CFU/mL (p ⬍ 0.0001) was seen 1 h after administration of the first dose on the last day of therapy. In comparison, the placebo group demonstrated nonstatistically significant reductions of 0.01 log10 CFU/mL on the first day and 0.08 log10 CFU/mL on the last day of study drug administration. In both groups, there were statistically nonsignificant changes in mean total oral microbial burden between the first and last days of therapy (0.17 log10 CFU/mL reduction in the iseganan group and 0.07 log10 CFU/mL reduction in the placebo group). The quantity and type of microflora colonizing the oral cavity was similar in the two groups at follow-up—approximately 28 days after RT completion. Emerging resistance to iseganan was not observed. The proportion of patients experiencing adverse events (AEs) determined by the investigator to be related to study drug, AEs leading to study drug discontinuation, serious AEs, and deaths are summarized in Table 5. No serious AE of a specific organ class or preferred term occurred, with ⬎1% increased frequency in the iseganan group than both the placebo and SOC groups.
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Nausea was the AE most frequently attributed to study drug administration and the only AE that occurred with ⱖ5% increased frequency in the iseganan group than both the placebo and SOC groups. Fifty-one percent of the patients in the iseganan group, 42% in the placebo group, and 46% in the SOC group experienced nausea at some time during the study. A total of 84 –91% of the patients in each study group who experienced nausea had mild to moderately severe nausea. Two percent of the patients in the iseganan group, 3% in the placebo group, and 1% in the SOC group experienced nausea as a serious AE. A clinical diagnosis of oral candidiasis was reported as an AE in 18% of the patients in the iseganan group, 12% in the placebo group, and 15% in the SOC group at some time during the study. Candida spp. infections not specified as oral candidiasis were reported in 15%, 17%, and 29% of the patients in these groups, respectively. Mean time to Candida spp. infection was 29, 32, and 36 days in the iseganan, placebo, and SOC groups, respectively. Candidiasis resolved while taking study drug in 36% of the patients receiving iseganan and 33% of the patients receiving placebo. For all study groups, 98 –100% of the patients with candidiasis took an antimicrobial agent at some time during the study and 96 –100% took an antifungal agent. In the iseganan and placebo groups, oral candidiasis was not associated with oropharyngeal overgrowth of yeast, as determined by microbial analyses of saliva samples. DISCUSSION This is the largest randomized controlled trial of an antimicrobial intervention for prevention of OM reported to date. Despite measurable antibacterial and anticandidal activity in the oral cavity of patients participating in this trial, iseganan failed to reduce the rate of ulcerative OM, decrease the severity of mucositis, or attenuate its clinical sequelae when compared with placebo. However, it is of interest that patients randomized to receive iseganan or placebo had improved outcomes compared with patients randomized to SOC alone. These findings suggest that emphasis on oral rinsing or the vehicle solution used in this study may significantly reduce the incidence and severity of RT-induced ulcerative OM and its associated clinical outcomes. Although rigorous oral hygiene has been a tenet of supportive care during head-and-neck RT for many years, its true impact on OM has not been formally investigated. The results from this study suggest that attention to rigorous oral hygiene may have a significant impact on the development of OM and its clinical sequelae. In our study, patients randomized to receive study drug (iseganan or placebo) were encouraged to comply with a rigorous study specific oral hygiene regimen in addition to institution specific practices for oral hygiene care. Patients randomized to receive study drug were instructed to rinse their mouths before each study drug administration and then swish and gargle the study drug solution for 2 min six times daily throughout the period of RT administration. Study-specific techniques were
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Table 4. Study outcomes Iseganan (n ⫽ 253)
Placebo (n ⫽ 171)
SOC (n ⫽ 87)
p value
9%
9%
2%
9% 24% 66% 2.6
9% 30% 60% 2.5
2% 18% 79% 2.8
Ise vs. Pbo 0.998 Ise vs. SOC 0.049 Pbo vs. SOC 0.041 Ise vs. Pbo 0.160 Ise vs. SOC 0.023
1.5
1.4
1.6
5.8
5.7
7.0
Average mouth pain
2.8
2.7
3.2
Mean peak difficulty swallowing
6.2
6.2
7.5
Average difficulty swallowing
3.2
3.2
4.1
50%
50%
60%
Completion of planned RT and CT Dose of RT less than planned
9%
10%
17%
Dose RT longer than planned
50%
42%
49%
Dose CT less than planned
33%
33%
26%
Endpoint Mucositis No ulceration Peak severity of mucositis No ulcer (grades 0, 1) Patchy ulceration (grade 2) Confluent ulceration (grades 3, 4) Mean peak severity OM Average OM Patient reported mouth pain/difficulty swallowing Mean peak mouth pain
Mean % days narcotic use
Ise Ise Ise Ise
vs. vs. vs. vs.
Pbo 0.160 SOC 0.023 Pbo 0.613 SOC 0.076
Ise Ise Ise Ise Ise Ise Ise Ise Ise Ise
vs. vs. vs. vs. vs. vs. vs. vs. vs. vs.
Pbo 0.501 SOC 0.140 Pbo 0.986 SOC 0.036 Pbo 0.486 SOC ⬍0.001 Pbo 0.987 SOC ⬍0.001 Pbo 0.862 SOC 0.037
Ise Ise Ise Ise Ise Ise
vs. vs. vs. vs. vs. vs.
Pbo 0.921 SOC 0.042 Pbo 0.140 SOC 0.978 Pbo 0.964 SOC 0.478
Abbreviations: SOC ⫽ institution-specific standard of care for oral hygiene; Ise ⫽ iseganan; Pbo ⫽ placebo; OM ⫽ oral mucositis; RT ⫽ radiation therapy; CT ⫽ computed tomography.
developed to help remind patients to comply with study drug administration. In addition, patients randomized to receive iseganan or placebo maintained diaries of study drug administration that they reviewed with study staff at least twice weekly. However, patients randomized to SOC alone did not routinely receive these interventions. Therefore, it is possible that methods used to ensure compliance with study drug administration during the execution of this study may have inadvertently improved oral hygiene measures. Alternatively, it is possible that, after oral rinsing, the vehicle solution (placebo) used in this study provided a physical or chemical barrier that protected the mucosa from
further injury. These questions could be investigated further in both preclinical and clinical studies. Previous studies of oral, topically administered antimicrobial, or antiseptic agents have reported mixed success in reducing OM and its clinically relevant sequelae (6 – 8, 12–14). The variable efficacy of these agents may be due to differences in spectrum, speed, and duration of antimicrobial activity as well as possible inactivation by chemically charged molecules found in saliva and the oral cavity. It was hoped that iseganan’s broad-spectrum and rapid microbicidal activity in the presence of saliva would overcome the potential shortcomings of previously tested conventional
Table 5. Summary of adverse events Type of adverse event
Iseganan ⫹ SOC (n ⫽ 253)
Placebo ⫹ SOC (n ⫽ 171)
SOC alone (n ⫽ 26)
Related adverse events Adverse events leading to drug D/C Serious adverse events Deaths
21% 2% 26% 1%
5% 1% 20% 2%
NA NA 31% 2%
Abbreviations: D/C ⫽ discontinuation; SOC ⫽ institution-specific standard of care for oral hygiene.
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I. J. Radiation Oncology
● Biology ● Physics
antimicrobial agents (11, 12). In addition, iseganan’s lack of systemic absorption after oral-topical administration, its unique mechanism of action that is unaffected by commonly encountered antimicrobial resistance mechanisms, and its low potential for engendering resistance were considered ideal characteristics for prolonged oral-topical administration as required for the indication of preventing OM (9, 11). It is possible that, despite measurable reductions in oral flora, iseganan could not penetrate the inflammatory pseudomembrane covering the wound or reduce the microbial burden at some undefined critical level within the submucosal tissues. The results of our study do not support the hypothesis that infection plays a major role in the pathogenesis of RTassociated OM or that oral topical administration of antimicrobial agents provides significant incremental benefit over frequent oral rinsing and conventional SOC treatment. If oral microflora do contribute to the development of RTassociated OM, attention to standard oral hygiene practices may be sufficient to remove topical debris and microorganisms within the oral cavity. In addition, other intervention strategies such as enhancement of mucosal stem cell regeneration or modulation of tissue injury, recovery, or inflammation may be worth pursuing. Results from our study indicate that iseganan oral solution is safe and well tolerated in patients with compromised oral mucosa while receiving RT for head-and-neck cancer. Investigations with iseganan in clinical settings where infection is a known and significant factor should continue. PG-015 PRINCIPAL INVESTIGATORS Hani Ashmalla, M.D., New York Methodist Hospital, Brooklyn, NY; Vilija Avizonis, M.D., Latter Day Saints Hospital, Salt Lake City, UT; Boris Bahoric, M.D., Nova Scotia Cancer Center, Halifax Nova Scotia, Canada; Etienne Bardet, M.D., Centre Rene Gauducheau, Saint-Herblain, France; Michael Beat, M.D., Brooke Army Medical Center, Fort Sam Houston TX; Jean Bourhis, M.D., Institute Gustave Roussy, Villejuif, France; Harmar Brereton, M.D., Radiation Medicine Associates of Scranton, Scranton, PA; Andrew Brown, M.D., Elliot Hospital, Manchester, NH; Roger Byhardt, M.D., Zablocki VA Medical Center, Milwaukee, WI; Giles Calais, M.D., Hoˆ pital Bretonneau Service Corad, Tours, France; Clifford Chao, M.D., Washington University, St. Louis, MO; Albert Clairmont, M.D., Atlanta Ear, Nose & Throat, Atlanta, GA; Anthony Cmelak, M.D., Vanderbilt-Ingram Cancer Center, Nashville, TN; Walter Curran, M.D., Jefferson Oncology Group, Philadelphia, PA; William Demas, M.D., Akron City Hospital,
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Akron, OH; Phillip Delvin, M.D., St. Anne’s Hospital, Fall River, MA; Samy El-Sayed, M.D., Ottawa Regional Cancer Center, Ottawa, Ontario, Canada; Joel Epstein, M.D., University of Washington, Seattle, WA; Adam Garden, M.D., MD Anderson Cancer Center, Houston, TX; Alex Hammond, M.D., University of Western Ontario, London, Ontario, Canada; Paul Harari, M.D., and Scott Tannehill, M.D., University of Wisconsin, Madison, WI; Michael Henke, M.D., Abteilung Strahlenheilkunde, Radiologische Universitaetsklinik, Freiburg, Germany; David Irwin, M.D., Alta Bates Comprehensive Cancer Center, Berkley, CA; Douglas Johnson, M.D., Florida Radiation Oncology Group, Jacksonville, FL; Guy Juilliard, M.D., UCLA Medical Center, Los Angeles, CA; Elizabeth Junor, M.D., Beatson Oncology Centre, Glasgow, Scotland, U.K.; Charles Kelley, M.D., Newcastle General Hospital, Newcastle upon Tyne, England, U.K.; Eric Lartigau, M.D., Service Unite de Radiotherapie Clinique Centre Oscar Lambret, Lille Cedex, France; Arnold Markoe, M.D., University of Miami, Miami, FL; Ruby Meredith, M.D., Ph.D., University of Alabama, Birmingham, AL; Charles Nichols, M.D., Gulf Coast Cancer Treatment Center, Panama City, FL; Matthew Parliament, M.D., University of Alberta, Edmonton, Alberta, Canada; Douglas Peterson, D.M.D., Ph.D., University of Connecticut Health Science Center, Farmington, CT; Pascal Pommier, M.D., Service de Radiotherapie Centre Leon Berard, Lyon, France; Adam Raben, M.D., Monmouth Medical Center, Long Branch, NJ; David Raben, M.D., University of Colorado, Aurora, CO; Murali Rajaraman, M.D., Nova Scotia Cancer Centre, Halifax, Nova Scotia, Canada; William Regine, M.D., University of Kentucky, Lexington, KY; David Rosenthal, M.D., University of Pennsylvania, Philadelphia, PA; Marvin Rotman, M.D., SUNY Health Science Center, Brooklyn, NY; Ulrich Schaefer, M.D., WWU Munster Strahlentherapie Radioonkologie, Munster, Germany; David Schwartz, M.D., Seattle VA/Puget Sound Health, Seattle, WA; Finbarr Sheehan, M.D., British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Eric Sherman, M.B., Fox Chase Cancer Center, Philadelphia, PA; Paul Song, M.D., INOVA-Fairfax Hospital, Falls Church, VA; John Suh, M.D., Cleveland Clinic Foundation, Cleveland, OH; Mohan Suntharalingam, M.D., University of Maryland, Baltimore, MD; Paul Symonds, M.B., Leicester Royal Infirmary, Leicester, England, U.K.; Andy Trotti, M.D., H. Lee Moffit Cancer Center, Tampa, FL; Renate Ulrich, M.D., Universitatsklinikum Charite, Berlin, Germany; Te Vuong, M.D., McGill University Hospital, Montreal, Quebec, Canada; and Padraig Warde, M.B., Princess Margaret Hospital, Toronto, Ontario, Canada.
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