Annals of Otology, Rhinology & Laryngology http://aor.sagepub.com/
High-Dose Sublesional Bevacizumab (Avastin) for Pediatric Recurrent Respiratory Papillomatosis Douglas R. Sidell, Michel Nassar, Robin T. Cotton, Steven M. Zeitels and Alessandro de Alarcon Ann Otol Rhinol Laryngol 2014 123: 214 DOI: 10.1177/0003489414522977 The online version of this article can be found at: http://aor.sagepub.com/content/123/3/214
Published by: http://www.sagepublications.com
Additional services and information for Annals of Otology, Rhinology & Laryngology can be found at: Email Alerts: http://aor.sagepub.com/cgi/alerts Subscriptions: http://aor.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Mar 14, 2014 What is This?
Downloaded from aor.sagepub.com at GEORGIAN COURT UNIV on November 10, 2014
522977
research-article2014
AORXXX10.1177/0003489414522977Annals of Otology, Rhinology & LaryngologySidell et al
Article
High-Dose Sublesional Bevacizumab (Avastin) for Pediatric Recurrent Respiratory Papillomatosis
Annals of Otology, Rhinology & Laryngology 2014, Vol. 123(3) 214–221 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003489414522977 aor.sagepub.com
Douglas R. Sidell, MD1, Michel Nassar, MD1, Robin T. Cotton, MD1, Steven M. Zeitels, MD3,4, and Alessandro de Alarcon, MD, MPH1,2
Abstract Objectives: We review and report the use of high-dose bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP) in pediatric patients. Methods: We included all patients with pediatric-onset RRP who underwent bevacizumab (25 mg/mL) injections by a single practitioner. A series of 5 consecutive subepithelial injections were administered at 4- to 6-week intervals with concomitant 532 nm KTP laser ablation. The lesions were staged according to the Derkay staging system. The outcomes included pretreatment and posttreatment Derkay scores, the time interval between procedures, and voice outcomes. The demographic data extracted included sex, age at diagnosis, and current age. Results: Nine patients were included in this study, with 1 patient lost to follow-up; their median age was 8 years (range, 3 to 21 years). The mean bevacizumab dose was 14.25 mg (range, 5 to 45 mg). There was a median Derkay score of 11.5 (range, 4 to 23) at the time of diagnosis and a median 58% improvement following therapy. All patients demonstrated an increased time interval between injections, for a median improvement of 2.05× (range, 1.6× to 3.25×). Conclusions: Evidence exists in support of vascular endothelial growth factor as an important factor in the development of RRP. Although some variability in response is demonstrated by this study, high-dose bevacizumab appears to yield promising results for pediatric patients with RRP. Keywords bevacizumab, papilloma, pediatrics, recurrent respiratory papillomatosis
Introduction Recurrent respiratory papillomatosis (RRP) is the most common neoplastic disease of the pediatric airway, with an estimated incidence of 4.3 per 100 000 children per year.1-4 Although multiple treatment strategies for RRP exist, surgical debulking of disease remains the mainstay of therapy in children. The primary objectives of treatment include maintaining airway patency, improving vocal function, and achieving remission.1 The clinical severity and natural history of RRP vary significantly among children, making a single effective treatment method elusive. The multitude of therapies used to treat RRP have come to reflect this variability, and despite more than a century of documented RRP management, a cure does not exist.1,5,6 Regardless of clinical presentation, there is sound evidence to suggest that vascular growth is one of the universal mechanisms underlying RRP proliferation and disease recurrence.5,7 At our institution, photoangiolytic laser therapy is frequently used in the management of pediatric RRP.
In contrast to cold excision, the KTP (potassium titanyl phosphate) laser is capable of providing selective angiolysis of vasculature associated with laryngeal papilloma, thereby limiting injury to the subepithelial superficial lamina propria of the vocal fold mucosa.4 Recently, the monoclonal antibody bevacizumab (Avastin) has shown promise as an 1
Division of Pediatric Otolaryngology–Head and Neck Surgery, Cincinnati Children’s Hospital Medical Center, Boston, Cincinnati, Ohio, USA 2 Department of Otolaryngology–Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA 3 Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, Boston, Massachusetts, USA 4 Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA Corresponding Author: Alessandro de Alarcon, MD, MPH, Division of Pediatric Otolaryngology– Head and Neck Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 2018, Cincinnati, OH 45229-3039, USA. Email: [email protected]
Downloaded from aor.sagepub.com at GEORGIAN COURT UNIV on November 10, 2014
215
Sidell et al adjuvant therapy used in conjunction with angiolytic laser therapy. Bevacizumab is a recombinant antibody designed to bind vascular endothelial growth factor (VEGF) and inhibit interaction with the VEGF receptor.8,9 It has been used systemically for more than a decade to inhibit neovascularization associated with metastatic carcinoma, and has also been administered locally to reduce non-neoplastic angiogenesis in patients with retinopathy or hereditary hemorrhagic telangiectasia.7 The first reported use of bevacizumab for RRP was by Zeitels et al2 in an adult population. In the initial study, doses administered to glottic papilloma demonstrated a net positive effect on both disease burden and voice outcomes. Subsequently, larger doses were applied to multifocal subsites of the larynx burdened by papilloma, again demonstrating the safe and effective reduction of RRP.2,5,7 These studies provided a first look into the efficacy and safety of this treatment method, and represented the first use of bevacizumab in the adult population. Despite mounting evidence in support of bevacizumab therapy for adult RRP, pediatric data remain sparse. To date, a single study evaluating low-dose bevacizumab for pediatric RRP has been performed.3 Results obtained from this small cohort have thus served as an important initial step in the use of bevacizumab for the safe treatment of pediatric patients with RRP. However, the question as to whether high-dose bevacizumab will improve outcomes in the pediatric population has not been answered. Extrapolating from data obtained in the adult population, we designed a highdose pediatric Avastin protocol to serve as an adjunct following KTP laser therapy at this institution. The purpose of this report is to describe our experience using high-dose intralesional bevacizumab to treat a cohort of pediatric patients with RRP.
Methods This investigation was approved by the Cincinnati Children’s Hospital Medical Center Institutional Review Board. A retrospective review of patients 21 years of age and younger with pediatric-onset RRP was performed. All patients previously enrolled in a single-surgeon bevacizumab injection protocol from January 2011 to March 2013 were included. Age criteria were based on the US Department of Health and Human Services Food and Drug Administration definition of a pediatric patient.10
Injection Protocol Parents of children with RRP were given information about the potential risks and benefits of bevacizumab therapy. They were then given the option to continue the current surgical therapy or to begin the bevacizumab injection protocol. An approved bevacizumab consent form was signed
before the protocol was begun. The parents were given the ability to withdraw their children from the protocol at any time. Female patients of potential childbearing age underwent preoperative pregnancy screening using urine beta human chorionic gonadotropin analysis. Routine serologic tests, including renal function assays, were offered to all patients during the course of the protocol. Treatment of RRP was performed under general anesthesia by a conventional suspension microlaryngoscopy technique. All patients underwent KTP laser debulking of visible disease followed by subepithelial injections of bevacizumab (25 mg/mL). For each patient, a series of 5 consecutive injections were performed at 4- to 6-week intervals. Laser ablation was not performed in the absence of visible disease.
Demographics and Injection Data The data extracted from charts and surgical records included injection dose, injection volume, age at diagnosis, age at the time of the protocol, and gender.
Disease Staging Lesions were staged according to the Derkay anatomic assessment scale before the initial injection of bevacizumab, and 4 to 6 weeks after the final injection. The Derkay staging system was designed in conjunction with the RRP Task Force and consists of functional and anatomic assessment parameters. The system has been demonstrated to provide excellent intrarater and interrater reliability between surgeons and is now the most universally used staging system for patients with RRP. The anatomic assessment component of this system assigns scores to the upper and lower aerodigestive tract, including each subdivision of the larynx and the esophagus, based on the visible disease burden.11,12 The subjective functional component of this system relies on vocal function, urgency of intervention, and interprocedure intervals for scoring. Because a predetermined injection schedule was instituted for this patient population, only the anatomic assessment component was used for the purposes of this report. The anatomic staging was performed by reviewing pretreatment and posttreatment videos for each patient. To reduce potential bias, we randomized and deidentified the intraoperative videos for each visit before reviewing them. A 2-tailed t-test was performed comparing preinjection and postinjection groups of Derkay scores. Statistical significance was set at a P level of .05.
Injection Interval The time intervals between procedures, both before and after the bevacizumab therapy protocol, were evaluated by
Downloaded from aor.sagepub.com at GEORGIAN COURT UNIV on November 10, 2014
216
Annals of Otology, Rhinology & Laryngology 123(3)
Table 1. Patient Demographics, Disease Severity, and Injection Interval. Initial Current Age at Age Anatomic Score Improvement Initial Diagnosis, During Derkay Anatomic in Derkay Injection Pt Sex y Protocol, y Score Derkay Score, % Interval, d 1 F 2 F 3 F 4 M 5 M 6 F 7 F 8 M Range Median
3 2a 1 3 0.4 5 2 4 0.4 to 5 2.5
3 21 7 4 10 9 16 4 3 to 21 8
4 3 23 13 14 13 7 9 3 to 23 11
4 1 12 9 7 0 0 3 0 to 12 6
0 66 48 30 50 100 100 66 0 to 100 58
Current Improvement Average Average Injection in Injection Injection Injection Interval, d Interval Volume, mL Dose, mg
51 8.6 26 1.96× 0.33 46 150 3.25× 0.48 12.0 18 37 2.05× 0.90 22.5 13 30 2.3× 0.47 11.8 42 68 1.6× 1.11 27.8 120 Observation 0.45 11.3 Observation 0.34 8.5
High-Dose Sublesional Bevacizumab (Avastin) for Pediatric Recurrent Respiratory Papillomatosis Douglas R. Sidell, Michel Nassar, Robin T. Cotton, Steven M. Zeitels and Alessandro de Alarcon Ann Otol Rhinol Laryngol 2014 123: 214 DOI: 10.1177/0003489414522977 The online version of this article can be found at: http://aor.sagepub.com/content/123/3/214
Published by: http://www.sagepublications.com
Additional services and information for Annals of Otology, Rhinology & Laryngology can be found at: Email Alerts: http://aor.sagepub.com/cgi/alerts Subscriptions: http://aor.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> Version of Record - Mar 14, 2014 What is This?
Downloaded from aor.sagepub.com at GEORGIAN COURT UNIV on November 10, 2014
522977
research-article2014
AORXXX10.1177/0003489414522977Annals of Otology, Rhinology & LaryngologySidell et al
Article
High-Dose Sublesional Bevacizumab (Avastin) for Pediatric Recurrent Respiratory Papillomatosis
Annals of Otology, Rhinology & Laryngology 2014, Vol. 123(3) 214–221 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003489414522977 aor.sagepub.com
Douglas R. Sidell, MD1, Michel Nassar, MD1, Robin T. Cotton, MD1, Steven M. Zeitels, MD3,4, and Alessandro de Alarcon, MD, MPH1,2
Abstract Objectives: We review and report the use of high-dose bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP) in pediatric patients. Methods: We included all patients with pediatric-onset RRP who underwent bevacizumab (25 mg/mL) injections by a single practitioner. A series of 5 consecutive subepithelial injections were administered at 4- to 6-week intervals with concomitant 532 nm KTP laser ablation. The lesions were staged according to the Derkay staging system. The outcomes included pretreatment and posttreatment Derkay scores, the time interval between procedures, and voice outcomes. The demographic data extracted included sex, age at diagnosis, and current age. Results: Nine patients were included in this study, with 1 patient lost to follow-up; their median age was 8 years (range, 3 to 21 years). The mean bevacizumab dose was 14.25 mg (range, 5 to 45 mg). There was a median Derkay score of 11.5 (range, 4 to 23) at the time of diagnosis and a median 58% improvement following therapy. All patients demonstrated an increased time interval between injections, for a median improvement of 2.05× (range, 1.6× to 3.25×). Conclusions: Evidence exists in support of vascular endothelial growth factor as an important factor in the development of RRP. Although some variability in response is demonstrated by this study, high-dose bevacizumab appears to yield promising results for pediatric patients with RRP. Keywords bevacizumab, papilloma, pediatrics, recurrent respiratory papillomatosis
Introduction Recurrent respiratory papillomatosis (RRP) is the most common neoplastic disease of the pediatric airway, with an estimated incidence of 4.3 per 100 000 children per year.1-4 Although multiple treatment strategies for RRP exist, surgical debulking of disease remains the mainstay of therapy in children. The primary objectives of treatment include maintaining airway patency, improving vocal function, and achieving remission.1 The clinical severity and natural history of RRP vary significantly among children, making a single effective treatment method elusive. The multitude of therapies used to treat RRP have come to reflect this variability, and despite more than a century of documented RRP management, a cure does not exist.1,5,6 Regardless of clinical presentation, there is sound evidence to suggest that vascular growth is one of the universal mechanisms underlying RRP proliferation and disease recurrence.5,7 At our institution, photoangiolytic laser therapy is frequently used in the management of pediatric RRP.
In contrast to cold excision, the KTP (potassium titanyl phosphate) laser is capable of providing selective angiolysis of vasculature associated with laryngeal papilloma, thereby limiting injury to the subepithelial superficial lamina propria of the vocal fold mucosa.4 Recently, the monoclonal antibody bevacizumab (Avastin) has shown promise as an 1
Division of Pediatric Otolaryngology–Head and Neck Surgery, Cincinnati Children’s Hospital Medical Center, Boston, Cincinnati, Ohio, USA 2 Department of Otolaryngology–Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA 3 Center for Laryngeal Surgery and Voice Rehabilitation, Massachusetts General Hospital, Boston, Massachusetts, USA 4 Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA Corresponding Author: Alessandro de Alarcon, MD, MPH, Division of Pediatric Otolaryngology– Head and Neck Surgery, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 2018, Cincinnati, OH 45229-3039, USA. Email: [email protected]
Downloaded from aor.sagepub.com at GEORGIAN COURT UNIV on November 10, 2014
215
Sidell et al adjuvant therapy used in conjunction with angiolytic laser therapy. Bevacizumab is a recombinant antibody designed to bind vascular endothelial growth factor (VEGF) and inhibit interaction with the VEGF receptor.8,9 It has been used systemically for more than a decade to inhibit neovascularization associated with metastatic carcinoma, and has also been administered locally to reduce non-neoplastic angiogenesis in patients with retinopathy or hereditary hemorrhagic telangiectasia.7 The first reported use of bevacizumab for RRP was by Zeitels et al2 in an adult population. In the initial study, doses administered to glottic papilloma demonstrated a net positive effect on both disease burden and voice outcomes. Subsequently, larger doses were applied to multifocal subsites of the larynx burdened by papilloma, again demonstrating the safe and effective reduction of RRP.2,5,7 These studies provided a first look into the efficacy and safety of this treatment method, and represented the first use of bevacizumab in the adult population. Despite mounting evidence in support of bevacizumab therapy for adult RRP, pediatric data remain sparse. To date, a single study evaluating low-dose bevacizumab for pediatric RRP has been performed.3 Results obtained from this small cohort have thus served as an important initial step in the use of bevacizumab for the safe treatment of pediatric patients with RRP. However, the question as to whether high-dose bevacizumab will improve outcomes in the pediatric population has not been answered. Extrapolating from data obtained in the adult population, we designed a highdose pediatric Avastin protocol to serve as an adjunct following KTP laser therapy at this institution. The purpose of this report is to describe our experience using high-dose intralesional bevacizumab to treat a cohort of pediatric patients with RRP.
Methods This investigation was approved by the Cincinnati Children’s Hospital Medical Center Institutional Review Board. A retrospective review of patients 21 years of age and younger with pediatric-onset RRP was performed. All patients previously enrolled in a single-surgeon bevacizumab injection protocol from January 2011 to March 2013 were included. Age criteria were based on the US Department of Health and Human Services Food and Drug Administration definition of a pediatric patient.10
Injection Protocol Parents of children with RRP were given information about the potential risks and benefits of bevacizumab therapy. They were then given the option to continue the current surgical therapy or to begin the bevacizumab injection protocol. An approved bevacizumab consent form was signed
before the protocol was begun. The parents were given the ability to withdraw their children from the protocol at any time. Female patients of potential childbearing age underwent preoperative pregnancy screening using urine beta human chorionic gonadotropin analysis. Routine serologic tests, including renal function assays, were offered to all patients during the course of the protocol. Treatment of RRP was performed under general anesthesia by a conventional suspension microlaryngoscopy technique. All patients underwent KTP laser debulking of visible disease followed by subepithelial injections of bevacizumab (25 mg/mL). For each patient, a series of 5 consecutive injections were performed at 4- to 6-week intervals. Laser ablation was not performed in the absence of visible disease.
Demographics and Injection Data The data extracted from charts and surgical records included injection dose, injection volume, age at diagnosis, age at the time of the protocol, and gender.
Disease Staging Lesions were staged according to the Derkay anatomic assessment scale before the initial injection of bevacizumab, and 4 to 6 weeks after the final injection. The Derkay staging system was designed in conjunction with the RRP Task Force and consists of functional and anatomic assessment parameters. The system has been demonstrated to provide excellent intrarater and interrater reliability between surgeons and is now the most universally used staging system for patients with RRP. The anatomic assessment component of this system assigns scores to the upper and lower aerodigestive tract, including each subdivision of the larynx and the esophagus, based on the visible disease burden.11,12 The subjective functional component of this system relies on vocal function, urgency of intervention, and interprocedure intervals for scoring. Because a predetermined injection schedule was instituted for this patient population, only the anatomic assessment component was used for the purposes of this report. The anatomic staging was performed by reviewing pretreatment and posttreatment videos for each patient. To reduce potential bias, we randomized and deidentified the intraoperative videos for each visit before reviewing them. A 2-tailed t-test was performed comparing preinjection and postinjection groups of Derkay scores. Statistical significance was set at a P level of .05.
Injection Interval The time intervals between procedures, both before and after the bevacizumab therapy protocol, were evaluated by
Downloaded from aor.sagepub.com at GEORGIAN COURT UNIV on November 10, 2014
216
Annals of Otology, Rhinology & Laryngology 123(3)
Table 1. Patient Demographics, Disease Severity, and Injection Interval. Initial Current Age at Age Anatomic Score Improvement Initial Diagnosis, During Derkay Anatomic in Derkay Injection Pt Sex y Protocol, y Score Derkay Score, % Interval, d 1 F 2 F 3 F 4 M 5 M 6 F 7 F 8 M Range Median
3 2a 1 3 0.4 5 2 4 0.4 to 5 2.5
3 21 7 4 10 9 16 4 3 to 21 8
4 3 23 13 14 13 7 9 3 to 23 11
4 1 12 9 7 0 0 3 0 to 12 6
0 66 48 30 50 100 100 66 0 to 100 58
Current Improvement Average Average Injection in Injection Injection Injection Interval, d Interval Volume, mL Dose, mg
51 8.6 26 1.96× 0.33 46 150 3.25× 0.48 12.0 18 37 2.05× 0.90 22.5 13 30 2.3× 0.47 11.8 42 68 1.6× 1.11 27.8 120 Observation 0.45 11.3 Observation 0.34 8.5
