Treatment Of Recurrent Respiratory Papillomatosis Research Articles

Update on HPV-associated head and neck cancers-highlights of the 2024 ASCO Annual Meeting

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is becoming increasingly important in head and neck oncology. At this year's conference of the American Society of Clinical Oncology (ASCO), alarge number of papers were presented on the topic of HPV-associated HNSCC, particularly with regard to neoadjuvant treatment approaches, radiation de-escalation strategies, therapeutic vaccines, and treatment monitoring. In this context, study results on the treatment of HPV-related recurrent respiratory papillomatosis (RRP) were also presented. Based on contributions to the 2024 ASCO Annual Meeting, an insight into the latest developments in HPV-associated diseases of the head and neck is provided. The papers were reviewed for clinical relevance and contextualized based on current therapeutic concepts. Alarge number of studies on liquid biopsies (LB) were presented. It was shown that although the methods for analyzing LBs for HPV-positive patients are well developed and can be used for diagnostics, risk classification, treatment management, or tumor follow-up, the methods vary considerably, and their clinical application has not yet been sufficiently validated. With regard to therapeutic HPV vaccination, three large studies were presented for the treatment of recurrent/metastatic HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The only randomized study was on the vaccine ISA101b (peltopepimut-S) and did not reach its primary endpoint; however, the vaccine seemed to be highly effective in patients with a combined positive score (CPS) ≥ 20. Furthermore, data from aphaseIstudy on PRGN2012, an adenovirus-based immunotherapy used therapeutically for the treatment of recurrent respiratory papillomatosis (RRP), were presented. PRGN2012 led to areduction in surgical interventions for RRP, and the US Food and Drug Administration (FDA) designated PRGN2012 as abreakthrough therapy and orphan drug. However, the vaccine is not yet approved for the treatment of RRP.

Successful Bevacizumab Therapy in a 25-Year-Old Patient with Recurrent Respiratory Papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a chronic condition caused primarily by human papilloma virus (HPV) types 6 and 11, leading to recurrent growths in the respiratory tract. These types of papilloma can cause significant morbidity due to airway obstruction, often requiring frequent surgical interventions. Traditional treatments, including surgical removal and adjunctive therapies like antivirals and immune modulators, often fail to prevent recurrence, impacting the patient's quality of life. This report presents a 25-year-old female with a long-standing history of RRP, diagnosed at age 2. Despite numerous interventions, including CO2 laser ablations, interferon therapy, HPV vaccination, and a laryngotomy with tracheal reconstruction, the patient continued to experience severe airway obstruction requiring frequent surgeries. In 2023, intravenous therapy with bevacizumab, vascular endothelial growth factor inhibitor was introduced, leading to a significant reduction in the frequency of surgical interventions from 8 to 4 per year. This reduction improved the patient's respiratory function and quality of life, highlighting bevacizumab's therapeutic potential. The case underscores the debilitating nature of RRP and the challenges of its management. Bevacizumab, by targeting vascular endothelial growth factor (VEGF), has shown promise in reducing papilloma growth and the need for frequent surgeries. This case supports the inclusion of bevacizumab as an adjunctive therapy in RRP treatment, warranting further research to confirm its long-term efficacy and safety. Recurrent respiratory papillomatosis is a rare and complex disease that severely impacts patients' quality of life.This case report demonstrates that bevacizumab can significantly reduce surgical interventions in recurrent respiratory papillomatosis (RRP), offering a promising treatment that improves management of this chronic condition.Bevacizumab, already used in treating various diseases by targeting VEGF, shows promise in managing RRP as well, highlighting its potential across multiple conditions and expanding its therapeutic versatility.

Quantifying Bevacizumab Efficacy in Recurrent Respiratory Papillomatosis.

To develop and validate a novel method for quantifying the efficacy of Bevacizumab (Bev) in treating Recurrent Respiratory Papillomatosis (RRP), and to evaluate the clinical outcomes of a three-dose Bev induction therapy followed by surgical intervention. Twenty-one RRP patients treated with a three-dose Bev regimen were included. A novel efficacy evaluation method using ImageJ software was developed to calculate the standardized lesion volume from laryngoscopic images. This was compared with the Derkay score. Clinical outcomes, including reduction rate, cumulative reduction rate, efficacy grading, recurrence, and adverse reactions, were analyzed. In the study cohort, the reduction rate was significantly higher after the first treatment compared with subsequent treatments. The overall response rate increased from 75% after the first treatment to 100% after the third. Among patients with localized lesions who underwent surgery, 76% experienced recurrence with a mean recurrence time of 114.23 days. Most recurrent lesions were smaller than at baseline. Adverse reactions included increased blood pressure in seven patients, which resolved without intervention. The new method showed a significant positive correlation with the Derkay score. In conclusion, based on the above findings, systemic Bev treatment for RRP is a safe and effective therapeutic approach, though further research is needed. Moreover, the new efficacy evaluation method we developed can significantly aid in studying the effectiveness of Bev treatment for RRP. 2 Laryngoscope, 2024.

Recurrent respiratory papillomatosis: comparing in-office and operating room treatments.

We report the management of recurrent respiratory papillomatosis (RRP) employing a protocol that includes both office-based (OB) and general anaesthesia (GA) procedures. Quality of life (QoL) outcomes in the OB cohort were compared to those obtained from an historical cohort treated only under GA. Patients affected by RRP from 2019 until 2023 ("new protocol") and from 2012 to 2019 ("historical protocol") were enrolled. In both groups the Derkay site score (DSS) was calculated. In patients adhering to the new protocol, questionnaires measuring QoL were prospectively administered (voice handicap hindex-10 [VHI-10] along with a specific questionnaire to measure the tolerance to the OB procedures). A cost analysis was also performed. In all, 35 patients composed the new protocol cohort and 13 the historical. In the first group, patients underwent a median of 4 treatments. At 2 years, 68% of patients were treated exclusively in the office. Overall, for the new protocol, median DSS and VHI-10 after one year were both significantly lower than those at baseline [2 vs 4 and 3 vs 14, respectively; p < 0.001]. No differences were found between the new and the historical protocol cohorts considering DSS over time. Treatment of RRP may be conducted successfully in an office-based setting reducing healthcare costs.

PRGN-2012, a novel gorilla adenovirus-based immunotherapy, provides the first treatment that leads to complete and durable responses in recurrent respiratory papillomatosis patients.

LBA6015 Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and, although rare, transformation into malignant cancer. There are no approved therapeutics. RRP is currently managed with frequent ablative procedures that can lead to irreversible laryngotracheal scarring and disability. PRGN-2012 is a gorilla adenovirus-based gene therapy/immunotherapy designed to generate HPV6/11-specific T cell immunity. The FDA has granted PRGN-2012 Breakthrough Therapy Designation for the treatment of RRP recognizing that this single arm study can serve as pivotal to support a licensing application. Methods: This pivotal trial (NCT04724980) evaluates the safety and efficacy of PRGN-2012 in patients with RRP requiring a minimum of 3 surgeries in the 12 months prior to treatment. Eligible patients received 4 subcutaneous (SC) injections of PRGN-2012 at dose level (DL) 1 (1x1011 Particle Units (PU) per injection; n=3) or DL2 (5x1011 PU per injection; n=35) over 12 weeks. The primary endpoint was the rate of complete response (CR), defined as no requirement for surgery in the 12 months following completion of treatment. Other key endpoints include duration of response, change in extent of papilloma growth (anatomic Derkay score) and vocal function. Results: PRGN-2012 was well-tolerated, with no serious adverse events, grade &gt; 2 treatment-related adverse events, or early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. PRGN-2012 treatment at DL2 significantly (p&lt;0.0001) decreased the requirement for surgery, with a median number of surgeries in the 12 month period decreasing from 4 (3-10) prior to treatment to 0 (0-7) surgeries post-treatment. Approximately 90% of patients experienced a decrease in the number of surgeries in the 12 months post-treatment compared to pre-treatment with PRGN-2012. The primary endpoint evaluation demonstrated a confirmed complete response in 17/31 (55%) of evaluable patients. The median duration of complete response has yet to be reached with a median follow up of 15 months (12 - 30) at the time of data cutoff (March 6, 2024). Additionally, PRGN-2012 treatment resulted in a significant reduction in Derkay score, improvement in vocal function and generation of HPV-specific immune responses. Conclusions: These data demonstrate the overall favorable safety profile and significant clinical benefit of PRGN-2012 in adult RRP patients. These findings support PRGN-2012 as a potential therapeutic option for this patient population where no FDA-approved therapeutics exist. Clinical trial information: NCT04724980 .

Advances in Recurrent Respiratory Papillomatosis Treatment: Adjuvant Intralesional Bevacizumab's Impact, Potential and Insights from a Case Series Study.

Recurrent respiratory papillomatosis is an aggressive benign disease characterised by the repeated growth of multiple warts involving the larynx as well as other parts of the respiratory tract. Recurrent respiratory papillomatosis is most commonly caused by human papillomaviruses 6 and 11. It requires multiple surgical procedures for tumour debulking.Our study aims to evaluate the impact and potential of adjuvant intralesional bevacizumab in the treatment of recurrent respiratory papillomatosis while providing valuable insights based on a case series analysis.A prospective study of a total of 13 patients with Recurrent respiratory papillomatosis attending a tertiary care hospital with ages ranging from 3 to 30years was conducted from February 2018 to February 2023 by intralesional bevacizumab 1ml with a concentration of 2.5mg/ml per dose, 3 injections, each once every 4weeks by calculating the number of operative procedures per year, duration of time between procedures, calculating the Derkay score before 1year of the first injection and after 1year of the last dose injection of bevacizumab treatment. Inclusion criteria are ages between 3 and 30years with recurrent respiratory papillomatosis who underwent at least 4 or more surgical procedures with no adjuvant therapies. In all our cases, the affected area was the larynx.Adjuvant therapy with intralesional bevacizumab increases the duration of time between surgical procedures and reduces the number of operative procedures each year with an overall improvement in the Derkay score. No adverse drug effects have been reported in our study.Intralesional Bevacizumab is an effective and safe adjuvant treatment option for recurrent respiratory papillomatosis. It increases the duration of time between surgical procedures and decreases the number of procedures per year with an overall improvement in the Derkay score.

The role of HPV11 E7 in modulating STING-dependent interferon β response in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare benign tumor caused mainly by the infection of the respiratory tract epithelial cells by the human papillomavirus (HPV) type 6/11. However, the specific mechanisms underlying the inhibition of the host's innate immune response by HPV remain unclear. For this purpose, we employed single-cell RNA sequencing to analyze the states of various immune cells in RRP samples post-HPV infection and utilized a cellular model of HPV infection to elucidate the mechanisms by which HPV evades the innate immune system in RRP. The results revealed distinct immune cell heterogeneity in RRP and demonstrated that HPV11 E7 can inhibit the phosphorylation of the stimulator of interferon genes protein, thereby circumventing the body's antiviral response. In vitro co-culture experiments demonstrated that stimulation of macrophages to produce interferon-beta induced the death of HPV-infected epithelial cells, also reducing HPV viral levels. In summary, our study preliminarily identifies the potential mechanisms by which HPV evades the host's antiviral immune response, as well as the latent antiviral functions exhibited by activated macrophages. This research serves as an initial exploration of antiviral immune evasion in RRP, laying a solid foundation for investigating immunotherapeutic approaches for the disease.IMPORTANCESurgical tumor reduction is the most common treatment for recurrent respiratory papillomatosis (RRP). One of the characteristics of RRP is its persistent recurrence, and multiple surgeries are usually required to control the symptoms. Recently, some adjuvant therapies have shown effectiveness, but none of them can completely clear human papillomavirus (HPV) infection, and thus, a localized antiviral immune response is significant for disease control; after all, HPV infection is limited to the epithelium. Inhibition of interferon-beta (IFN-β) secretion by HPV11 E7 viral proteins in epithelial cells by affecting stimulator of interferon genes phosphorylation may account for the persistence of low-risk HPV replication in the RRP. Moreover, suppression of the IFN-I pathway in RRP cell types might provide clues regarding the hyporeactive function of local immune cells. However, activation of macrophage groups to produce IFN-β can still destroy HPV-infected cells.

Systemic Bevacizumab for Recurrent Respiratory Papillomatosis: A Single Institution's Experience.

Medical therapies to limit disease recurrence are critically needed for recurrent respiratory papillomatosis (RRP). Systemic bevacizumab is emerging as an exciting adjuvant therapy toward this end, but uptake has been poor due to the lack of experience and awareness of best prescribing practices. The objective of this study was to describe a single tertiary care academic medical center's experience using systemic bevacizumab for the treatment of RRP. A retrospective review was performed to identify patients with RRP on systemic bevacizumab. Demographic and clinical characteristics, findings on imaging reports, and disease response at all anatomic subsites involved in papilloma were documented. Of the 17 RRP patients on systemic bevacizumab, 9 (52.9%) were male, and 12 (70.6%) were diagnosed with juvenile-onset RRP. The total lifetime number of surgeries was high, with more than half (n = 9; 52.9%) undergoing more than 50 surgeries. Following induction of systemic bevacizumab, a significant reduction in patients with laryngeal (n = 15; 94.1% vs. n = 7; 41.2%, p < 0.001) and tracheal (n = 11; 64.7% vs. n = 5; 29.4%, p = 0.04) RRP was noted. Surgical frequency was significantly lower following systemic bevacizumab (2.5 vs. 0.5 surgeries per year; p < 0.001). The most common complications were new-onset hypertension (n = 4; 23.5%) and proteinuria (n = 5; 29.4%). Systemic bevacizumab is effective in reducing the number of surgeries needed for RRP while exhibiting a relatively safe complication profile. Papillomas in the larynx and trachea are most responsive to systemic bevacizumab, while pulmonary RRP is most likely to exhibit a partial-to-stable response. 4 Laryngoscope, 134:3253-3259, 2024.

Systemic bevacizumab for treatment of recurrent respiratory papillomatosis.

To characterize treatment response of recurrent respiratory papillomatosis (RRP) including adult-onset RRP (AORRP) and juvenile-onset RRP (JORRP) to systemic bevacizumab (bev), and share our treatment regimen experience. Patients were enrolled in bev treatment based on a pathologically confirmed diagnosis of squamous papilloma. According to lesion characteristics and medical history, systemic bev was used as preoperative adjuvant therapy, postoperative adjuvant therapy, or primary therapy. The assessment of treatment response relied on the morphological changes of lesions. Vocalization and voice-related quality of life were evaluated using the voice handicap index-30 (VHI-30) for adults and the pediatric VHI (pVHI) for children. Adverse effect was monitored through patient self-reported symptoms and regular follow-ups. This study included 24 patients, comprising nine AORRP and 15 JORRP cases. In AORRP, all patients (100%) exhibited various degrees of response to systemic bev, with 5 (55.56%) achieving complete response (CR). Among JORRP patients, 14 (93.33%) showed a response to systemic bev, with 8 (53.33%) achieving CR and currently being followed up. No instances of aggravation were observed during systemic bev treatment. A total of 21 patients (21/24, 87.50%) reported voice improvement, accompanied by reduced VHI-30 or pVHI scores across all aspects, including total, functional, physical, and emotional dimensions. No grade 3 or higher adverse events occurred. The most common adverse events were grade 1 gum bleeding (n = 4, 16.67%) and grade 1 proteinuria (n = 4, 16.67%). Systemic bev can be used as a powerful therapy for both AORRP and JORRP. The findings provide a reference to the systemic bev treatment for RRP.

Indications, Efficacy, Safety, and Clinical Outcomes of 585 nm Pulsed Dye Laser in Non-Malignant Laryngeal Lesions: A Systematic Review.

The objective of this manuscript was to review the indications, efficacy, and safety of a 585 nm pulsed dye laser (PDL) in non-malignant laryngeal lesions. Following the PRISMA statement recommendations, three independent authors searched for articles published in PubMed/MEDLINE, the Cochrane Library, Google Scholar, Scielo, and Web of Science. A bias analysis was performed following NICE guidance tools. From the 506 identified publications, 19 observational studies met the inclusion criteria. The PDL improves vocal quality objectively and subjectively in vascular lesions (p < 0.005) and improves vocal quality in patients with dysplasia/leukoplasia without changing the natural history of the disease compared to other treatments. Reinke's edema and granulomas require an average of 1.5 PDL sessions for resolution. Treatment of recurrent respiratory papillomatosis requires multiple sessions, with complete remission achieved in 50-70% of patients. Regardless of the lesion, the tolerance of the procedure under local anesthesia is exceptional (84-97%), and the results in terms of regression and vocal quality are promising. The complication rate is minimal, and the procedure does not interfere with other treatment alternatives. There is no consensus on laser settings. The lack of consistent use in evaluating vocal outcomes, whether objective or subjective, prevents the comparability between studies. The 585 nm pulsed dye laser appears to be an effective and safe therapeutic option in patients with non-malignant laryngeal pathology. Future controlled studies are needed to compare the 585 nm pulsed dye laser with other lasers or cold instrument procedures.

Use of Intralesional Cidofovir in Treatment of Recurrent Respiratory Papillomatosis

Use of Intralesional Cidofovir in Treatment of Recurrent Respiratory Papillomatosis

Recurrent laryngeal papillomatosis: multimodal therapeutic strategies. Literature review and multicentre retrospective study.

Recurrent respiratory papillomatosis (RRP) is a benign, rare disease caused by Human Papilloma Virus (HPV) that can be divided into juvenile and adult forms. The course of the disease is variable, but is usually more aggressive in the juvenile form. The standard surgical treatment is represented by CO2 laser resection, although photoangiolytic lasers represent a valid alternative. Adjuvant therapies have been proposed for disease control in case of frequent surgical resections or spreading into the lower airways. In recent years, the development of immunotherapy led to the use of bevacizumab either intratumorally or intravenously, but the most promising therapeutic development is represented by HPV vaccination. This paper aims to present a narrative review of the literature and the experience of three different University Centres in the treatment of RRP. A retrospective analysis of the clinical charts of all patients affected by laryngeal papillomatosis and treated in three different University Centres between 2002 and 2022 was performed. The following parameters were collected: sex, age at first evaluation, sites of larynx involved, HPV type, type of first surgical treatment, presence and number of recurrences, surgical treatment of recurrences, adjuvant therapies, side effects and status at last follow-up. Seventy-eight patients were available for evaluation. Of these, 88% had adult onset RRP (Ao-RRP) and 12% juvenile onset RRP (Jo-RRP). The glottis was the most frequently involved subsite; all patients were submitted to surgical resection with CO2 laser under general anaesthesia. Recurrences appeared in 79% of the patients, the patients who did not recur were all adults. The mean number of recurrences was 9 (range 1-110). Recurrences were more frequent in children (M = 20; range 2-110) than adults (M = 5; range 1-21). Thirty-two (52%) of the 62 patients who recurred were re-treated with CO2 laser under general anaesthesia, while office-based treatment with a photoangiolytic laser was preferred in the remaining 30 (48%) patients. Adjuvant treatments were applied in 26 patients. The analysis of the course of the disease showed that in the 9 patients with Jo-RRP, 6 (67%) were free of lesions at the last follow-up, while the other 3 (33%) had papillomas. Of the 69 patients with Ao-RRP, 53 (77%) were alive and free of disease at the last visit, 14 (21%) were alive with disease, 1 (1%) was lost at follow-up and 1 (1%) died for other disease. Severe side effects were not observed except for 2 patients, who developed posterior glottic stenosis. Our results confirmed the literature review. RRP is a potentially aggressive disease, especially in juvenile onset. Surgical resection is still first-line treatment, but in case of multiple recurrences the use of adjuvant therapies must be taken into consideration.

The Efficacy of Human Papillomavirus Vaccination as an Adjuvant Therapy in Recurrent Respiratory Papillomatosis.

To characterize the efficacy of human papillomavirus (HPV) vaccination as an adjuvant therapy in recurrent respiratory papillomatosis (RRP). PubMed, Embase, Cochrane, Google Scholar, ClinicalTrials.gov, and Web of Science databases were queried for articles published before April 2021. All retrieved studies (n=870) were independently analyzed by two reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement using predefined inclusion and exclusion criteria.13 studies met inclusion criteria. A random-effects meta-analysis was performed to study intersurgical interval (ISI) and number of surgical procedures per year before and after vaccination. The systematic review included 13 studies, comprising 243 patients. All studies utilized the Gardasil® quadrivalent vaccine, and one study (Yiu et al. 2019) utilized both the quadrivalent and Gardasil® 9-valent vaccines. Our meta-analysis included 62 patients with ISI data across 4 studies, and 111 patients with data on the number of surgical procedures per month across 7 studies. The mean number of surgical procedures decreased by 4.43 per year after vaccination (95% CI, -7.48 to -1.37). Mean ISI increased after vaccination, with a mean difference of 15.73 months (95% CI, 1.46-29.99). Two studies reported on HPV sero-conversion, with HPV seropositivity of 100% prior to vaccination and 25.93% after vaccination. The addition of HPV vaccination was associated with an increase in time between surgeries and reduction in the number of surgical procedures required. HPV vaccination may be a beneficial adjuvant treatment for RRP. NA Laryngoscope, 133:2046-2054, 2023.

Safety of different surgical modalities for recurrent respiratory papillomatosis resection: A systematic review and meta-analysis.

Currently, the most common surgical modalities used for recurrent respiratory papillomatosis (RRP) resection are microdebrider, carbon dioxide (CO2 ) laser and potassium-titanyl-phosphate (KTP) laser. However, complication rates vary among different surgical modalities and have been controversial in different studies. This study systematically reviews the available studies which reported intra-operative and post-operative complications, aiming to compare the safety of microdebrider, CO2 laser and KTP laser. Meta-analysis. Seven electronic databases (PubMed/MEDLINE, EMBASE[Ovid], Scopus, Cochrane Library and Web of Science) were searched from inception through 28 April 2022. Randomised controlled, prospective or retrospective observational studies that recorded the complications of three different surgical modalities for RRP resection were included in the meta-analysis. Outcomes of interest were intra-operative and post-operative complications, and complication rate was calculated to evaluate the safety of surgical methods. Twenty different studies were included in quantitative synthesis. Only one study compared outcomes of those three kinds of treatment modalities simultaneously, two studies compared microdebrider and CO2 laser, and the remaining studies focussed on only one of three treatments. The weighted average complication rate for microdebrider was 0.03 (95% confidence interval [CI] 0.00-0.21), n= 6, for CO2 laser treatment was 0.16 (95% CI 0.09-0.25), n= 14 and for KTP laser treatment was 0.04 (95% CI 0.00-0.14), n= 4. The limited evidence demonstrated that CO2 lasers in the surgical treatment of RRP may lead to more surgical complications, and microdebrider and KTP lasers may be safer. However, the heterogeneous data limit any strong comparison of outcomes of different treatment of laryngeal papillomas. Future randomised controlled trials that directly compare the safety of different surgical modalities are needed.

Our experience in developing and operating the Airway Intervention Registry for Recurrent Respiratory Papillomatosis (AIR-RRP): national data collection [version 2; peer review: 2 approved

Recurrent respiratory papillomatosis (RRP) is characterised by benign wart-like growths in the respiratory tract caused by the human papillomavirus (HPV). These warts vary in size and grow quickly, causing voice changes and airway obstruction. Whilst the condition is rare, RRP is more common and aggressive in children. There is currently no curative treatment for HPV, therefore RRP is managed by maintaining a safe airway and a serviceable voice by repeated surgery to remove the growths. A lack of specific diagnostic codes prevents reliable case ascertainment of RRP from routine administrative databases such as Hospital Episode Statistics. In 2017 a cross-sectional survey identified 918 RRP patients in the UK, half of whom had received surgical intervention for RRP in the previous 12 months with 16 different interventions. Randomised controlled trials for RRP interventions are difficult due to the rarity of the disease, variation in severity and progression and non-standard care across the NHS. Consequently, there is a lack of definitive efficacy and safety evidence. The only national guidance for RRP interventions is "Radiofrequency cold ablation for respiratory papillomatosis" (NICE IPG434, 2017) which recommended further data collection due to lack of evidence. However, due to the wide variation in RRP management across the NHS, clinical opinion favoured that any data collection should include a comparison of safety and efficacy of all RRP interventions in order to advise which improved patient outcomes and quality of life. To address lack of evidence, and inform the future care of RRP patients, we developed a registry and used it to collect real-world data from patients receiving treatment for RRP in NHS hospitals across the UK. The purpose of this paper is to share lessons learned from this national data collection exercise to inform future clinical registry development.

Metformin for the Treatment of Recurrent Respiratory Papillomatosis.

Metformin is an oral agent used for the management of type 2 diabetes. As a result of its ability to alter cellular metabolic requirements, metformin also possesses antiproliferative properties. Metformin has been shown to reduce mutagenesis in several malignancies, however has never been described as a treatment option for recurrent respiratory papillomatosis (RRP). The aim of this study is to present a case series of non-diabetic patients with adult-onset RRP who were treated with metformin. Case series. Five patients (age 48 ± 17.82, range 35-68, 4 males, 1 female) were identified with a history of laryngeal RRP who were treated with 500 mg of metformin twice daily. Follow-up time ranged from 11 to 105 months. Two patients had spontaneous regression of RRP lesions within months of starting metformin. Four patients had reduced time intervals between surgical procedures after starting metformin. All patients tolerated metformin well with only minor side effects of self-limiting light-headedness, facial flushing or gastrointestinal upset. Metformin is a low-risk medication that was used to reduce progression and burden of disease in 5 patients with RRP. Further studies should investigate the sole or adjunct use of metformin for treatment of RRP.

Abstract 4121: Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma

Abstract Background: Recurrent respiratory papillomatosis (RRP) is a human papilloma virus (HPV) associated benign disease, which, in rare cases, can develop into lung squamous cell carcinoma. Treatment options are limited with no approved systemic adjuvant therapy and the disease requires frequent surgical resection to prevent airway obstruction. Therefore, expanding available treatment options remains a highly important, but unmet need in RRP. Herein, we present a case of RRP with squamous cell carcinoma of lung that demonstrated durable stable disease with nivolumab and subsequent bevacizumab. Case presentation: A 48-year-old woman with long standing RRP since teenager, who underwent multiple microsuspension laryngoscopies, debridements including laryngeal lesions, and ultimately, 5 years ago, video assisted thoracic surgery (VATS) resection of right upper lobe mass, confirming squamous cell carcinoma, has been managed with debulking surgery on tracheal lesions by ENT on regular basis. Nivolumab, a programmed death-1 blockade, 3 mg/kg every 2 weeks was started given squamous cell carcinoma of lung. Stable disease (SD) in lung lesions was achieved on nivolumab for one year but she required more frequent debulking of tracheal lesions. After multidisciplinary discussion with Otorhinolaryngology, she was started on bevacizumab, vascular endothelial growth factor inhibitor, 10 mg/kg every 6 weeks. Follow-up CT scans in 10 weeks showed a decrease in size of a left lower lobe mass to 27 mm from 32 mm in the previous image. After one year, administration of bevacizumab was spaced out to every 12 weeks. She requires less debulking surgery and the last debulking surgery was approximately 3 years ago. She maintains SD for over 4 years since starting bevacizumab. Discussion: Our patient with RRP and squamous cell carcinoma of lung demonstrated SD on nivolumab before she was switched to bevacizumab. In addition, her SD on bevacizumab of more than 4 years with 12 weeks of maintenance interval is encouraging as there is no current standard of care treatment for RRP. Despite difficulty in running clinical trials in RRP due to its rareness, additional studies evaluating the efficacy of PD-1 inhibitor or anti-VEGF monoclonal antibody on RRP are warranted. Citation Format: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Young Kwang Chae. Durable stable disease with nivolumab, PD-1 inhibitor, and subsequent bevacizumab, Anti-VEGF monoclonal antibody, in long standing recurrent respiratory papillomatosis with lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4121.

Our experience in developing and operating the Airway Intervention Registry for Recurrent Respiratory Papillomatosis (AIR-RRP): national data collection

Recurrent respiratory papillomatosis (RRP) is characterised by benign wart-like growths in the respiratory tract caused by the human papillomavirus (HPV). These warts vary in size and grow quickly, causing voice changes and airway obstruction. Whilst the condition is rare, RRP is more common and aggressive in children. There is currently no curative treatment for HPV, therefore RRP is managed by maintaining a safe airway and a serviceable voice by repeated surgery to remove the growths. A lack of specific diagnostic codes prevents reliable case ascertainment of RRP from routine administrative databases such as Hospital Episode Statistics. To determine RRP burden in the UK, we conducted a cross-sectional survey of ENT consultants; 283 responded, identifying 918 RRP patients, half of whom received surgical intervention for RRP in the previous 12 months with 16 different interventions reported. Randomised controlled trials for RRP interventions are difficult due to the rarity of the disease, variation in severity and progression and non-standard care across the NHS. Consequently, there is a lack of definitive efficacy and safety evidence. The only national guidance for RRP interventions is “Radiofrequency cold ablation for respiratory papillomatosis” (NICE IPG434, 2017) which recommended further data collection due to lack of evidence. However, due to the wide variation in RRP management across the NHS, clinical opinion favoured that any data collection should include a comparison of safety and efficacy of all RRP interventions in order to advise which improved patient outcomes and quality of life. To address lack of evidence, and inform the future care of RRP patients, we developed a registry and used it to collect real-world data from patients receiving treatment for RRP in NHS hospitals across the UK. The purpose of this paper is to share lessons learned from this national data collection exercise to inform future clinical registry development.

Comparison of Treatment for Recurrent Respiratory Papillomatosis at a Public County Versus Private Academic Hospital

ObjectiveTo compare patient, disease and treatment characteristics of patients treated for recurrent respiratory papillomatosis (RRP) at a public county versus a private hospital. MethodsA retrospective cohort study was conducted of adult patients undergoing treatment for RRP at a tertiary-care academic center (TAC, n = 48) versus public safety net hospital (PSNH, n = 14), both staffed by the same Otolaryngology providers. ResultsThere was no difference between cohorts in age, gender, medical comorbidities, history of juvenile-onset presentation, or history of prior treatment at a different institution. PSNH patients were more likely to be Hispanic/Latino, primarily speak Spanish, have public or no insurance, and reside in a zip code with lower median income compared with TAC patients. Despite living significantly closer to the hospital, PSNH patients were more likely than TAC patients to present with respiratory symptoms (50% versus 20.8%, P = 0.04), and exhibit more than one involved laryngeal subsite at their first surgical intervention (78.6% versus 27.1%, P = 0.001). They also had high rates of referral for otolaryngologic care via the emergency department (42.9%) rather than outpatient specialty referral (35.7%) and were more likely than TAC patients to require urgent intervention (21.4% versus 2.1%, P = 0.03). There was no difference in time interval from first clinic visit to procedure date or total number of treatments. ConclusionsPSNH patients present with more severe and symptomatic RRP disease compared with TAC patients. This finding may be related to sociodemographic disparities leading to poorer access in care.

Systemic Bevacizumab Treatment for Recurrent Respiratory Papillomatosis: Long-Term Follow-Up.

Systemic bevacizumab is a new adjuvant therapy for recurrent respiratory papillomatosis (RRP) that has shown promising preliminary results in children. The objective of this study was to report the largest series to date that includes long-term follow-up data on bevacizumab treatment. Retrospective chart review. Retrospective review of seven pediatric patients treated within the past 6 years with systemic bevacizumab for RRP refractory to traditional debridement. All seven patients had a significant reduction in disease burden after initiation of systemic bevacizumab. There have been no major complications associated with systemic therapy so far. Median duration of bevacizumab treatment was 2.13 years. Three of the seven patients have been on treatment for over 3 years with the longest duration of treatment in our first patient now at 5.5 years. One patient experienced significant disease recurrence on two occasions when therapy was temporarily discontinued and was recently diagnosed with squamous cell carcinoma of the lung. Systemic bevacizumab is an effective therapy for cases of severe RRP with promising results both in short-term and long-term follow-up. Side effects are minimal. Patients must be followed closely to determine appropriate dosing intervals to control disease and to screen for disease progression. 4 Laryngoscope, 132:2071-2075, 2022.