Until recently, the only treatment we could give children with recurrent respiratory papillomatosis (RRP) was to regularly surgically remove the benign tumors to keep the airway open and work to keep pulmonary involvement at bay with a collection of adjuvant therapies such as cidofovir, interferon, propranolol, celecoxib, Gardasil, interferon, and leflunomide.
Children continue to have diminished quality of life; the more severe their disease, the more disruptive it is, with some children requiring tracheostomy. With the inherent need for multiple surgical interventions to debride the lesions, they also risk vocal cord damage, particularly scarring; complications from repeated anesthesia; and malignant transformation of the benign papillomas, which occurs in 3 to 5% of cases.
In 2011-12, Michael Mohr, MD, a hematologist at the University Hospital Muenster, Muenster, Germany, tried infusions of the cancer drug bevacizumab on five patients with advanced, progressive RRP. All 5 patients showed an immediate response to bevacizumab treatment. The results were published in 2014.
From weekly debridements to zero
One long-time patient of the Center for Pediatric Airway Disorders at Children’s Hospital of Philadelphia (CHOP) had RRP so aggressive that she needed weekly debridements of her laryngotracheal papillomas to prevent tracheal obstruction despite an indwelling tracheostomy tube. She was 12 years old when her mother, desperate for help, agreed to systemic bevacizumab (Avastin).
Treatment for RRP Gives Hannah Her Voice
Within 6 weeks of therapy, there was remarkable improvement with no recurrence of laryngotracheal papillomas. Following 3 months of treatment, I was able to remove her tracheostomy tube. After 5 months, a scan showed complete resolution of the pulmonary RRP nodules. She has experienced no complications from the bevacizumab and continues on maintenance therapy every 2 to 3 months under the supervision of my colleague, oncologist Elizabeth Fox, MD.
When this case was published in Laryngoscope, I began receiving calls from around the world from physicians seeking more information. In an effort to consolidate experiences with bevacizumab in the United States, Dr. Mohr, Simon Best, MD, an otolaryngologist at Johns Hopkins University, and I conducted a survey that found 8 patients who had been treated with bevacizumab at that time. Save for 1 patient who was diagnosed with malignant transformation and therefore discontinued bevacizumab, all patients had partial or complete response. We are now compiling an international Delphi study to look at the experiences around the world with this treatment modality.
Additional excellent results at CHOP
Since that survey, I have treated 2 additional patients, a 5-year-old male and a 14-year-old male.
Patient No. 2, came to CHOP following an emergency tracheostomy during diagnostic surgery at another facility when he was 3 years old. We diagnosed him with vocal fold, trachea and lung papillomas and performed a debridement. One month later, in June 2017, he received his first intravenous Avastin treatment, and in 3 weeks the papillomas were gone and we were able to take his tracheostomy tube out that day. He now has an infusion every 2 to 3 months. His voice is normal, and has required no further surgical debridements. Since he only had 2 surgical procedures in his lifetime relating to vocal fold papillomas, he has been able to avoid scarring of his larynx.
Patient No. 3 had been a long-time patient of the Center for Pediatric Airway Disorders at CHOP who underwent numerous surgeries to remove papillomas on his vocal folds every 2 to 3 months. He received his first dose of Avastin in August 2017 and hasn’t had any papillomas since. He receives maintenance infusions every 2 to 3 months, and I screen his vocal folds in the office every 6 months.
We have additional RRP patients from among the approximately 20 we see regularly who would benefit from Avastin therapy, but the biggest hurdle has been insurance approval, even though, from a purely financial standpoint, it makes sense since treatment with Avastin is less expensive than debridement surgery with anesthesia.
The end of RRP is possible
As remarkable as the preliminary results of treating severe RRP with Avastin appear to be, my hope is that within a generation such treatments won’t be necessary. It’s certainly possible, if the human papillomavirus (HPV) vaccine is universally embraced.
Today, 1 in 4 Americans are infected with HPV, according to the Centers for Disease Control. Even with those high numbers, RRP is — thankfully — rare, with estimated occurrence of 2 in 100,000 kids in the United States.
When we think of HPV complications, we usually think of cervical cancer or penile, head, neck and oral cancers in adults. That’s why there is such a big push to have all adolescents receive the HPV vaccine. Young patients contract RRP through maternal HPV. While there is still much to be learned about transmission, we do know RRP can be transmitted even when the baby is born by caesarean section.
However, if all adolescents were vaccinated again HPV, it would lead to the eventual elimination of RRP.
Aussies ahead of Americans
Coincidently, I was recently discussing an upcoming speaking engagement in Australia, and when I mentioned I could lecture on our RRP-Avastin experience, the organizer told me there would be no interest. HPV vaccinations are provided free in schools in Australia (since 2007 for girls and since 2013 for boys). As a result, the HPV rate among women 18 to 24 dropped from 22.7% in 2005 to 1.1% in 2015. As is the case elsewhere in the world, decreasing rates of cervical and other HPV-related cancers was Australia’s prime motivation. A happy side benefit has been the virtual elimination of RRP in children.
That is my hope for the United States. The National Cancer Institute reports that in the United States only about 63% of girls and 50% of boys 13 to 17 years old had started the HPV vaccine series during 2015 — substantially lower than rates for other vaccines routinely given to boys and girls at age 11 or 12, such as Tdap. If given before age 15, only 2 doses of Gardasil 9 are needed to provide the same protection as 3 doses given to older patients.
Each and every physician has a duty to counsel families on the huge upside of HPV vaccination. Focusing on the cancer-preventing benefits of the HPV vaccine — about 34,000 HPV-associated cancers are diagnosed each year and 4,000 people die — versus the HPV-prevention benefits, can steer nervous parents away from the sexual overtones that have apparently resulted in low vaccination rates.
References
Mohr M, Schliemann C, Biermann C, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett. 2014;8(5): 1912–1918. Accessed November 23, 2018.
Simon R. Best S, Mohr M, Zur K. Systemic Bevacizumab for recurrent respiratory papillomatosis: a national survey. Laryngoscope. 2017;127(10): 2225–2229. Accessed November 21, 2018.
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Until recently, the only treatment we could give children with recurrent respiratory papillomatosis (RRP) was to regularly surgically remove the benign tumors to keep the airway open and work to keep pulmonary involvement at bay with a collection of adjuvant therapies such as cidofovir, interferon, propranolol, celecoxib, Gardasil, interferon, and leflunomide.
Children continue to have diminished quality of life; the more severe their disease, the more disruptive it is, with some children requiring tracheostomy. With the inherent need for multiple surgical interventions to debride the lesions, they also risk vocal cord damage, particularly scarring; complications from repeated anesthesia; and malignant transformation of the benign papillomas, which occurs in 3 to 5% of cases.
In 2011-12, Michael Mohr, MD, a hematologist at the University Hospital Muenster, Muenster, Germany, tried infusions of the cancer drug bevacizumab on five patients with advanced, progressive RRP. All 5 patients showed an immediate response to bevacizumab treatment. The results were published in 2014.
From weekly debridements to zero
One long-time patient of the Center for Pediatric Airway Disorders at Children’s Hospital of Philadelphia (CHOP) had RRP so aggressive that she needed weekly debridements of her laryngotracheal papillomas to prevent tracheal obstruction despite an indwelling tracheostomy tube. She was 12 years old when her mother, desperate for help, agreed to systemic bevacizumab (Avastin).
Treatment for RRP Gives Hannah Her Voice
Within 6 weeks of therapy, there was remarkable improvement with no recurrence of laryngotracheal papillomas. Following 3 months of treatment, I was able to remove her tracheostomy tube. After 5 months, a scan showed complete resolution of the pulmonary RRP nodules. She has experienced no complications from the bevacizumab and continues on maintenance therapy every 2 to 3 months under the supervision of my colleague, oncologist Elizabeth Fox, MD.
When this case was published in Laryngoscope, I began receiving calls from around the world from physicians seeking more information. In an effort to consolidate experiences with bevacizumab in the United States, Dr. Mohr, Simon Best, MD, an otolaryngologist at Johns Hopkins University, and I conducted a survey that found 8 patients who had been treated with bevacizumab at that time. Save for 1 patient who was diagnosed with malignant transformation and therefore discontinued bevacizumab, all patients had partial or complete response. We are now compiling an international Delphi study to look at the experiences around the world with this treatment modality.
Additional excellent results at CHOP
Since that survey, I have treated 2 additional patients, a 5-year-old male and a 14-year-old male.
Patient No. 2, came to CHOP following an emergency tracheostomy during diagnostic surgery at another facility when he was 3 years old. We diagnosed him with vocal fold, trachea and lung papillomas and performed a debridement. One month later, in June 2017, he received his first intravenous Avastin treatment, and in 3 weeks the papillomas were gone and we were able to take his tracheostomy tube out that day. He now has an infusion every 2 to 3 months. His voice is normal, and has required no further surgical debridements. Since he only had 2 surgical procedures in his lifetime relating to vocal fold papillomas, he has been able to avoid scarring of his larynx.
Patient No. 3 had been a long-time patient of the Center for Pediatric Airway Disorders at CHOP who underwent numerous surgeries to remove papillomas on his vocal folds every 2 to 3 months. He received his first dose of Avastin in August 2017 and hasn’t had any papillomas since. He receives maintenance infusions every 2 to 3 months, and I screen his vocal folds in the office every 6 months.
We have additional RRP patients from among the approximately 20 we see regularly who would benefit from Avastin therapy, but the biggest hurdle has been insurance approval, even though, from a purely financial standpoint, it makes sense since treatment with Avastin is less expensive than debridement surgery with anesthesia.
The end of RRP is possible
As remarkable as the preliminary results of treating severe RRP with Avastin appear to be, my hope is that within a generation such treatments won’t be necessary. It’s certainly possible, if the human papillomavirus (HPV) vaccine is universally embraced.
Today, 1 in 4 Americans are infected with HPV, according to the Centers for Disease Control. Even with those high numbers, RRP is — thankfully — rare, with estimated occurrence of 2 in 100,000 kids in the United States.
When we think of HPV complications, we usually think of cervical cancer or penile, head, neck and oral cancers in adults. That’s why there is such a big push to have all adolescents receive the HPV vaccine. Young patients contract RRP through maternal HPV. While there is still much to be learned about transmission, we do know RRP can be transmitted even when the baby is born by caesarean section.
However, if all adolescents were vaccinated again HPV, it would lead to the eventual elimination of RRP.
Aussies ahead of Americans
Coincidently, I was recently discussing an upcoming speaking engagement in Australia, and when I mentioned I could lecture on our RRP-Avastin experience, the organizer told me there would be no interest. HPV vaccinations are provided free in schools in Australia (since 2007 for girls and since 2013 for boys). As a result, the HPV rate among women 18 to 24 dropped from 22.7% in 2005 to 1.1% in 2015. As is the case elsewhere in the world, decreasing rates of cervical and other HPV-related cancers was Australia’s prime motivation. A happy side benefit has been the virtual elimination of RRP in children.
That is my hope for the United States. The National Cancer Institute reports that in the United States only about 63% of girls and 50% of boys 13 to 17 years old had started the HPV vaccine series during 2015 — substantially lower than rates for other vaccines routinely given to boys and girls at age 11 or 12, such as Tdap. If given before age 15, only 2 doses of Gardasil 9 are needed to provide the same protection as 3 doses given to older patients.
Each and every physician has a duty to counsel families on the huge upside of HPV vaccination. Focusing on the cancer-preventing benefits of the HPV vaccine — about 34,000 HPV-associated cancers are diagnosed each year and 4,000 people die — versus the HPV-prevention benefits, can steer nervous parents away from the sexual overtones that have apparently resulted in low vaccination rates.
References
Mohr M, Schliemann C, Biermann C, et al. Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis. Oncol Lett. 2014;8(5): 1912–1918. Accessed November 23, 2018.
Simon R. Best S, Mohr M, Zur K. Systemic Bevacizumab for recurrent respiratory papillomatosis: a national survey. Laryngoscope. 2017;127(10): 2225–2229. Accessed November 21, 2018.
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