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Respiratory recurrent papillomatosis (RRP) is a fatal disease with no known cure. In severe RRP cases, systemic bevacizumab (SB) could be used as adjuvant therapy. SB may be a promissory treatment and control option for RRP. More research is needed to evaluate the efficiency and adverse effects in various populations.
- adjuvant therapy child
- adult
- adult-onset recurrent respiratory papillomatosis juvenile-onset papillomatosis
1. Introduction
Recurrent respiratory papillomatosis (RRP) and recurrent cutaneous papillomatosis (RCP) are devastating diseases with a high risk of long-term complications that impact patients’ and their families’ quality of life. The juvenile-onset RRP (JO-RRP) incidence rate is 4.3 per 100,000, whereas the adult-onset RRP (AO-RRP) incidence rate is 1.8 per 100,000 [1]. The two types of human papillomavirus (HPV) that cause RRP and RCP are HPV 6 and HPV 11. RRP and RCP are distinguished by the recurring growth of papillomas in the respiratory and gastrointestinal tracts, which can obstruct them in severe cases. There is no treatment for systemic papillomatosis [2].
Extra laryngeal papillomatosis has been seen in up to 30% of cases, with the oral cavity, trachea, and bronchi being the most common sites [3][4]. These patients have recurrent bronchiectasis, pneumonia, and decreased lung function [3][4].
2. Systemic Bevacizumab Studies
Table 1 summarizes the clinical characteristics of patients with RRP before SB treatment. The studies included were published between 2009 and 2021. A total of 34 patients were described in these studies from the United States (three case reports; n = 3, four case series; n = 12), India (one case report; n = 1), Germany (one case report; n = 1, one case series; n = 5), Colombia (one case series; n = 3), Argentina (one case report; n = 1), Chile (one case report; n = 1), and Spain (one case series; n = 2). In total, In total, 17 and 34 patients were under 18 years old and were adults, respectively. The median age for those under 18 years old was 8 yr (min = 0.58 and max = 16), and the median for adults was 34 years (min = 18 and max = 87). There were 23 males (67.6%).
Table 1. Clinical characteristics of patients with RRP prior systemic bevacizumab treatment. CR, Complete Regression, PR, Partial Regression, VGPR, very good partial remission, NA Not Applicable.
| Study | Author | Country | Year | Age at Treatment Start | Gender | Age at Onset | Larynx | Trachea | Lung | Number of Surgical Interventions Needed | Surgical Intervals | Prior Therapy |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Best et al. [5] | United States | 2017 | 20 | F | Juvenile | Y | Y | Y | -- | 3 weeks | Local: Cidofovir, bevacizumab, photodynamic therapy. Systemic. Interferon alpha |
| 2 | Best et al. [5] | United States | 2017 | 12 | F | Juvenile | Y | Y | Y | -- | 1–4 weeks | Local: Cidofovir Systemic: Interferon alpha, propanolol, celecoxib, Gardasil |
| 3 | Best et al. [5] | United States | 2017 | 16 | F | Juvenile | Y | N | N | -- | 4–6 weeks | Local: Cidofovir Systemic: Celecoxib |
| 4 | Best et al. [5] | United States | 2017 | 10 | M | Juvenile | Y | Y | Y | -- | 4 weeks | Local: Cidofovir Systemic: Interferon alpha, indole 3 carbinol, celecoxib |
| 5 | Best et al. [5] | United States | 2017 | 18 | M | Juvenile | Y | Y | Y | -- | 6 weeks | Local: Cidofovir, Bevacizumab Systemic: Interferon, leflunomide |
| 6 | Best et al. [5] | United States | 2017 | 21 | M | Juvenile | Y | Y | Y | -- | 6 weeks | Local: Cidofovir |
| 7 | Best et al. [5] | United States | 2017 | 86 | M | Adult | N | N | Y | -- | 3 months | Local: Cidofovir |
| 8 | Best et al. [5] | United States | 2017 | 62 | M | Adult | N | Y | Y | -- | 12 months | None |
| 9 | Cuestas et al. [6] | Argentina | 2019 | 6 | M | Juvenile | N | Y | Y | 2 | 4 weeks | None |
| 10 | Nagel et al. [7] | Germany | 2009 | 32 | M | Juvenile | N | Y | N | 4 per year during 12 years | 8 weeks | Local: Interferon, Cidofovir |
| 11 | Gates et al. [8] | United States | 2020 | 0.583333 | M | Juvenile | Y | Y | N | -- | 10 months | None |
| 12 | Zur et al. [9] | United States | 2016 | 12 | F | Juvenile | Y | Y | Y | >500 | 1–4 weeks | Local: Cidofovir, interferon alpha Systemic: Celecoxib, Propanolol, Azythormycin, Gardasil |
| 13 | Mhor et al. [10] | Germany | 2014 | 43 | M | Juvenile | N | Y | Y | >30 | -- | Multiple laser ablations |
| 14 | Mhor et al. [10] | Germany | 2014 | 49 | M | Adult | Y | N | N | 2 | 6 months | 2 laser ablation |
| 15 | Mhor et al. [10] | Germany | 2014 | 56 | F | Adult | Y | N | N | 16 | -- | 16 Laser ablations |
| 16 | Mhor et al. [10] | Germany | 2014 | 8 | F | Juvenile | Y | Y | Y | >30 | -- | Multiple laser ablations Local: interferon-alpha, cidofovir and celecoxib |
| 17 | Mhor et al. [10] | Germany | 2014 | 34 | M | Adult | Y | N | N | 6 | -- | laser vaporization and radical surgery via midfacial degloving, radiotherapy, |
| 18 | Fernandez-Bussy et al. [11] | Chile | 2017 | 42 | M | Adult | N | Y | N | 3 | -- | Local: ablation with argon plasma coagulation |
| 19 | Carnevale et al. [12] | Spain | 2018 | 5 | M | Juvenile | Y | Y | Y | 10 | -- | Multiples surgeries and laser ablations Local: Intepheron alpha, Cidofovir Systemic: Gardasil |
| 20 | Carnevale et al. [12] | Spain | 2018 | 9 | F | Juvenile | Y | Y | N | 47 | -- | Mulple surgeries |
| 21 | Hamdi et al. [13] | United States | 2020 | 12 | M | Juvenile | Y | Y | Y | 54 | -- | Multiples surgeries and laser ablations Local: Intepheron alpha, Cidofovir Systemic: Indole 3 Carbinol |
| 22 | Hamdi et al. [13] | United States | 2020 | 6 | M | Juvenile | Y | N | N | 34 | - | Local: Cidofovir |
| 23 | Bedoya et al. [14] | United States | 2017 | 87 | M | Adult | N | N | Y | 5 | -- | Local: Cidofovir, intralesional stent Systemic: Gardasil |
| 24 | Bedoya et al. [14] | United States | 2017 | 63 | M | Adult | Y | Y | Y | >6 | -- | -- |
| 25 | Evers et al. [15] | United States | 2020 | Betweenn 8 and 56 | Both | Juvenile and adult | Y | Y | Y | >10 | -- | Lobe resection, surgical interventions, laser ablations, radiochemotherapy |
| 27 | Ortiz et al. [16] | Colombia | 2021 | Betweenn 1 and 8 | Both | Juvenile | Y | Y | Y | >10 | -- | Debridement procedures |
| 28 | Gorelik et al. [17] | United States | 2021 | 5 | F | Juvenile | Y | N | N | 1 | -- | Debridement procedures |
| 29 | Goyal et al. [18] | India | 2021 | 4 and 24 | F | Juvenile | Y | N | N | >10 | -- | Local Bevacizumab |
Twenty-six of the 34 patients had laryngeal lesions, 19 had tracheal lesions, and 17 had lung lesions. Twelve patients had tracheal, laryngeal, and lung lesions. Before bevacizumab therapy, 24 of the 34 patients had undergone surgical procedures. The reported interventions had a median of 13 interventions (min = 3 interventions and max = 500 interventions).
Table 2 summarizes SB treatment, dosage, and outcomes in patients with RRP. Various doses were reported at various schemes. The most commonly reported SB dose was 10 mg/kg, which was received by 25 (73.5%) patients. The initial dose intervals with this dose ranged from 2 to 5 weeks. Two patients received 5 mg/kg with a 2-week interval between doses, and one received the same dose but with a 3-week interval. Two patients were given 15 mg/kg at 3-week intervals. The authors reported an initial dose of 5 mg/kg in four patients, followed by one increase to 7.5 mg/kg and two increases to 10 mg/kg.
Table 2. Systemic bevacizumab treatment, dosage and outcomes in patients with RRP. CR, Complete Regression, PR, Partial Regression, VGPR, very good partial remission, NA Not Applicable.
| Case | Author | Country | Year | Prior Therapy | Dose (mg/kg) | Inicial Dosing Interval (q Week) | Duration of Treatment (Months) | Stable Dosing Interval (q Week) | Total Cycles Received | Response | Pulmonary Response | Surgical Interval Post Bevacizumab | Side Events |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Best et al. [5] | United States | 2017 | Local: Cidofovir, bevacizumab, photodynamic therapy. Systemic. Interferon alpha |
10 | 3 | 12 | 8 | -- | PR | Not known | q3 months | Treatment changed secondary to diagnosis of malignancy |
| 2 | Best et al. [5] | United States | 2017 | Local: Cidofovir Systemic: Interferon alpha, propanolol, celecoxib, Gardasil |
10 | 4 | 21 | 8 | -- | PR | CR | q4 months | Proteinuria |
| 3 | Best et al. [5] | United States | 2017 | Local: Cidofovir Systemic: Celecoxib |
10 | 2 | 10 | 12 | -- | CR | . | No surgery required | None |
| 4 | Best et al. [5] | United States | 2017 | Local: Cidofovir Systemic: Interferon alpha, indole 3 carbinol, celecoxib |
5 | 3 | 18 | 3 | -- | PR | Stable | q6 months | None |
| 5 | Best et al. [5] | United States | 2017 | Local: Cidofovir, Bevacizumab Systemic: Interferon, leflunomide |
10 | 3 | 7 | 6 | -- | PR | Not known | q6 week with no excision needed | Hemoptysis |
| 6 | Best et al. [5] | United States | 2017 | Local: Cidofovir | 10 | 3 | 5 | 12 | -- | PR | Not known | q3 months | None |
| 7 | Best et al. [5] | United States | 2017 | Local: Cidofovir | 10 | 3 | 10 | 8 | -- | PR | PR | No surgery required | None |
| 8 | Best et al. [5] | United States | 2017 | None | 10 | 2 | 8 | 6 | -- | PR | PR | No surgery required | None |
| 9 | Cuestas et al. [6] | Argentina | 2019 | None | 10 | 4 | 6 | 12 | -- | PR | PR | No surgery required | None |
| 10 | Nagel et al. [7] | Germany | 2009 | Local: Interferon, Cidofovir | 10 | 3 | 6 | 10 | -- | CR | CR | No surgery required | None |
| 11 | Gates et al. [8] | United States | 2020 | None | 5 and then 10 | 4 | 12 | . | -- | PR | - | No surgery required | None |
| 12 | Zur et al. [9] | United States | 2016 | Local: Cidofovir, interferon alpha Systemic: Celecoxib, Propanolol, Azythormycin, Gardasil |
10 | 4–5 | 15.5 | 14 | - | CR | CR | Tracheal debridement at 12 months after bevacizumab starting. Laryngeal debribement at 15 months after bevacizumab starting. |
Mild proteinuria |
| 13 | Mhor et al. [10] | Germany | 2014 | Multiple laser ablations | 10 | 2 | 27 | 16 | 16 | VGPR | PR | No surgery required | Hypertension |
| 14 | Mhor et al. [10] | Germany | 2014 | 2 laser ablation | 10 | 3 | 2 | . | 3 | PR | NA | Laryngectomy for malignant transformation | None |
| 15 | Mhor et al. [10] | Germany | 2014 | 16 Laser ablations | 10 | -- | . | . | 6 | VGPR | NA | One infraglottic lesion, which had not responded to the same extent was treated with additional laser therapy a los 14 días | None |
| 16 | Mhor et al. [10] | Germany | 2014 | Multiple laser ablations Local: interferon-alpha, cidofovir and celecoxib |
5 | 2 | 2 | 12 | 9 | VGPR | CR | One surgery due to granulloma at the distal end of the tracheal cannula | None |
| 17 | Mhor et al. [10] | Germany | 2014 | laser vaporization and radical surgery via midfacial degloving, radiotherapy, | 15 | 3 | 2 | . | 6 | CR | NA | No surgery required | None |
| 18 | Fernandez-Bussy et al. [11] | Chile | 2017 | Local: ablation with argon plasma coagulation | 5 and then 10 | 3 | 4 | 12 | 6 | CR | NA | No surgery required | None |
| 19 | Carnevale et al. [12] | Spain | 2018 | Multiples surgeries and laser ablations Local: Intepheron alpha, Cidofovir Systemic: Gardasil |
10 | 4 | 46 | 10 | -- | CR | CR | Two surgical procedures due to laryngeal lesions | Mild proteinuria |
| 20 | Carnevale et al. [12] | Spain | 2018 | Mulple surgeries | 5 and then 7.5 | 3 | 6 | 3 | 8 | CR | NA | No surgery required | None |
| 21 | Hamdi et al. [13] | United States | 2020 | Multiples surgeries and laser ablations Local: Intepheron alpha, Cidofovir Systemic: Indole 3 Carbinol |
10 | 3 | 54 | 3 | 15 | CR | PR | Seven microdebriders | None |
| 22 | Hamdi et al. [13] | United States | 2020 | Local: Cidofovir | 10 | 1 | . | . | 1 | CR | CR | One surgery needed | None |
| 23 | Bedoya et al. [14] | United States | 2017 | Local: Cidofovir, intralesional stent Systemic: Gardasil |
5 | 2 | -- | 6 | - | VGPR | VGPR | No surgery required | Hemoptysis |
| 24 | Bedoya et al. [14] | United States | 2017 | -- | 10 | 2 | -- | 3 | -- | VGPR | VGPR | No surgery required | Mild Increase of basal hypertension |
| 25 | Evers et al. [15] | United States | 2020 | middle lobe resection with lymphadenectomy | 10 | 2 | -- | 3 | 68 | VGPR | VGPR | 51 months | Proteinuria, Hypertension |
| 26 | Evers et al. [15] | United States | 2020 | -- | 10 | 3 | -- | 3 | 3 | PR | NA | laser ablation | None |
| 27 | Evers et al. [15] | United States | 2020 | Laser ablations | 10 | 10 | -- | -- | 34 | CR | NA | 17 months | Proteinuria, Hypertension |
| 28 | Evers et al. [15] | United States | 2020 | Laser ablations | 5 | 2 | -- | -- | 33 | CR | VGPR | 32 months | None |
| 29 | Evers et al. [15] | United States | 2020 | -- | 15 | 3 | -- | -- | 15 | PR | NA | -- | None |
| 30 | Ortiz et al. [16] | Colombia | 2021 | Tracheostomy and surgical debridement | 10 | 3 | -- | -- | 3 | VGPR | NA | -- | None |
| 31 | Ortiz et al. [16] | Colombia | 2021 | Tracheostomy | 10 | 3 | -- | -- | 3 | CR | NA | -- | None |
| 32 | Ortiz et al. [16] | Colombia | 2021 | Debridement | 10 | 3 | -- | -- | 4 | CR | NA | -- | None |
| 33 | Gorelik et al. [17] | United States | 2021 | Surgical debridement, Intralesional Bevacizumab | 10 | 3 | -- | -- | 8 | CR | NA | -- | None |
| 34 | Goyal et al. [18] | India | 2021 | three doses of HPV vaccine Cervarix | 10 | 3 | -- | -- | -- | VGPR | NA | -- | None |
This entry is adapted from the peer-reviewed paper 10.3390/children10010054
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