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Highlights of the RRP meeting/CME course at Johns Hopkins, 30 May 2014:
RRP patients/family members' perspectives
[The following report is based on coordinated input from all those RRP families who attended the meeting] On Friday May 30, 2014, a CME course, "Updates in Recurrent Respiratory Papilloma: Clinical and Research Perspective", was held at Johns Hopkins in Baltimore, MD. It was inspiring to see a novel symposium with CME credit offered for a discussion focused specifically on RRP and opened up to the RRP patient/family community. This offered a unique opportunity for an interaction among ENTs, RRP researchers and the patient community. Some key "take away" points:
• Although this conference was organized by a surgical department, with much of the target audience being otolaryngologists, whose primary focus is voice and airway management;
there was a clear message that the cure for this disease is going to be medical and not
surgical.
• Based on need for surgery, US RRP (annual) incidence is estimated at 1:100000 with
prevalence estimated to be a factor of 4-5 greater. However, both incidence and prevalence
would be much greater if RRP impact on voice is considered.
• KTP laser is becoming the surgical tool of choice for managing RRP especially for those
who can be treated in the office, but is also finding increased use in the OR. It has the capability of removing papillomas without impacting underlying epithelium. • The speakers addressed these adjunctive treatments of interest:
Avastin: Intralesional injections of the antiangiogenic agent bevacizumab (Avastin)
continues to show promise for RRP patients. Systemic application may be effective in some
cases of RRP more distally in the respiratory tract.
Celebrex: The study of Celebrex was designed around sound theory of the relationship
between COX-2 and PGE2. A clinical trial designed to measure the effectiveness of
Celebrex on RRP is showing some very promising results. It wasn't clear if any of the
responders had distal respiratory involvement.
HPV Vaccine: The HPV L1 vaccine Gardasil generates antibodies that effectively prevent
HPV 6,11,16,18 infections. This is being seen in new data that show a significant decline in
HPV in young adults in countries, such as Australia, were inoculation compliance is high.
This should result in a future reduction of RRP incidence. Gardasil is not designed to be
effective for existing HPV infections, however, based on experimental treatment of dogs with
persistent canine papilloma there is some evidence that an L1 vaccine could be used to treat
persistent infection. [Not clear why this should work? Thought that for therapeutic impact
against existing infection there needs to be activation of T cells, which is more likely
achieved by targeting E6 and/or E7 proteins?]
Artemisinin – An herbal medicine also known as sweet worm wood that is widely used to
treat Malaria. It is cytotoxic to HPV expressing cell lines and along with iron-dependent
DHA-induced apoptosis, suggests that it may be useful for treating RRP. We are unaware of any coordinated/scientific study to investigate the efficacy of this potential RRP treatment and feel it deserves more attention. • Some new research directions:
Anti-PD1 therapy: Significant research as to why HPV evades the immune system indicates
that the PD-1:PD-L1 pathway may inhibit host immune responses against HPV. This implies
that anti-PD1 therapy may help RRP patients who express PD-1:PD-L1. A phase 1B study
(MK-3475 Merck) using Merck's anti-PD1 drug currently involves head & neck cancer
patients, but no efficacy results are available yet.
Customized personalized treatments for RRP: The use of "conditionally reprogrammed
cells" may offer the ability to provide personalized targeted therapy for RRP patients. By
reproducing an individual's tumor cells and testing a variety of possible therapies, an optimal
treatment may be determined.
Another approach involves a xenograft model – growing RRP patients' tumors in NSG mice
(immumo suppressed) to test a variety of potential treatments. Among other drugs, this
approach has been used to successfully test systemic Avastin. (Note: possible
immunotherapies cannot be tested in this way.)
• RRP Specimen Biobank: A formally coordinated effort between patients, doctors and
researchers could allow a central research facility to collect pathology samples from patients, without the need for IRB approvals from each medical facility. Georgetown University Medical Center is presently taking initial steps to establish this biobank. • Pulmonary papillomas and malignant transformation: Although there was a presentation
acknowledging pulmonary papillomatosis and some discussions regarding screening, much more attention is needed to the issue of malignant transformation and new directions for treatment. Given the imperative for medical involvement and potential role of systemic therapy here, the absence of representation from medical oncology at the conference was disappointing. This manifestation of RRP involves about 95% of the disease morbidity/mortality and remains a major challenge which very much needs to be addressed by the RRP clinical / research community. Some presentation details:
• RRP by the Numbers: Epidemiologic Gestalt
Farrel Buchinsky, Allegheny Health Network, Pediatric Otolaryngology
Incidence 1/100000 vs. 4/100000 (early estimates by RRP Task Force)
prevalence 4-5 times incidence
Norway study indicates median age of diagnosis – children 4, adults 34
Remission – 44% go into remission in < 4years
HPV types in general population HPV6 2.3%, HPV11 0.3%
28% of pregnant women have HPV, but 0.9% HPV6, 0.6% HPV11
AORRP appears to relate to number of lifetime sexual partners
In Australia, Gardasil compliance is high and new data shows significant decline in HPV
in young adults
• RRP in the 21st Century: A Patient's Perspective – Pulmonary Papilloma &
Malignant Transformation
Jennifer Woo, Georgetown University School of Medicine ; RRP Foundation, President
Pulmonary papilloma most common in younger diagnoses and HPV11 more so than
HPV6, - extension to pulmonary is estimated to occur in up to 5%
Aggressive pulmonary spread and carcinoma often develops in 20s & 30s
Does HPV11 represent a "middle risk" for oncogenic progression?
HPV related progression to lung cancer do not seem to be universally associated with
smoking, prior irradiation or other environmental factors
Are RRP-related lung cancers biologically distinct from other lung cancer?
Need to develop and adopt consensus-based screening guidelines for pulmonary RRP.
• Approaches to RRP Care: General Philosophies
Lee Akst, Johns Hopkins, Otolaryngology-Head and Neck Surgery The disease COMES BACK => this is a frustrating disease for everyone ! Epithelial disease requires thorough, but superficial debridement Treatment = remove disease when active symptoms present. Goal during surgery – preserve the airway/ voice and minimize scarring Risk – cumulative scarring from multiple surgeries. KTP procedures are gaining more support from Doctors and Patients…. Office visit vs. OR - patient's preference (when KTP is available) When there is an airway risk – should be operated on in OR instead of in office KTP
• Unwieldy Workhorse: Operative Management of RRP with the CO2 Laser
Clint Allen, Johns Hopkins, Otolaryngology-Head and Neck Surgery Use of CO2 laser for RRP has been declining recently. CO2 wavelength 10600nm (targets water). Early studies showed some thermal injury. Power and other parameters can be adjusted to minimize, but not completely eliminate, thermal injury. CO2 laser may be more useful for disease located above vocal cords (in expert hands). • A Weapon of Minor Destruction: KTP Angiolytic Laser Use in the OR
Nazaneen Grant, Georgetown University Hospital, Otolaryngology-Head and Neck Surgery KTP is an angiolytic laser - selectively destroying microvasculature (this is relate to its operation at the wavelength of 532 nm), which enables it to "peel off " papillomas without impacting underlying epithelium. There is a retrogression or obliteration of blood vessels, as in embryologic development. KTP may not be appropriate for small children where considerable debulking is necessary and the microstructure is unclear. KTP lasers are also commonly used in ophthalmology, urology, and otology. • Office-based KTP Laser Treatment of Laryngeal Papilloma
Alexander Hillel, Johns Hopkins, Otolaryngology-Head and Neck Surgery No anesthetic, reduced post op pain 84% in a study used no pain meds 5% cannot tolerate the procedure Not as good for bulky disease Discomfort is usually mild You can use topical anesthesia Typically use the pulse setting epithelium can be preserved In office procedure - KTP laser allows patients to stay awake without general anesthesia , 87 % of patients prefer . Advantages of using KTP for doctors: Preserve epithelium Photocoagulation/ can adjust pulse widths of laser for more precision Thinner fiber Fast Bloodless procedure allows deeper removal of papillomas. Patient PROs: No General Anesthesia Total time less, more convenient. (Average time is 79 minutes in office vs. an average time of 300 minutes for the Operating Room) Reduce Post op pain Mild discomfort during procedure Lower threshold of recurrence More frequent Smell of tissue Best Candidates – those who cannot tolerate anesthesia, less papilloma, secondary procedure Other Considerations: • Treatment of RRP in Children: Strategies for Safe and Efficient Surgery
David Tunkel, Johns Hopkins, Otolaryngology-Head and Neck Surgery Identify the presenting signs and symptoms for children with RRP Discuss the surgical indications and goals for treatment of children with RRP Because considerable debulking is necessary in children, the microdebrider is more often used than KTP laser. • Medical and Surgical Management of Severe Pediatric RRP
Diego Preciado, Childrens National Medical Center, Dept. of Otolaryngology Adjuncts used for treating invasive tracheobronchial papillomas: Cidofovir –very effective for many but might induce dysplasia, carcinoma? Interferon – alpha – effective but very high relapse rate; significant side effects I3C,DIM – no side effects, but not clear how effective Particular severe case has not responded well to these adjuvants [We need some new approaches!] • Avastin, Office-based Treatment, and the Future of RRP Care
Steve Zeitels, Mass. General Hospital, Ctr. for Laryngeal Surgery and Voice
Rehabilitation
Estimated RRP prevalence based on airway & voice impact:
20000 Pediatric RRP: 80% airway & >95%voice; 20000 Adult: 15% Airway &
>95%voice
RRP is an angiogenic lesion, so photoangiolytic lasers, particularly the pulsed-KTP (532
nm) is effective. The efficacy is enhanced by intralesional injection of an anti-angiogenic
drug (Avastin) in combination with this angiogenic laser.
For distal RRP involvement , i.e., tracheal and below, intralesional injection is difficult,
so intravenous (IV) administration is suggested.
There is a problem with IV Avastin if lung cancer is present because this cancer causes
bleeding which can be a problem with Avastin. But this is not an issue with RRP. So, IV
Avastin may be useful for pulmonary RRP if no cancer is involved.
Perhaps other VEGF inhibitors (i.e., angiogenesis inhibitors) can be found that work
better than Avastin.
• The Biology of HPV and the Great Escape: How HPV Evades the Immune System
Sara Pai, Mass. General Hospital, Ctr. for Laryngeal Surgery and Voice Rehabilitation
75% of sexually active people have or will be infected with HPV in their lifetime (only
about 10% will present with disease).
CD4+ (commanders) & CD8+(soldiers) are T-cells that play significant roles in
controlling HPV. Some people express a high level of PD1/PD-L1 (receptor/protein),
which appears to "turn off" some CD8+ T cell activity and inhibit host immune responses
against HPV (and some cancers).
Trials involving cancer patients who express PD1/PD-L1 are currently underway using
anti-PD1 drugs that are designed to be effective in reducing PD1 expression thereby
enhancing T cell activity. One such study is Merck's Phase 1B study of MK-3475. It is
hoped that this approach can be extended to RRP patients with deep respiratory
involvement.
• Adjuvant Care of RRP
Simon Best, Johns Hopkins University School of Medicine Discussion of different drugs and compounds that have been used in RRP or are under investigation Evaluation of evidence for and against the use of various adjuvant treatments in RRP and future directions in RRP research Cidofovir – Based on Hopkins study involving 162 patients (15 JORRP), it has shown efficacy but should be used cautiously as it may produce significant vocal fold scarring with some risk of nephrotoxicity. The Hopkins study does not indicate a significant dysplasia risk. DIM – P450 inhibitor that affects the metabolism of estrogen. Rosen et al., phase 1 study – 35 patients, 1/3, 1/3, 1/3 complete, partial, no response. According to the RRPF website, DIM is the most common adjuvant therapy among RRP patients with 55% overall positive response rate. Artemisinin - An herbal medicine also known as sweet wormwood that is widely used to treat Malaria. It has been used to treat some cancers by "starving" cancer cells of iron, which they need to proliferate. It may also be useful for treating RRP as a similar situation applies to HPV and there is some anecdotal evidence to support this. Avastin (systemic) – Based on the early positive responses in a German pilot study (not yet published) of RRP patients with deep respiratory involvement, IV Avastin was used in a particular case of tracheal papilloma using 4 cycles of IV Avastin. Proposed 3 week dosing, then 6 week and try to space it out to 3months. 10mg/kg. Preliminary results are encouraging. Xenograft Model – uses NSG mice (immumo suppressed) to grow individual RRP tumors with the goal of producing personalized and targeted therapies. • The Role of Prostaglandin E2 in RRP
Bettie Steinberg, Laboratory of Papilomavirus Research, Hofstra North Shore-LIJ School of Medicine RRP patients have widespread latent infection, but it is the activation of the infection that causes the recurrence of RRP. Trauma, reflux are some possible triggers for activation. Specific defect in recognizing HPV might be associated with elevated COX-2 -> PGE2 levels. COX-2 appears to be generated by the RRP patient not from the papilloma cells. The virus turns up the receptors. Celebrex inhibits COX-2, so it may be able to reduce papilloma recurrence. EP4 appears to be the key. Preliminary results from a multi-center 24 month double-blinded clinical trial using Celebrex with RRP patients (1yr celebrex-1yr placebo) with cross over – 52 patients (37 analyzable) – histories include 2years of at least 3 surgeries/yr 50% responded – 25% partial, 25% complete (These results are still blinded and the mechanism of response is still being studied) Does not eliminate latent viral DNA even after a clinical response • Treatment of Pulmonary Disease
David Feller-Kopman , Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine In most cases of pulmonary RRP, patients have undergone at least 20 recurrences. No new treatment options discussed for tracheobronchial papillomatosis, other than perhaps IV Avastin. Need new medicines and/or new ways to delivery adjuvants directly to lung tissues. In addition to CT scans some other screening options that were mentioned are: Endobronchial ultra-sound – improved imaging (EBUS) Optical coherence Therapy (OCT) Some other guidance for ENT surgeons: Monitor signs of spreading into bronchial tubes with each RRP procedure. Avoid jet ventilation as there is a risk of downward spread of viral particles. Pulmonary RRP sometimes develop into calcified pulmonary nodules and often progress to cancerous tumors. No suggestions were presented on how best to treat these situations • HPV by the Millions; RRP by the Thousands: Susceptibility Insights
Farrel Buchinsky, Allegheny Health Network, Pediatric Otolaryngology Discussion of what can and what cannot be understood through genetic studies in recurrent respiratory papillomatosis.
RRP is a fairly rare disease that is not genetic but perhaps the susceptibility is.
Family concurrence data (source?): 11/1859 had two people with RRP, i.e., never a
spouse, identical twins, uncle/nephew, Siblings (years apart). The lack of "contact" in
these family member occurrences, suggests genetics more likely than contagion.
RRP Genetics study by Buchinsky, et al., has enrolled 608 patients and 797 parents
between 2004 and 2012. Thus far they have completed genotyping of 94 families and
have looked at MHC/HLA typing in hopes that it may help to predict what adjunct
therapies might be effective for individual RRP patients. [Note: major
histocompatibility complex (MHC) is a set of cell surface molecules encoded by a large
gene family in all vertebrates and the human leukocyte antigen (HLA) system is the name
of the locus of genes that encode for MHC in humans.]
Other misc findings:
In a Danish study over 15-20 years involving 1.2 million mothers (Silverberg, 2003)
there were 57 children born who developed RRP. Of this population of mothers 3012
had condyloma and from this much smaller subset 21 children were born who
subsequently developed RRP. [Is this very significant increase in RRP births due to
greater viral transmission or genetic factors affecting HPV susceptibility or a
combination of the both?]
An HPV serology study in RRP patients indicates that most do not show a serologic
response (lack of HPV antibodies in blood samples), especially JORRP patients.
However, after Gardasil vaccination, RRP patients have a strong antibody response
similar to people who do not have RRP.
• The Development of the HPV Vaccine
C. Richard Schlegel, Department of Pathology Georgetown University Hospital The HPV shell contains L1 (95%) and L2 (5%) proteins. HPV vaccines, such as, Gardasil, target type specific L1 proteins to generate antibody immunity that effectively prevent new infections. Gardasil was designed to prevent HPV 6,11,16,18 and a recent new vaccine version adds HPV 31,33,52,58. Canine papilloma vaccine experiments: L1 vaccine developed that prevents mucosal CPV infections in dogs In a 4 dog trial with the L1 vaccine existing lesions cleared in 16 weeks In a 15 dog trial 50% of lesions were cleared Does this imply an L1 HPV vaccine might show efficacy clearing existing lesions in humans if L1 is expressed? • Use of Conditionally Reprogrammed Cells for RRP Studies
Hang Yuan, Molecular Oncology, Georgetown University Hospital Discussion of new cell technology to analyze data from patients' cells with the goal of providing customized personalized therapy Growing HPV cells in the lab via a new approach called "conditionally reprogrammed cells" that is an extension of HeLa cell research. [Note: the first time scientists were able to keep alive and grow cells cultured from other cells, used cells from cervical cancer patient Henrietta Lacks in 1951(Hence the abbreviation HeLa) . After growing the tumor cells in the lab they can then be injected into a xenograft mouse which allows for testing a variety of drugs on the actual tumor. In an actual clinical case of an RRP patient (type HPV 11) with a 20 year history of 350 surgeries, pulmonary disease was diagnosed in 2008 and did not respond to IV cidofovir. Using conditional reprogramming, cell cultures from the lung tumor tissue and normal lung tissue were generated. Drug testing with this approach identified vorinostat (an HDAC inhibitor drug approved for treating a form of Lymphoma) as a potential therapeutic agent. After 3 months of treatment, lung tumors had stabilized with continued impact after 15 months. Georgetown researchers are seeking IRB approval to serve as a collection center for RRP tissue samples to further their study of testing adjuvant therapies to treat RRP. LIST OF PRESENTERS AND AFFILIATIONS:
ACTIVITY CO-DIRECTORS
Lee Akst, MD
Assistant Professor of Otolaryngology – Head and Neck Surgery Director, Johns Hopkins
Voice Center Johns Hopkins University School of Medicine Baltimore, Maryland
Nazaneen Grant, MD
Assistant Professor of Otolaryngology - Head and Neck Surgery
Georgetown University Hospital
Washington, DC
OTHER SPEAKERS
Clint Allen, MD
Assistant Professor of Otolaryngology- Head and Neck Surgery
Johns Hopkins University School of Medicine
Baltimore, Maryland
Simon Best, MD Assistant Professor of Otolaryngology- Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland Farrel Buchinsky, MD Allegheny Health Network Associate Professor Pediatric Otolaryngology Pittsburgh, Pennsylvania David Feller-Kopman, MD Associate Professor of Medicine, Pulmonary and Critical Care Medicine Director, Interventional Pulmonology Johns Hopkins University School of Medicine Baltimore, Maryland Alexander Hillel, MD Assistant Professor of Otolaryngology- Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland Sara Pai, MD, PhD Associate Professor, Center for Laryngeal Surgery and Voice Rehabilitation Massachusetts General Hospital Boston, Massachusetts Diego Preciado, MD Assistant Professor of Surgery and Pediatrics George Washington University School of Medicine and Health Sciences Faculty, Otolaryngology Children's National Medical Center Washington, DC C. Richard Schlegel, MD Chairman and Professor, Department of Pathology Lombardi Comprehensive Cancer Center Georgetown University Hospital Washington, DC Bettie Steinberg, PhD Professor and Dean, Elmezzi Graduate School of Molecular Medicine Professor and Chair, Department of Molecular Medicine Chief Scientific Officer Investigator, Center for Oncology and Cell Biology Director, Laboratory of Papilomavirus Research The Feinstein Institute for Medical Research Hofstra North Shore-LIJ School of Medicine Hempstead, New York David Tunkel, MD Professor of Pediatrics and Otolaryngology - Head and Neck Surgery Division Chief, Pediatric Otolaryngology Johns Hopkins University School of Medicine Baltimore, Maryland Jennifer Woo, MS Recurrent Respiratory Papillomatosis Foundation, President MD Candidate Georgetown University School of Medicine Washington, DC Hang Yuan, PhD Assistant Professor of Molecular Oncology Georgetown University Hospital Washington, DC Steven Zeitels, MD Chief, Center for Laryngeal Surgery and Voice Rehabilitation Massachusetts General Hospital Boston, Massachusetts

Source: http://rrpf.org/meetings/Hopkins2014/HopkinsRRPcoursePatientsFamiliesPerspective.pdf