Combination Therapy Papillomatosis With Celecoxib and Erlotinib ...

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Regression of Recurrent Respiratory Papillomatosis With Celecoxib and Erlotinib Combination Therapy Atikun Limsukon, Irawan Susanto, Guy W. Soo Hoo, Steven M. Dubinett and Raj K. Batra Chest 2009;136;924-926 DOI 10.1378/chest.08-2639 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/136/3/924.full.html

Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2009by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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CHEST Regression of Recurrent Respiratory Papillomatosis With Celecoxib and Erlotinib Combination Therapy Atikun Limsukon, MD; Irawan Susanto, MD, FCCP; Guy W. Soo Hoo, MD, FCCP; Steven M. Dubinett, MD; and Raj K. Batra, MD

Recurrent respiratory papillomatosis (RRP) can be difficult to manage. Symptoms are related to recurrent tracheobronchial papillomas and are usually treated with bronchoscopic removal. Other modalities are added when the papilloma burden becomes too great or recurrence is too frequent, but with limited efficacy. We report a patient with progressive RRP that had become refractory to available therapy. Because papillomas overexpress epidermal growth factor receptor, along with increased expression of cyclooxygenase-2 and prostaglandin E2, it was reasoned that a combination therapy of erlotinib and celecoxib would be effective in controlling papilloma growth. After institutional approval and informed patient consent, this combination was initiated. There was a striking improvement in the number and appearance of respiratory tract papillomas, with elimination of the need for repeated papManuscript received November 5, 2008; revision accepted February 9, 2009. Affiliations: From the Division of Pulmonary and Critical Care Medicine (Drs. Limsukon, Soo Hoo, Dubinett, and Batra), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA; the Division of Pulmonary and Critical Care Medicine (Drs. Susanto and Dubinett), David Geffen School of Medicine at UCLA, Los Angeles, CA; and the Division of Pulmonary and Critical Care Medicine (Dr. Limsukon), Cedars-Sinai Medical Center, Los Angeles, CA. Funding/Support: Dr. Soo Hoo has received grants from Chiron, Novartis and Forest, and was involved in a conference sponsored by Cardinal Health. Dr. Dubinett serves on the scientific advisory board for Tragara Pharmaceuticals. Dr. Batra has received grants from the Department of Veterans Affairs and the National Institutes of Health, and was a site-principal investigator for Fujirebio Diagnostics, Inc. Drs. Limsukon and Susanto have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Raj K. Batra, MD, Department of Medicine, Pulmonary and Critical Care Section, Wadsworth Gene Medicine Program and the Stem Cell Institute, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Box 111Q (Pulmonary Medicine), Los Angeles, CA 90073; e-mail: [email protected] DOI: 10.1378/chest.08-2639

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illoma removal. Pretreatment and posttreatment images document this response, and the improvement has now been maintained for nearly 2 years with effective therapy. (CHEST 2009; 136:924 –926) Abbreviations: COX ⫽ cyclooxygenase; EGFR ⫽ epidermal growth factor receptor; PGE2 ⫽ prostaglandin E2; RRP ⫽ recurrent respiratory papillomatosis; VAGLAHS ⫽ Veterans Affairs Greater Los Angeles Healthcare System

58-year-old man with a history of laryngeal cancer, A which had been surgically resected and was fol-

lowed by a laryngectomy tube placement in 2001, was being clinically monitored for recurrent respiratory papillomatosis (RRP). The disease was diagnosed by bronchoscopy and biopsy in 2003, and was associated with the development of progressive shortness of breath due to repeated airway obstruction. Papillomas have recurred with increasing frequency since 2005, and the management of symptoms necessitated their bronchoscopic removal with forceps and/or electrocautery using an argon plasma coagulator every 3 to 4 weeks. In February 2006, the patient began receiving IV cidofovir; however, following a transient response, bronchoscopic removal and electrocauterization of the papillomas was again required monthly. By October 2006, the rate of papilloma recurrence accelerated even further, and the disease also began to circumferentially involve the mainstem and segmental bronchi. Following an extensive discussion with the patient concerning the rationale behind the use of the proposed agents, therapy with cidofovir was discontinued, and therapy with celecoxib, an “antiinflammatory” cyclooxygenase (COX)-2 inhibitor that may have antineoplastic effects, and erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was initiated in June 2007 at doses of 400 and 150 mg/d, respectively. The theoretical and clinical rationale for the proposed off-label use of this combination therapy was presented to, and subsequently approved by, the Pharmacy and Therapeutics Committee of Veterans Affairs Greater Los Angeles Healthcare System. The decision to use this combination was undertaken after consultation with the Veterans Affairs Greater Los Angeles Healthcare System Research Service, with the conclusion that the use of these agents represented off-label use of US Food and Drug Administration products in medical practice. The patient had a remarkable clinical response. This was correlated with a decline in the rate of papilloma recurrence, as well as a progressive regression of disease, evidenced by visual inspection within a few months (Fig 1, 2). Although the patient still undergoes surveillance bronchoscopy every 3 months, there has been no further growth of papillomas, and he has not

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Figure 1. Pretreatment view of the major carina and distal trachea demonstrating diffuse low rising papilloma and a few obstructing papillomas. This figure can be found in color as supplement in the online version of this article.

required further cauterization over the last 6 months. Aside from an acneiform eruption attributable to the use of erlotinib, the patient has continued to tolerate the combination therapy and clinically maintains a functional status that is markedly improved from that of June 2007.

Figure 2. Representative view demonstrating marked improvement of the mucosa at the major carina 10 months after therapy. This figure can be found in color as a supplement in the online version of this article. www.chestjournal.org

RRP is a benign, but devastating disease that is caused by a mucosal infection with a nonenveloped DNA virus termed the human papilloma virus, type 6 and 11.1,2 The incidence in the United States is estimated at 4.3 per 100,000 children and 1.8 per 100,000 adults. Vertical transmission during delivery through an infected birth canal is presumed to be the major mode of transmitting the infection to children; in adults, infection presumably develops as a sexually transmitted disease following oralgenital contact. Although spontaneous remission is reported in juvenile-onset RRP, its occurrence is highly variable and unpredictable.3 The rate of spontaneous remission in adult-onset RRP is unknown. Patients present with hoarseness, cough, stridor, dyspnea, and progressive respiratory distress, and management generally entails repeated surgical removal of papillomas. Adjunctive therapy to surgical debulking has previously utilized antiviral agents, interferons, indole 3-carbinol, retinoids, and photodynamic therapy.2 Currently, therapy with intralesional or systemic cidofovir has been favored based on case reports.4 Because the patient’s disease progressed while receiving standard therapy, we approached him for considering a rational experimental combination regimen. Compared to normal mucosa, EGFR is selectively over expressed in papillomas.5 This receptor amplification is largely attributable to increased recycling rather than to enhanced DNA transcription, and the effects of EGFR signaling are comodulated by both the phospho-Akt and phosphomitogen-activated protein kinase (or MAPK) pathways.6 – 8 COX-2 is also up-regulated as a result of this crosssignaling, and its up-regulation results in increased prostaglandin E2 (PGE2) expression in papillomas.7–9 EGFR blockade can suppress COX-2 activity and PGE2 expression indirectly; these activities can also be directly inhibited by celecoxib, a selective COX-2 inhibitor. Blocking PGE2 biosynthesis is associated with enhanced apoptosis of human papilloma virus-infected cells.8 Because both EGFR and COX-2 were potential targets that were contributing to the growth of the papillomas, we suggested a combination therapy using an EGFR-tyrosine kinase inhibitor and a COX-2 inhibitor. The rationale for this combination therapy is underscored by emerging concepts that EGFR and COX-2 signaling pathways interact to regulate cell proliferation, migration, and invasion.10,11 Blocking PGE2 biosynthesis through the COX-2 pathway is particularly important because PGE2 may be responsible for resistance to EGFR inhibitors in some clinical settings.11 A clinical trial utilizing celecoxib was initiated for RRP (ClinicalTrials.gov Identifier: NCT00571701) in February 2008; it is unclear whether this patient would have met the entry criteria for that trial. The combination regimen we utilized was initiated in June 2007 on the basis of rapid clinical deterioration, and an existing sound basic and pharmacologic rationale. Importantly, there was no prospective intent to conduct clinical research, and this report originates simply because of the surprising and durable clinical response that was evidenced with the combination CHEST / 136 / 3 / SEPTEMBER, 2009

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celecoxib and erlotinib therapy in a patient with RRP whose disease was refractory to antiviral (cidofovir) therapy. The effectiveness of this intervention in this patient supports the consideration of the regimen in clinical trials that assess this combination in patients with refractory disease.

References 1 Steinberg BM, Topp WC, Schneider PS, et al. Laryngeal papillomavirus infection during clinical remission. N Engl J Med 1983; 308:1261–1264 2 Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope 2008; 118:1236 –1247 3 Bauman NM, Smith RJ. Recurrent respiratory papillomatosis. Pediatr Clin North Am 1996; 43:1385–1401 4 Chadha NK, James AL. Antiviral agents for the treatment of recurrent respiratory papillomatosis: a systematic review of the English-language literature. Otolaryngol Head Neck Surg 2007; 136:863– 869 5 Vambutas A, Di Lorenzo TP, Steinberg BM. Laryngeal papilloma cells have high levels of epidermal growth factor receptor and respond to epidermal growth factor by a decrease in epithelial differentiation. Cancer Res 1993; 53:910 –914 6 Johnston D, Hall H, DiLorenzo TP, et al. Elevation of the epidermal growth factor receptor and dependent signaling in human papillomavirus-infected laryngeal papillomas. Cancer Res 1999; 59:968 –974 7 Zhang P, Steinberg BM. Overexpression of PTEN/MMAC1 and decreased activation of Akt in human papillomavirus-infected laryngeal papillomas. Cancer Res 2000; 60:1457–1462 8 Wu R, Abramson AL, Shikowitz MJ, et al. Epidermal growth factor-induced cyclooxygenase-2 expression is mediated through phosphatidylinositol-3 kinase, not mitogen-activated protein/ extracellular signal-regulated kinase kinase, in recurrent respiratory papillomas. Clin Cancer Res 2005; 11:6155– 6161 9 Wu R, Coniglio SJ, Chan A, et al. Up-regulation of Rac1 by epidermal growth factor mediates COX-2 expression in recurrent respiratory papillomas. Mol Med 2007; 13:143–150 10 Coffey RJ, Hawkey CJ, Damstrup L, et al. Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells. Proc Natl Acad Sci U S A 1997; 94:657– 662 11 Krysan K, Reckamp KL, Dalwadi H, et al. Prostaglandin E2 activates mitogen-activated protein kinase/Erk pathway signaling and cell proliferation in non-small cell lung cancer cells in an epidermal growth factor receptor-independent manner. Cancer Res 2005; 65:6275– 6281

Utility of [18F]2-Fluoro-2Deoxyglucose-PET in Sporadic and Tuberous Sclerosis-Associated Lymphangioleiomyomatosis Lisa R. Young, MD; David N. Franz, MD; Preeti Nagarkatte, MD; Christopher D. M. Fletcher, MD; Kathryn A. Wikenheiser-Brokamp, MD, PhD; Matthew D. Galsky, MD; Thomas C. Corbridge, MD, FCCP; Anna P. Lam, MD; Michael J. Gelfand, MD; and Francis X. McCormack, MD, FCCP

Mutations in tuberous sclerosis complex (TSC) genes are associated with dysregulated mammalian target of rapamycin (mTOR)/Akt signaling and unusual neoplasms called perivascular epithelioid cell tumors (PEComas), including angiomyolipomas (AMLs) and lymphangioleiomyomatosis (LAM). Tools that quantify metabolic activity and total body burden of AML and LAM cells would be valuable for the assessment of disease progression and the response to therapy in patients with TSC and LAM. Our hypothesis was that constitutive activation of mTOR in LAM and AML cells would result in increased glucose uptake of [18F]2-fluoro-2-deoxyglucose (FDG) on PET scanning, as has been suggested by a single prior case report. After institutional review board approval, FDG-PET scanning was performed in six LAM patients. Six additional LAM patients underwent FDGPET scanning for clinical evaluation of suspected malignancy. Pleural uptake related to prior therapy was identified in four individuals with a remote history of talc pleurodesis. Focal increased uptake was observed in a supraclavicular lymph node in a patient with Hodgkin lymphoma and in a lung nodule in a patient with a biopsy-documented primary lung adenocarcinoma. In one TSC-LAM patient with a biopsydocumented malignant uterine PEComa, robust uptake was noted in metastatic nodules in the lung but not in the LAM-involved lung parenchyma or the patient’s massive abdominal lymphangioleiomyomas. No abnormal uptake was identified in the AMLs or LAM lesions in any patients. This pilot study suggests that FDG-PET scans are negative in patients with benign PEComas and therefore are not likely to be useful for estimating the burden of disease in patients with TSC or LAM, but that FDG-PET scans can be used to identify or exclude other neoplasms in these patients. (CHEST 2009; 136:926 –933) Abbreviations: AML ⫽ angiomyolipoma; FDG ⫽ [18F]2-fluoro2-deoxyglucose; HMB-45 ⫽ human melanoma black-45; LAM ⫽ lymphangioleiomyomatosis; LUL ⫽ left upper lobe; mTOR ⫽ Manuscript received February 8, 2009; revision accepted March 9, 2009. Affiliations: From the Department of Pulmonary, Critical Care, and Sleep Medicine (Drs. Young and McCormack), University of Cincinnati College of Medicine, Cincinnati, OH; the Departments of Pulmonary Medicine (Dr. Young), Neurology (Dr. Franz), Pathology & Laboratory Medicine and Pulmonary Biology (Dr. Wikenheiser-Brokamp), and Radiology (Dr. Gelfand), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Northeast Nephrology (Dr. Nagarkatte), Joliet, IL; the Department of Pathology (Dr. Fletcher), Brigham and Women’s Hospital, Boston, MA; Comprehensive Cancer Centers of Nevada (Dr. Galsky), Las Vegas, NV; and the Department of Pulmonary and Critical Care (Drs. Corbridge and Lam), Northwestern University, Chicago, IL. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Francis X. McCormack, MD, Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267; e-mail: Frank. [email protected] DOI: 10.1378/chest.09-0336

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Regression of Recurrent Respiratory Papillomatosis With Celecoxib and Erlotinib Combination Therapy Atikun Limsukon, Irawan Susanto, Guy W. Soo Hoo, Steven M. Dubinett and Raj K. Batra Chest 2009;136; 924-926 DOI 10.1378/chest.08-2639 This information is current as of August 1, 2011 Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/136/3/924.full.html References This article cites 11 articles, 7 of which can be accessed free at: http://chestjournal.chestpubs.org/content/136/3/924.full.html#ref-list-1 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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