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Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients
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ORIGINAL CLINICAL SCIENCE
Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients Aniket Vadnerkar, MD,a M. Hong Nguyen, MD,a Dimitra Mitsani, MD,a Maria Crespo, MD,a Joseph Pilewski, MD,a Yoshiya Toyoda, MD, PhD,b Christian Bermudez, MD,b Eun J. Kwak, MD,a Fernanda P. Silveira, MD,a and Cornelius J. Clancy, MDa,c From the Departments of aMedicine and bCardiothoracic Surgery, University of Pittsburgh Medical Center; and the c Department of Medicine, Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania.
KEYWORDS: voriconazole; squamous cell cancer; lung transplantation; alemtuzumab; risk factors
BACKGROUND: Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS: We performed a retrospective, case– control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS: SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p ⫽ 0.02), residence in locations with high levels of sun exposure (p ⫽ 0.0001), single-lung transplant (p ⫽ 0.02) and duration (p ⫽ 0.03) and cumulative dose (p ⫽ 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] ⫽ 2.1; p ⫽ 0.04) and residence in locations with high sun exposure (HR ⫽ 3.8; p ⫽ 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS: Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients. J Heart Lung Transplant 2010;29:1240 – 4 Copyright © 2010 Published by Elsevier Inc.
Skin cancer is the most common malignancy after solidorgan transplantation.1–3 Squamous cell carcinoma (SCC) of the skin is up to 4-fold more common among transplant recipients than basal cell carcinoma, which is the reverse of the pattern in the general population.1,4,5 After kidney and Corresponding author: Cornelius J. Clancy, MD, University of Pittsburgh, Scaife Hall, Suite 871, 3550 Terrace Street Pittsburgh, PA 15261 Phone: 412-383-5193, Fax: 412-648-8455 E-mail address: [email protected] 1053-2498/$ -see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.healun.2010.05.022
heart transplantation, the incidence of non-melanoma skin cancer increases steadily from 5%, 10% to 27%, and 40% to 60% at 2, 10, and 20 years, respectively.6 – 8 Older age at transplant, excessive sun exposure and intensive immunosuppression are risk factors.9 –12 Skin cancer has been less well characterized after lung transplantation, but the incidence appears to be lower than for other solid-organ transplants because long-term survival is poorer. According to the registry of the International Society of Heart and Lung Transplantation (ISHLT), the prevalence of skin cancer
Vadnerker et al.
Voriconazole and Cutaneous Squamous Cell Cancer
among adult lung transplant recipients surviving 1 and 5 years is 0.7% and 6.5%, respectively.13 Prolonged voriconazole therapy is increasingly used for prevention and treatment of invasive fungal infections after hematopoietic stem cell (HSCT) and lung transplantation.14 –16 Three case reports and one multicenter case series reported the development of photosensitivity and multifocal SCC in 8 immunocompromised patients receiving prolonged voriconazole therapy (range 13 to 60 months).17–20 The investigators in the case series hypothesized a causal association between voriconazole exposure and SCC, but they did not identify risk factors among their patients. Moreover, the series was comprised of HSCT recipients (n ⫽ 6) and patients with human immunodeficiency virus (HIV) infection and Wegener granulomatosis (1 each). The study did not include solid-organ transplant recipients, who typically receive longer and more intensive immunosuppressive therapy. Voriconazole has been used as universal anti-fungal prophylaxis after lung transplantation at our center since the introduction of alemtuzumab, a potent anti-CD52 monoclonal antibody, as standard induction therapy in 2003. The primary objective of the present study was to determine the risk factors for SCC of the skin among our lung transplant recipients. In particular, we tested the hypothesis that voriconazole exposure was an independent risk factor. We also sought to describe the epidemiology, extent of disease and outcomes among patients with SCC.
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A patient was considered to be resident of a region with high levels of sun exposure if he or she resided within the United States south of 35° north latitude, which correlates with areas of high to very high ultraviolet (UV) index as classified by the U.S. National Oceanic and Atmospheric Administration. Roughly speaking, 35° north forms a line from southern North Carolina through southern New Mexico, Arizona and California. The consistency of patients’ residence in a region was confirmed by tracking pharmacy prescription records. Controls. Controls were defined as patients who did not develop SCC after lung transplantation as of last follow-up. Three controls were randomly identified for every case of SCC. Controls were matched by month and year of lung transplantation, and survival time post-transplant.
Immunosuppression and anti-microbial prophylaxis
Methods
The immunosuppression protocol included alemtuzumab or thymoglobulin induction therapy, followed by tacrolimus, mycophenolate mofetil and prednisone. The anti-microbial prophylaxis regimen consisted of voriconazole, valganciclovir and trimethoprim/sulfamethoxazole. Voriconazole was given intravenously at 6 mg/kg per dose for two doses starting immediately post-transplant, followed by oral voriconazole 200 mg twice daily. The duration of voriconazole prophylaxis was at the discretion of providers, guided by patients’ bronchoalveolar lavage microbiologic findings and clinical events.
Patients
Statistical analysis
Patients undergoing lung or heart–lung transplantation at the University of Pittsburgh Medical Center (UPMC) between January 2003 and December 2008 were eligible for inclusion in the study. Patients were excluded if they were diagnosed with cancer of any type prior to transplantation. This study was approved by the Institutional Review Board of UPMC.
GraphPad INSTAT software (GraphPad Software, Inc., San Diego, CA) was used for statistical analysis. Comparison of dichotomous variables was made using chi-square or Fisher’s exact test. Continuous variables were reported as median ⫾ standard deviation and the difference between groups was calculated using the Mann–Whitney U-test. p ⱕ 0.05 was considered significant. Multivariate analysis was performed on variables with p ⬍ 0.1 by univariate analysis.
Cases. Patients who developed SCC after transplantation were identified from the UPMC Cardiothoracic Transplant database. The patients’ inpatient charts, clinic notes and electronic medical records were reviewed. Individual patients’ pathology records were verified for accuracy. Relevant clinical data included age at transplant, gender, race, tobacco use, geographic location of the recipient post–lung transplantation, length of follow-up, pre-transplant history of cancer, type of transplant, number of rejection episodes, interval between date of transplantation and diagnosis of skin cancer, type of skin cancer, location of malignancy, number of lesions, progression to metastases, recurrence and cause of death. The data on immunosuppressive regimens and cumulative doses and total durations of voriconazole use for individual patients in the inpatient and outpatient settings were obtained from the UPMC pharmacy record and Cardiothoracic Transplant database, respectively.
Results Patients with SCC Over the 6-year period culminating in December 2008, a total of 543 patients underwent lung transplantation at UPMC. Among these patients, 352 received double-lung transplant, 167 single-lung transplant and 24 heart–lung transplant. Overall, 3.1% (17 of 543) of patients developed one or more episodes of SCC over a median follow-up period of 36 months (range 11 to 82 months). The median time to development of SCC after lung transplantation was 19 months (range 2 to 59 months). The rate of basal cell
1242 Table 1
The Journal of Heart and Lung Transplantation, Vol 29, No 11, November 2010 Demographics and Characteristics of Study Participantsa
Factora
Cases (n ⫽ 17)
Controls (n ⫽ 51)
Median age in years (range) Gender (males) Ethnicity (Caucasian) Smoking status (smokers) Residence in region with high sun exposure Type of lung transplant Single-lung transplant Double-lung transplant Induction Alemtuzumab Thymoglobulin Patients with ⱖ1 episode of allograft rejection requiring treatment Patients with ⱖ1 episode of CMV infection
63 88% 100% 71% 35%
56 (22-76) 57% (29) 96% (49) 67% (34) 0%
0.02 0.02 NS (1.0) NS (1.0) 0.0001
59% (10) 41% (7)
28% (14) 72% (37)
0.03 0.03
94% (16) 6% (1) 47% (8)
92% (47) 8% (4) 55% (28)
NS (1.0)
35% (6)
24% (12)
NS (0.4)
(42-75) (15) (17) (12) (6)
p-value
NS (0.6)
CMV, cytomegalovirus; NS, not significant. a All data are shown as percent (n) unless otherwise indicated.
cancer in our population was 0.7% (4 of 543), resulting in an SCC to basal cell cancer ratio of 4:1.
Demographics and patient characteristics Demographics and patient characteristics for cases and controls are summarized in Table 1. All cases were among whites of European descent. There were no significant differences in ethnicity, smoking status or cytomegalovirus (CMV) infection between case and control groups. Moreover, induction and maintenance immunosuppressive regimens did not differ between the groups. Eighty-eight percent (15 of 17) of cases were receiving the standard triple immunosuppressive regimen (a calcineurin inhibitor, mycophenolate and prednisone) within 6 months prior to the diagnosis of SCC, compared with 86% (44 of 51) of controls at comparable time-points after transplant. The remaining cases and controls all received prednisone and a calcineurin inhibitor or mycophenolate mofetil. The doses of prednisone were similar for the two groups (median 5 mg/day). There were no differences between cases and controls in the percentages who required augmented immunosuppression for acute cellular rejection (Table 1), the number of acute rejection episodes (medians 0 and 1, respectively; ranges 0 to 6 and 0 to 7, respectively), number of bronchiolitis obliterans episodes (0 and 2, respectively) or the agents used to treat rejection. Six cases resided in geographic areas associated with high levels of UV sun exposure (Florida, n ⫽ 5; South Carolina, n ⫽ 1), whereas none of the controls resided in these areas.
Voriconazole therapy The cases received voriconazole therapy for a significantly longer duration (median 284 days, range 68 to 1,458 days) than the controls (median 161 days, range 19 to 1,263 days) (p ⫽ 0.03). Voriconazole prophylaxis was extended beyond 6 months for 76% (13 of 17) and 45% (23 of 51) of cases
and controls, respectively. Among cases, the indications for extending voriconazole included fungal colonization of the respiratory tract (n ⫽ 6), augmented immunosuppression for acute rejection (n ⫽ 4) and unclear reasons (n ⫽ 3). The same indications were cited in 6, 10 and 7 controls, respectively. No one in either group received voriconazole for treatment of an invasive fungal infection. As a result of longer prophylaxis, the cases received significantly higher cumulative doses of voriconazole (median 76 g, range 28 to 295 g) than the controls (median 53 g, range 7 to 470 g) (p ⫽ 0.03).
Risk factors for SCC By univariate analysis, greater age at the time of transplant (p ⫽ 0.02), male gender (p ⫽ 0.02), residence in a location with high levels of sun exposure (p ⫽ 0.0001), single-lung transplant (p ⫽ 0.03) and duration (p ⫽ 0.03) and cumulative dose of voriconazole (p ⫽ 0.03) were significantly associated with SCC (Table 1). Multivariate regression, using a model that included factors with p ⬍ 0.1 by univariate analysis, identified duration of voriconazole therapy (hazard ratio [HR] ⫽ 2.1; p ⫽ 0.04) and residence in locations with high-levels of sun exposure (HR ⫽ 3.8; p ⫽ 0.0004) as independent risk factors for SCC.
Clinical details of SCC cases, treatment and outcome SCC lesions were located on the head and neck in 94% (16 of 17) of cases. Fifty-three percent (9 of 17) of cases had more than one skin lesion at the time of diagnosis. Twentynine percent (5 of 17) of cases were taking voriconazole at the time that the diagnosis of SCC was made. Forty-seven percent (8 of 17) of cases developed one or more independent SCC lesions at follow-up. All 15 cases of SCC were treated surgically. Moh’s micrographic surgery was used in cases with head and neck lesions. In 12% (2 of 17) of cases, more aggressive treatment was necessary due to extensive
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disease. One patient required parotidectomy for local spread of SCC. A second patient with SCC of the scalp developed extensive metastases to lymph nodes of the head and neck, necessitating a partial craniectomy and radical neck dissection. Adjunctive radiation therapy was used in 24% (4 of 17) of cases in which lesions were incompletely excised. Immunosuppression was reduced in 24% (4 of 17) of cases upon diagnosis of SCC, including the 2 cases with extensive local disease or metastases. All cases and controls were alive at median follow-up of 36 months.
Discussion We found that 3.1% (17 of 543) of patients who underwent lung transplantation during a 6-year period at our center developed SCC of the skin at median follow-up of 36 months, a rate within the 0.7% to 6.4% range previously reported for lung transplant recipients surviving at least 1 year.21 Consistent with reports from other solid-organ transplant populations, the rate of SCC among our patients was 4-fold greater than that of basal cell carcinoma.1,4,5 The most important findings of our study are that prolonged therapy with voriconazole and residence in locations with high levels of sun exposure proved to be independent risk factors for SCC. To our knowledge, this is the first study to determine risk factors for SCC among lung transplant recipients. More importantly, the study is the first to conclusively identify voriconazole exposure as an independent risk factor for SCC in any population. As such, the data corroborate an association between voriconazole and SCC that was suggested by earlier case reports and a case series of 8 immunosuppressed hosts who had not undergone solidorgan transplantation.17–20 Although the link between voriconazole exposure and SCC is newly recognized, dermatologic complications such as photosensitivity, photoaging and pseudophorphyria have been described in patients receiving the drug.22–25 It has been postulated that prolonged voriconazole therapy may cause chronic phototoxicity that leads to development of SCC in transplant recipients and other patients with significantly impaired immune surveillance.18 In this retrospective review, we were not able to determine if episodes of photosensitivity or other dermatologic lesions occurred in patients prior to SCC. Voriconazole-associated phototoxicity has been suggested to stem from the accumulation of phototoxic retinoid compounds due to the drug’s inhibition of all-trans retinol (vitamin A) metabolism.23,26 Alternatively, voriconazole’s principal metabolite (voriconazole N-oxide) also has been proposed as an etiologic agent, because it acts as a chromophore by absorbing ultraviolet A and B spectrum.18,27 In considering pathogenesis, however, it is important to note that photosensitivity skin reactions due to voriconazole are believed to be idiosyncratic, whereas SCC among our patients was related to the extent of drug exposure.19,20,28 Therefore, even if the previously described voriconazole-related skin reactions are proven to be linked to the subsequent development of SCC, it will be
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as part of some complex, multistep pathogenic processes. Of note, voriconazole therapeutic drug monitoring was not routinely performed in lung transplant recipients prior to 2008, nor were voriconazole metabolites measured. As such, we cannot assess the association between levels of voriconazole and its metabolites and the risk of SCC. It is not surprising that SCC was also significantly linked to residence in areas of significant sun exposure, in particular the southern states of Florida and South Carolina. Previous studies have shown that the incidence of SCC is higher in southern states like Arizona than in northern states like New Hampshire,29,30 as well as in countries with high levels of sun exposure like Australia.4 Experimental data suggest that UV radiation is a keratinocyte mutagen, acting like a tumor initiator and promoter.31 In support of a role for sun exposure, we found that 94% (16 of 17) of our patients developed SCC in sun-exposed parts of the body. It is further notable that the median age of cases in our series was 63 years (range 42 to 75 years). Indeed, cumulative sun exposure over a lifetime has been proposed as one of several factors that account for higher rates of skin cancer with advanced age,32 along with decreased immune surveillance resulting from age-related T-cell dysfunction and increased susceptibility to the effects of immunosuppressive agents.33 In a previous study of transplant recipients, 80% of cutaneous neoplasms among patients ⬍40 years of age were located on the dorsum of the hands, forearms or upper trunk, whereas 80% of malignancies among older transplant recipients were located on the head.5 Although advanced age has been shown to be a major risk factor for SCC in kidney and heart transplant recipients,9,11 we found it to be significant by univariate but not multivariate analysis. In part, the lack of an association by multivariate analysis may reflect the fact that the median age for lung transplant recipients at the UPMC during the study period was almost 60 years. The median time to the development of SCC in our patients of 19 months was shorter than the 4.1 years described for HSCT recipients who received voriconazole in the earlier case series.18 The reasons for this disparity are unclear, but it is intriguing to speculate that the intensive induction immunosuppression by alemtuzumab may have lowered the threshold for the development of SCC lesions. Unfortunately, we were unable to distinguish the precise contribution of alemtuzumab to the development of SCC because induction therapy with the agent was almost universal at our center. As for all case– control studies, it is important to acknowledge that our findings may stem from unrecognized confounding effects rather than residence in sunny locales or voriconazole exposure. We excluded an obvious confounder, however, by demonstrating that longer durations of voriconazole prophylaxis were not associated with increased rates of rejection or augmented immunosuppression. The roles of sun and voriconazole exposure suggested by this report require confirmation in more robust follow-up studies. In particular, it will be important to define interactions between the level of immunosuppression, voriconazole use, UV exposure and other risk factors. At present,
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The Journal of Heart and Lung Transplantation, Vol 29, No 11, November 2010
we are using voriconazole prophylaxis cautiously in our lung transplant recipients, especially among older patients residing in sunny locations. In patients requiring prolonged voriconazole, we recommend diligent skin examination, avoidance of excess sunlight and liberal use of sunscreens. The fact that all of our patients with SCC were still alive highlights the importance of closely monitoring patients to facilitate early diagnosis and treatment. Nevertheless, other studies have reported SCC to be particularly aggressive in heart and lung transplant recipients,34,35 and 2 of our patients developed extensive disease requiring major surgery and adjunctive radiation therapy. Longer term follow-up may demonstrate that outcomes are less optimistic than suggested by our relatively short-term data.
Disclosure statement This study was supported by a National Institutes of Health (NIH) Institutional Training Grant T32 (AI007333 to A.V.), a Ruth L. Kirschstein National Research Service Award and a program project award from the NIH Mycology Research Unit (5P01AI061537-02 to M.H.N. and C.J.C.) M.H.N. received research funding from Pfizer, Enzon Pharmaceutical and Merck; E.J.K. and F.P.S. received research funding from Pfizer; and C.J.C. received research funding from Pfizer, Astellas, Merck and Ortho-McNeil.
References 1. Webb MC, Compton F, Andrews PA, et al. Skin tumours posttransplantation: a retrospective analysis of 28 years’ experience at a single centre. Transplant Proc 1997;29:828-30. 2. Winkelhorst JT, Brokelman WJ, Tiggeler RG, et al. Incidence and clinical course of de-novo malignancies in renal allograft recipients. Eur J Surg Oncol 2001;27:409-13. 3. Sanchez EQ, Marubashi S, Jung G, et al. De novo tumors after liver transplantation: a single-institution experience. Liver Transplant 2002; 8:285-91. 4. Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation 1996;61:715-21. 5. Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol 1995;33:222-9. 6. Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905-13. 7. Ramsay HM, Reece SM, Fryer AA, et al. Seven-year prospective study of nonmelanoma skin cancer incidence in U.K. renal transplant recipients. Transplantation 2007;84:437-9. 8. Bordea C, Wojnarowska F, Millard PR, et al. Skin cancers in renaltransplant recipients occur more frequently than previously recognized in a temperate climate. Transplantation 2004;77:574-9. 9. Fortina AB, Caforio AL, Piaserico S, et al. Skin cancer in heart transplant recipients: frequency and risk factor analysis. J Heart Lung Transplant 2000;19:249-55. 10. Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 1999;40:177-86.
11. Fuente MJ, Sabat M, Roca J, et al. A prospective study of the incidence of skin cancer and its risk factors in a Spanish Mediterranean population of kidney transplant recipients. Br J Dermatol 2003;149:1221-6. 12. Lindelof B, Sigurgeirsson B, Gabel H, et al. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 2000;143: 513-9. 13. Trulock EP, Edwards LB, Taylor DO, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-first official adult lung and heart–lung transplant report—2004. J Heart Lung Transplant 2004;23:804-15. 14. Bow EJ. Long-term antifungal prophylaxis in high-risk hematopoietic stem cell transplant recipients. Med Mycol 2005;43(suppl 1):S277-87. 15. Cadena J, Levine DJ, Angel LF, et al. Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness. Am J Transplant 2009;9:2085-91. 16. Husain S, Paterson DL, Studer S, et al. Voriconazole prophylaxis in lung transplant recipients. Am J Transplant 2006;6:3008-16. 17. Brunel AS, Fraisse T, Lechiche C, et al. Multifocal squamous cell carcinomas in an HIV-infected patient with a long-term voriconazole therapy. AIDS 2008;22:905-6. 18. Cowen EW, Nguyen JC, Miller DD, et al. Chronic phototoxicity and aggressive squamous cell carcinoma of the skin in children and adults during treatment with voriconazole. J Am Acad Dermatol 2010;62:31-7. 19. McCarthy KL, Playford EG, Looke DF, et al. Severe photosensitivity causing multifocal squamous cell carcinomas secondary to prolonged voriconazole therapy. Clin Infect Dis 2007;44:e55-6. 20. Vanacker A, Fabre G, Van Dorpe J, et al. Aggressive cutaneous squamous cell carcinoma associated with prolonged voriconazole therapy in a renal transplant patient. Am J Transplant 2008;8:877-80. 21. Amital A, Shitrit D, Raviv Y, et al. Development of malignancy following lung transplantation. Transplantation 2006;81:547-51. 22. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002;34:563-71. 23. Denning DW, Griffiths CE. Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole. Clin Exp Dermatol 2001;26:648-53. 24. Dolan CK, Hall MA, Blazes DL, et al. Pseudoporphyria as a result of voriconazole use: a case report. Int J Dermatol 2004;43:768-71. 25. Racette AJ, Roenigk HH Jr, Hansen R, et al. Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol 2005;52(suppl):S81-5. 26. Van Wauwe JP, Coene MC, Goossens J, et al. Effects of cytochrome P-450 inhibitors on the in vivo metabolism of all-trans-retinoic acid in rats. J Pharmacol Exp Ther 1990;252:365-9. 27. Murayama N, Imai N, Nakane T, et al. Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochem Pharmacol 2007;73:2020-6. 28. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 2003;36:630-7. 29. Karagas MR, Greenberg ER, Spencer SK, et al. Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. Int J Cancer 1999;81:555-9. 30. Harris RB, Griffith K, Moon TE. Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985–1996. J Am Acad Dermatol 2001;45:528-36. 31. Grossman D, Leffell DJ. The molecular basis of nonmelanoma skin cancer: new understanding. Arch Dermatol 1997;133:1263-70. 32. Ulrich C, Schmook T, Sachse MM, et al. Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients. Dermatol Surg 2004;30:622-7. 33. Ben-Yehuda A, Weksler ME. Immune senescence: mechanisms and clinical implications. Cancer Invest 1992;10:525-31. 34. Adamson R, Obispo E, Dychter S, et al. High incidence and clinical course of aggressive skin cancer in heart transplant patients: a singlecenter study. Transplant Proc 1998;30:1124-6. 35. Veness MJ, Quinn DI, Ong CS, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer 1999;85:1758-64.
ORIGINAL CLINICAL SCIENCE
Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients Aniket Vadnerkar, MD,a M. Hong Nguyen, MD,a Dimitra Mitsani, MD,a Maria Crespo, MD,a Joseph Pilewski, MD,a Yoshiya Toyoda, MD, PhD,b Christian Bermudez, MD,b Eun J. Kwak, MD,a Fernanda P. Silveira, MD,a and Cornelius J. Clancy, MDa,c From the Departments of aMedicine and bCardiothoracic Surgery, University of Pittsburgh Medical Center; and the c Department of Medicine, Pittsburgh VA Healthcare System, Pittsburgh, Pennsylvania.
KEYWORDS: voriconazole; squamous cell cancer; lung transplantation; alemtuzumab; risk factors
BACKGROUND: Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS: We performed a retrospective, case– control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS: SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p ⫽ 0.02), residence in locations with high levels of sun exposure (p ⫽ 0.0001), single-lung transplant (p ⫽ 0.02) and duration (p ⫽ 0.03) and cumulative dose (p ⫽ 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] ⫽ 2.1; p ⫽ 0.04) and residence in locations with high sun exposure (HR ⫽ 3.8; p ⫽ 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS: Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients. J Heart Lung Transplant 2010;29:1240 – 4 Copyright © 2010 Published by Elsevier Inc.
Skin cancer is the most common malignancy after solidorgan transplantation.1–3 Squamous cell carcinoma (SCC) of the skin is up to 4-fold more common among transplant recipients than basal cell carcinoma, which is the reverse of the pattern in the general population.1,4,5 After kidney and Corresponding author: Cornelius J. Clancy, MD, University of Pittsburgh, Scaife Hall, Suite 871, 3550 Terrace Street Pittsburgh, PA 15261 Phone: 412-383-5193, Fax: 412-648-8455 E-mail address: [email protected] 1053-2498/$ -see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.healun.2010.05.022
heart transplantation, the incidence of non-melanoma skin cancer increases steadily from 5%, 10% to 27%, and 40% to 60% at 2, 10, and 20 years, respectively.6 – 8 Older age at transplant, excessive sun exposure and intensive immunosuppression are risk factors.9 –12 Skin cancer has been less well characterized after lung transplantation, but the incidence appears to be lower than for other solid-organ transplants because long-term survival is poorer. According to the registry of the International Society of Heart and Lung Transplantation (ISHLT), the prevalence of skin cancer
Vadnerker et al.
Voriconazole and Cutaneous Squamous Cell Cancer
among adult lung transplant recipients surviving 1 and 5 years is 0.7% and 6.5%, respectively.13 Prolonged voriconazole therapy is increasingly used for prevention and treatment of invasive fungal infections after hematopoietic stem cell (HSCT) and lung transplantation.14 –16 Three case reports and one multicenter case series reported the development of photosensitivity and multifocal SCC in 8 immunocompromised patients receiving prolonged voriconazole therapy (range 13 to 60 months).17–20 The investigators in the case series hypothesized a causal association between voriconazole exposure and SCC, but they did not identify risk factors among their patients. Moreover, the series was comprised of HSCT recipients (n ⫽ 6) and patients with human immunodeficiency virus (HIV) infection and Wegener granulomatosis (1 each). The study did not include solid-organ transplant recipients, who typically receive longer and more intensive immunosuppressive therapy. Voriconazole has been used as universal anti-fungal prophylaxis after lung transplantation at our center since the introduction of alemtuzumab, a potent anti-CD52 monoclonal antibody, as standard induction therapy in 2003. The primary objective of the present study was to determine the risk factors for SCC of the skin among our lung transplant recipients. In particular, we tested the hypothesis that voriconazole exposure was an independent risk factor. We also sought to describe the epidemiology, extent of disease and outcomes among patients with SCC.
1241
A patient was considered to be resident of a region with high levels of sun exposure if he or she resided within the United States south of 35° north latitude, which correlates with areas of high to very high ultraviolet (UV) index as classified by the U.S. National Oceanic and Atmospheric Administration. Roughly speaking, 35° north forms a line from southern North Carolina through southern New Mexico, Arizona and California. The consistency of patients’ residence in a region was confirmed by tracking pharmacy prescription records. Controls. Controls were defined as patients who did not develop SCC after lung transplantation as of last follow-up. Three controls were randomly identified for every case of SCC. Controls were matched by month and year of lung transplantation, and survival time post-transplant.
Immunosuppression and anti-microbial prophylaxis
Methods
The immunosuppression protocol included alemtuzumab or thymoglobulin induction therapy, followed by tacrolimus, mycophenolate mofetil and prednisone. The anti-microbial prophylaxis regimen consisted of voriconazole, valganciclovir and trimethoprim/sulfamethoxazole. Voriconazole was given intravenously at 6 mg/kg per dose for two doses starting immediately post-transplant, followed by oral voriconazole 200 mg twice daily. The duration of voriconazole prophylaxis was at the discretion of providers, guided by patients’ bronchoalveolar lavage microbiologic findings and clinical events.
Patients
Statistical analysis
Patients undergoing lung or heart–lung transplantation at the University of Pittsburgh Medical Center (UPMC) between January 2003 and December 2008 were eligible for inclusion in the study. Patients were excluded if they were diagnosed with cancer of any type prior to transplantation. This study was approved by the Institutional Review Board of UPMC.
GraphPad INSTAT software (GraphPad Software, Inc., San Diego, CA) was used for statistical analysis. Comparison of dichotomous variables was made using chi-square or Fisher’s exact test. Continuous variables were reported as median ⫾ standard deviation and the difference between groups was calculated using the Mann–Whitney U-test. p ⱕ 0.05 was considered significant. Multivariate analysis was performed on variables with p ⬍ 0.1 by univariate analysis.
Cases. Patients who developed SCC after transplantation were identified from the UPMC Cardiothoracic Transplant database. The patients’ inpatient charts, clinic notes and electronic medical records were reviewed. Individual patients’ pathology records were verified for accuracy. Relevant clinical data included age at transplant, gender, race, tobacco use, geographic location of the recipient post–lung transplantation, length of follow-up, pre-transplant history of cancer, type of transplant, number of rejection episodes, interval between date of transplantation and diagnosis of skin cancer, type of skin cancer, location of malignancy, number of lesions, progression to metastases, recurrence and cause of death. The data on immunosuppressive regimens and cumulative doses and total durations of voriconazole use for individual patients in the inpatient and outpatient settings were obtained from the UPMC pharmacy record and Cardiothoracic Transplant database, respectively.
Results Patients with SCC Over the 6-year period culminating in December 2008, a total of 543 patients underwent lung transplantation at UPMC. Among these patients, 352 received double-lung transplant, 167 single-lung transplant and 24 heart–lung transplant. Overall, 3.1% (17 of 543) of patients developed one or more episodes of SCC over a median follow-up period of 36 months (range 11 to 82 months). The median time to development of SCC after lung transplantation was 19 months (range 2 to 59 months). The rate of basal cell
1242 Table 1
The Journal of Heart and Lung Transplantation, Vol 29, No 11, November 2010 Demographics and Characteristics of Study Participantsa
Factora
Cases (n ⫽ 17)
Controls (n ⫽ 51)
Median age in years (range) Gender (males) Ethnicity (Caucasian) Smoking status (smokers) Residence in region with high sun exposure Type of lung transplant Single-lung transplant Double-lung transplant Induction Alemtuzumab Thymoglobulin Patients with ⱖ1 episode of allograft rejection requiring treatment Patients with ⱖ1 episode of CMV infection
63 88% 100% 71% 35%
56 (22-76) 57% (29) 96% (49) 67% (34) 0%
0.02 0.02 NS (1.0) NS (1.0) 0.0001
59% (10) 41% (7)
28% (14) 72% (37)
0.03 0.03
94% (16) 6% (1) 47% (8)
92% (47) 8% (4) 55% (28)
NS (1.0)
35% (6)
24% (12)
NS (0.4)
(42-75) (15) (17) (12) (6)
p-value
NS (0.6)
CMV, cytomegalovirus; NS, not significant. a All data are shown as percent (n) unless otherwise indicated.
cancer in our population was 0.7% (4 of 543), resulting in an SCC to basal cell cancer ratio of 4:1.
Demographics and patient characteristics Demographics and patient characteristics for cases and controls are summarized in Table 1. All cases were among whites of European descent. There were no significant differences in ethnicity, smoking status or cytomegalovirus (CMV) infection between case and control groups. Moreover, induction and maintenance immunosuppressive regimens did not differ between the groups. Eighty-eight percent (15 of 17) of cases were receiving the standard triple immunosuppressive regimen (a calcineurin inhibitor, mycophenolate and prednisone) within 6 months prior to the diagnosis of SCC, compared with 86% (44 of 51) of controls at comparable time-points after transplant. The remaining cases and controls all received prednisone and a calcineurin inhibitor or mycophenolate mofetil. The doses of prednisone were similar for the two groups (median 5 mg/day). There were no differences between cases and controls in the percentages who required augmented immunosuppression for acute cellular rejection (Table 1), the number of acute rejection episodes (medians 0 and 1, respectively; ranges 0 to 6 and 0 to 7, respectively), number of bronchiolitis obliterans episodes (0 and 2, respectively) or the agents used to treat rejection. Six cases resided in geographic areas associated with high levels of UV sun exposure (Florida, n ⫽ 5; South Carolina, n ⫽ 1), whereas none of the controls resided in these areas.
Voriconazole therapy The cases received voriconazole therapy for a significantly longer duration (median 284 days, range 68 to 1,458 days) than the controls (median 161 days, range 19 to 1,263 days) (p ⫽ 0.03). Voriconazole prophylaxis was extended beyond 6 months for 76% (13 of 17) and 45% (23 of 51) of cases
and controls, respectively. Among cases, the indications for extending voriconazole included fungal colonization of the respiratory tract (n ⫽ 6), augmented immunosuppression for acute rejection (n ⫽ 4) and unclear reasons (n ⫽ 3). The same indications were cited in 6, 10 and 7 controls, respectively. No one in either group received voriconazole for treatment of an invasive fungal infection. As a result of longer prophylaxis, the cases received significantly higher cumulative doses of voriconazole (median 76 g, range 28 to 295 g) than the controls (median 53 g, range 7 to 470 g) (p ⫽ 0.03).
Risk factors for SCC By univariate analysis, greater age at the time of transplant (p ⫽ 0.02), male gender (p ⫽ 0.02), residence in a location with high levels of sun exposure (p ⫽ 0.0001), single-lung transplant (p ⫽ 0.03) and duration (p ⫽ 0.03) and cumulative dose of voriconazole (p ⫽ 0.03) were significantly associated with SCC (Table 1). Multivariate regression, using a model that included factors with p ⬍ 0.1 by univariate analysis, identified duration of voriconazole therapy (hazard ratio [HR] ⫽ 2.1; p ⫽ 0.04) and residence in locations with high-levels of sun exposure (HR ⫽ 3.8; p ⫽ 0.0004) as independent risk factors for SCC.
Clinical details of SCC cases, treatment and outcome SCC lesions were located on the head and neck in 94% (16 of 17) of cases. Fifty-three percent (9 of 17) of cases had more than one skin lesion at the time of diagnosis. Twentynine percent (5 of 17) of cases were taking voriconazole at the time that the diagnosis of SCC was made. Forty-seven percent (8 of 17) of cases developed one or more independent SCC lesions at follow-up. All 15 cases of SCC were treated surgically. Moh’s micrographic surgery was used in cases with head and neck lesions. In 12% (2 of 17) of cases, more aggressive treatment was necessary due to extensive
Vadnerker et al.
Voriconazole and Cutaneous Squamous Cell Cancer
disease. One patient required parotidectomy for local spread of SCC. A second patient with SCC of the scalp developed extensive metastases to lymph nodes of the head and neck, necessitating a partial craniectomy and radical neck dissection. Adjunctive radiation therapy was used in 24% (4 of 17) of cases in which lesions were incompletely excised. Immunosuppression was reduced in 24% (4 of 17) of cases upon diagnosis of SCC, including the 2 cases with extensive local disease or metastases. All cases and controls were alive at median follow-up of 36 months.
Discussion We found that 3.1% (17 of 543) of patients who underwent lung transplantation during a 6-year period at our center developed SCC of the skin at median follow-up of 36 months, a rate within the 0.7% to 6.4% range previously reported for lung transplant recipients surviving at least 1 year.21 Consistent with reports from other solid-organ transplant populations, the rate of SCC among our patients was 4-fold greater than that of basal cell carcinoma.1,4,5 The most important findings of our study are that prolonged therapy with voriconazole and residence in locations with high levels of sun exposure proved to be independent risk factors for SCC. To our knowledge, this is the first study to determine risk factors for SCC among lung transplant recipients. More importantly, the study is the first to conclusively identify voriconazole exposure as an independent risk factor for SCC in any population. As such, the data corroborate an association between voriconazole and SCC that was suggested by earlier case reports and a case series of 8 immunosuppressed hosts who had not undergone solidorgan transplantation.17–20 Although the link between voriconazole exposure and SCC is newly recognized, dermatologic complications such as photosensitivity, photoaging and pseudophorphyria have been described in patients receiving the drug.22–25 It has been postulated that prolonged voriconazole therapy may cause chronic phototoxicity that leads to development of SCC in transplant recipients and other patients with significantly impaired immune surveillance.18 In this retrospective review, we were not able to determine if episodes of photosensitivity or other dermatologic lesions occurred in patients prior to SCC. Voriconazole-associated phototoxicity has been suggested to stem from the accumulation of phototoxic retinoid compounds due to the drug’s inhibition of all-trans retinol (vitamin A) metabolism.23,26 Alternatively, voriconazole’s principal metabolite (voriconazole N-oxide) also has been proposed as an etiologic agent, because it acts as a chromophore by absorbing ultraviolet A and B spectrum.18,27 In considering pathogenesis, however, it is important to note that photosensitivity skin reactions due to voriconazole are believed to be idiosyncratic, whereas SCC among our patients was related to the extent of drug exposure.19,20,28 Therefore, even if the previously described voriconazole-related skin reactions are proven to be linked to the subsequent development of SCC, it will be
1243
as part of some complex, multistep pathogenic processes. Of note, voriconazole therapeutic drug monitoring was not routinely performed in lung transplant recipients prior to 2008, nor were voriconazole metabolites measured. As such, we cannot assess the association between levels of voriconazole and its metabolites and the risk of SCC. It is not surprising that SCC was also significantly linked to residence in areas of significant sun exposure, in particular the southern states of Florida and South Carolina. Previous studies have shown that the incidence of SCC is higher in southern states like Arizona than in northern states like New Hampshire,29,30 as well as in countries with high levels of sun exposure like Australia.4 Experimental data suggest that UV radiation is a keratinocyte mutagen, acting like a tumor initiator and promoter.31 In support of a role for sun exposure, we found that 94% (16 of 17) of our patients developed SCC in sun-exposed parts of the body. It is further notable that the median age of cases in our series was 63 years (range 42 to 75 years). Indeed, cumulative sun exposure over a lifetime has been proposed as one of several factors that account for higher rates of skin cancer with advanced age,32 along with decreased immune surveillance resulting from age-related T-cell dysfunction and increased susceptibility to the effects of immunosuppressive agents.33 In a previous study of transplant recipients, 80% of cutaneous neoplasms among patients ⬍40 years of age were located on the dorsum of the hands, forearms or upper trunk, whereas 80% of malignancies among older transplant recipients were located on the head.5 Although advanced age has been shown to be a major risk factor for SCC in kidney and heart transplant recipients,9,11 we found it to be significant by univariate but not multivariate analysis. In part, the lack of an association by multivariate analysis may reflect the fact that the median age for lung transplant recipients at the UPMC during the study period was almost 60 years. The median time to the development of SCC in our patients of 19 months was shorter than the 4.1 years described for HSCT recipients who received voriconazole in the earlier case series.18 The reasons for this disparity are unclear, but it is intriguing to speculate that the intensive induction immunosuppression by alemtuzumab may have lowered the threshold for the development of SCC lesions. Unfortunately, we were unable to distinguish the precise contribution of alemtuzumab to the development of SCC because induction therapy with the agent was almost universal at our center. As for all case– control studies, it is important to acknowledge that our findings may stem from unrecognized confounding effects rather than residence in sunny locales or voriconazole exposure. We excluded an obvious confounder, however, by demonstrating that longer durations of voriconazole prophylaxis were not associated with increased rates of rejection or augmented immunosuppression. The roles of sun and voriconazole exposure suggested by this report require confirmation in more robust follow-up studies. In particular, it will be important to define interactions between the level of immunosuppression, voriconazole use, UV exposure and other risk factors. At present,
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The Journal of Heart and Lung Transplantation, Vol 29, No 11, November 2010
we are using voriconazole prophylaxis cautiously in our lung transplant recipients, especially among older patients residing in sunny locations. In patients requiring prolonged voriconazole, we recommend diligent skin examination, avoidance of excess sunlight and liberal use of sunscreens. The fact that all of our patients with SCC were still alive highlights the importance of closely monitoring patients to facilitate early diagnosis and treatment. Nevertheless, other studies have reported SCC to be particularly aggressive in heart and lung transplant recipients,34,35 and 2 of our patients developed extensive disease requiring major surgery and adjunctive radiation therapy. Longer term follow-up may demonstrate that outcomes are less optimistic than suggested by our relatively short-term data.
Disclosure statement This study was supported by a National Institutes of Health (NIH) Institutional Training Grant T32 (AI007333 to A.V.), a Ruth L. Kirschstein National Research Service Award and a program project award from the NIH Mycology Research Unit (5P01AI061537-02 to M.H.N. and C.J.C.) M.H.N. received research funding from Pfizer, Enzon Pharmaceutical and Merck; E.J.K. and F.P.S. received research funding from Pfizer; and C.J.C. received research funding from Pfizer, Astellas, Merck and Ortho-McNeil.
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