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    Professionals & Researchers

    Cidofovir (by RRP Taskforce, Cautionary)

    The following was published by the RRP Taskforce Recommendations (2005):

    "Cidofovir for Recurrent Respiratory Papillomatosis (RRP): A Plea for Caution"

    Cidofovir (Vistide®, Gilead Sciences) has been widely embraced by the otolaryngology community for the treatment of RRP, and has generated quite a bit of enthusiasm because we may at last have a true antiviral agent for this disease. A majority of pediatric otolaryngology groups have reported trying this medication on at least one patient.[1]

    Cidofovir is a nucleotide analogue that is readily incorporated into the growing DNA chain of both viruses and mammals. The FDA has only approved its use for CMV retinitis in AIDS patients. It has modest effectiveness for this indication, producing a statistically significant slowing of the progression of visual loss seen in this complication of HIV or full blown AIDS. It has significant nephrotoxicity, and other effective, less toxic oral antiviral agents for CMV retinitis are now available (2). Cidofovir’s main advantage over other regimens lies in its dosing schedule of every two weeks instead of daily. This convenience comes at a cost of requiring a vigorous hydration schedule and probenicid washout to prevent renal damage (3). Given all of the above, cidofovir is rarely used now for its approved indication.

    The actual efficacy of cidofovir for the treatment of RRP remains unknown. Most, though not all studies (4-8) and clinicians we have polled1 report that as many as 40-50% of patients will achieve durable remission after cidofovir, many will improve and there can be as many as 20% nonresponders. Most of these studies have been performed in children with severe disease (requiring frequent surgery) though many clinicians are now utilizing Cidofovir shortly after the diagnosis has been made and with lesser degrees of severity. As with all medications that are prescribed by physicians outside of their FDA indication, physicians utilizing Cidofovir for RRP vs. CMV retinitis must be prepared to assume additional liability for any adverse outcomes associated with its use.

    In rodents, Cidofovir has been shown to be a carcinogen. Consider the following from the PDR (3):

    Chronic, two-year carcinogenicity studies in rats and mice have not been carried out to evaluate the carcinogenic potential of cidofovir. However, a 26-week toxicology study evaluating once weekly subscapular subcutaneous injections of cidofovir in rats was terminated at 19 weeks because of the induction, in females, of palpable masses, the first of which was detected after six doses. The masses were diagnosed as mammary adenocarcinomas, which developed at doses as low as 0.6 mg/kg/week, equivalent to 0.04 times the human systemic exposure at the recommended intravenous VISTIDE dose based on AUC comparisons.

    In a 26-week intravenous toxicology study in which rats received 0.6, 3, or 15 mg/kg cidofovir once weekly, a significant increase in mammary adenocarcinomas in female rats as well as a significant incidence of Zymbal's gland carcinomas in male and female rats were seen at the high dose but not at the lower two doses. The high dose was equivalent to 1.1 times the human systemic exposure at the recommended dose of VISTIDE, based on comparisons of AUC measurements. In light of the results of these studies, cidofovir should be considered to be a carcinogen in rats as well as a potential carcinogen in humans.

    James Farrelly, PhD, a toxicologist with the FDA, presented the studies used to generate that warning at the FDA approval meetings (9). He kindly provided the RRP Task Force with the “raw data” from these studies. In the higher dose study, using doses equivalent to the recommended doses for CMV retinitis, 22/37 female rats developed adenocarcinoma of the breast, and 6/32 male rats developed Zymbal’s gland carcinoma (10). Even at the lower dose regimen, equivalent to 1/25th of the recommended systemic dose for humans, fully 20% of the rats developed cancer. It is noteworthy that the development of mammary adenocarcinoma in rats is a frequent occurrence in rat pharmacologic studies. Interestingly, the 26-week toxicology studies described above were not the usual long-term studies typically performed to look for cancer induction, but were set up to look at more subacute general toxicity, including nephrotoxicity. Note also that some tumors arose after only six doses.

    When assessing how a compound with the potential of carcinogenicity came to be approved, one needs to remember the context in which it was evaluated back in 1996. At that time, the diagnosis of AIDS was a death sentence. Activists were clamoring for rapid access to anything even potentially therapeutic. The antiretroviral therapy regimens that have subsequently proved so successful were in their infancy. Patients whose immune responses were so crippled that they could contract CMV retinitis had an extremely limited life expectancy. In that context, approval of cidofovir made sense, particularly since the effectiveness of alternate regimens for CMV retinitis was less well-established, and more detailed investigations into the actual carcinogenicity of cidofovir in other animal models would take longer than the expected lifespan of the patients for whom the drug was intended.

    Another background point to be considered: cidofovir injected intralesionally is absorbed to some degree into the bloodstream. This was confirmed in a paper presented at the 2003 ASPO meeting by Dr. Patrick Froelich of Lyon, France and recently published in Laryngoscope (11). He measured the blood concentration of cidofovir in 35 patients following intralesional injection and found levels within a range of 0.01-0.1 times the recommended dose for CMV retinitis. In one adult the levels reached the upper end of recommended therapeutic levels to prevent nephrotoxicity. This puts the levels into the ranges that were highly carcinogenic in rats. Of course, rats are not humans but it raises some concerns for nephrotoxicity risk for humans with extensive disease as well as the possibility of carcinogenicity. There is also some comfort in looking at Gilead’s primate data. Cynomolgus monkeys received intravenous cidofovir, alone and in conjunction with concomitant oral probenecid, intravenously once weekly for 52 weeks at doses resulting in exposures of approximately 0.7 times the human systemic exposure at the recommended dose of VISTIDE. No tumors were detected. However, the study was not designed as a carcinogenicity study due to the small number of animals at each dose and the short duration of treatment.

    Putting this in perspective is difficult given the following: to date, we do not know what the risk is in humans, nor do we know what additional co-factors may correspond with either an adverse event or successful trial. From Snoeck's initial Belgian study (12). it would seem that cidofovir patients, who have had exposure to radiation therapy or tobacco, may be predisposed to develop squamous cell carcinoma. Lindsay et al have presented some comforting histologic data regarding their series of cidofovir-treated children in San Diego showing no dysplastic changes but this is a relatively small cohort. The RRP Task Force has asked its members and colleagues to voluntarily report cases of dysplasia and/or malignant transformation occurring in patients who have received cidofovir. Only a handful of these patients have been identified to this point. This is a little less comforting considering that follow-up time has generally been short (few RRP patients have been followed for as long as seven years after initiation of cidofovir therapy). With the recent Vioxx and Celebrex debacles, the FDA has been under pressure to intensify its post marketing surveillance of approved drugs.

    Until more is known about the long-term safety profile of cidofovir in humans, the RRP Task Force recommends the following:

    1) Given the promising results reported in pediatric and adult patients, cidofovir should be routinely presented as a treatment option in moderate to severely afflicted RRP patients. i.e.; those patients whose disease is not improving on surgical therapy alone or in conjunction with less potentially morbid adjuvant measures and/or requiring surgical intervention greater than 3 times a year. With appropriate consent, cidofovir therapy should be a viable option in patents whose disease severity is resulting in a need for frequent surgery, worsening airway compromise or severely impaired communication or those who otherwise may be considered candidates for tracheostomy.

    2) Patients with more mild disease, particularly children, should be discouraged from seeking treatment with cidofovir, until a better understanding of the long-term implications of the use of this drug have been established. With appropriate informed consent, cidofovir could still be utilized on a case-by-case basis, at the discretion of the prescribing physician, for the more mildly affected patient.

    3) As with all surgical procedures, informed consent should be obtained and documented in the patient's record. At a minimum, this should include a frank discussion of the nephrotoxic and carcinogenic potential of this drug.

    4) Adverse responses, particularly evidence of dysplasia or malignant transformation to squamous cell carcinoma, either locally or remotely, should be reported simultaneously to the FDA (form 3500 or 3500A) and to the RRP Task Force through email communication with its Chairman, Craig Derkay, MD. (derkaycs@chkd.com)

    Bibliography:

    1. Schraff S, Derkay CS, Burke B, Lawson L. ASPO Member’s Experience with Recurrent Respiratory Papillomatosis (RRP) and the Use of Adjuvant Therapy. Archives Otolaryngology-HNS 2004; 130:1039-42

    2. See RF, Rao NA. Cytomegalovirus retinitis in the era of combined highly active Antiretroviral therapy. Ophthalmol Clin North Am. 2002 Dec; 15(4):529-36,viii

    3. Gilead Sciences, Inc. Physicians’ Desk Reference. Monvale, NJ: Thomson; 2003. p. 1428-32

    4. Akst LM, Lee W, Discolo C, Knott D, Younes A, Koltai PJ. Stepped-dose protocol of cidofovir therapy in recurrent respiratory papillomatosis in children. Arch Otolaryngol Head Neck Surg. 2003 Aug;129(8):841-6.

    5. Peyton Shirley W, Wiatrak B. Is cidofovir useful adjuvant therapy for recurrent respiratory papillomatosis in children? International Journal Pediatric Otolaryngology; 2004 April: 68(4) 413-418

    6. Bielamowicz S, Villagomez V, Stager SV, Wilson WR. Intralesional cidofovi therapy for laryngeal papilloma in an adult cohort. Laryngoscope 2002; 112:696-699

    7. Chhetri DK, Shapiro NL. A scheduled protocol for the treatment of juvenile recurrent respiratory papillomatosis with intralesional cidofovir. Arch Otolaryngol Head Neck Surg. 2003 Oct;129(10):1081-5.

    8. Pransky SM, Albright JT, Magit AE. Long-term follow-up of pediatric recurrent respiratory papillomatosis managed with intralesional cidofovir.Laryngoscope. 2003 Sep;113(9):1583-7.

    9. http://www.fda.gov/cder/foi/adcomm/96/avdac_joint_031496_summmin_ac.pdf

    10. Farrelly J. Personal Communication, 12/17/2003.

    11. Naiman AN, Roger G, Gagnieu MC, Bordenave J, Mathaut S, Ayari S, Nicollas R, Bour JB, Garabedian N, Froehlich P. Cidofovir plasma assays after local injection in respiratory papillomatosis. Laryngoscope. 2004 Jul;114(7):1151-6.

    12. Snoeck R, Wellens W, Deslooves C, VanranstM, NaesenesL, DeClereE,

    FeenstraL. Treatment of severe laryngeal papillomatosis with

    Intralesional injections of cidofovir. Medical Virology 1198; 54:219-225

    13. Lindsey F, Pranksy S, Brewster D, Magit A, Stapler R, Schick P. . P,BloomD. Histologic review of cidofovir treated respiratory papillomatosis.Presented at American Bronchoesophagologic Association, Friday, April 30, 2004. Phoenix, AZ

    [1] Derkay CS. American Society of Pediatric Otolaryngology (ASPO) Member’s Experience with Recurrent Respiratory Papillomatosis (RRP) and the Use of Adjuvant Therapy. Presented May 5, 2003, American Society of Pediatric Otolaryngology Nashville, TN.