CEBP Infection and Cancer: Biology, Therapeutics, and Prevention Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Cancer Epidemiology Biomarkers & Prevention Vol. 13, 1250-1252, July 2004
© 2004 American Association for Cancer Research

Short Communication

Irreversible Ototoxicity Associated with Difluoromethylornithine

Christopher D. Lao1, Patricia Backoff3, Lawrence I. Shotland4, Deborah McCarty5, Tracy Eaton1, Frank G. Ondrey6, Jaye L. Viner7, Stuart Jon Spechler5, Ernest T. Hawk7 and Dean E. Brenner1,2,3

1 Departments of Internal Medicine and 2 Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan; 3 Ann Arbor VA Medical Center, Ann Arbor, Michigan; 4 James H. Quillen VA Medical Center, Mountain Home, Tennessee; 5 Dallas VA Medical Center, Dallas, Texas; 6 Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota; and 7 Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Dean E. Brenner, 2150 Cancer Center and Geriatrics Center, University of Michigan Medical Center, Ann Arbor, MI 48109-0930. Phone: (734) 647-1417; Fax: (734) 647-9817. E-mail: dbrenner{at}umich.edu


   Abstract
Top
 Abstract
Introduction
 Case Report
 Discussion
 References
 
Difluoromethylornithine (DFMO) is a potent, irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines that promote cellular proliferation. DFMO has been tested as a potential cancer therapeutic and chemopreventive agent in clinical trials. Reversible hearing loss is a recognized toxicity of DFMO that usually occurs at doses above 2 g/m2/d, and generally when the cumulative dose exceeds 250 g/m2. In a recently completed Barrett's esophagus chemoprevention trial, a participant developed a 15-dB decrease in hearing at frequencies of 250, 2,000, and 3,000 Hz in the right ear and a ≥20-dB decrease in hearing at 4,000 to 6,000 Hz in the left ear after taking 0.5 g/m2/d DFMO for approximately 13 weeks (cumulative dose of 45 g/m2). The threshold shifts persisted 7 months after DFMO was discontinued. There was no obvious impact on the participant's clinical hearing, but these findings were consistent with irreversible hearing loss. This is the first case reported of irreversible ototoxicity in a clinical trial participant receiving DFMO and, thus, trial participants should be made aware of this small but important risk.


   Introduction
Top
 Abstract
 Introduction
Case Report
 Discussion
 References
 
Difluoromethylornithine (DFMO) is a potent, irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme in the synthesis of polyamines involved in cellular proliferation. DFMO is approved by the Food and Drug Administration for the treatment of meningoencephalitis associated with Trypanosoma brucei var. gambiense (African sleeping sickness). DFMO has been shown to have antineoplastic activity in vitro and has been studied as a cancer therapeutic and chemopreventive agent (1). Reversible hearing loss is a recognized toxicity of DFMO (2-5), but there have been no previous reports of permanent threshold shifts. We now report a case of irreversible hearing loss presumably due to DFMO in a clinical trial participant.


   Case Report
Top
 Abstract
 Introduction
 Case Report
Discussion
 References
 
The participant is a 57-year-old man with a history of asthma, hypertension, coronary artery disease, and Barrett's esophagus who was enrolled in a Barrett's esophagus chemoprevention trial in February 2000. This double blind trial randomized individuals to receive 0.5 g/m2/d DFMO or placebo. After written informed consent was obtained, the participant was randomized to DFMO (actual dose: 900 mg daily). Concomitant medications included 40 mg lisinopril daily since 1994; 50 mg metoprolol twice daily since 1994; 30 mg lansoprazole twice daily since 1999; and albuterol and ipratropium bromide inhalers since 1993. He previously worked as a building contractor and had a smoking history of greater than 20 years duration. Physical exam was unremarkable and baseline audiologic evaluation revealed a mild bilateral sensorineural hearing loss at 3,000 Hz (30 dB HL; Fig. 1). Eleven weeks after initiation of DFMO, follow-up audiologic evaluation showed a ≥15-dB decrease in hearing at 250, 1,000, 2,000, and 3,000 Hz in the right ear and a 15-dB decrease in hearing at 4,000 and 6,000 Hz in the left ear (Fig. 1). The participant was taken off the study drug and retesting 3 and 16 weeks later noted failure of pure tone thresholds to return to pre-study levels. The hearing loss was not recognized by the participant and word recognition scores were not significantly affected by the threshold shifts identified on audiometric testing. The participant had no systemic symptoms and laboratory studies were normal. Otolaryngologic examination and comprehensive audiologic evaluation, including air and bone conduction thresholds, middle ear immittance, and otoacoustic emissions, confirmed significant threshold shifts that were sensorineural in nature. Results of repeat audiologic testing 29 weeks after discontinuation of DFMO were consistent with permanent hearing loss (Fig. 1).



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  		Figure 1. Audiograms of the participant over time. A. Audiograms of the right ear. B. Audiograms of the left ear. •, Baseline; {Delta}, 11 weeks from start of DFMO; {blacktriangledown}, 42 weeks from start of DFMO (29 weeks from discontinuation of DFMO).

 
It was the impression of the investigators that the participant was compliant with the study drug. The participant denied excessive noise or other known ototoxic exposures during the study period. Thus, it was felt that the irreversible hearing loss was caused by DFMO. Although the hearing loss had no apparent impact on his activities of daily living, this was an unexpected serious adverse event. Due to the previously unreported irreversible nature of the hearing loss, the event was appropriately reported to all regulatory and monitoring authorities.


   Discussion
Top
 Abstract
 Introduction
 Case Report
 Discussion
References
 
Temporary hearing loss is a known toxicity of DFMO that most often occurs with daily doses above 2 g/m2 and generally when the cumulative dose exceeds 250 g/m2 (3-8). Before this case, there have been no reports of irreversible hearing loss due to DFMO, regardless of dose (9-17).

Numerous treatment and chemoprevention trials have reported reversible hearing loss due to DFMO (3-6, 8), but few clinical studies have been designed to examine this relationship (7, 8, 18). Doyle et al. (18) performed rigorious follow-up of 123 participants in a DFMO chemoprevention trial (17) (doses of 0.075 g/m2/d to 0.4 g/m2/d) with pure tone audiometry (250 to 2,000 Hz) and distortion product otoacoustic emissions (DPOAEs). Statistically significant mean threshold shifts of 2 to 3 dB occurred in the two highest dosage groups at 250 and 500 Hz. However, none of the 20 participants with suspected clinically significant threshold shifts (≥15 dB at one-octave interval) was noted to have irreversible hearing loss (reported in ref. 17). Other investigators have reported hearing loss associated with DFMO that was allegedly reversible, but complete recovery in all participants was not always documented (7, 8). In 1991, Croghan et al. (7) reported ototoxicity in patients given DFMO at doses ranging from 2 to 12 g/m2/d for metastatic melanoma. Fifty-eight patients developed pure tone threshold shifts while on study, but recovery of hearing was not fully assessable due to insufficient follow-up audiograms. Pasic et al. (8) reported audiometric results on subjects taking DFMO at daily doses between 0.5 and 3 g/m2 for 6 to 12 months on phase I and II trials. Fifteen of 66 subjects developed threshold shifts > 15 dB at two-octave intervals. All subjects who underwent serial audiologic testing had reversal of threshold shifts regardless of DFMO dose; however, only 10 of 15 subjects were tested.

Serial monitoring for toxicities is extremely important in chemoprevention trials, because safety data are a critical part of any drug profile. Shotland et al. (19) published recommendations for audiologic testing in cancer prevention trials similar to the protocol used in this Barrett's esophagus trial. They advocate audiometric monitoring using a pre-determined schedule to detect and address ototoxicity that may arise during investigational testing. The audiometric testing in this trial included pure tone audiometry (250 to 8,000 Hz octave frequencies and 3,000 to 6,000 Hz one-half octave frequencies) done in a sound suite. Evaluations were done after week 8 following the first dose, at week 26, and at week 52 (study completion). This monitoring was more rigorous than most previous studies and allowed for the detection and follow-up of asymptomatic individuals. Thus, it is possible that irreversible hearing loss is a side effect of DFMO that has simply been under-recognized due to less rigorous monitoring.

The mechanism of hearing loss due to DFMO is unknown, but it is believed to be related to polyamine depletion in the cochlea. Polyamines and ornithine decarboxylase have been detected in the cochleas of experimental animals (20, 21) and their inhibition by DFMO has resulted in cochlear dysfunction (22). Polyamines are important in the functioning of voltage-dependent ion channels, which are essential for the maintenance of the electrolytic concentration and positive polarization of the endolymph (21, 23). Theoretically, disruption of this endocochlear potential by DFMO can lead to varying degrees of ototoxicity, including irreversible hearing loss.

Hearing loss due to DFMO might also occur when the stereocilia of hair cells are disrupted, damaged, or lost. Interestingly, DFMO seems to affect low- as well as high-frequency hearing with preferential loss of inner hair cells (20, 24, 25). Other ototoxic agents, for example, aminoglycosides and cisplatin, result primarily in high-frequency loss related to outer hair cell damage (26). Permanent hearing loss has resulted from inner and/or outer hair cell loss and has been associated with excessive noise exposure (27), higher doses of ototoxic drugs (26), and concomitant exposures to both (28). For individuals taking DFMO, age, gender, renal function, and previous hearing loss have not been consistently correlated with subsequent ototoxicity (3, 7, 8) Thus, it is unclear why the participant developed permanent hearing loss given the lack of excessive noise exposure and relatively limited drug exposure (daily dose of 0.5 g/m2/d and cumulative dose of approximately 45 g/m2).

The incidence of irreversible hearing loss due to DFMO exposure may be underestimated given the inadequacies of previous monitoring techniques and protocols. Participants in clinical trials using DFMO should be informed of the risk of irreversible hearing loss, and should be monitored closely for early detection of ototoxicity (19).


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 3/03; revised 11/20/03; accepted 3/ 8/04.


   References
Top
 Abstract
 Introduction
 Case Report
 Discussion
 References
 

  1. Meyskens FL Jr, Gerner EW. Development of difluoromethylornithine (DFMO) as a chemoprevention agent. Clin Cancer Res 1999;5:945-51.[Abstract/Free Full Text]
  2. Abeloff MD, Slavik M, Luk GD, et al. Phase I trial and pharmacokinetic studies of {alpha}-difluoromethylornithine—an inhibitor of polyamine biosynthesis. J Clin Oncol 1984;2:124-30.[Abstract]
  3. Croghan MK, Booth A, Meyskens FL Jr. A phase I trial of recombinant interferon-{alpha} and {alpha}-difluoromethylornithine in metastatic melanoma. J Biol Response Modif 1988;7:409-15.[Medline]
  4. Meyskens FL, Kingsley EM, Glattke T, Loescher L, Booth A. A phase II study of {alpha}-difluoromethylornithine (DFMO) for the treatment of metastatic melanoma. Invest New Drugs 1986;4:257-62.[Medline]
  5. Abeloff MD, Rosen ST, Luk GD, Baylin SB, Zeltzman M, Sjoerdsma A. Phase II trials of {alpha}-difluoromethylornithine, an inhibitor of polyamine synthesis, in advanced small cell lung cancer and colon cancer. Cancer Treat Rep 1986;70:843-5.[Medline]
  6. Ajani JA, Ota DM, Grossie VB Jr, et al. Evaluation of continuous-infusion {alpha}-difluoromethylornithine therapy for colorectal carcinoma. Cancer Chemother Pharmacol 1990;26:223-6.[Medline]
  7. Croghan MK, Aickin MG, Meyskens FL. Dose-related {alpha}-difluoromethylornithine ototoxicity. Am J Clin Oncol 1991;14:331-5.[Medline]
  8. Pasic TR, Heisey D, Love RR. {alpha}-Difluoromethylornithine ototoxicity. Chemoprevention clinical trial results. Arch Otolaryngol Head Neck Surg 1997;123:1281-6.[Abstract]
  9. Creaven PJ, Pendyala L, Petrelli NJ. Evaluation of {alpha}-difluoromethylornithine as a potential chemopreventive agent: tolerance to daily oral administration in humans. Cancer Epidemiol, Biomarkers & Prev 1993;2:243-7.[Abstract]
  10. Loprinzi CL, Messing EM, O'Fallon JR, et al. Toxicity evaluation of difluoromethylornithine: doses for chemoprevention trials. Cancer Epidemiol, Biomarkers & Prev 1996;5:371-4.[Abstract]
  11. Meyskens FL Jr, Emerson SS, Pelot D, et al. Dose de-escalation chemoprevention trial of {alpha}-difluoromethylornithine in patients with colon polyps. J Natl Cancer Inst 1994;86:1122-30.[Abstract/Free Full Text]
  12. Love RR, Carbone PP, Verma AK, et al. Randomized phase I chemoprevention dose-seeking study of {alpha}-difluoromethylornithine. J Natl Cancer Inst 1993;85:732-37.[Abstract/Free Full Text]
  13. Carbone PP, Douglas JA, Larson PO, et al. Phase I chemoprevention study of piroxicam and {alpha}-difluoromethylornithine. Cancer Epidemiol, Biomarkers & Prev 1998;7:907-12.[Abstract]
  14. Mitchell MF, Tortolero-Luna G, Lee JJ, et al. Phase I dose de-escalation trial of {alpha}-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia. Clin Cancer Res 1998;4:303-10.[Abstract]
  15. Boyle JO, Meyskens FL Jr, Garewal HS, Gerner EW. Polyamine contents in rectal and buccal mucosae in humans treated with oral difluoromethylornithine. Cancer Epidemiol, Biomarkers & Prev 1992;1:131-5.[Abstract]
  16. Love RR, Jacoby R, Newton MA, et al. A randomized, placebo-controlled trial of low-dose {alpha}-difluoromethylornithine in individuals at risk for colorectal cancer. Cancer Epidemiol, Biomarkers & Prev 1998;7:989-92.[Abstract]
  17. Meyskens FL Jr, Gerner EW, Emerson S, et al. Effect of {alpha}-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention. J Natl Cancer Inst 1998;90:1212-8.[Abstract/Free Full Text]
  18. Doyle KJ, McLaren CE, Shanks JE, Galus CM, Meyskens FL. Effects of difluoromethylornithine chemoprevention on audiometry thresholds and otoacoustic emissions. Arch Otolaryngol Head Neck Surg 2001;127:553-8.[Abstract/Free Full Text]
  19. Shotland LI, Ondrey FG, Mayo KA, Viner JL. Recommendations for cancer prevention trials using potentially ototoxic test agents. J Clin Oncol 2001;19:1658-63.[Abstract/Free Full Text]
  20. Salzer SJ, Mattox DE, Brownell WE. Cochlear damage and increased threshold in {alpha}-difluoromethylornithine (DFMO) treated guinea pigs. Hear Res 1990;46:101-12.[CrossRef][Medline]
  21. Schweitzer L, Casseday JH, Sjoerdsma A, McCann PP, Bartolome JV. Identification of polyamines in the cochlea of the rat and their potential role in hearing. Brain Res Bull 1986;16:215-8.[CrossRef][Medline]
  22. Henley CM, Rybak LP. Ototoxicity in developing mammals. Brain Res Brain Res Rev 1995;20:68-90.[CrossRef][Medline]
  23. Ficker E, Taglialatela M, Wible BA, Henley CM, Brown AM. Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science 1994;266:1068-72.[Abstract/Free Full Text]
  24. Salvi RJ, Wang J, Ding D, Stecker N, Arnold S. Auditory deprivation of the central auditory system resulting from selective inner hair cell loss: animal model of auditory neuropathy. Scand Audiol Suppl 1999;51:1-12.[Medline]
  25. McWilliams ML, Chen GD, Fechter LD. Characterization of the ototoxicity of difluoromethylornithine and its enantiomers. Toxicol Sci 2000;56:124-32.[Abstract/Free Full Text]
  26. Schweitzer VG. Ototoxicity of chemotherapeutic agents. Otolaryngol Clin North Am 1993;26:759-89.[Medline]
  27. Spoendlin H. Primary structural changes in the organ of Corti after acoustic overstimulation. Acta Otolaryngol 1971;71:166-76.[Medline]
  28. Gratton MA, Salvi RJ, Kamen BA, Saunders SS. Interaction of cisplatin and noise on the peripheral auditory system. Hear Res 1990;50:211-23.[CrossRef][Medline]



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