Mitomycin/Mitotane
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Mitomycin/Mitotane 753 Mitomycin is used, with other antineoplastic agents, in Thiotepa has been applied postoperatively as 0.05% eye drops lenticular opacities, and retinopathy. Other adverse ef- the treatment of many solid tumours including those of for several weeks, but pterygium may still recur2 and adverse ef- fects include hypersensitivity reactions, haematuria, al- fects include conjunctival injection, granuloma, hypertrophic the bladder, breast, cervix, eye, liver, lung, stomach, conjunctiva, and black deposits in the conjunctival fornix.1 Depig- buminuria, skin rashes, fever, myalgia, haemorrhagic and prostate as indicated by the cross-references given mentation of the eyelids may also be a problem, so patients cystitis, flushing, hypertension, and orthostatic hypo- below. Mitomycin has been tried in other neoplasms should avoid direct sunlight during thiotepa use.1 tension. including those of the gastrointestinal tract, head and Mitomycin has been applied topically to the surgical site, or giv- neck, pancreas, in melanoma, sarcomas, and in leukae- en as eye drops postoperatively.1 The optimal intra-operative ex- Precautions mias. posure time and concentration are uncertain: concentrations of 0.02 or 0.04% have been applied for up to 5 minutes,1,3 and low- Mitotane inhibits the adrenal cortex and adrenocortical Dosage regimens include an initial dose of 10 to dose treatment with mitomycin 0.02% for 30 seconds has been insufficiency may develop during treatment; cortico- 20 mg/m2 intravenously; subsequent doses are repeat- reported to be effective with few complications.4 Postoperative steroid therapy is often required. In trauma, infection, ed at intervals of 6 to 8 weeks if blood counts permit, treatment has generally been given as 0.02, 0.04, or 0.1% eye or shock the drug should be temporarily withdrawn drops for up to 2 weeks, but the higher concentrations and longer and corticosteroids should be given systemically. Mi- and should be reduced according to the previous hae- treatment periods have been associated with more adverse ef- matological response. Another suggested regimen is fects,1 some of which may be severe and sight-threatening (see totane should be given with care to patients with renal 2mg/m2 daily for 5 days, repeated after 2 days. Other also Effects on the Eyes, above). Comparisons of intra-operative or hepatic impairment. Before mitotane therapy is be- regimens may be used, particularly in combination. with postoperative use suggest that pterygium recurrence rates gun, all possible tumour tissue from large metastases are similar.1,5 Doses are adjusted according to the effect on bone mar- should be surgically removed, in order to minimise A range of β-irradiation doses and fractionation methods have possible infarction or haemorrhage in the tumour. Pa- row and treatment should not be repeated until the leu- been used. Long-term complications include posterior subcapsu- cocyte and platelet counts are above acceptable levels lar changes of the lens, atrophy and ulceration of the sclera, and tients should not drive or operate machinery. Behav- (see also Bone-marrow Depression, p.639). scleral necrosis leading to endophthalmitis.1 In one retrospective ioural and neurological assessments should be carried 6 Mitomycin is also used as a bladder instillation: 10 to study, intra-operative use of 0.04% mitomycin was more effec- out regularly in patients who have been receiving treat- tive than β-irradiation in preventing recurrence after surgery. In ment for 2 years or more. Plasma concentrations 40 mg is instilled once weekly or three times a week 7 another study, postoperative mitomycin 0.02% for one week should be monitored to guide dosage; the therapeutic for a total of 20 doses in the treatment of superficial was less effective than radiation therapy. window lies between 14 and 20 micrograms/mL (see bladder tumours. For the prevention of recurrent blad- 1. Hoffman RS, Power WJ. Current options in pterygium manage- ment. Int Ophthalmol Clin 1999; 39: 15–26. also Therapeutic Drug Monitoring, below). der tumours 20 mg may be instilled every 2 weeks, or 2. Chapman-Smith JS. Pterygium treatment with triethylene thio- 40 mg monthly or 3-monthly. Alternatively 4 to 10 mg phosphoramide. Aust N Z J Ophthalmol 1992; 20: 129–31. may be instilled once weekly or three times a week. 3. Anduze AL. Pterygium surgery with mitomycin-C: ten-year re- Interactions sults. Ophthalmic Surg Lasers 2001; 32: 341–5. Mitotane may induce hepatic microsomal enzymes These doses are usually given in 10 to 40 mL of water 4. Cheng H-C, et al. Low-dose intraoperative mitomycin C as che- for injection. The solution should be retained in the moadjuvant for pterygium surgery. Cornea 2001; 20: 24–9. and enhance the metabolism of some other drugs, in- bladder for at least 1 hour. 5. Oguz H, et al. Intraoperative application versus postoperative cluding coumarin anticoagulants. mitomycin C eye drops in pterygium surgery. Acta Ophthalmol Mitomycin has been given by the intra-arterial route in Scand 1999; 77: 147–50. Spironolactone. Mitotane in a dose of up to 3 g daily in a 65- the treatment of liver tumours, sometimes as an infu- 6. Amano S, et al. Comparative study of intraoperative mitomycin year-old patient with Cushing’s syndrome appeared to be inef- C and β irradiation in pterygium surgery. Br J Ophthalmol 2000; fective and did not produce the usual adverse effects associated sion of microcapsules designed to produce localised 84: 618–21. with mitotane while the patient was also receiving spironolac- embolisation. 7. Şimşek T, et al. Comparative efficacy of β-irradiation and mito- 1 mycin-C in primary and recurrent pterygium. Eur J Ophthalmol tone. Mitomycin is used for its effect on fibroblasts to im- 2001; 11: 126–32. 1. Wortsman J, Soler NG. Mitotane: spironolactone antagonism in prove outcomes and reduce scarring in certain types of Preparations Cushing’s syndrome. JAMA 1977; 238: 2527. surgery, notably in glaucoma (see below). USP 31: Mitomycin for Injection. Pharmacokinetics ◊ References. Proprietary Preparations (details are given in Part 3) Up to 40% of a dose of mitotane is absorbed from the 1. Abraham LM, et al. Mitomycin: clinical applications in ophthal- Arg.: Asomutan; Crisofimina; Datisan†; Maximiton; Mitocyna; Mitokebir; mic practice. Drugs 2006; 66: 321–40. Mitonovag; Mitotie; Oncotaxina†; Sintemicina; Vetio; Braz.: Mitocin; Ca- gastrointestinal tract; absorption increases with food. 2. Bolenz C, et al. Intravesical mitomycin C for superficial transi- nad.: Mutamycin; Chile: Metomit†; Fin.: Mitostat; Mutamycin; Fr.: Amety- After daily doses of 5 to 15 g, concentrations in the tional cell carcinoma. Expert Rev Anticancer Ther 2006; 6: cine; Ger.: Ametycine; Mitem; Mito-extra; Mito-medac; India: Mitocin; 1273–82. Mex.: Ifamit†; Mitocin-C; Mitolem; Mitotie; Mixandex; Norw.: Mutamycin; blood of 7 to 90 micrograms/mL of unchanged drug Philipp.: Mytoxid; Swed.: Mutamycin; Switz.: Mutamycine†; USA: Mi- 3. Tabaee A, et al. Mitomycin C and endoscopic sinus surgery: tozytrex; Mutamycin. and 29 to 54 micrograms/mL of metabolite have been where are we? Curr Opin Otolaryngol Head Neck Surg 2007; 15: reported. Mitotane has been detected in the blood for 40–3. 4. Warner D, Brietzke SE. Mitomycin C and airway surgery: how about 6 to 9 weeks after stopping treatment. It is widely well does it work? Otolaryngol Head Neck Surg 2008; 138: distributed and appears to be stored mainly in fatty tis- 700–9. Mitotane (USAN, rINN) sues. It is metabolised in the liver and other tissues and Glaucoma. Mitomycin, like fluorouracil, is effective in im- CB-313; o,p′DDD; Mitotaani; Mitotan; Mitotano; Mitotanum; excreted as metabolites in urine and bile. From 10 to proving the outcome of glaucoma filtering surgery in selected NSC-38721; WR-13045. 1,1-Dichloro-2-(2-chlorophenyl)-2-(4- 25% of a dose has been recovered in the urine as a wa- patients when used as an adjunct to prevent the formation of scar chlorophenyl)ethane. tissue (see p.1873). Fluorouracil is usually given as a regimen of ter-soluble metabolite. multiple injections but mitomycin given as a single intra-opera- Митотан Therapeutic drug monitoring. Monitoring of mitotane and tive topical application in usual concentrations ranging from 0.2 C14H10Cl4 = 320.0. its major metabolite o,p′-DDE in 2 patients receiving mitotane in to 0.5 mg/mL appears to be of similar efficacy.1,2 A systematic CAS — 53-19-0. review of 11 studies concluded that intra-operative mitomycin low doses for Cushing’s disease demonstrated that there is a pro- ATC — L01XX23. longed lag time in the plasma concentration changes in response reduced the chances of failure in high-risk patients, and in those ATC Vet — QL01XX23. 1 having their first trabeculectomy.3 However it was noted that the to alterations in dosage, presumably because of the lipophilicity of both compounds which leads to accumulation in adipose tis- nature of the data might have led to overestimation of the effect 2 and that there was some evidence of an increased risk of cataract sue. A study in adrenal carcinoma found that mitotane is prefer- 4 Cl Cl entially distributed into the very-low-density lipoprotein with mitomycin. Late hypotony is also a problem. For other po- Cl tential complications see Effects on the Eye, above. (VLDL) fraction of the serum of patients with hypertriglyceri- daemia, whereas under normolipidaemic conditions, it is bound 1. Skuta GL, et al. Intraoperative mitomycin versus postoperative 5-fluorouracil in high-risk glaucoma filtering surgery. Ophthal- to high-density lipoproteins and albumin. Because VLDL is not mology 1992; 99: 438–44. incorporated into the human adrenal cells, mitotane’s lipophilic- 2. Katz GJ, et al. Mitomycin C versus 5-fluorouracil in high-risk ity has implications for treatment and monitoring in patients with glaucoma filtering surgery: extended follow-up.