SECTION 11

Oncolytic Agents

Class: Antineoplastic Agents

Generic names: 1. Bleomycin; 2. dactinomycin; 3. daunorubicin; 4. doxorubicin; 5. mitomycin.

Proprietary names: 1. Blenoxane; 2. Cosmegen;

3. Cerubidine, Daunoxome; 4. Adriamycin PFS, Doxil, Rubex;

5. Mutamycin, Mytozytrex.

Primary use

Systemic

These antibiotics are used in a variety of malignant conditions. Bleomycin is a polypeptide antibiotic used in the management of squamous cell carcinomas, lymphomas and testicular carcinomas. Dactinomycin is an antibiotic used in the management of choriocarcinoma, rhabdomyosarcoma, Wilms’ tumor, testicular neoplasms and carcinoid syndrome. Daunorubicin is used in the treatment of acute leukemia, and doxorubicin is used in sarcomas, lymphomas and leukemia. Mitomycin is useful in the therapy of disseminated adenocarcinoma of the stomach or ­pancreas.

Ophthalmic

Mitomycin is used as an adjunct in the surgical treatment of pterygia and glaucoma. It may also be used in the management of carcinoma in situ and primary acquired melanosis.

Ocular side effects

Systemic administration

Certain 

1.Eyelids or conjunctiva

a.Conjunctivitis

b.Allergic reactions

c.Erythema

d.Edema

e.Hyperpigmentation

f.Angioneurotic edema

g.Urticaria

h.Loss of eyelashes or eyebrows

2.Decreased vision

3.Lacrimation

Probable 

1. May aggravate herpes infections

2. Ocular teratogenic effects

Possible 

1. Eyelids or conjunctiva – erythema multiforme

2. Subconjunctival or retinal hemorrhages secondary to drug-induced anemia

Inadvertent ocular exposure (doxorubicin)

Certain 

1. Keratoconjunctivitis

2. Chemosis

3. Subepithelial dot infiltrates

4. Transitory anterior uveitis

Local ophthalmic use or exposure – mitomycin

Certain

1.Irritation

a.Lacrimation

b.Hyperemia

c.Photophobia

d.Ocular pain

2.Eyelids or conjunctiva

a.Allergic or irritative reactions

b.Hyperemia

c.Erythema

d.Blepharitis

e.Conjunctivitis

f.Edema

g.Granuloma

h.Avascularity

i.Symblepharon (Fig. 7.11a)

3.Cornea

a.Punctate keratitis

b.Edema

c.Delayed wound healing

d.Erosion (epithelial and stromal)

e.Perforation

f.Crystalline epithelial deposits

g.Recurrence of herpes simplex

h.Astigmatism

i.Ulceration

4.Sclera

a.Erosion

b.Delayed wound healing

c.Perforation

d.Avascularity

e.Necrotizing scleritis

f.Calcium deposits

g.Yellowish plaques

h.Scleritis (anterior and posterior)

5.Uvea

a.Iridocyclitis

b.Hypopigmentation of iris

c.Hyperemia

6.Glaucoma

7.Punctal occlusion

8.Hypotony – occasionally persistent

9.Filtering blebs

a.Thinned wall

b.Excessive size

c.Overfiltration

d.Spontaneous leaks

e.Late bleb infections

10.Cataract formation

11.Choroidal effusions

Clinical significance

All of these agents are antimetabolites and, when given systemically, may be concentrated in the tears and cause irritation of the conjunctiva, cornea and lid margin. This usually occurs within a few days after drug exposure and may return to normal a few days after the drug is stopped. Conjunctivitis and blurred vision are the most frequent drug-induced side effects. Blum (1975) stated that up to 25% of patients on doxorubicin may have increased lacrimation. The cause may be secondary to ocular irritation. Which drug causes which ocular side effect is often difficult to determine because these agents are often used in combination. Megadoses of mitomycin

• 11 Sectionagents Oncolytic

effects side ocular induced-Drug •Pa7 rt

and carmustine (Cruciani et al 1994) cause changes in the tear film in all patients with changes to the corneal and conjunctival epithelium. Young et al (1993) described transient cortical blindness due to bleomycin along with other drugs. These drugs may be cofactors in cataractogenesis. In most instances, this group of drugs is only given systemically for cancer therapy and their systemic side effects are often so severe that ocular side effects may be insignificant to the overall clinical disability.

Inadvertent topical ocular exposure causes only transitory ocular effects. Keratoconjunctivitis, with or without punctate subepithelial dot infiltrates, may occur. These effects resolve after a few days without sequelae. McLoon et al (1988) reported muscle loss secondary to direct injection of doxorubicin in the management of blepharospasm.

The topical ocular use of these drugs is limited to mitomycin, which has been in clinical use for over two decades. During this time much has been learnt about how to limit local side effects and improve the risk-benefit ratio of this potent agent. This drug is used in glaucoma filtering surgery to inhibit wound healing, in pterygium surgery to limit recurrence, in dacryocystorhinostomy to decrease fibrous tissue growth, scarring and granulation, in refractive surgery to limit post-operative corneal haze, in cicatrical ocular surface disease to limit scaring, and for treatment of ocular surface malignancies. The ocular complications that occur are due directly to the concentration, duration of application and the surface to which it is applied. Patient acceptance of the frequency and extent of the ocular complications is dependent on the severity of the disease being treated. Mitomycin action on ocular tissue mimics that of ionizing radiation with probable resultant lifelong effects on tissue. A major characteristic of this chemical is that some side effects are immune mediated and may manifest themselves months after exposure. Irritative signs and symptoms are usually short-lived and seldom last more than a few weeks after discontinuing the drug. The most serious side effects are probably immune mediated. Although these may affect many areas, a longterm effect on both fibroblast activity and vascular endothelial cells is most evident. This could account for severe non-responsive corneal and scleral melts that may mimic scleromalacia perforans and/or necrotizing scleritis. Cases in the literature report perforation and, in some instances, the loss of the eye. Porcelainization of the conjunctiva and sclera (avascularity) has been permanent. As with systemic exposure, local recurrence of herpes simplex and calcification of tissue in direct contact with mitomycin can occur. Robin et al (1997) pointed out that the length of exposure may be more important than the concentration of the drug. In their

Fig. 7.11a  Topical ocular mitomycin-induced symblepharon.

series, the most important complications were cataract formation and persistent choroidal effusion, which are secondary to hypotony. There are more than 60 papers in the literature describing various aspects of complications from topical ocular application of mitomycin. The Higginbotham (1997) editorial summarizes and gives perspective on its use in glaucoma surgery. Abraham et al (2006) give a complete review of this drug’s use in ophthalmology. What role mitomycin C has in corneal dysplasias and primary acquired melanosis is still being developed. The complications for high-dose or frequent application seem acceptable to date, if the bare scleral is not exposed. Gebhardt (1998) pointed out these agents as a potential carcinogenic hazard. See references for additional information on specific side effects.

References And Further Reading

Abraham LM, Selva D, Casson R, et al. Mitomycin: clinical application in ophthalmic practice. Drugs 66: 321–340, 2006.

Al-Hazmi A, Zwaan J, Awad A, et al. Effectiveness and complications of mitomycin C use during pediatric glaucoma surgery. Ophthalmology 105(10): 1915–1919, 1998.

Billing K, Karagiannis A, Selva D. Punctal-canalicular stenosis associated with mitomycin-C for corneal epithelial dysplasia. Am J Ophthalmol 136: 746–747, 2003.

Bindish R, Condon GP, Schlosser JD, et al. Efficacy and safety of mito- mycin-c in primary trabeculectomy. Ophthalmology 109: 1336–1342, 2002.

Blum R. An overview of studies with adriamycin in the United States. Cancer Chemother Rep 6: 247–251, 1975.

Carrasco MA, Rapuano CJ, Cohen EJ, et al. Scleral ulceration after preoperative injection of mitomycin c in the pterygium head. Arch Ophthalmol 120: 1585–1586, 2002.

Cartsburg O, Kallen C, Hillenkamp J, et al. Topical mitomycin c and radiation induce conjunctival DNA-polyploidy. Anal Cell Pathol 23: 65–74, 2001.

Cruciani F, Tamanti N, Abdolrahimzadeh S, et al. Ocular toxicity of ­systemic chemotherapy with megadoses of carmustine and mitomycin. Ann Ophthalmol 26: 97–100, 1994.

Dafgard-Kopp E, Seregard S. Epiphora as a side effect of topical mitomycin c. Br J Ophthalmol 88: 1422–1424, 2004.

Danias J, Rosenbaum J, Podos SM. Diffuse retinal heorrhages (ocular decompression syndrome) after trabeculectomy with mitomycin c for neovascular glaucoma. Acta Ophthalmol Scand 78: 468–469, 2000.

Daugelience L, Yamamoto T, Kitazawa Y. Cataract development after traveculectomy with mitomycin c: a 1-year study. Surv Ophthalmol 45: 165, 2000.

DeBry PW, Perkins TW, Heatley G, et al. Incidence of late-onset bleb- ­related complications following trabeculectomy. Arch Ophthalmol 120: 297–300, 2002.

Dev S, Herndon L, Shields MB. Retinal vein occlusion after trabeculectomy with mitomycin C. Am J Ophthalmol 122(4): 574–575, 1996.

Dudney BW, Malecha M. Limbal stem cell deficiency following topical mitomycin c treatment of conjunctival-corneal intraepithelial neoplasia. Am J Ophthalmol 137: 950–951, 2004.

Fourman S. Scleritis after glaucoma filtering surgery with mitomycin C. Ophthalmology 102(10): 1569–1571, 1995.

Gebhardt DOE. Topical mitomycin C for the treatment of conjunctival and corneal epithelial dysplasia and neoplasia. Am J Ophthalmol 125(3): 416–417, 1998.

Gupta S, Basti S. Corneoscleral, ciliary body, and vitreoretinal toxicity after excessive instillation of mitomycin C [letter]. Am J Ophthalmol 114: 503–504, 1992.

Higginbotham EJ. Adjunctive use of mitomycin in filtration surgery: is it worth the risk? Arch Ophthalmol 115(8): 969–974, 1068–1069 , 1997.

Khong JJ, Muecke J. Complications of mitomycin c therapy in 100 eyes with ocular surface neoplasia. Br J Ophthalmol 90: 819–822, 2006.

Kirschen McLoon L, Wirtschafter JD, Cameron JD. Muscle loss from doxorubicin injections into the eyelids of a patient with blepharospasm. Am J Ophthalmol 116(5): 646–648, 1993.

Knowles RS, Virden JE. Handling of injectable antineoplastic agents. BMJ 2: 589, 1980.

Kymionis GD, Tsiklis NS, Ginis H, et al. Dry eye after photorefractive keratectomy with adjuvant mitomycin c. J Refract Surg 22: 511–513, 2006.

agents Oncolytic • 11 Section

effects side ocular induced• 7 Part-Drug