Eyes – Ocular complications

Contents

25.1 Ocular Toxicity Associated

with High-dose Cytarabine Arabinoside . . . 383

25.1.1 Incidence and Etiology . . . 383

25.1.2 Prevention . . . 384

25.1.3 Treatment . . . 384

25.1.4 Prognosis . . . 384

25.2 Cataracts . . . 384

25.2.1 Incidence . . . 384

25.2.2 Etiology . . . 384

25.2.3 Prevention . . . 385

25.2.4 Treatment . . . 385

25.2.5 Prognosis . . . 385

References . . . 385

25.1 Ocular Toxicity Associated with High-dose Cytarabine Arabinoside 25.1.1 Incidence and Etiology

Keratoconjunctivitis is a known side effect of sys- temic high-dose cytarabine arabinoside (HDAC).

HDAC may be given as doses of 4–6 g/m

/day twice a day for usually 2–4 days (Barrios et al. 1987). Corneal toxicity associated with HDAC is a function of tear concentration that causes an inhibition of corneal ep- ithelial DNA synthesis (Ritch et al. 1983). Symptoms include photophobia, foreign body sensation, and ex- cessive tearing (Higa et al. 1991).

The incidence appears to be related to the duration of cytarabine arabinoside (also referred to as cyto- sine or ara-c) therapy, the intraocular fluid concen- tration of the drug, the cerebrospinal fluid (CSF) pharmacokinetics, and the use of corticosteroid eye drops (Higa et al. 1991):

▬ Extended periods of administration of HDAC (6–8 days) appear to increase the likelihood of eye problems.

▬ High levels of cytarabine arabinoside have been found in the CSF, tears, and aqueous humor of patients treated with HDAC. Conventional doses of cytarabine arabinoside (100 mg/m

/day) also cross the blood-brain barrier but cause a low con- centration in the CSF, accounting for the absence of ocular reactions. Any reaction that does occur in conventional dose therapy may be attributed to allergic reaction.

▬ Cytarabine arabinoside undergoes slower inacti- vation in the CSF.

Eyes – Ocular complications

Chapter 25 383

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Chapter 25

384 D. Tomlinson

▬ Compared with no therapy, the use of eye drops can decrease the incidence of ocular symptoms from about 40% to 20% or less (Itoh et al. 1999;

Higa et al. 1991; Barrios et al. 1987).

25.1.2 Prevention

Generally, all treatment schedules that include HDAC also incorporate the administration of corticosteroid eye drops as routine prophylaxis against ocular toxic reactions. The frequency of administration of eye drops (prednisolone 1%) varies from every 2 hours to every 8 hours (Gococo et al. 1991; Higa et al. 1991).

Eye-drop administration begins before the first dose of HDAC and usually extends to 48 hours following the last dose. Results regarding the optimum fre- quency of eye-drop administration are inconclusive, and even 5 minutes of drug exposure to the corneal epithelium has been associated with cell injury (Go- coco et al. 1991).

Research involving the use of eye drops for ocular toxicity associated with HDAC is always subject to small numbers of patients. Higa et al. (1991) com- pared the efficacy of corticosteroid eye drops and ar- tificial tears. They suggested that eye drops decrease ocular toxicity by diluting intraocular concentrations of cytarabine arabinoside and concluded that artifi- cial tears appeared to be as effective as corticosteroid eye drops if a rigorous administration schedule is employed. However, although glucocorticoid eye drops should not be used indiscriminately, they are safe and efficacious given over short periods of time (Gococo et al. 1991). A study by Itoh and colleagues (1999) suggested that the incidence could be reduced further with additional eye washing with 0.9% saline and monitoring for proper technique of eye-drop ad- ministration (including eye closure and nasolacrimal occlusion). These procedures were performed on 34 patients, and no ocular toxicity was observed in these cases. It is important to remember that these proce- dures may be more difficult to adhere to in a young pediatric population.

25.1.3 Treatment

Ocular toxicity that occurs despite prophylaxis will usually continue to be treated with corticosteroid eye drops. More severe reactions may require referral to an ophthalmologist. Very rarely would the treatment need to be discontinued.

25.1.4 Prognosis

The associated conjunctivitis usually resolves in af- fected patients within 7 days of discontinuation of HDAC (Barrios et al. 1987). Glucocorticoid eye drops will probably remain the prophylactic choice against HDAC-induced keratoconjunctivitis. However, rigor- ous administration of artificial tears may also de- crease the incidence of ocular reaction (Higa 1991).

25.2 Cataracts 25.2.1 Incidence

The incidence of cataracts in children who receive a conditioning treatment of total body irradiation (TBI) prior to bone marrow transplant (BMT) has been reported to be 95% (20 of 21children) to 100%

(21 children) (Holmstrom et al. 2002; Frisk et al.

2002). Busulfan has also been related to cataract de- velopment, with Holmstrom et al. (2002) reporting an incidence of 21% (five of 24 children).

25.2.2 Etiology

Opacity of the crystalline lens is referred to as a cataract. Several cataractogenic factors involved in cytotoxic therapy include ionizing radiation, corti- costeroid treatment, and chemotherapeutic agents.

Further factors related to radiation include the total

dose, fractionation scheme, and dose rate (van Kem-

pen-Harteveld et al. 2002). Autologous BMT patients

appear to have a slower progression of cataracts than

allogenic BMT patients (Frisk et al. 200). This may be

due to less need for corticosteroids after autologous

BMT (Aristei et al. 2002; van Kempen-Harteveld

2002).

Chapter 25 385 Eyes – Ocular complications

25.2.3 Prevention

To minimize the risk of cataracts with TBI, it would appear that steroid therapy should be minimized and that TBI regimens should include appropriate biolog- ic effective doses (van Kempen-Harteveld et al. 2002).

Eyes are not shielded during TBI because the orbit and the central nervous system are potential sites for residual disease.

25.2.4 Treatment

Surgical repair of cataracts is the treatment of choice, including extracapsular cataract extraction and in- traocular lens implantation.

25.2.5 Prognosis

Therapy-induced cataracts are not considered a se- vere complication because visual acuity can be re- stored by surgical treatment without significant com- plications. However, early diagnosis of cataracts in children is important in order to prevent the devel- opment of amblyopia (Holmstrom et al. 2002). Long- term follow-up should assess those children at risk for developing cataracts.

References

Aristei C, Alessandro M, Santucci A, Aversa F, Tabillo A, Carot- ti A, Latini RA, Cagini C, Latini P (2002) Cataracts in pa- tients receiving stem cell transplantation after conditioning with total body irradiation. Bone Marrow Transplant 29(6):

503–507

Barrios NJ, Tebbi CK, Freeman AI, Brecher ML (1987) Toxicity of high-dose ara-c in children and adolescents. Cancer 60:

165–167

Frisk P, Hagberg H, Mandahl A, Soderberg P, Lonnerholm G (2000) Cataracts after autologous bone marrow transplan- tation in children. Acta Paediatrica 89(7): 814–819 Gococo KO, Lazarus HM, Lass JH (1991) The use of prophylac-

tic eye drops during high-dose cytosine arabinoside thera- py. Cancer 69(11): 2866–2867

Higa GM (1991) Reply to Gococo et al. Cancer 69(11): 2867 Higa GM, Gockerman JP, Hunt AL, Jones MR, Horne BJ (1991)

The use of prophylactic eye drops during high-dose cyto- sine arabinoside therapy. Cancer 68: 1691–1693

Holstrom G, Borstrom B, Calissendorff B (2002) Cataract in children after bone marrow transplantation: relation to conditioning regimen. Acta Opthalmology Scandinavia 80(2):211–215

Itoh M, Aoyama T, Yamamura Y, Nakajima K, Nakamura K, Ko- taki H, Matsuyama T, Saitoh T, Kami M, Chiba S, Hirai H, Yazaki Y, Iga T (1999) Effects of the rational use of corticos- teroids eye drops for the prevention of ocular toxicity in high-dose cytosine arabinoside therapy. Yakugaku Zasshi 119(3): 229–235

Ritch PS, Hansen RM, Hener DK (1983) Ocular toxicity from high dose cytosine arabinoside. Cancer 51: 430–32 Van Kempen-Harteveld ML, Belkacemi Y, Kal HB, Labopin M,

Frassoni F (2002) Dose-effect relationship for cataract in- duction after single-dose total body irradiation and bone marrow transplantation for acute leukemia. International Journal of Radiation Oncology, Biology and Physics 52(5):

1367–1374