Antimitotic and Immunosuppressive Chemotherapy
Joel S. Mindel
Table Of Contents
FOLIC ACID ANALOGS|
|Few ophthalmologists are sufficiently familiar with the actions, toxicities, and
side effects of antimitotic and immunosuppressive agents to
administer them without the aid of an internist trained in the treatment
of neoplastic diseases. With regard to cancer chemotherapy, the treatment
of metastatic tumors to the eye and orbit will largely be omitted. The
reason is that the drugs chosen to treat metastases are those
effective against the primary lesion without particular regard for the
site(s) to which the cancer has spread.|
Therapy of the most common primary tumors of the eye and orbit will be mentioned. The drugs used are discussed one-by-one. A difficulty with this approach is that currently combinations of drugs are used, often with ionizing radiation, thermotherapy, or cryotherapy. It is impossible to assess the value of each component. Further, the effectiveness of the combinations is difficult to assess because there are few, if any, controlled randomized trials. Summaries of several specific retinoblastoma studies will demonstrate some of these problems:
With regard to the use of these antimitotic and immunosuppressive agents in inflammations, they are usually reserved for when useful vision is threatened or corticosteroids cannot be administered. The patients must be willing to have frequent laboratory studies and accept the possibility of life-threatening bone marrow depression. Immunosuppressive agents may cause oncogenesis6,7 and can promote the growth and spread of malignancies. Andrasch and co-workers unknowingly treated a 78-year-old patient with lymphoma cells in the vitreous for “uveitis.”8,9 After many months of treatment with prednisone and chlorambucil the patient died from central nervous system (CNS) involvement.
|PART 1: ANTIMETABOLITES|
|FOLIC ACID ANALOGS|
Methotrexate has been used to treat retinoblastoma metastatic to the central nervous system.10 Intrathecal methotrexate, 0.25 to 0.50 mg/kg, was given every other day until no tumor cells were present in the cerebrospinal fluid. While some prolongation of life may have occurred, the treatment was not curative.
Abramson and co-workers stated that initially they used methotrexate to treat orbital rhabdomyosarcoma but ultimately preferred a combination of other drugs.11
A patient with vitreous and spinal fluid involvement by non-Hodgkin lymphoma was treated with a single course of intravenous methrotrexate 1.5 gm/m2 bolus over 1 hour followed by 300 mg/m2 per hour over 24 hours for a total of 8.4 g in the 24-hour period.12 Seven and 74 hours after initiation of treatment, the respective anterior chamber, serum, and spinal fluid levels of methrotrexate were 55.7, 219, and 2.5 micromoles/L and 1.2, 0.5 and 0.2 micromoles/L. The minimal methrotrexate tumoricidal level is 1 micromole/L. Methrotrexate normally penetrates more poorly into the eye and spinal fluid. The better penetration found here was probably the result of breakdown in the blood—brain and blood—ocular barriers because of tumor cell infiltration. Direct intravitreal injection of methrotrexate has been used to avoid the need for radiation therapy of intraocular lymphoma cells.13 Methrotrexate, 400 micrograms in 0.1 ML, was injected intravitreally.14 Twice-weekly induction injections were required for 1 or 2 months, followed by monthly injections. All 26 eyes of 16 patients were clinically clear of cells after a maximum of 12 injections. Of the 16 patients, 14 were also treated with systemic chemotherapy. In six eyes of three patients there were recurrences 12 to 24 months later. In all six of these eyes, a repeat course of intravitreal methrotrexate was effective. Adverse effects were cataract (73% incidence), corneal epitheliopathy (58% incidence), maculopathy (42% incidence), vitreous hemorrhage (8% incidence), optic atrophy (4% incidence), and sterile endophthalmitis (4% incidence).
Corticosteroid-resistant uveitis has been successfully treated with methotrexate. Wong and Hersh gave methotrexate, 25 mg/M2, to patients with pars planitis.15 Each dose was injected intravenously within a 1- to 2-minute period every 4 days for 6 weeks. All six patients improved within 3 weeks, but five of the six relapsed when treatment was discontinued. Similar improvements followed by relapses were reported in additional subjects with pars planitis16 and in subjects with sympathetic ophthalmia.16–18 A prolonged remission occurred in a patient with orbital pseudotumor.18 Lazar and co-workers, using a similar dose regimen, reported successes in uveitis patients with sarcoidosis, juvenile rheumatoid arthritis, and uveitis of unknown origin.18 A patient with presumed toxoplasmosis uveitis did not improve. Owen and Cohen treated three severe cases of Reiter's syndrome successfully by giving methotrexate, 0.3 mg/kg, 1 day every week; one of the patients could not be tapered off the drug, however.19 The progression of bilateral Mooren's ulcers was arrested using 6- to 8-week courses of intravenous methotrexate, 25 or 50 mg/wk.20,21
Toxicities were frequent. Wong reported that 47% of patients had abnormal liver studies (i.e., increased serum glutamic oxaloacetic transaminase, increased serum glutamic pyruvic transaminase, and increased sodium sulfobromophthalein [Bromsulphalein] retention).16 The enzyme elevations occurred within 72 hours of starting methotrexate and returned to normal 1 to 2 weeks after discontinuing the medication. Pneumonitis occurred in two subjects on methotrexate therapy for 11 and 22 weeks. Lazar and co-workers18 reported that of 17 patients, 13 had gastrointestinal symptoms of anorexia, nausea, or vomiting; 11 had stomatitis; 5 had alopecia; 4 had secondary infections; and 4 had reductions in their white blood cell count below 4000/mm3 or in their platelet count below 100,000/mm3. Chemical, but not symptomatic, evidence of liver disease was found in four of the 17 patients. Only one patient was without side effects. There appeared to be no correlation between the severity of side effects and the degree of ocular improvement.
Methrotrexate has been used to replace corticosteroids in treatments in which corticosteroid side effects might prevent continued therapy. For example, oral methrotrexate appeared to allow reduction of corticosteroid dosage in three patients with sarcoid-associated optic neuropathy.22 Methrotrexate, in doses less than 20 mg per week, does not appear to effect bone density.23,24 The two ocular-involving diseases in which methrotrexate has been used to reduce corticosteroid need are temporal arteritis and sarcoidosis. Two prospective studies from the same medical center, one of them masked, randomized and placebo-controlled, concluded that methrotrexate was an effective substitute that allowed reduced corticosteroid dosage when treating temporal arteritis.25,26 However, two other prospective, randomized, masked, and placebo-controlled studies, one of which was multicentered, provided evidence that methrotrexate treatment did not reduce the cumulative corticosteroid dose needed, nor did it reduce the treatment-related corticosteroid side effects in temporal arteritis.27,28 These conflicting results are difficult to resolve.
Fluorouracil (5-FU) is converted intracellularly to fluorodeoxyuracil monophosphate. Fluorouracil monophosphate is an inhibitor of thymidylate synthetase and, hence, of DNA synthesis. Fluorouracil is also incorporated into transcribed RNA, resulting in abnormal ribosomes and messenger RNA. The antifungal agent fluorocytosine may exert its effect by being converted to fluorouracil.
Topical chemotherapy alone, although usually not sufficient for invasive malignancies of the cornea and conjunctiva, has been used for epithelial dysplasias and noninvasive tumors. Topical 5-FU, 1% eye drops, administered four times daily for 4 weeks has successfully treated squamous cell carcinoma of the conjunctiva in seven of eight patients with mean follow-up of 27 months.29 The eighth patient required a second course of treatment. Neoplastic cells were completely replaced by normal epithelium within 3 months. One case has been reported which failed to respond to topical mitomycin C, 0.02% administered four times daily for 2 weeks but did respond to topical 5-FU, 1% administered four times daily for a total of 7 weeks; treatment had to be interrupted because of the development of a severe corneal epithelial ulcer. A limbal autograft transplant was required 24 months after the initiation of 5-FU treatment.30 However, another case has been reported which failed to fully respond to 6 months of 5-FU, 1% eye drop treatment, four times a day for 4 days a week but did respond to topical mitomycin C.31 The other six patients in this series, exhibiting epithelial dysplasia or carcinoma in situ of the conjunctiva and/or cornea, did respond to topical 5-FU. Complications of 5-FU topical treatment, besides epithelial defects, included corneal opacification and persistent erythema of the lid skin. Stenosis of the lacrimal punctum and/or ducts, which has been observed with systemic 5-FU treatment, has not been reported with topical treatment.
5-FU, 0.01% has been applied, on a sponge, to the bare sclera of 20 eyes for a 5-minute period after pterygium removal. The incidence of pterygium recurrence was higher (60%) in the 5-FU group than in the 20 control eyes (35%).32 The authors concluded that 5-FU, at this concentration, was ineffective.
Abramson and co-workers treated rhabdomyosarcoma of the orbit with fluorouracil but found other agents superior.11
Pyrimidine analogs have been investigated as treatments for ocular disorders in which nontumor cellular proliferations occur. Examples of such conditions are proliferative vitreoretinopathy and postoperative subconjunctival fibrosis. While some studies have looked at other drugs, e.g., cytosine arabinoside (Ara-C),33 the major focus has been on 5-fluorouracil.
5-FU has been injected into the anterior chamber to treat a retrocorneal downgrowth following corneal transplantation.34 Two injections of viscoclastic materials containing 0.2 mg 5-FU in the first and, when that failed to halt progression, 1.0 mg in the second, were effective. However, the graft failed and had to be replaced. This patient was aphakic. Concerns have been expressed about the effect of 5-FU on the lens in phakic subjects. An immediate marked anterior lens opacification occurred after injecting 5 mg of 5-FU adjacent to an encapsulated bleb after filtering surgery.35 The acuity fell to finger counting at one foot, but lens clarity and full acuity returned within 24 hours. A single case report claimed successful treatment of epithelial down-growth onto the corneal endothelium in an aphakic eye using two anterior chamber injections of 0.5 mg of 5-FU.36 The injections were separated by 2 weeks.
Fluorouracil mitigated proliferative vitreoretinopathy by dual action: reduced cell mitosis and reduced membrane contractility.37 Rabbits had an intraocular injection of cultured retinal pigment epithelial cells followed by intravitreal fluorouracil, 0.5 mg per day for 1 week. The incidence of retinal detachment 2 weeks after cell injection was significantly less in fluorouracil-treated eyes (6 of 14 eyes) than in control eyes (12 of 12 eyes).38 The drug also decreased proliferation of human RPE cells in vitro.39 Fluorouracil has been injected in human eyes: 10 mg intravitreally following evacuation of vitreous hemorrhage caused by neovascular proliferation. Efficacy could not be determined, because too few eyes were utilized.40 In an uncontrolled study,41 patients with advanced proliferative vitreoretinopathy were treated with surgery plus various combinations of multiple subconjunctival injections of 5-fluorouracil, 10 mg and intravitreal 5-fluorouracil, 1 mg. At 6 months 60% of the retinas remained attached, an incidence of success somewhat higher than the surgeons would have expected if fluorouracil had not been used. In a prospective, masked, randomized placebo controlled study of 174 patients, vitrectomy infusion fluid containing 5-FU, 0.2 mg/ML plus low-molecular-weight heparin 5 IU/ML, significantly reduced the incidence of postoperative proliferative vitreoretinopathy, 12.6% versus 26.4% in the group receiving placebo.42 There were no differences in the incidences of postoperative hyphemas and complication rates.
The retinal toxicity of 5-fluorouracil has been investigated in rabbit eyes.43 There was no alteration of the b-wave amplitude of the electroretinogram until vitreous cavity concentrations were maintained at 0.1 mg/ML for 1 hour. Injecting 0.5 mg of fluorouracil every 24 hours for 7 days in vitrectomized eyes reduced pigment epithelial cell mitosis but did not alter retinal histology or the electroretinogram response.44 If 1.25 mg 5-FU were injected daily for 1 week, both photoreceptor histology and electroretinogram response were markedly altered with partial recovery after 5 weeks. Little intravitreal 5-fluorouracil reached the aqueous humor within 4 hours of injection if the lens were entirely intact (0.6% drug recovery) or if only the anterior lens capsule were intact (10% drug recovery).45
5-Fluorouracil has been used in glaucoma filtration surgery to prevent failure from postoperative fibrosis. Proliferation of cultures of rabbit conjunctival fibroblasts could be inhibited 50% at concentrations of 0.2 μg/ML.46 Single subconjunctival injections of 5 mg fluorouracil maintained rabbit corneal, conjunctival, and scleral drug levels above this 50% inhibitory level for at least 24 hours.47 Eye drops of 5-fluorouracil appeared considerably more toxic to rabbit corneal epithelium than were subconjunctival injections.48,49
Several small nonrandomized50,51 and randomized52 studies of patients suggested that postoperative subconjunctival injections of 5-fluorouracil improved the results of filtering surgery except in the presence of neovascular glaucoma.53 The major complications of therapy were conjunctival wound leaks, corneal epithelial defects, and suprachoroidal hemorrhages.54 A larger randomized study55 of 213 glaucoma patients who were followed-up for 1 year after receiving subconjunctival 5-fluorouracil, 5 mg in 0.5 ML, documented the therapeutic efficacy of the drug. Treatment was begun on the day after surgery in 105 eyes and consisted of two injections daily on days 1 to 7 and one injection daily on days 8 to 14. The 108 control eyes did not receive placebo injections. At 1 year, 27% of the treated group and 50% of the control group had intraocular pressures of 21 mm Hg or greater or had to have additional filtration surgery. Subconjunctival injections, even when begun 3 to 15 days postoperatively if clinical signs suggested early bleb failure, appeared effective.56 The 213 patients in the large randomized study were followed-up. In a subsequent report of the 5-year follow-up data, 51% of the 5-FU group and 74% of the control group were classified as having failed; this difference was significant (p<0.001).57 A retrospective study came to the same conclusion: 5-FU increased the success rate but there was a progressive loss of pressure control with time.58 Loss of control in eyes considered successfully treated at 1 year was 39% at 5 years, 56% at 10 years, and 59% at 14 years.
Lower total doses of injected 5-FU have been tested post-trabeculectomy, e.g., three doses of 5 mg each. These provided no significant benefit to the intraocular pressure reduction at 1 year.59
An alternative technique has used a soaked pledget to apply 5-FU to the scleral bed during trabeculectomy surgery.60–62 Soaking solutions of 25 to 50 mg 5-FU per ML have been used. Appling the pledget for 5 minutes appeared to be effective but none of the studies had control groups and supplementary conjunctival 5-FU injections were often given postoperatively. Side effects, consisting of conjunctival wound leaks, epithelial defects, hypotony, choroidal effusions/hemorrhages, and hyphemas/vitreous hemorrhages, seemed to occur less if the subconjunctival injections could be avoided. A masked, randomized trial in 103 patients compared the primary trabeculectomy results of applying topical 5-FU, 50 mg/ML on a pledget for 5 minutes, to topical mitomycin C, 0.2 mg/ML on a pledget for 2 minutes.63 The results were statistically similar at 12 months posttrabeculectomy with 94% of 5-FU eyes and 80% of mitomycin C eyes having pressures of 21 mm Hg or less.
Wirostko and Halbert produced uveitis in rabbits by injecting bovine serum albumin intravitreally.64 A marked inflammation occurred in 5 to 9 days. Serum antibodies to albumin were detectable within 9 days. When mercaptopurine, 5 mg/kg per day, was given intramuscularly for 14 days beginning with the intravitreal injection, there was a marked reduction in the uveitis. During treatment, antibody levels to bovine serum albumin were decreased. In 26% of the rabbits, antibody levels were undetectable. However, after discontinuing therapy, a slow steady increase in antibody levels occurred.
Mercaptopurine has been used, in daily doses of 2 to 2.7 mg/kg for 8 to 35 days, to treat pars planitis, idiopathic uveitis, sympathetic ophthalmitis, and acute histoplasmosis chorioretinitis.65 Most, but not all, patients had improvement of their acuity or visual fields and/or reduction in cell, flare, or lesion size. Relapses commonly occurred when therapy was discontinued. Several patients received two courses of therapy.
This drug is a derivative of mercaptopurine and slowly releases free mercaptopurine after it is administered. As a result, toxicity is reduced.
Rabbits66–68 had delayed healing of penetrating corneal incisions when given azathioprine, 48 mg/kg, every other day beginning at the time of wounding and continued through postoperative day 10. The ability of azathioprine to suppress corneal heterograft reactions was tested in three groups of 15 rabbits each. All grafts were clear 42 days after transplantation if intramuscular azathioprine, 48 mg/kg, were given every other day from the time of surgery through postoperative day 10 and if topical methylprednisolone, 0.1% ointment, twice per day, were applied beginning on day 10. Twelve of 15 grafts remained clear on day 42 after using the corticosteroid ointment alone beginning on postoperative day 11. Only one of 12 grafts remained clear when azathioprine alone was given for 10 days. In another group of rabbits, topical azathioprine, 0.1% or 1% in petrolatum or water-soluble ointment, applied three times per day, failed to prevent rejection. Cleasby and co-workers found that azathioprine, 20 mg/kg per day, delayed rabbit graft rejections, but that 10 mg/kg did not.69 However, maintenance on 5 mg/kg per day azathioprine plus 0.5 mg/kg per day prednisolone was effective.
Azathioprine has been given to patients whose ages ranged from 3 to 68 years with Graves disease and a number of other inflammatory conditions. Burrow and co-workers treated five patients with Graves disease who had positive assays for long-acting thyroid stimulating protein (LATS).70 Azathioprine, 2 mg/kg per day, was administered for up to 36 weeks. There was no improvement (i.e., no decrease in exophthalmos or increase in ocular movements) despite evidence of suppression of primary and secondary humoral immune responses and of delayed hypersensitivity. The chemosis and conjunctival injection of one patient was somewhat reduced by the therapy. Another study, using a matched control, confirmed that a 1-year treatment course of azathioprine was ineffective in altering thyroid ophthalmopathy.71
A 2-year randomized, placebo-controlled masked study demonstrated that azathioprine, 2.5 mg/kg per day reduced the incidence of uveitis and hypopyon in patients with Behçet's syndrome.72 Scleritis and uveitis from rheumatoid arthritis, Wegener's granulomatosis, herpes zoster, Vogt-Koyanagi-Harada syndrome, pars planitis, and sympathetic ophthalmia have been successfully treated with combinations of azathioprine and systemic corticosteroids.73–77 Not all patients responded. Initial doses ranged from 1.5 to 3.0 mg/kg per day azathioprine followed by maintenance doses of 1.0 to 1.5 mg/kg per day. Some investigators did not administer the drug on a body weight basis but instead used fixed doses of 50 to 200 mg/day. Exacerbations of disease frequently occurred when therapy was tapered.
In those studies in which azathioprine, cyclophosphamide, and chlorambucil were used, chlorambucil and especially cyclophosphamide were considered superior because side effects and toxicity were less frequent.77 Andrasch and co-workers stated that in 10 of 22 patients begun on azathioprine, adverse side effects, or poor therapeutic responses necessitated a change to chlorambucil.9 Adverse effects included skin rash, arthralgia, fever, leukopenia, thrombocytopenia, and gastrointestinal symptoms. Mild to moderate leukopenia occurred in 10 of 20 patients receiving 1.5 to 3.0 mg/kg per day azathioprine.73 This was adequately treated by decreasing or discontinuing the drug. These authors performed a complete blood cell count, including a platelet count, twice per week. In a study demonstrating the effectiveness of immunosuppressive therapy in cicatricial ocular pemphigoid, five of 18 patients initially treated with cyclophosphamide had azathioprine either substituted or added to their regimen78 because of cyclophosphamide intolerance or ineffectiveness. However, azathioprine was not tolerated or was ineffective in four of them.
Hahnenberger injected 100 μg vinblastine into the vitreous cavities of cats.79 Hypopyons developed and the corneas became inflamed and opaque. Corneal sensation disappeared after the third day and was not fully recovered 1 month later. The irides appeared to function normally 1 month postinjection but were supersensitive to pilocarpine and norepinephrine injected intramuscularly in doses that did not cause untreated eyes to respond.
Bhattacherjee and Eakins found that topical vinblastine, 2 μg to 5 μg, lowered rabbit intraocular pressure for more than 24 hours without causing irritation or pupil constriction.80
Twenty patients enucleated for primary ocular melanoma but without evidence of metastases were treated prophylactically with a five drug combination chemotherapy.81 Nineteen were treated within 1 month after enucleation and one patient was treated 1 year after enucleation. Intravenous vinblastine, 5 mg/m2 body surface, was one of the drugs used. With a median follow-up of 6 years, 17 patients, i.e., 89%, were disease-free, which was considerably better than the 38% to 65% incidence of disease-free patients at 5 years reported in the literature.
Vincristine has been used to treat retinoblastoma82 and orbital rhabdomyosarcoma11 in combination with cyclophosphamide. Vincristine, 2 mg/m2, was given intravenously once each week for 12 weeks beginning on the day that the diagnosis of rhabdomyosarcoma was confirmed pathologically. The maximum single dose was 2 mg. Too few patients were treated to evaluate whether chemotherapy plus irradiation was superior to irradiation alone. When the disease was confined to the orbit, the 3-year survival rate was 66% from irradiation alone and 91% from combination therapy. When the sinuses were invaded, the survival rate after irradiation was 44% whereas that from irradiation plus chemotherapy was 50%.
Colchicine interferes with mitosis and microtubular function. Colchicine does not inhibit actin filament formation and, therefore, does not affect rat corneal epithelial cell migration during wound healing.83–84 However, its use has been associated with nonhealing corneal ulcers in a small number of patients.85 Doses of 10 or 100 μg were injected intravitreally into pigeons. Transmission along the optic nerve was not affected, but there was reduced synaptic transmission at the ganglion cell axon terminals. This was interpreted as evidence of colchicine interference with axonal transport.86
Beebe and co-workers reported that colchicine, 10-10 M, added to tissue cultures, prevented elongation and increased volume of chicken lens cells.87 This concentration was too low to affect microtubular function, suggesting that colchicine had additional sites of action.
Hahnenberger injected 100 or 300 μg colchicine unilaterally into the vitreous cavities of cats.79 Corneal sensation disappeared after the third day, and 1 month later it had not fully recovered. The consensual light responses of the injected and control eyes were temporarily abolished. These results indicate that colchicine causes dysfunction in both sensory and motor neurons.
Topical application of 5 μg of colchicine caused a 2-mm Hg reduction in rabbit intraocular pressure 24 hours later without evidence of irritation. Maximum hypotension occurred with 50 μg colchicine. The pressure was reduced 10 mm Hg at 24 hours. However, at this dose, conjunctival irritation and miosis were present. The decrease in intraocular pressure was slow in onset. It began 8 hours after administration and was at maximum at 24 hours. Intravenous colchicine, 1 mg/kg, did not lower intraocular pressure. Lumicolchicine, an inactive isomer of colchicine, was ineffective topically.80
Mizushima and co-workers treated 157 patients with ocular involvement from Behçet's disease with colchicine.88 Most received 0.5 mg twice per day for more than 1 year. Doses ranged from 0.5 to 1.5 mg/day. Colchicine was stated to be far more effective than indomethacin or flufenamic acid. Two-thirds of patients had a reduction of 50% or more in the number of ocular attacks compared with the preceding year. Of the one-third of patients who did not respond, 7% had more attacks than the preceding year. Side effects associated with therapy were gastrointestinal symptoms (nausea, gastritis, and diarrhea), oligospermia, amenorrhea, hair loss, and malaise.
Hijikata and Masuda divided 91 patients with Behçet's disease into four therapy groups89: group 1 received only cyclophosphamide, 50 to 100 mg/ day; group 2 received only colchicine, 0.5 to 1.0 mg/day; group 3 received a combination of cyclophosphamide, 50 mg/day, plus colchicine, 0.5 mg/day; and group 4 received various combinations of systemic corticosteroids, nonsteroidal antiinflammatory drugs, antibiotics, and desensitization agents. The average length of treatment for these groups ranged from 1.7 to 2.2 years. The results are difficult to interpret because certain patients were excluded from the analysis (e.g., those with severe cataracts and glaucoma) and because some patients were on different regimens at different times. The authors interpreted their data as indicating therapy with colchicine and/or cyclophosphamide (groups 1 to 3) was superior to the other forms of treatment (group 4) in preventing deterioration of acuity and in reducing the frequency of attacks.
Mechlorethamine is unstable in water. Therefore, once in solution, it must be injected without delay. Chlorambucil and cyclophosphamide are more stable and can be given orally. Cyclophosphamide is the most widely used of the nitrogen mustards. It is a prodrug and must be hydroxylated by cytochromes to become effective. The ultimate antitumor metabolite is believed to be phosphoramide mustard, but this is a subject of controversy.90 Unlike the other nitrogen mustards, cyclophosphamide does not cause severe central nervous system stimulation. Therefore, there is less nausea and vomiting, and convulsions, paralysis and cholinomimetic side effects do not occur.
McCarthy produced an anterior uveitis by injecting rabbits with live tubercle bacilli.91 The inflammation was partially inhibited if mechlorethamine, 8 to 16 mg, were given intravenously over the 10- to 12-day period after inoculation. This suggested the drug had a bacteriostatic effect.
Jampol and co-workers treated a single patient with corticosteroid-resistant rheumatoid sclerouveitis with a total dose 0.4 mg/kg mechlorethamine given over a period of 3 days.92 This patient could then be controlled with steroids for several months.
Abramson and co-workers initially used chlorambucil, in combination with radiation, to treat orbital rhabdomyosarcoma.11 They subsequently preferred using cyclophosphamide and vincristine.
Chlorambucil has been used successfully to control Behçet's disease, rheumatoid scleritis and uveitis, orbital pseudotumor, sympathetic ophthalmitis, Vogt-Koyanagi-Harada syndrome, pars planitis, herpes zoster uveitis, and uveitis of unknown origin.93–100 Not all patients responded, and exacerbations were common when medication was tapered. Initial oral doses ranged from 0.1 to 0.2 mg/kg, or fixed doses of 5 to 24 mg/day were given in divided doses after meals. Godfrey and co-workers used an initial dose of 2 mg/day to determine if idiosyncratic sensitivity was present.95 Doses were then increased 2 mg/day each week, with as much as 22 mg/day being given. Chlorambucil was almost always used in conjunction with systemic corticosteroids. A therapeutic response was evident after a mean period of 3.5 weeks using doses of chlorambucil of 6 to 8 mg/day; maximum improvement occurred after a mean period of 4.3 months. When tapering of medications was begun, corticosteroids were usually discontinued first. The most common toxicity was a fall in the white blood cell count or platelet count. While some bone marrow depression was common (e.g., Godfrey and co-workers95 found evidence of it in 28 of 31 patients), it was unusual for it to require cessation of treatment. Gastrointestinal symptoms, such as anorexia, nausea, burning, and diarrhea, and skin rashes were also relatively common.
The greatest success has been in the treatment of Behçet's disease. Mamo and Azzam controlled all 10 of their patients using chlorambucil for up to 17 months.93 In all but one patient, topical and systemic corticosteroids could be discontinued approximately 2 weeks after starting chlorambucil. Abdalla and Bahgat reported favorable results in seven patients with Behçet's disease treated with chlorambucil and systemic corticosteroids.94 Two patients had chlorambucil discontinued for 3 weeks because their white blood cell counts fell below 3500/mm3. Godfrey and co-workers,95 Dining and Perkins,96 and Mamo97 reported control in a total of 22 of 23 patients with Behçet's disease. Tricoulis reported successes in five patients, two of whom had been unsuccessfully treated with azathioprine.98
In sympathetic ophthalmitis patients, chlorambucil doses were increased relatively rapidly over a short period until bone marrow suppression occurred. The initial dose of chlorambucil was 2 mg/day orally and was increased by 2 mg/day each week. Control of the intraocular inflammation appeared to coincide with bone marrow suppression. The drug was then discontinued and the disease could be controlled with topical steroids alone.101
The enthusiasm for chlorambucil has been tempered by the demonstration that its use produced testicular atrophy102 and leukemia.103 In patients with polycythemia vera, the incidence of acute leukemia was 13-times greater in those treated with chlorambucil than in those treated with phlebotomy alone. Use of a low total dose of chlorambucil may avert these problems. Sperm counts remain in the normal range if less than 6.1 mg/kg is given104 and acute leukemia becomes rare if less than 1 g is given.105 This latter information in particular has altered the way in which the drug is prescribed.
Abramson and co-workers reported that treatment of orbital rhabdomyosarcoma with either irradiation alone (25 patients) or irradiation plus chemotherapy (33 patients) was effective.11 The overall mean survival rate, approximately 70% in patients followed-up an average of 5.2 years, was superior to that from surgical therapy alone. Initially chlorambucil, 5-fluorouracil, and methotrexate were used. Subsequently, the preferred chemotherapy regimen consisted of cyclophosphamide and vincristine, with dactinomycin added at the conclusion of radiotherapy. Cyclophosphamide, 10 mg/kg per day, was given intravenously beginning the day the pathologic diagnosis was made and was continued for 5 days. During week 13 of therapy, cyclophosphamide, 10 mg/kg per day, was given orally for 7 days. From weeks 21 to 104, cyclophosphamide, 2.5 mg/kg per day, was given orally. Vincristine was given intravenously beginning the day the pathologic diagnosis was made and was continued for 12 weeks. Dactinomycin, 0.015 mg/kg per day, was given intravenously for 5 days of each week during weeks 18, 30, 42, and 54. When the sinuses were invaded, the survival rate after irradiation plus chemotherapy was approximately the same as that following irradiation alone, being approximately 50%. When the disease was confined to the orbit only, the 3-year survival rate after irradiation alone (66%) was less than that after irradiation plus chemotherapy (91%). However, too few patients (17) were in this category of the study to permit a statistical analysis for significance.
Oral and intravenous cyclophosphamide has been used in the treatment of retinoblastoma but without apparent value.10,82,106 Wolff and co-workers used intrathecal cyclophosphamide, 4 to 8 mg/ kg every other day for 8 days, to treat central nervous system spread of the disease; some slight prolongation of life may have occurred.10 Malik and co-workers107 also reported only a limited response of CNS retinoblastoma to a combination of intravenous cyclophosphamide and vincristine.
Because of evidence that the ophthalmopathy of Graves disease was caused by an immune system abnormality, cyclophosphamide therapy was attempted by Bigos and co-workers in three patients with this disease.108 Varying degrees of success occurred in all three. Patient 1 was treated for a coexisting pelvic tumor with intravenous cyclophosphamide, 700 mg/mo, and doxorubicin, 500 mg/mo. Both were administered for 1 year. After 2 months of treatment, the patient's diplopia, present for 5 years, and foreign body sensation disappeared. Proptosis was unaffected. When the drugs were discontinued, there was no recurrence of symptoms and the patient remained stable during 22 months of follow-up. Patient 2 was placed on cyclophosphamide, 150 mg/day, and primary gaze diplopia, but not lateral gaze diplopia, resolved. Cyclophosphamide was discontinued after 15 months of treatment. After 28 months of follow-up, the primary position diplopia had not returned. Proptosis was unaffected by therapy. Patient 3 had 20/80 (6/24)* vision and disc edema caused by thyroid ophthalmopathy. Within 3 months of beginning oral therapy with cyclophosphamide, 8.5 mg/ day, the disc edema disappeared and the vision improved to 20/20 (6/6). After 2 years of follow-up, there was no return of signs or symptoms. Just as in the other two patients, proptosis was unaffected.
*Metric equivalent given in parenthesis following Snellen notation.
Cyclophosphamide has been successfully used in intraocular inflammations. Animal studies suggested that it preferentially reduced the number of B lymphocytes.109 Oh injected herpes simplex type 1 virus into rabbit eyes to produce uveitis.110,111 Intramuscular cyclophosphamide, 80 mg, every other day, did not alter the inflammation found during the first 6 days. Thereafter, the inflammation was somewhat suppressed but virus growth was more abundant. Circulating antibody levels were decreased. Similar doses of cyclophosphamide, begun 8 days before a secondary herpes simplex uveitis, had little effect. Presumably the secondary immune response was more resistant to suppression.
Patients with uveitis have been treated with daily oral doses of 25 to 250 mg cyclophosphamide.112,113 The 250-mg dose, calculated on a weight basis, was 5 mg/kg per day. Intravenous therapy with 1 g/m2 per week has also been administered.16 Corticosteroids usually were given until the signs and symptoms remitted.92,114,115 Hijikata and Ma-suda used cyclophosphamide plus colchicine.89 Duration of therapy, using tapering medications, was for a minimum of 3 weeks. Hemorrhagic cystitis caused discontinuation of therapy in a patient treated 2 years with 150 mg/day. Other toxicities included bone marrow suppression, nausea, diarrhea, hemorrhagic gastritis, alopecia, sterility, and cardiac toxicity. Kende and co-workers reported temporary blurring of vision in 17% of children given large doses of cyclophosphamide.116 Blurring began in minutes to 24 hours after administration of the drug, could occur at any time during the course of therapy, and lasted less than 1 hour or up to 2 weeks. Continuation of therapy did not cause a recurrence.
Successful control has been reported for sympathetic ophthalmitis, orbital pseudotumor, orbital vasculitis, corneal transplant rejection, pars planitis, ocular Behçet's disease, rheumatoid sclerouveitis, uveitis associated with polyarteritis nodosa and systemic lupus erythematosus, ocular Wegener's granulomatosis, and pyoderma gan-grenosum scleritis.16,21,77,89,92,112–115,117 Not all cases responded. Those that did respond did so after days to weeks of therapy. Buckley and Gills treated five patients with presumed toxoplasmosis retinitis.112 The response was variable. In two patients, the inflammation decreased. Permanent remissions have been reported in patients with Wegener's granulomatosis.92 The response of ocular cicatricial pemphigoid to cyclophosphamide was variable and difficult to assess because the disease itself did not always progress.118 However, the overall results seemed better in the treated groups. Chronic therapy with cyclophosphamide has been associated with chromosome damage,119 carcinoma of the bladder,120 and leukemia.121 In rheumatoid arthritis patients in whom necrotizing scleritis or keratitis developed, cytotoxic immunosuppressive therapy not only improved the ocular outcome but also reduced the lethal effects of the systemic vasculitis.122 Nine of 17 patients who were managed without immunosuppressive therapy died. Only one of 11 patients treated with cyclophosphamide died.
Ifsomide is a nitrogen mustard-type of alkylating agent that must be metabolically activated. Its cytotoxic activity is primarily because of cross-linking DNA and RNA. The drug is administered parentally. Activation and subsequent degradation of ifosfamide take place in the liver. Excretion is largely in the urine. The larger the dose, the more likely the drug will be excreted in the urine unmetabolized. The drug is renal and hepatotoxic.
Ifosfamide has been used with combination irradiation, vincristine and dactinomycin or etoposide to treat rhabdomyosarcoma of the orbit.
Triethylenemelamine (TEM) has been used to treat retinoblastomas with unfavorable prognoses, often in combination with radiotherapy. TEM was injected, under direct observation, into the internal carotid artery. Krementz and co-workers gave 0.03 mg/kg per day for 7 to 10 days.123 Ellsworth injected a single dose of 0.08 to 0.1 mg/kg.124 Bishop and Madison occasionally gave a second injection of 0.08 to 0.1 mg/kg approximately 6 to 8 weeks after the first.125 It is difficult to evaluate efficacy. The largest series was that of Reese and Ellsworth.126,127 Between 1960 and 1965, 116 patients with poor prognoses were treated with TEM and radiotherapy.124 There was an average 5-year follow-up. The 5-year cure rate in patients with multiple tumors, some of which were larger than 10 disc diameters, or with tumors anterior to the ora serrata, was 69%. That in patients with tumors involving more than half the retina or with vitreous seeding was 34%. That in patients with orbital involvement was 30%. The visual acuities in these survivors were not given.
Thiotepa (triethylenethiophosphoramide) 1% in sesame or olive oil temporarily inhibited rabbit corneal vascularization when applied three or four times a day.128,129 At a 0.05% concentration in Ringer's solution, it has been used topically in humans to prevent recurrence of pterygia. At this concentration, Liddy and Morgan stated that the drug is stable for more than 15 days when stored at 3°C.130 Thiotepa is applied topically after the removal of the pterygium in the hope that it will prevent the corneal neovascularization associated with recurrences. Olander and co-workers, after a thorough review of the literature, found it impossible to compare the prophylactic value of thiotepa with that of β-irradiation.131 Different authors have not been uniform in their frequency of treatments; control groups are often inadequate or lacking altogether.
Thiotepa 0.05%, with and without topical corticosteroids, has been applied every 3 hours for 3 to 8 weeks after “bare sclera” removal of pterygia. Treatment began 1 to 7 days after surgery.130,132,133 Follow-up periods in general ranged from 2 to 3 years. Recurrence rates in the treated eyes ranged from 6% to 8%. In a control group of 48 patients, Kleis and Guillermo reported a 31% recurrence rate.
Concentrations as high as 0.2% have been used without signs of toxicity.134 However, the 0.05% solution has occasionally caused depigmentation of the skin and poliosis around the treated eye.135 These may be late occurrences (e.g., 8 months after discontinuing therapy).136 Joselson and Muller reported that 85% of 46 patients treated with 0.05% thiotepa had a steroid-resistant, extended postoperative hyperemia; one patient had conjunctival hypertrophy 3 weeks after the drug was discontinued.137 In guinea pigs, lid and lash toxicity occurred when 1% thiotepa was given every 4 hours.138 In rats, 0.22% thiotepa, eight times per day for 6 weeks, produced both cataracts and corneal vascularization.139 Berkow and co-workers attempted to treat a corneal graft reaction with 1% thiotepa in peanut oil, twice per day for 23 days.140 Progressive depigmentation of the lids occurred in this black patient over the next 6 months. When the other eye was grafted, 1% thiotepa was used twice a day for only 3 days. Again, the skin became depigmented. The grafts remained clear bilaterally, but there was no return of skin pigment during the 5-year follow-up. Because a similar depigmentation occurred when thiotepa was placed on the patient's forearm, as a patch test, these authors considered the response to be idiosyncratic.
Rabbits with epitheliomas implanted bilaterally into their anterior chambers were treated with unilateral carmustine (BCNU) or dacarbazine (DTIC).141 The drugs were injected either subconjunctivally or into the anterior chamber every 3 days for 18 days. Both drugs, given in either location, were successful in delaying tumor growth. Carmustine, unlike dacarbazine, is lipophilic and when given intravenously penetrated the eye in sufficient quantities to be effective. The doses used were dacarbazine, 0.6 mg per anterior chamber injection and 1.5 mg per subconjunctival injection; carmustine, 0.2 mg per anterior chamber injection, 0.5 mg per subconjunctival injection, 2.25 mg/kg, intravenously, four times in 12 days when used in combination therapy, and 3.13 mg/kg, intravenously, four times in 12 days when used alone.
Carmustine has been injected into the carotid arteries of patients with brain tumors. A complication was ipsilateral ischemic ocular disease. This could be avoided by advancing the catheter tip beyond the take-off of the ophthalmic artery before injecting the drug.142–144
Dacarbazine could be injected intravitreally into rabbit eyes in 1-mg doses, and the injections repeated four times, without ocular damage. However, injections of 2 mg caused vitreous hemorrhage beginning with the second injection and retinal damage beginning with the third injection.145
Dacarbazine has been used to treat malignant melanoma elsewhere in the body. Intravitreal injections would be of questionable value in primary ocular malignant melanoma because the drug, in passing through the retina to reach the tumor in the choroid, might damage the neurosensory epithelium. Wilczek used 14C-labeled dacarbazine to evaluate rabbit and monkey eye penetration.146 In rabbits, 0.5 mg was injected intravenously or 0.125 mg was injected retrobulbarly. Monkey eyes received 1.0 to 7.5 mg of unlabeled dacarbazine retrobulbarly, twice per day for a total of four injections (i.e., a total of 4 to 30 mg). Retrobulbar injection was superior, using these doses, to intravenous therapy. Maximum concentrations occurred shortly after injection. Although those monkey eyes receiving retrobulbar injections of 1 to 2.5 mg showed no gross or histopathologic changes 2 weeks after the four injections, those eyes with injections of 5 mg and higher did develop orbital inflammation, retinitis, and uveitis.
Dactinomycin (actinomycin D, Cosmegen) has been used in combination therapy of metastatic retinoblastoma. Prolongation of life resulted but cure did not. Wolff and co-workers treated seven patients in whom the longest posttreatment survival was 48 months.10 Patients initially received cyclophosphamide followed by 7 days of combination therapy: dactinomycin, 75 μg/kg per day intravenous (IV) in divided doses; methotrexate, 2.5 mg/day orally; and cyclophosphamide, 5 mg/kg per day IV.
Abramson and co-workers used dactinomycin at the conclusion of radiotherapy for orbital rhabdomyosarcoma.11 Dactinomycin 0.075 mg/kg per week was given intravenously in divided doses every 12 weeks until a total dose of 0.3 mg/kg had been given.
Tan treated 1 patient with retinoblastoma and 14 patients with rhabdomyosarcoma using doxorubicin (adriablastina, Adriamycin).147 Children received 0.5 mg/kg per day for a total dose of 2 to 4 mg/ kg. Adults received 0.4 mg/kg per day for 3 days, rest for 4 days, and repeated administration, for a total dose of 2.5 mg/kg. Doxorubicin was administered intravenously as a 2-mg/ML solution in normal saline. Each dose was injected during a 2- to 3-minute period. Repeat courses were tolerated 3 to 4 weeks later in children. Adults were maintained on a weekly dose of 0.4 mg/kg.
The main toxicity was bone marrow depression: leukopenia and thrombocytopenia developed in 64% of children at an average total dose of 3 mg/kg. Alopecia, oral ulcers, fever, gastrointestinal symptoms of nausea and vomiting, and cardiac myopathy occurred.
Bigos and co-workers found that a patient with Graves disease and endocrine ophthalmopathy had resolution of his diplopia and ocular irritation, but not his proptosis, when treated with chemotherapy for a pelvic tumor.108 The patient received, for 1 year, doxorubicin, 500 mg/mo, intravenously, and cyclophosphamide, 700 mg/mo, intravenously. When therapy was discontinued, the patient remained stable, with follow-up being 22 months.
Systemic doxorubicin, in combination with cisplatin, has been used to treat basal cell and squamous cell carcinomas of the lids148 in patients who refused surgery or in whom surgery was contraindicated. The responses to therapy were excellent, but treatment efficacy was attributed primarily to the cisplatin. Intravenous doxorubicin with intracarotid cisplatin have been radiographically shown to reduce tumor size in adenocarcinoma of the lacrimal gland before orbital exenteration.149
Doxorubicin injections have been used to destroy striated muscle, i.e., produce a chemomyectomy, in patients with blepharospasm and hemifacial spasm.150 Symptomatic relief was achieved in nine of 18 blepharospasm patients and five of six hemifacial spasm patients. Bupivacaine was injected into each eyelid followed by 2 ML of doxorubicin 0.5 mg/ML given in 0.1-ML to 0.2-ML doses. Injections were repeated at intervals of 10 or more weeks until relief was achieved or the patient no longer wished to continue. However, local complications were frequent and included a skin ulcer, ectropion, entropion, redundant edematous conjunctiva, skin hyperpigmentation, and diplopia.
Mitomycin C is an antimitotic antibiotic that inhibits DNA synthesis. It requires enzymatic activation before generating DNA-alkylating moieties. Multiple enzymes are capable of this bioreduction activation.151 One of the enzymes, NAD(P)H:quinone oxidoreductase (NQ01) has been identified in normal, dysplastic and neoplastic conjunctival and corneal epithelial cells, in fibroblasts, in all retinal layers, and in optic nerve fascicles and arachnoid; the staining is minimal in photoreceptor outer segments and optic nerve pia and dura.152 Variations in the activities of the activating enzymes of different individuals may partially explain the differences found in the effectiveness and toxicity of mitomycin C.
Mitomycin C has been used topically after surgical removal of pterygia to prevent recurrences. Hayasaki and co-workers153 studied 99 eyes of 80 patients. All had surgical removal of their primary pterygia and postoperative application of topical corticosteroids and antibiotics. Mitomycin C, 0.02% in 0.9% NaCl, twice per day for the first 5 postoperative days, significantly reduced the recurrence of pterygia (7% in 29 eyes). The 31 eyes not receiving mitomycin C had a 32% recurrence rate. Reduced recurrence rates, but not superior to that of the 0.02% solution of mitomycin C, were achieved by 2000-cGy radiation (15%) and mitomycin C, 0.04%, three times per day for 1 week (11%). However, intraoperative application of 0.04% mitomycin C was found significantly more effective than 2160 cGy radiation.154 Singh and co-workers,155 using 0.04% and 0.1% solutions of mitomycin after pterygium surgery, also found the drug effective. However, the 1% solution caused some epithelial breakdown, irritation and lacrimation. Mitomycin C 0.02%, applied for 5 minutes on a sponge, and leaving the sclera bare provided a significantly lower recurrence rate, 4%, than removal using only a bare sclera, 46.7%.156 Using a conjunctival autograph was just as effective as drops of 0.02% mitomycin C, twice daily for 5 days in preventing recurrence.157 Applying mitomycin C intraoperatively seems to be as effective as using drops postoperatively.158,159
In cases of recurrent pterygia, treatment after tumor excision with either a conjunctival autograft or a sponge containing 0.02% mitomycin C for 3 minutes, provided similar recurrence rates.160
Intraoperative application and postoperative eye drops of mitomycin C after pterygium removal have been associated with severe scleral melting.161–163
Topical mitomycin C, 0.02% and 0.04%, four times daily for 7 to 28 days has been used successfully to treat corneal-conjunctival intraepithelial neoplasia and partially excised conjunctival squamous cell carcinoma. Multiple retreatments are often required and, even then, some patients had regrowth.164–167
Topical mitomycin drops have been used to treat acquired conjunctival melanosis and conjunctival melanomas.168–170 Multiple courses may be required. As expected, melanosis tended to respond better than melanomas; nodular melanomas were resistant to therapy. Secondary conjunctival epithelial microscopic changes after the topical use of mitomycin C for acquired conjunctival malanosis include nuclear enlargement and chromatin smudging-hyperchromasia;171 these superficial changes should not be confused with recurrence of atypical melanocytes but could be confused with recurrence of intraepithelial neoplasia.
The success rate of dacryocystorhinostomy is high, approximately 90%. Application of 0.02% mitomycin C to the osteotomy site for 30 minutes has resulted in larger openings and an even higher success rate.172 Simply probing the nasolacrimal duct and then irrigating with three applications of 1 ML 0.02% mitomycin successfully treated 25% of patients with epiphora; another 47% had had moderate relief.173
While drops of mitomycin C have not been effective in treating subepithelial fibrosis occurring after refractive corneal surgery, single 2-minute sponge applications of 0.02% to the debrided surface have controlled this condition.174 Other uses of mitomycin C have been to control progressive conjunctival scarring in ocular pemphigoid by using subconjunctival injections and to prevent the reformation of lysed conjunctival adhesions by using a topical 0.04% solution for 3 to 5 minutes.175,176
Glaucoma filtration surgery failures are often due to post-operative scarring. Mitomycin C has been effective in increasing the success rate. Part of its efficacy may be caused by reduced fibroblast migration. Cultures of human Tenon's capsule fibroblasts showed significantly reduced motility for up to 48 days after 5 minutes of exposure to mitomycin C; 5-fluorouracil seemed even more effective.177
When a sponge soaked with 0.05% mitomycin C was placed on the trabeculectomy bed for 0.5 to 1 minute, the intraocular hypotensive effect at 30 to 36 months postoperative was similar to that achieved with a 3- to 5-minute application and was significantly better than placebo.178 A 2-minute application of 0.02% mitomycin C was as effective as a 5-minute exposure but the complication rates were the same.179 At 2 years, a 5-minute application of 0.05% mitomycin C was associated with a 78% reduction in intraocular pressure and with the need for fewer medications, but there was a 2.2% incidence of bacterial endophthalmitis and a 4.5% incidence of revision-requiring hypotony.180
Mitomycin 0.04%, held in the scleral bed for 5 minutes produced similar lens and corneal endothelial cell changes as injecting a total of 50 to 80 mg of fluorouracil subconjunctivally for a 3-week period: 27% in both groups had evidence of cataract progression and there was a 7% to 8% reduction in endothelial cells.181 Macular folds associated with hypotony occurred in 6.4% of patients in each treatment group using 0.02% mitomycin for 2 minutes, 0.02% mitomycin for 4 minutes, or 0.04% mitomycin for 2 minutes; the visual acuity recovered fully in one-third of these patients.182 In a study of 123 trabeculectomy eyes in which mitomycin C had been used 5 years previously, the mean preoperative intraocular pressure had been 25.8 mm Hg and at 5 years postoperative was 9.9 mm Hg.183 The incidence of hypotony maculopathy was 8.9%, of bleb leak was 14.6%, of bleb infection was 5.7%, and of endophthalmitis was 0.8%. Cataract surgery was performed in 55.3% of the eyes during the follow-up period. Repeat trabeculectomy for bleb failure was performed in 4.9% of eyes and trabeculectomy revision, primarily to increase filtration, was performed in 8.9% of eyes.
Using human donor eyes, it was shown that irrigation after applying mitomycin C reduced the superficial scleral concentration by approximately 50% but left the deep intrascleral concentration unchanged.184 The deeper sclera could act as a drug reservoir. This might contribute to both the efficacy and toxicity/side effects of the drug. To reduce the latter, mitomycin has been applied postoperatively to the filtering bleb only. Sponges with 0.005% mitomycin C were placed on the filter bleb for 5 minutes each on days 1, 2, and 3 postoperatively.185 The technique appeared equally effective to intraoperative application and the complication incidence was lower when evaluated at 1 year postoperatively.186
Intraoperative application of mitomycin C has been studied in several glaucoma subgroups:
A different type of filtering procedure is the optic nerve sheath fenestration used for treating the elevated cerebral spinal fluid pressure causing pseudotumor cerebri. Scarring down of the incisional opening is a common cause of failure. Six patients had their optic nerve sheaths treated for 5 minutes with mitomycin C, 0.05%, before the incision was made through this dural tissue.200 In 4 patients the procedure was successful. The fifth patient required a neurosurgical shunt and the sixth required a repeat sheath fenestration. There were no toxicities or side effects that could be attributed to the use of mitomycin.
Cyclosporin A is a fungal metabolite with potent immunosuppressant activity and relatively little bone marrow toxicity. It has markedly improved the success of organ transplantation, especially renal transplantation. Cyclosporine is a cyclic polypeptide consisting of 11 amino acids.201 It has several unusual structural features, which include having a D-alanine, rather than the usual L-form, and having seven N-methylated amino acids. This latter may contribute to its resistance to gastrointestinal degradation, allowing the drug to be given orally. Cyclosporine has about 30% bioavailability, but there is marked interindividual variability. 202 Newer formulations of cyclosporine with better bioavailability have been developed, as have more potent and/or less toxic fungal metabolites, e.g., tacrolimus and cyclosporine G. 203–206
Cyclosporine specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during the first 24 hours of antigenic exposure. It is much more effective in preventing the primary immune response than in preventing the secondary response by the sensitized cytotoxic lymphocytes. Cyclosporine interferes with the ability of helper T cells to induce a cellular immune response to an antigen. The drug inhibits interleukin II production, a factor necessary for the induction of cytotoxic T-lymphocyte proliferation.207–209 Other cyclosporine effects are the reduction in prostacyclin synthesis and the competition with prolactin for a common binding site on the surface of the T-lymphocytes.210,211
Cyclosporine is extensively metabolized by cytochrome P–450 liver microsomal enzymes. Most of the drug is excreted by the gastrointestinal tract even after intravenous administration. Oral doses of the drug for organ transplant patients usually range from 10 to 50 mg/kg per day. Monitoring the blood level of cyclosporine provides optimum management of dosage.
The most important toxicity produced by cyclosporin A is to the kidneys. Awareness of this problem has resulted in use of lower doses and more rapid tapering. In a retrospective analysis of 1663 renal transplant recipients with median follow-up of 3 years, there was little evidence of progressive toxic nephropathy from cyclosporine use.212 A potentially lethal form of lymphoma, associated with Epstein-Barr viral infection, is reversible if the drug is stopped.213Although immunosuppressive agents, in general, are associated with an increase incidence of lymphomas, there is no evidence that cyclosporine treatment poses a greater risk than the other drugs.214
Cyclosporin, 2% in olive oil, was given to one eye of 30 normal volunteers, two drops every 6 hours for 12 applications. Aqueous humor levels were assayed from different groups of five subjects over a 12-hour period after the last drop. The maximum aqueous humor level occurred at 4 hours with a mean ± standard deviation (SD) value of 24 ± 9 μg/ML.215 In seven patients reeiving oral cyclosporin A after keratoplasty, the blood levels of unmetabolized and metabolized drug were, respectively, 100 to 150 nanograms and 100 to 702 nanograms per ML blood. The corresponding aqueous humor levels ranged from 58 to 540 nanograms per ML. 216
A number of rabbit studies have shown that cyclosporin A, applied topically,217–221 injected retrobulbarly,222 or given systemically by intramuscular injection,223–225 prolonged the survival of corneal grafts and/or reduced the incidence of graft rejection. Topical cyclosporine has been used to treat 11 high-risk corneal transplant patients, i.e., those having previous graft failures, large areas of deep stromal vascularization, or previous severe alkali burns.226 Cyclosporin A, 2% in olive oil, was administered every 2 hours while awake beginning 1 to 2 days before surgery. After 4 days of treatment, cyclosporine drop frequency was reduced to four times per day for 3 months; topical corticosteroids were also given. Ten of the 11 patients had clear corneas during the follow-up periods that ranged from 6 to 24 months. Good results have been reported for treating corneal graft rejections refractory to corticosteroid therapy.227 Cyclosporine A 0.5% was instilled 4 to 6 times per day in 16 eyes. Nine eyes were cured within 11 weeks, and six other eyes were much improved and one eye failed to respond. Hill228 compared the results in high-risk corneal transplant patients treated with corticosteroids to those given corticosteroids plus systemic cyclosporine. The initial cyclosporine dose, 15 mg/kg per day, was given intravenously at surgery and the next day followed by 7.5 mg/kg per day for 2 days. The dose was then adjusted to maintain a level of 250 to 400 nanograms/ML whole blood; this usually required 4 to 4.5 mg/kg per day. Treatment was initially for a year, but the results appeared as good when maintained only 4 months. The use of systemic cyclosporine significantly improved the results of surgery. Of the 18 patients treated, one rejection occurred 13 months after transplantation (1 month after a complete course of treatment); one occurred 3 months after transplantation (2 months after discontinuing treatment because of an allergic reaction to cyclosporine); and three additional grafts had transient but successfully treated rejection episodes. Eighty-nine percent of the cyclosporine-plus-corticosteroid treated corneas were surviving at a mean length of 21.6 months (range 12 to 49 months) after surgery. The same author reported a subsequent series of high-risk keratoplasty patients who benefited from systemic cyclosporine. However, keratolimbal allografts had a poor 2-year survival rate despite use of topical and systemic cyclosporine.229 Others have failed to find sufficient benefit, compared to corticosteroid treatment230–232 alone to justify the potential toxicity and cost of cyclosporine treatment.
Oral cyclosporine has been used, with apparent efficacy, to treat corneal melting syndromes such as Mooren's ulcer, and those associated with rheumatoid arthritis and Wegener's granulomatosis.233–237 Cyclosporin A, e.g., 2.5 mg per kg per day, was used in conjunction with corticosteroids. Successful treatment using topical 2% cyclosporin A has been reported in rheumatoid corneal ulcerations.238
Conjunctiva from atopic eyes before and after 3 months of treatment with topical 2% cyclosporin A drops or placebo demonstrated significant drug effects: the total number of leukocytes, CD3+T cells, CD4+ cells, CD8+ cells, CD20+B cells, neutrophils, and macrophages were reduced.239 Topical cyclosporin A, 2% drops and 4% ointment, has been used with good results in ligneous conjunctivitis and vernal conjunctivitis.240,241 However, in vernal conjunctivitis, symptoms usually rapidly recurred when treatment was stopped.
Topical and systemic administration of cyclosporine improved the subjective symptoms of patients with dry eyes, but has not consistently improved their lacrimation as measured using the Schirmer's test.242,243 Treatment increased the number of goblet cells and reduced the conjunctival epithelium turnover rate.244 When lacrimal fluid production was measured in seven kidney transplant patients, it did increase during systemic cyclosporin A treatment.245 Before cyclosporine treatment, the mean ±standard error tear production was 19.4±1.5 mm of Schirmer strip wetting per 4 minutes. After 1 to 2 months of cyclosporine treatment, the tear production was 28.4±2.4 mm per 4 minutes (p<0.01) and after 9 to 18 months of treatment the tear production was 24.4±2.1 mm per 4 minutes (p<0.05). Cyclosporine 0.05% topically is of more limited value in increasing tear fluid production. Only 15% of approximately 1200 patients treated 6 months twice per day showed an increase in Schirmer wetting. No significant improvement was found in those patients simultaneously using topical antiinflammatory drugs or using punctal plugs, suggesting these other modalities were as effective. Using this twice per day eye drop regimen, blood levels of cyclosporin A were below the detection level of 0.1 ng/ML. There were no increased incidences of bacterial or yeast infections.246 Ocular burning occurred in 17% of patients. Conjunctival hyperemia, epiphora or foreign body sensation occurred in 1% to 5% of patients. Similar application of 0.1% cyclosporin A eye drops resulted in 5.5% (7 of 128) of patients having resultant blood levels of 0.1 ng/ML or higher; none of the blood levels exceeded 0.3 ng/ML.247
Cyclosporin A, administered systemically, has been effective in reducing the severity of uveitis in experimental animals.248–252 Aqueous humor and cerebrospinal fluid samples were obtained 6 and 24 hours, respectively, after the last ingestion of oral cyclosporin A in patients with mild uveitis. The frequencies and doses of the drug were not stated. The mean aqueous humor cyclosporine concentration, 44 ng/ML, was 40% ± 24% (mean ± SD) that of the plasma level.253 Cyclosporine was not detectable in the cerebrospinal fluid; the limit of sensitivity of the assay method was not stated.
Cyclosporine can be effective in patients with posterior uveitic diseases who are resistant to corticosteroid treatment. Behçet's disease, idiopathic uveitis, pars planitis, sarcoidosis, sympathetic ophthalmia, birdshot chorioretinopathy, and Vogt-Koyanaga-Harada syndrome have all been treated successfully.254–259 The initial dose was 10 mg/kg per day, which was then titrated according to clinical response or to a protocol. Some patients required a maintenance dose of 15 mg/kg per day,255 whereas others only needed 2 mg/kg per day.256 Patients were evaluated by visual acuity, fluorescein angiogram, and a subjective estimation of the severity of inflammation. In general, visual acuity improved within the first 2 weeks. Although the uveitis of Behçet's disease was better controlled by cyclosporine, systemic symptoms, such as skin lesions and arthritis, were not.257 Control of uveitis was maintained for prolonged periods (years). A small number of patients could eventually be weaned away from the drug without experiencing recurrences. BenEzra and co-workers258 reported that prolonged discontinuation of cyclosporine was possible in four of 24 patients. A patient with coexisting multiple sclerosis not only had her uveitis improve but also had her neurologic status improve, including P100 latency on visual evoked response testing; as multiple sclerosis, like uveitis, waxes and wanes spontaneously, the patient's neurologic improvement could not be attributed with certainty to cyclosporine.260
Optimum control of inflammation, while maintaining stable renal function, was achieved for a mean ±standard deviation of 16±10 months in a group of 8 patients with bilateral steroid-resistant azathioprine-resistant uveitis by adjusting the cyclosporine blood level 6 hours after the morning dose to 150 to 250 nanograms per ML. The mean dose was 3.9±1.4 mg/kg per day.261
Cyclosporin A has been reported to suppress idiopathic orbital inflammatory pseudotumor in a diabetic patient who could not tolerate corticosteroids.262 She was begun on 5 mg/kg per day and maintained for 10 months on 2 mg/kg per day. When the drug was discontinued her symptoms returned and she was treated with 2000 cGy. Proptosis in thyroid ophthalmopathy has also responded to cyclosporine, as well as extraocular muscle swelling and dysfunction.263–266 Initial doses of cyclosporine varied from 3 to 10 mg/kg per day. However, not all patients improved, which might have been the result of permanent fibrotic changes that occurred prior to initiating therapy.267–269
It was hoped that the toxicity of cyclosporine would be qualitatively different in patients not as ill and debilitated as those requiring major organ, e.g., kidney and liver, transplantation. Unfortunately, this does not seem to be the case. Renal toxicity remains a major problem with higher doses and prolonged usage.270 Palestine and co-workers271 reported nephrotoxicity in eight of 26 patients treated more than 1 month for uveitis. In these eight patients, the creatinines rose by more than 1.6 mg/dL in males and 1.3 mg/dL in females. Reduction in the dose of cyclosporine normalized the renal function in 3 to 4 weeks. However, Deray and co-workers272 reported only a partial return to normal values. Moreover, renal biopsy of patients receiving cyclosporine for an average of 2 years showed interstitial fibrosis and/ or tubular atrophy even in those with normal renal function.273 Other cyclosporine side effects have included hepatotoxicity, hypomagnesemia, hirsutism, gingivitis, and dysesthesias. Central nervous system symptoms and findings associated with cyclosporine have been visual hallucinations, transient cortical blindness, disc edema, and occipital lobe seizures.274–277 It may be that some of these effects were caused by graft-versus-host-disease after bone marrow transplantation when inadequate levels of cyclosporine were being used. The acute form of graft-versus-host-disease develops 3 to 4 weeks after bone marrow transplantation and in up to 80% of patients; it is characterized by hepatic dysfunction and skin and muscle changes. The chronic form, developing 3 to 6 months after bone marrow transplantation and in up to 50% of patients may, in addition, cause corneal epithelial defects, corneal melting, retinal cotton wool spots and hemorrhages, and optic disc edema.278,279
Tacrolimus, like cyclosporin, is a macrolide immunosuppressant produced by a fungus. It is much more potent and no more toxic than cyclosporine. The drug has at least two actions. It inhibits T-lymphocyte activation possibly by limiting interleukin-2 gene expression in T-helper lymphocytes. In addition, tacrolimus binds to the steroid receptor-associated heat-shock protein 56, which results in transcription inhibition of proinflammatory cytokine formation including granulocyte-macrophage colony-stimulating factor, interleukins-1, 3, 4, 5, 6, and 8, and tumor necrosis factor alpha. Bioavailability after oral administration is variable, between 5% and 65%, and can be reduced depending on the type of food ingested. Approximately 99% of the absorbed drug is metabolized by the liver. Systemic administration is associated with increased incidences of nephrotoxicity, neurotoxicity (hallucinations, tremors, confusion, and seizures) and new-onset diabetes. Tacrolimus is available in oral, injectable, and topical preparations. Oral capsules contain 1 mg or 5 mg tacrolimus. The injectable form contains 5 mg per ML. For adults, 0.03% and 0.1% ointments are available, and for children a 0.03% ointment is available.
Topical tacrolimus 0.03%, twice per day to each eye lid, has been used successfully in a small number of adult subjects, ages 44 to 62 years, with atopic blepharitis refractory to topical corticosteroid treatment.280 Eyelid erythema and eczema were substantially reduced in 1 to 3 weeks. Patients were able to discontinue topical corticosteroid use. No adverse effects were noticed after continuous treatment for 5 to 14 months.
Systemic tacrolimus, 2 to 12 milligrams per day, has been successfully used for periods of 12 to 46 months to prevent corneal and limbal epithelial allograft rejections.281 Trough levels of 10 to 20 nanograms tacrolimus per ML of blood have been sufficient to control ocular surface breakdown in graft-versus-host disease282 resistant to cyclosporine treatment. Six patients with posterior ocular inflammatory disease were treated by using trough levels of 1 to 15 nanograms tacrolimus per ML blood.283 Three patients had Behcet's uveitis, one had pars planitis, and two had retinal vasculitis. Four of the patients had not responded adequately to cyclosporine and prednisolone therapies and two of the patients had demonstrated cyslosporine toxicity. The ocular uveitis and vasculitis were adequately controlled while on tacrolimus. Duration of treatment was from 4 to 23 months.
Etoposide is derived from podophyllotoxin. Its mechanism of action is unknown. It is a topoisomerase II inhibitor that inhibits DNA synthesis premitosis, with maximum effects during the S and G2 phases of cell division. It can be administered orally or parenterally. More of the drug is renal excreted than is gastrointestinal excreted. Etoposide produces anemia, leukopenia, and thrombocytopenia.
Etoposide has been used with irradiation and in combination with vincristine and ifosfamide to treat rhabdomyosarcoma of the orbit. It has been in combination with vincristine and carboplatin in the treatment of retinoblastoma.284
Dapsone, a sulfone, is effective in suppressing mucocutaneous bullous eruptions. Its mechanism of action is unknown. IgA levels and complement deposition are not affected. The drug has been successfully used in mild to moderate ocular cicatricial pemphigoid.285 Its chief unwanted side effect is hemolytic anemia. Azulfidine, a precursor of sulfapyridine, and sulfapyridine have also been shown to be similarly effective.286,287 Azulfidine use was associated with hemolytic anemia in two of nine patients; this problem did not occur in any of the 20 patients taking sulfapyridine.
The naturally occurring interferons are cytokines with immunoregulatory, antiviral, antitumor and cell growth regulatory functions. There are three subtypes: alpha, beta, and gamma interferons. Two beta recombinant products that are available are interferon beta-1a and interferon beta-1b. Their 161 amino acid structures differ in only two ways: interferon beta-1a is glycosylated at amino acid 80 and they have one different amino acid. Both have little tendency to stimulate antibody production against them because they are so similar to the natural occurring beta interferon. However, large doses and frequent use can cause an immune response.
These beta interferons are available for the treatment of multiple sclerosis. The published studies defining their value do not separate out their effectiveness in preventing recurrent optic neuritis. However, in one major study, 50% of the subjects presented with optic neuritis and two or more “clinically silent” brain MRI lesions.288,289 Interferon beta-1a was begun after initial treatment with intravenous methylprednisolone (1 gram per day for 3 days) followed by oral prednisone (1 mg per kg for 11 days and then tapering doses on days 12 to 14). After the intravenous methylprednisolone, weekly intramuscular injections of interferon beta-1a were begun, using 30 micrograms or placebo. During the 3-year follow-up, the group treated with interferon beta-1a had a significantly lower probability of developing clinically definite multiple sclerosis and a higher probability of reductions in the volume of MRI identified brain lesions and the number of new and enlarging lesions. However, the majority of patients treated with interferon beta-1a developed evidence of progressive disease within 3 years. The evidence of clinically definite multiple sclerosis was 28% in interferon-treated patients and 37% in placebo-treated patients; an additional 33% and 38% of treated and placebo patients, respectively, had MRI evidence of progression.
The progressive course of multiple sclerosis has generally been divided into five types: relapsing-remitting, primary progressive, secondary progressive, progressive-relapsing, and acute rapidly progressive.290 Treatment for 4 years of relapsing-remitting multiple sclerosis, defined as existing in patients demonstrating at least two relapses in the previous 2 years, demonstrated that interferon beta-1a therapy was associated with a reduction in new relapses and MRI lesions.291 However, in a 3-year study of secondary progressive multiple sclerosis, interferon beta-1a did not significantly alter disability progression.292 In patients receiving three times per week doses of interferon beta-1a of 22 micrograms and 44 micrograms, the incidences of neutralizing antibodies over a 4-year period were, respectively, 23.7% and 14.3%; presence of neutralizing antibodies was associated with a reduced therapeutic response.
Interferon alphas are available in two forms, 2a and 2b. Topical alpha interferon was of no value in reducing viral shedding or the clinical duration of adenovirus conjunctivitis.293 Subconjunctival injections of interferon alpha in four of five patients with conjunctival lymphomas provided complete resolution for the 12- to 36-month follow-up periods.294 Subconjunctival and perilesional injections of interferon alpha-2b produced complete clinical resolution of intraepithelial neoplasia in five patients with this sqamous cell carcinoma-precursor condition. However, the follow-up range was only 2 to 11 months.295 Case reports of only one or two patients have indicated success in treating conjunctival papillomata (topical treatment), Mooren's ulcer associated with hepatitis-C (systemic treatment) renal cell carcinoma metastatic to the iris (systemic treatment) and orbital hemangioma (systemic treatment).296–299 The majority of patients weith choroidal neovascular membranes causing macular degeneration failed to show any antiangiogenic benefit from systemic administration of interferon alpha-2A.300–303 However, antibodies to interferon alpha-2A have been detected in 24 of 34 (71%) of patients receiving the drug, which may explain the poor results.304
The primary adverse side effect with interferon treatment has been a flu-like syndrome, but leukopenia, fever, and nausea also can develop.
Mycophenolate mofetil is an orally administered drug which is de-esterified to its active metabiolite, mycophenolic acid, a noncompetitive reversible inhibitor of inosine monophosphate dehydrogenase. This inhibits synthesis of purine nucleotides and DNA resulting in reduced T and B cell proliferation. The drug also inhibits B lymphocyte formation of antibody. Mycophenolate mofetil, in doses of 2 grams per day, was effective in controlling refractory uveitis in 18 of 20 patients encompassing two studies. The doses of corticosteroids and cyclosporine could frequently be reduced.305,306 Side effects were generally mild.
In a prospective randomized trial of keratoplasty patients considered at high risk for failing, 21 patients received mycophenolate mofetil, 2 grams per day, and corticosteroids. Another 20 patients received cyclosporin A, in doses achieving whole blood trough levels of 120 to 150 nanograms per ML, and corticosteroids. Mycophenolate mofetil and cyclosporin A were equally effective; two patients in each subgroup showed signs of graft rejection within the first 6 postoperative months.307
Antitumor Necrosis Factor Antibodies
Tumor necrosis factors alpha and beta (the latter also, confusingly, referred to as lymphotoxin alpha) are cytokines produced by macrophages and T-cell lymphocytes. Both of these tumor necrosis factors react with two different receptors on cell surfaces. Etanercept is a soluble form of one of the receptors. It binds to both types of tumor necrosis factors, rendering them inactive. Etanercept is of proven value in treating active rheumatoid arthritis. A side effect is an increased incidence of infections and its use should be discontinued if one develops or if there is an exposure to Herpes zoster. Infliximab is a monoclonal antibody that binds specifically to tumor necrosis factor alpha but not to tumor necrosis factor beta. Infliximab is of proven efficacy in treating active rheumatoid arthritis and active Crohn's disease. Use of the antitumor necrosis factor therapies may result in antibody formation. Rarely does this antibody cause a lupus-like autoimmune syndrome.
In a masked randomized prospective study of 20 uveitis patients controlled with methrotrexate, half were treated with etanercept, 25 mg subcutaneously twice weekly and half placebo.308 Methrotrexate taper was begun 2 weeks after the first injection. Two patients prematurely left the etanercept group for reasons unrelated to the drug's effects. Three of eight patients in the entanercept group and five of 10 patients in the placebo group had relapses of their uveitis. There was no significant benefit to using etanercept.
In a prospective but uncontrolled study of seven patients with acute onset HLA—B27-associated anterior uveitis, a single dose of infliximab seemed of value in controlling the inflammation.309 A single case report of an 18 year old with Behcet's disease uveitis uncontrolled with systemic corticosteroids stated that infliximab 5 mg/kg intravenously at weeks 0, 2, 4, and 8 was associated with a complete remission not only of the uveitis but also of all systemic findings by the time of the second injection.310 The remission was maintained for up to 8 weeks after the last injection.
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