Antimitotic and Immunosuppressive Chemotherapy
Brian K. Do
Alan H. Friedman
Joel S. Mindel
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 primarily one by one, but special attention will be paid to chemotherapeutic regimens used in the treatment of retinoblastoma, which often consist of multiple drugs.
With regard to the use of these antimitotic and immunosuppressive agents in inflammation, 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. Further, immunosuppressive agents may cause oncogenesis1, 2 and can promote the growth and spread of malignancies. For example, Andrasch and coworkers unknowingly treated a 78-year-old patient with lymphoma cells in the vitreous for “uveitis.”3, 4 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 CNS.5 Intrathecal methotrexate, 0.25 to 0.50 mg per 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 coworkers6 stated that initially they used methotrexate to treat orbital rhabdomyosarcoma, but ultimately preferred a combination of other drugs.
A patient with vitreous and spinal fluid involvement by non-Hodgkin lymphoma was treated with a single course of intravenous methotrexate 1.5 g per m2 bolus over 1 hour followed by 300 mg/m2/hour over 24 hours for a total of 8.4 g in the 24-hour period.7 Seven and 74 hours after initiation of treatment, the respective anterior chamber, serum, and spinal fluid levels of methotrexate were 55.7, 219, and 2.5 µmol per L and 1.2, 0.5, and 0.2 µmol per L. The minimal methotrexate tumoricidal level is 1 µmol per L. Methotrexate 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 methotrexate has been used to avoid the need for radiation therapy of intraocular lymphoma cells.8 Methotrexate, 400 µg in 0.1 mL, was injected intravitreally.9 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 methotrexate 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 Hersh10 gave methotrexate, 25 mg per m2, to patients with pars planitis. 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 planitis11 and in subjects with sympathetic ophthalmia.12, 13 and 14 A prolonged remission occurred in a patient with orbital pseudotumor.14 Lazar and coworkers,14 using a similar dose regimen, reported successes in uveitis patients with sarcoidosis, juvenile rheumatoid arthritis, and uveitis of unknown origin. A patient with presumed toxoplasmosis uveitis, however, did not improve. Owen and Cohen15 treated three severe cases of reactive arthritis successfully by giving methotrexate, 0.3 mg per kg, 1 day every week; one of the patients could not be tapered off the drug, however. The progression of bilateral Mooren ulcers was arrested using 6- to 8-week courses of intravenous methotrexate, 25 or 50 mg per week.11, 16
improvements followed by relapses were reported in additional subjects with pars planitis11 and in subjects with sympathetic ophthalmia.12, 13 and 14 A prolonged remission occurred in a patient with orbital pseudotumor.14 Lazar and coworkers,14 using a similar dose regimen, reported successes in uveitis patients with sarcoidosis, juvenile rheumatoid arthritis, and uveitis of unknown origin. A patient with presumed toxoplasmosis uveitis, however, did not improve. Owen and Cohen15 treated three severe cases of reactive arthritis successfully by giving methotrexate, 0.3 mg per kg, 1 day every week; one of the patients could not be tapered off the drug, however. The progression of bilateral Mooren ulcers was arrested using 6- to 8-week courses of intravenous methotrexate, 25 or 50 mg per week.11, 16
Toxicities were frequent. Wong12 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). 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 coworkers14 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 4,000 per mm3 or in their platelet count below 100,000 per mm3. Chemical, but not symptomatic, evidence of liver disease was found in 4 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.
Methotrexate has been used to replace corticosteroids in treatments in which corticosteroid side effects might prevent continued therapy. For example, oral methotrexate appeared to allow reduction of corticosteroid dosage in three patients with sarcoid-associated optic neuropathy.17 Methotrexate, in doses less than 20 mg per week, does not appear to affect bone density.18, 19 The two ocular-involving diseases in which methotrexate 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 methotrexate was an effective substitute that allowed reduced corticosteroid dosage when treating temporal arteritis.20, 21 However, two other prospective, randomized, masked, and placebo-controlled studies, one of which was multicentered, provided evidence that methotrexate treatment did not reduce the cumulative corticosteroid dose needed, nor did it reduce the treatment-related corticosteroid side effects in temporal arteritis.22, 23 These conflicting results are difficult to resolve.
Pyrimidine Analogs
Fluorouracil (5-FU) is converted intracellularly to fluorodeoxyuracil monophosphate. Fluorouracil monophosphate is an inhibitor of thymidylate synthetase and, hence, of DNA synthesis. 5-FU 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 5-FU.
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.24 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 that 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.25 However, another case has been reported that 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.26 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%).27 The authors concluded that 5-FU, at this concentration, was ineffective.
Abramson and coworkers6 treated rhabdomyosarcoma of the orbit with 5-FU but found other agents superior.
Pyrimidine analogs have been investigated as treatments for ocular disorders in which nontumor cellular
proliferations occur. Examples of such conditions are proliferative vitreoretinopathy (PVR) and postoperative subconjunctival fibrosis. While some studies have looked at other drugs, for example, cytosine arabinoside (Ara-C),28 the major focus has been on 5-FU.
proliferations occur. Examples of such conditions are proliferative vitreoretinopathy (PVR) and postoperative subconjunctival fibrosis. While some studies have looked at other drugs, for example, cytosine arabinoside (Ara-C),28 the major focus has been on 5-FU.
5-FU has been injected into the anterior chamber to treat a retrocorneal downgrowth following corneal transplantation.29 Two injections of viscoelastic 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.30 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 downgrowth onto the corneal endothelium in an aphakic eye using two anterior chamber injections of 0.5 mg of 5-FU.31 The injections were separated by 2 weeks.
5-FU mitigated PVR by dual action: reduced cell mitosis and reduced membrane contractility.32 Rabbits had an intraocular injection of cultured retinal pigment epithelial (RPE) cells followed by intravitreal 5-FU, 0.5 mg per day for 1 week. The incidence of retinal detachment 2 weeks after cell injection was significantly less in 5-FUtreated eyes (6 of 14 eyes) than in control eyes (12 of 12 eyes).33 The drug also decreased the proliferation of human RPE cells in vitro.34 5-FU 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.35 In an uncontrolled study,36 patients with advanced PVR were treated with surgery plus various combinations of multiple subconjunctival injections of 5-FU, 10 mg and intravitreal 5-FU, 1 mg. At 6 months, 60% of the retinas remained attached, an incidence of success somewhat higher than the surgeons would have expected if 5-FU had not been used. In a prospective, masked, randomized placebo-controlled study of 174 patients, vitrectomy infusion fluid containing 5-FU, 0.2 mg per mL plus low-molecular-weight heparin 5 IU per mL significantly reduced the incidence of postoperative PVR, 12.6% versus 26.4% in the group receiving placebo.37 There were no differences in the incidences of postoperative hyphemas and complication rates.
The retinal toxicity of 5-FU has been investigated in rabbit eyes.38 There was no alteration of the b-wave amplitude of the electroretinogram (ERG) until vitreous cavity concentrations were maintained at 0.1 mg per mL for 1 hour. Injecting 0.5 mg of 5-FU every 24 hours for 7 days in vitrectomized eyes reduced pigment epithelial cell mitosis, but did not alter retinal histology or the ERG response.39 If 1.25 mg 5-FU were injected daily for 1 week, both photoreceptor histology and ERG response were markedly altered with partial recovery after 5 weeks. Little intravitreal 5-FU 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).40
5-FU 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 per mL.41 Single subconjunctival injections of 5 mg 5-FU maintained rabbit corneal, conjunctival, and scleral drug levels above this 50% inhibitory level for at least 24 hours.42 Eye drops of 5-FU appeared considerably more toxic to rabbit corneal epithelium than were subconjunctival injections.43, 44
Several small nonrandomized45, 46 and randomized47 studies of patients suggested that postoperative subconjunctival injections of 5-FU improved the results of filtering surgery except in the presence of neovascular glaucoma.48 The major complications of therapy were conjunctival wound leaks, corneal epithelial defects, and suprachoroidal hemorrhages.49 A larger randomized study50 of 213 glaucoma patients who were followed up for 1 year after receiving subconjunctival 5-FU, 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 to be effective.51 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 < .001).52 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.53 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 posttrabeculectomy, for example, three doses of 5 mg each. These provided no significant benefit to the intraocular pressure reduction at 1 year.54
An alternative technique has used a soaked pledget to apply 5-FU to the scleral bed during trabeculectomy surgery.55, 56 and 57 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 per mL on a pledget for 5 minutes, to topical mitomycin C, 0.2 mg per mL on a pledget for 2 minutes.58 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.
Purine Analogs
Mercaptopurine
Wirostko and Halbert59 produced uveitis in rabbits by injecting bovine serum albumin intravitreally. A marked inflammation occurred in 5 to 9 days. Serum antibodies to albumin were detectable within 9 days. When mercaptopurine, 5 mg/kg/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 and steady increase in antibody levels occurred.
Mercaptopurine has been used, in daily doses of 2 to 2.7 mg per kg for 8 to 35 days, to treat pars planitis, idiopathic uveitis, sympathetic ophthalmitis, and acute histoplasmosis chorioretinitis.60 In most, but not all, patients there was 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.
Azathioprine
This drug is a derivative of mercaptopurine and slowly releases free mercaptopurine after it is administered. As a result, toxicity is reduced.
Rabbits61, 62 and 63 had delayed healing of penetrating corneal incisions when given azathioprine, 48 mg per 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 per kg, was given every other day from the time of surgery through postoperative day 10 and if topical methylprednisolone, 0.1% ointment, twice per day, was 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 1 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 coworkers64 found that azathioprine, 20 mg/kg/day, delayed rabbit graft rejections, but that 10 mg per kg did not. However, maintenance on 5 mg/kg/day azathioprine plus 0.5 mg/kg/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 coworkers65 treated five patients with Graves disease who had positive assays for long-acting thyroid-stimulating protein (LATS). Azathioprine, 2 mg/kg/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.66
A 2-year randomized, placebo-controlled masked study demonstrated that azathioprine, 2.5 mg/kg/day reduced the incidence of uveitis and hypopyon in patients with Behçet syndrome.67 Scleritis and uveitis from rheumatoid arthritis, Wegener granulomatosis, herpes zoster, Vogt-Koyanagi-Harada syndrome, pars planitis, and sympathetic ophthalmia have been successfully treated with combinations of azathioprine and systemic corticosteroids.68, 69, 70, 71 and 72 Not all patients responded. Initial doses ranged from 1.5 to 3.0 mg/kg/day azathioprine followed by maintenance doses of 1.0 to 1.5 mg/kg/day. Some investigators did not administer the drug on a body-weight basis but instead used fixed doses of 50 to 200 mg per 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.72 Andrasch and coworkers4 stated that in 10 of 22 patients begun on azathioprine, adverse side effects, or poor therapeutic responses
necessitated a change to chlorambucil. 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/day azathioprine.68 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, 5 of 18 patients initially treated with cyclophosphamide had azathioprine either substituted or added to their regimen73 because of cyclophosphamide intolerance or ineffectiveness. However, azathioprine was not tolerated or was ineffective in four of them.
necessitated a change to chlorambucil. 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/day azathioprine.68 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, 5 of 18 patients initially treated with cyclophosphamide had azathioprine either substituted or added to their regimen73 because of cyclophosphamide intolerance or ineffectiveness. However, azathioprine was not tolerated or was ineffective in four of them.
Vinca Alkaloids
Vinblastine
Hahnenberger injected 100 µg vinblastine into the vitreous cavities of cats.74 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 Eakins75 found that topical vinblastine, 2 to 5 µg, lowered rabbit intraocular pressure for more than 24 hours without causing irritation or pupil constriction. However, several case reports indicate the potential for toxic ocular damage secondary to local exposure to vinblastine.76, 77 and 78 Findings included epithelial keratitis, dry eyes, and subepithelial corneal scars.
Twenty patients enucleated for primary ocular melanoma but without evidence of metastases were treated prophylactically with a five-drug combination chemotherapy.79 Nineteen were treated within 1 month after enucleation, and one patient was treated 1 year after enucleation. Intravenous vinblastine, 5 mg per m2 body surface, was one of the drugs used. With a median follow-up of 6 years, 17 patients, that is 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 retinoblastoma80 and orbital rhabdomyosarcoma6 in combination with cyclophosphamide. Vincristine, 2 mg per 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%.
Nonvinca Alkaloids
Colchicine
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.81, 82 However, its use has been associated with nonhealing corneal ulcers in a small number of patients.83 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.84
Beebe and coworkers85 reported that colchicine, 10-10 M, added to tissue cultures, prevented elongation and increased the volume of chicken lens cells. This concentration was too low to affect microtubular function, suggesting that colchicine had additional sites of action.
Hahnenberger74 injected 100 or 300 µg colchicine unilaterally into the vitreous cavities of cats. 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 beginning 8 hours after administration and reaching its peak at 24 hours. Intravenous colchicine, 1 mg per kg, did not, however, lower intraocular pressure. Lumicolchicine, an inactive isomer of colchicine, was ineffective topically.75
Mizushima and coworkers86 treated 157 patients with ocular involvement from Behçet disease with colchicine. Most received 0.5 mg twice per day for more than 1 year. Doses ranged from 0.5 to 1.5 mg per 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.
symptoms (nausea, gastritis, and diarrhea), oligospermia, amenorrhea, hair loss, and malaise.
Hijikata and Masuda87 divided 91 patients with Behçet disease into four therapy groups: group 1 received only cyclophosphamide, 50 to 100 mg per day; group 2 received only colchicine, 0.5 to 1.0 mg per day; group 3 received a combination of cyclophosphamide, 50 mg per day, plus colchicine, 0.5 mg per day; and group 4 received various combinations of systemic corticosteroids, nonsteroidal anti-inflammatory 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.
Alkylating Agents
Nitrogen Mustards
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.88 Unlike the other nitrogen mustards, cyclophosphamide does not cause severe CNS stimulation. Therefore, there is less nausea and vomiting, and convulsions, paralysis, and cholinomimetic side effects do not occur.
Mechlorethamine
McCarthy89 produced an anterior uveitis by injecting rabbits with live tubercle bacilli. The inflammation was partially inhibited if mechlorethamine, 8 to 16 mg, was given intravenously over the 10- to 12-day period after inoculation. This suggested the drug had a bacteriostatic effect.
Jampol and coworkers90 treated a single patient with corticosteroid-resistant rheumatoid sclerouveitis with a total dose 0.4 mg per kg mechlorethamine given over a period of 3 days. This patient could then be controlled with steroids for several months.
Chlorambucil
Abramson and coworkers6 initially used chlorambucil, in combination with radiation, to treat orbital rhabdomyosarcoma. They subsequently preferred using cyclophosphamide and vincristine.
Chlorambucil has been used successfully to control Behçet disease, rheumatoid scleritis and uveitis, orbital pseudotumor, sympathetic ophthalmitis, Vogt-Koyanagi-Harada syndrome, pars planitis, herpes zoster uveitis, and uveitis of unknown origin.91, 92, 93, 94, 95, 96, 97 and 98 Not all patients responded, however, and exacerbations were common when medication was tapered. Initial oral doses ranged from 0.1 to 0.2 mg per kg, or fixed doses of 5 to 24 mg per day were given in divided doses after meals. Godfrey and coworkers93 used an initial dose of 2 mg per day to determine whether idiosyncratic sensitivity was present. Doses were then increased by 2 mg per day each week, with as much as 22 mg per day being given. It should be noted that 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 per 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, and while some bone marrow depression was common (e.g., Godfrey and coworkers93 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 of chlorambucil has been in the treatment of Behçet disease. Mamo and Azzam91 controlled all 10 of their patients using chlorambucil for up to 17 months. In all but one patient, topical and systemic corticosteroids could be discontinued approximately 2 weeks after starting chlorambucil. Abdalla and Bahgat92 reported favorable results in seven patients with Behçet disease treated with chlorambucil and systemic corticosteroids. Two patients had chlorambucil discontinued for 3 weeks because their white blood cell counts fell below 3,500 per mm3. Godfrey and coworkers,93 Dinning and Perkins,94 and Mamo95 reported control in a total of 22 of 23 patients with Behçet disease. Tricoulis96 reported successes in five patients, two of whom had been unsuccessfully treated with azathioprine.
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 per day orally and was increased by 2 mg per 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.99
The enthusiasm for chlorambucil has been tempered by the demonstration that its use produced testicular atrophy100 and leukemia.101 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 per kg is given,102 and acute leukemia becomes rare if less than 1 g is given.103 This latter information in particular has altered the way in which the drug is prescribed.
Cyclophosphamide
Abramson and coworkers6 reported that treatment of orbital rhabdomyosarcoma with either irradiation alone (25 patients) or irradiation plus chemotherapy (33 patients) was effective. 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-FU, 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/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/day, was given orally for 7 days. From weeks 21 to 104, cyclophosphamide, 2.5 mg/kg/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/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.5, 80, 104 Wolff and coworkers5 used intrathecal cyclophosphamide, 4 to 8 mg per kg every other day for 8 days, to treat CNS spread of the disease; some slight prolongation of life may have occurred. Malik and coworkers105 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 coworkers106 in three patients with this disease. Varying degrees of success occurred in all three. Patient 1 was treated for a coexisting pelvic tumor with intravenous cyclophosphamide, 700 mg per mol, and doxorubicin, 500 mg per mol. 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 per 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 disk edema caused by thyroid ophthalmopathy. Within 3 months of beginning oral therapy with cyclophosphamide, 8.5 mg per day, the disk 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.
Cyclophosphamide has been successfully used in intraocular inflammations. Animal studies suggested that it preferentially reduced the number of B lymphocytes.107 Oh injected herpes simplex type 1 virus into rabbit eyes to produce uveitis.108, 109 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.110, 111 The 250-mg dose, calculated on a weight basis, was 5 mg/kg/day. Intravenous therapy with 1 g/m2/week has also been administered.12 Corticosteroids were usually given until the signs and symptoms remitted.90, 112, 113 Hijikata and Masuda87 used cyclophosphamide plus colchicine. The duration of therapy, using tapering medications, was for a minimum of 3 weeks. Hemorrhagic cystitis caused discontinuation of therapy in a patient treated for 2 years with 150 mg per day. Other toxicities included bone marrow suppression, nausea, diarrhea, hemorrhagic gastritis, alopecia, sterility, and cardiac toxicity. Kende and coworkers114 reported
temporary blurring of vision in 17% of children given large doses of cyclophosphamide. 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.
temporary blurring of vision in 17% of children given large doses of cyclophosphamide. 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 disease, rheumatoid sclerouveitis, uveitis associated with polyarteritis nodosa and systemic lupus erythematosus, ocular Wegener granulomatosis, and pyoderma gangrenosum scleritis.11, 12, 72, 87, 90, 110, 111, 112 and 113, 115 Not all cases responded. Those that did respond did so after days to weeks of therapy. Buckley and Gills110 treated five patients with presumed toxoplasmosis retinitis. The response was variable. In two patients, the inflammation decreased. Permanent remissions have been reported in patients with Wegener granulomatosis.90 The response of ocular cicatricial pemphigoid to cyclophosphamide was variable and difficult to assess because the disease itself did not always progress.116 However, the overall results seemed better in the treated groups. Chronic therapy with cyclophosphamide has been associated with chromosome damage,117 carcinoma of the bladder,118 and leukemia.119 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.120 Nine of 17 patients who were managed without immunosuppressive therapy died. Only 1 of 11 patients treated with cyclophosphamide died.
Ifosfamide
Ifosfamide 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. Administered parentally, the drug’s activation and subsequent degradation take place in the liver, and 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 nephrotoxic and hepatotoxic.
Ifosfamide has been used with combination irradiation, vincristine and dactinomycin, or etoposide to treat rhabdomyosarcoma of the orbit.
Ethylenimine Derivatives
Triethylenemelamine
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 coworkers121 gave 0.03 mg/kg/day for 7 to 10 days. Ellsworth122 injected a single dose of 0.08 to 0.1 mg per kg. Bishop and Madson123 occasionally gave a second injection of 0.08 to 0.1 mg per kg approximately 6 to 8 weeks after the first. It is difficult to evaluate the efficacy. The largest series was that of Reese and Ellsworth.124, 125 Between 1960 and 1965, 116 patients with poor prognoses were treated with TEM and radiotherapy.122 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 disk 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
Thiotepa (triethylenethiophosphoramide) 1% in sesame or olive oil temporarily inhibited rabbit corneal vascularization when applied three or four times a day.126, 127 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 Morgan128 stated that the drug is stable for more than 15 days when stored at 3??C. 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 coworkers,129 after a thorough review of the literature, found it impossible to compare the prophylactic value of thiotepa with that of β-irradiation. 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.128, 130, 131 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.132 However, the 0.05% solution has occasionally caused depigmentation of the skin and poliosis around the treated eye.133 These may be late occurrences (e.g., 8 months after discontinuing therapy).134 Joselson and Muller135 reported that 85% of 46 patients treated with 0.05% thiotepa had a steroid-resistant, extended postoperative hyperemia; 1 patient had conjunctival hypertrophy 3 weeks after the drug was discontinued. In guinea pigs, lid and lash toxicity occurred when 1% thiotepa was given every 4 hours.136 In rats, 0.22% thiotepa, eight times per day for 6 weeks, produced both
cataracts and corneal vascularization.137 Berkow and coworkers138 attempted to treat a corneal graft reaction with 1% thiotepa in peanut oil, twice per day for 23 days. 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.
cataracts and corneal vascularization.137 Berkow and coworkers138 attempted to treat a corneal graft reaction with 1% thiotepa in peanut oil, twice per day for 23 days. 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.
One study from the Moorfields Eye Hospital showed significant inhibition of contraction of collagen lattices containing RPE cells and proliferation of RPE cells by thiotepa at concentrations above 0.06 mg per mL after 5 or 30 minutes’ exposures. It was concluded that thiotepa may be useful in the modulation of PVR.139
Nitrosoureas
Rabbits with epitheliomas implanted bilaterally into their anterior chambers were treated with unilateral carmustine (BCNU) or dacarbazine (DTIC).140 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 per kg, intravenously, four times in 12 days when used in combination therapy, and 3.13 mg per 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 takeoff of the ophthalmic artery before injecting the drug.141, 142 and 143 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.144
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
