Cataract formation has been recognized in bone marrow transplant recipients as one of the first and most frequently occurring late complications of total-body irradiation (TBI) [8-10]. Single-dose TBI of 10 Gy or more causes cataract formation in all patients [11, 12]. Fractionation of the TBI dose to reduce this effect on the lens resulted in cataract formation in fewer than 20% of the patients after 4 years [11]. However, this therapy must be studied in a group of patients with a longer follow-up period. The minimal dose to allow lens opacification to develop in experimental models [13] and long-term observation of Hiroshima survivors [14] suggest that the risk after fractionated TBI may be understated. Therefore, we tried to determine the incidence of cataract formation resulting from different regimens used as preparation for bone marrow transplant and to evaluate the influence of other risk factors.

Methods

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Study Design

This study was part of a prospective, controlled cohort study to evaluate late effects of bone marrow transplantation. Some results involving ischemic microvascular lesions of the ocular fundus [15] and chronic cyclosporine-associated nephrotoxicity [16] have been reported. All patients were examined according to a standardized protocol before bone marrow transplantation; 3, 6, and 12 months after transplantation; and once per year thereafter. The examination included full clinical and ophthalmologic evaluations by a senior-level ophthalmologist, which consisted of a visual acuity test and slit-lamp and fundus examinations after pupillary dilatation. The dates of first manifestations of cataracts and of operations were recorded.

Patients

Participants included all patients who had bone marrow transplantations at the Kantonsspital, Basel, Switzerland, between 1979 and December 1991 for malignant hematologic diseases or severe aplastic anemia. During this time, 290 patients received either allogeneic (n = 256), autologous (n = 27), or syngeneic (n = 7) bone marrow transplants. All patients with a follow-up period of at least 180 days were included in this study of cataract formation.

Preparative Regimens and Prevention of Graft-versus-Host Disease

The basic bone marrow transplant protocol remained the same throughout the entire study period and has been reported in detail [17, 18]. Briefly, patients with a malignant hematologic disease were treated with cyclophosphamide, 60 mg/kg body weight per day on 2 consecutive days, followed by TBI. Starting in April 1986, this treatment was preceded by etoposide (VP-16), 30 mg/kg, given on day 9 before transplant. Patients with severe aplastic anemia received cyclophosphamide alone, 50 mg/kg per day, for a period of 4 days. Patients with a malignant disease and previous irradiation were given preparatory doses of cyclophosphamide and busulfan. For prevention of GVHD, patients were given cyclosporine A alone and, starting in 1991, cyclosporine A combined with methotrexate. From December 1985 to December 1989, the bone marrow of patients older than 25 years with malignant diseases was depleted of T cells by counterflow elutriation [19]. Patients with autologous or syngeneic bone marrow transplants received no treatment to prevent GVHD. Starting in 1982, high-dose methylprednisolone was applied as the first line of treatment for GVHD of grade II or more: This therapy included 1000 mg on the first day and 500 mg on the second day followed by 0.5 mg/kg per day. This treatment was repeated as many as three times if necessary. Patients with chronic GVHD were treated with cyclosporine A alone or in combination with prednisone in an initial dose of 1 mg/kg per day.

Irradiation Protocol

Total-body irradiation was applied by a linear accelerator (Philips SL 75-5, 4.2 MeV; Crawley, United Kingdom) throughout the entire study period. Radiation parameters were adapted as required. From 1979 to September 1985, TBI was given in a single dose calculated as a maximal lung dose of 10 Gy and at a rate of 7.5 cGy/min. In the first 18 patients, the lung was shielded after a dose of 8 Gy. Thereafter shielding was discontinued. Since October 1985, TBI was fractionated in 6 doses of 2 Gy on 3 consecutive days before bone marrow transplantation [12]. The first 16 patients were irradiated at a dose rate of 20 cGy/min. Thereafter, this dose rate was reduced to 3.5 cGy/min. The applied dose was calculated to be the maximal lung dose. No shielding of the eyes was ever applied.

Statistical Analyses

All medians and ranges of numeric variables were calculated by the NCSS statistical program and compared using the chi-square test. Analyses of the risk for cataract formation and the probability of operation were done according to the method of Kaplan and Meier [20]. For the univariate analysis, the log-rank test with two-sided significance levels was used to compare risk groups for cataract formation [21]. Proportional-hazards regression analysis was used to relate potential risk factors to the development of cataracts [22, 23]. A forced-entry regression of all tested variables, such as age, sex, TBI, type of irradiation, chronic GVHD, as well as treatment with prednisone for more than 3 months after bone marrow transplantation, was used.

Results

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Patients

One hundred ninety-seven of 290 (68%) patients had follow-up periods of at least 180 days after bone marrow transplantation and could be evaluated for cataract formation. Their primary characteristics are listed in Table 1. There were 105 male and 92 female patients between 2 and 50 years old (median age, 25 years). Of 164 patients treated with TBI, 74 received single-dose TBI and 90 received fractionated TBI. Thirty-three patients were given chemotherapy alone as preparatory treatment.

As expected from the treatment protocols, the three groups of patients differed with respect to type of bone marrow transplant, disease, and median follow-up period. In addition, more women were prepared with single-dose TBI, but fewer with fractionated TBI or chemotherapy alone. Allogeneic bone marrow transplant predominated in all treatment groups. In preparation for autologous bone marrow transplantation, most patients received either fractionated TBI or chemotherapy alone. Most patients with hematologic cancers received TBI, whereas all patients with severe aplastic anemia were given preparatory chemotherapy alone. Furthermore, during the study, new indications for bone marrow transplant were tested. Thus, myelodysplastic syndromes or lymphoma has been treated by bone marrow transplantation only since 1986. At this time, all patients received fractionated TBI.

Survival

As of 1 January 1992, the actuarial probability of survival according to Kaplan and Meier analysis for the 290 patients treated during this study was 43% (95% CI, 35% to 51%) at 15 years. Of 197 patients who survived the first 180 days, 134 (68%) were alive 0.5 to 16 years after transplantation (median survival, 3.4 years), 110 of them after a preparatory regimen of TBI (45 received single-dose TBI and 65 fractionated TBI) and 24 after chemotherapy alone.

Cataract Formation

No patient showed lens opacification in pretransplant ophthalmologic evaluations. After bone marrow transplantation, cataracts developed in 70 of the 197 patients (36%) within 3 to 63 months (median, 38.4 months). Forty-six patients (23%) needed surgical correction of their cataracts. There were important differences based on the type of preparative regimen used before transplant (Table 2).

Single-Dose, Total-Body Irradiation

After single-dose TBI, cataracts developed in 51 of the 74 (69%) patients (Table 2). Lens opacification started as early as 3 months after bone marrow transplantation and was observed in all 51 patients (CI, 93% to 100%) alive 3.5 years after surgery (Figure 1). Forty-four (59%) patients needed surgical repair of cataracts, which included simple lens extraction in 6 patients and simultaneous implant of new lenses in 34 patients. In 4 patients, the operation was done at another institution and the type of surgery was unknown. The probability of being operated on was 85% (CI, 75% to 95%) 6 years after bone marrow transplant. After 9 years, all patients alive needed surgical repair of their lenses (Figure 2). The cataract surgery was done as early as 2 years after bone marrow transplantation in some patients. The median time to surgery, however, was 4.1 years after transplantation. The interval between the onset of cataracts and surgical treatment was about 1.5 years. Twenty-four of the 44 (55%) patients having surgery showed residual lens opacifications called "after-cataract," 16 (36%) of them requiring yag-laser therapy. Visual acuity improved after treatment in most patients. However, 4 of the 44 (10%) patients treated with surgery have residual visual damage that interferes with normal daily activity despite surgical correction.

View larger version (15K): [in this window] [in a new window]   Figure 1. The probability of cataract development in 197 patients who were given preparatory single-dose, total-body irradiation, fractionated irradiation, or chemotherapy alone (no irradiation) and then bone marrow transplantation. TBI = total body irradiation; fTBI = fractionated total body irradiation; STBI = single-dose, total body irradiation.

View larger version (10K): [in this window] [in a new window]   Figure 2. The probability of requiring cataract surgery in 197 patients who were given preparatory single-dose or fractionated total-body irradiation and then bone marrow transplantation.

Fractionated Total-Body Irradiation

Cataracts developed in 18 of the 90 (20%) patients treated with fractionated TBI (Table 2). Three and one half years after bone marrow transplant, when all patients with single-dose TBI had lens opacification, the actuarial probability of cataract formation in the patients with fractionated TBI was only 29% (CI, 13% to 44%). However, at 6 years, this risk was 83% (CI, 63% to 100%). Throughout the entire period of observation, the probability of cataract formation increased continuously without a plateau (Figure 1). Lens opacification developed later in patients who received fractionated TBI, and progression of cataract formation was slower (P < 0.01). After a median follow-up period of 2.1 years (range, 0.5 to 6.2 years), only 2 of the 18 (11%) patients with cataracts and 2.5% of all those given preparatory fractionated TBI needed surgical repair. The probability of needing an operation was 20% (95% CI, 0% to 49%) at 6 years (Figure 2). Compared with patients who received single-dose TBI, there is a much lower risk (P < 0.01). After-cataract developed in the 2 patients who had surgery. These 2 patients had no decrease in visual acuity and did not need yag-laser correction.

Chemotherapy without Total-Body Irradiation

Only 1 of the 33 (3%) patients treated with chemotherapy alone showed cataract formation after bone marrow transplantation. Lens opacification was not progressive and this patient did not need surgical repair. The risk for cataract formation after chemotherapy alone at 6 years is 5% compared with 83% and 100% in patients treated with fractionated TBI and single-dose TBI, respectively (both P < 0.01).

Other Risk Factors

Using univariate analysis, we looked for additional factors associated with cataract formation (Table 3). Age and sex of the patients did not influence incidence or time course of this late ophthalmologic complication. In contrast, patients with chronic GVHD (P = 0.002) and those treated for more than 3 months with prednisone (P = 0.02) had a greater occurrence of lens opacification. Cataract formation was observed 2.2 years earlier in patients treated with fractionated TBI who had chronic GVHD (P = 0.005) compared with those patients without GVHD. Steroid therapy for more than 3 months was associated with a 27% greater incidence and a 0.8-year earlier onset of cataracts in patients treated with TBI (P = 0.001).

The Cox regression analysis Table 4 confirmed that the preparatory regimen (TBI compared with chemotherapy alone) before bone marrow transplantation, and the type of TBI (single-dose compared with fractionated) were the most important factors influencing cataract formation. The relative risk for cataract formation in patients given TBI was 21 times (CI, 4.4 to 304) that of patients given preparatory chemotherapy alone, and the risk of patients given single-dose TBI was 7.4 times (CI, 3.5 to 15.5) that of patients receiving fractionated TBI. The multivariable analysis also clarified the role of chronic GVHD and steroid therapy: Therapy for more than 3 months with prednisone doubled the risk for cataract formation (relative risk, 2.9). In contrast, chronic GVHD appeared not to specifically influence cataract formation.

Discussion

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Disorders of the eye after bone marrow transplantation include infectious complications, hemorrhage, the keratoconjunctivitis sicca syndrome, microvasculopathy in the ocular fundus, [15, 24-26] and, most frequently, late-onset cataract formation. Total-body irradiation, especially when applied in a single session, plays a central role in cataract formation [11, 12, 27, 28]. Cataracts developed in all of our patients treated with single-dose TBI within 3.5 years, and all needed cataract surgery within 10 years after bone marrow transplantation. The short latency period of 1.6 years between onset and operation illustrates that cataracts form rapidly after single-dose TBI.

One reason fractionated TBI was introduced was to spare the lenses, and early reports support this concept. Similar to patients given preparatory chemotherapy alone, patients receiving fractionated TBI initially showed a low risk for developing cataract [11, 29-31]. However, with long-term follow-up, the probability of cataract formation after fractionated TBI appears to be 83% at 6 years. In contrast, the risk remains low in patients not treated with irradiation. The hazard curve fails to form a plateau, suggesting that eventually all patients treated with fractionated TBI develop lens opacification. Nevertheless, essential differences exist between single-dose TBI and fractionated TBI. The latency period between bone marrow transplantation and cataract formation is longer, and lens opacification progresses more slowly with fractionated TBI. The probability that patients will need cataract surgery is 21% for fractionated TBI and 85% for single-dose TBI at 6 years. However, in both groups of patients, the curve shows a continuous increase and most surviving patients eventually need surgery.

The slightly longer median follow-up time after bone marrow transplantation cannot alone explain the discrepancy between previous, more optimistic reports and our results. The difference might be due to systematic annual follow-up examinations, which allow earlier detection of minor changes. Such a prospective evaluation for late complications may be easier to do in a medium-sized transplantation center with most patients living within short distances.

Experimental data corroborate the finding that cataracts eventually develop in all patients treated with fractionated TBI. The lowest dose to induce cataracts with experimental radiation was found to be 2 Gy [32]. With fractionation of irradiation, the lens tolerates a higher dose without necessarily progression of opacification, and the latency period between radiation and cataract formation is increased [33]. The threshold dose to cause cataract formation is approximately 5.5 Gy. However, this is a lower dose than is used in most TBI regimens. Furthermore, a significant excess risk for cataract formation was observed among survivors of the 1945 atomic bomb attacks on Hiroshima and Nagasaki, who received more than 3 Gy of irradiation [14].

Other factors, such as age and sex, did not influence the rate of cataract formation. Steroids are known to cause cataracts in patients not treated with bone marrow transplantation [34-36], and chronic GVHD, when analyzed separately, has been described as a risk factor. In our analysis, only the long-term use of steroids during the post-transplant period appeared to increase the risk in patients given preparatory TBI, resulting in a higher incidence and earlier onset of cataract formation. These results are confirmed by multivariate analysis, which shows that treatment with prednisone is associated with a threefold increase in the risk for cataract formation. The apparent effect of chronic GVHD in univariate analysis was inconsistent in the multivariate analysis. This makes sense because lenses have no vascular irrigation and cannot be the target of GVHD, and the univariate effect probably reflects the close relation between GVHD and steroid therapy.

Cataract extraction after bone marrow transplantation appeared to be successful, but nearly two thirds of the patients needed repeated surgery because of after-cataracts. Residual lens opacification is a well-known complication after extracapsular surgery and simple yag-laser treatment usually corrects it. Nevertheless, nearly 10% of patients having cataract surgery had residual visual impairment. In cases of simultaneous keratoconjunctivitis sicca, lens implant is preferred to simple extraction because contact lenses are not well tolerated.

Because TBI is the major preparatory regimen for patients with malignant hematologic disorders, preventive treatment is essential for this late complication that interferes with patients' quality of life. Because isolated ocular leukemic relapse is rarely observed, lens shielding should be considered for patients treated with TBI.

Abbreviations

GVHD: graft-versus-host disease

TBI: total-body irradiation