Adjuvant chemotherapy and tamoxifen clearly reduce recurrence and death rates after surgery for operable breast cancer,1, 2 and tamoxifen reduces contralateral breast cancer2 and breast cancer incidence in high-risk women.3 However, concern about possible side effects is an important issue, particularly when prescribing adjuvant or chemopreventive treatments to healthy4 or possibly cured patients after surgery. Certain side effects of chemotherapy and hormone therapy are well recognized,5 whereas ocular toxicity is less frequently described in reports from adjuvant treatment clinical trials and is probably underestimated.6, 7
Chemotherapy-induced ocular toxicity is fairly common and not easy to prevent. Modern chemotherapy regimens result in a significant increase in this side effect,8 but even with cyclophosphamide, methotrexate, 5-fluorouracil combination (CMF), ocular toxicity is reported in 18–42% of patients.6, 9 Ocular side effects of tamoxifen were first reported in 1978 in patients receiving very high doses.10 Other studies, however, suggest that even lower daily doses commonly used for prolonged periods in adjuvant treatments may be associated with ocular side effects.7 Cataract, visual acuity impairment, retinal deposits, macular edema, corneal opacities, and optic neuritis are the main manifestations reported7 with variable frequency depending on tamoxifen dose, treatment duration, and study design.
Estimation of the true incidence of these treatment-related side effects is not easy as information is often derived from retrospective case series, cross-sectional studies, or case–control studies, all of which can be biased. Tamoxifen-related ocular toxicity is reported uncommonly, especially in randomized trials with conventional doses (20–40 mg per day).5, 7, 8, 11 Data on ocular toxicity due to selective estrogen-receptor modulators (SERMs) other than tamoxifen are even more limited.12, 13 Randomized controlled trials may underestimate the problem if side effects are not specifically assessed with clinical or instrumental examination at scheduled times.
The objective of the present study was to retrospectively review ocular toxicity incidence and timing after adjuvant chemoendocrine treatment for early breast cancer in a large number of patients from International Breast Cancer Study Group (IBCSG) trials involving SERMs conducted from 1978 to 1999.
MATERIALS AND METHODS
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- MATERIALS AND METHODS
The IBCSG enrolled 5257 eligible patients with operable breast cancer in trials involving the use of tamoxifen or toremifene: Trials III, IV, VII, IX, 11–93, 12–93, and 14–93 (Table 1). There were 309 patients randomized to observation, and the remaining 4948 patients were randomized to receive tamoxifen or toremifene alone or with chemotherapy, (administered either concurrent with or preceding hormone therapy). The duration of hormone therapy for Trials III and IV was 1 year, and for Trials VII, IX, 11–93, 12–93, and 14–93, the duration was 5 years.
Table 1. Characteristics of IBCSG Trials III, IV, VII, IX, 11–93, 12–93, and 14–93
|Trial||Population||Yrs of accrual||No. of eligible patients||Treatment groups||Median follow-up (yrs)|
|III||Postmenopausal < 65 yrs old||1978–1981||463||Observation||20|
| || || || ||p+T × 12 months|| |
| || || || ||CMFp+T × 12 months|| |
|IV||Postmenopausal 66–80 yrs old||1978–1981||320||Observation||20|
| || || || ||p + T×12 mos|| |
|VII||Postmenopausal with positive nodes||1986–1993||1212||T alone||10|
| || || || ||T + delayed CMF|| |
| || || || ||T + early CMF×3|| |
| || || || ||T + CMF×3 + delayed CMF|| |
|IX||Postmenopausal with negative nodes||1988–1999||1669||T alone||6|
| || || || ||CMF×3 + T|| |
|11–93||Premenopausal with positive nodes||1993–1998||174||OFS + T alone||5|
| || || || ||OFS + AC×4 + T|| |
|12–93||Postmenopausal with positive nodes||1993–1999||450||CT + T||4|
| || || || ||CT + Tor|| |
| || || || ||T alone|| |
| || || || ||Tor alone|| |
|14–93||Postmenopausal with positive nodes||1993–1999||969||AC×4 + CMF×3 + T||4|
| || || || ||AC×4 + Gap + CMF×3 + T|| |
| || || || ||AC×4 + CMF×3 + Tor|| |
| || || || ||AC×4 + Gap + CMF ×3 + Tor|| |
|Total|| || ||5257|| || |
We retrieved all toxicity information on patients who were assigned to tamoxifen or toremifene and searched for any ocular toxicity, which was coded as “eye disorders” in the IBCSG database. According to IBCSG toxicity criteria that were used for all of these trials, “eye disorders” are graded as follows: Grade 1: tearing; Grade 2: tearing and pain; Grade 3: objective lesion (e.g., punctate keratitis). Because the definition of “eye disorder” did not include all ocular disorders, we retrieved all “other” toxicities and searched database comment fields for ocular disorders. The medical investigator (L.G.) reviewed case report forms for 538 patients to determine whether the toxicity occurred during chemotherapy and hormonal therapy. Only 46 patients had ocular toxicity during endocrine therapy. For these cases, a new form was sent to collect information on specific eye disorders as follows: cataract development, impaired visual acuity, optical neuritis, ophthalmic thrombosis, other ocular complaints, and results of formal ophthalmic evaluation if it was performed. Of 46 forms sent, 42 were returned.
We used Trial IX (postmenopausal patients were randomly assigned to receive tamoxifen 20 mg per day alone for 5 yrs or classic CMF for 3 cycles followed by tamoxifen for up to 5 yrs) to construct an “ocular toxicity profile.” The cumulative number of patients according to time to first appearance of ocular toxicity is graphically reported. The ocular toxicity degree reported by each patient during different chemotherapy cycles (1st, 2nd, 3rd CMF) and subsequent hormone therapy was recorded. The same methodologic approach was subsequently used to build a similar ocular toxicity profile for Trial 14–93 (postmenopausal or perimenopausal patients were randomly assigned to receive 4 cycles of doxorubicin and cyclophosphamide (AC) followed by, with or without a gap of 16 weeks, 3 cycles of CMF and then tamoxifen or toremifene for 5 yrs).
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- MATERIALS AND METHODS
Ocular toxicity due to adjuvant chemoendocrine treatment for early breast cancer is generally viewed as a marginal problem, and it is rarely studied in depth. After exposure to chemotherapy, a wide spectrum of ocular side effects has been described. Conjunctivitis and keratitis are the most frequent toxic manifestations,6, 8, 9, 14 with CMF symptoms developing in 18–42% of patients.6, 9 Ocular toxicity in patients receiving tamoxifen is based on anecdotal observations.15, 16 Since the first observation in 1978,10 other case reports,17–31 several cross-sectional studies,32–42 and two prospective studies43, 44 have been published with evaluation of patients treated with different doses of tamoxifen, even in the adjuvant setting. Limited information is available from prospective randomized controlled trials.45 On the basis of results of these studies, tamoxifen appears to fulfill five of seven criteria that Naranjo46 used to establish causality of drug-induced side effects,47 and tamoxifen seems a probable cause of retinal toxicity and less commonly a cause of keratopathy. Retinal alterations include small refractile or crystalline dot-like yellowish deposits in the area surrounding the macula, in the nerve, and in plexiform layers. Extensive deposits may result in macular edema and impaired visual acuity.7 Visual acuity may improve with tamoxifen withdrawal along with resolution of macular edema, but retinal deposits often do not regress.7 Keratopathies are corneal opacities in the form of subepithelial deposits, whorls, or linear opacities; they are often not responsible for any deterioration in vision and are generally reversible after tamoxifen withdrawal.43 Optic neuritis has been described in some reports,18, 20 but it remains a rare event, and its causal relation with tamoxifen is doubtful.7 Finally, a prospective chemopreventive trial3 and a population case–control study found a higher incidence of cataracts, especially in standard or long-term users of chemotherapy.48 This finding was recently challenged by a new case–control study,49 although median tamoxifen exposure in this population was only 2.6 years.
Recently, Flaxel et al.50 documented ocular penetration of tamoxifen and its metabolite, although no relation was found between serum and intraocular levels of the drug. The mechanism by which tamoxifen could induce keratopathies and retinopathy seems similar to that of drugs such as chloroquine, chlorpromazine, thioridazine, and amiodarone.47, 51 The mechanism by which tamoxifen can induce cataracts is not fully understood; however, existing epidemiologic and experimental data indicate an estrogen-protective effect on the eye and lens, which could be challenged by tamoxifen.52, 53 The observation that tamoxifen may block chloride channels, which are associated with P-glycoprotein, is a possible mechanism for cataract development.54–57 Data on incidence of ocular toxicity after tamoxifen therapy are conflicting. Incidence of ocular toxicity from cross-sectional studies range from 0.9% to 11.7%,33, 34, 36–43 with some studies finding no ocular toxicity at all.32, 35 Whereas in two prospective studies, ocular toxicity occurred in 6.3%43 and 12%44 of patients. There are several possible confounding elements in the interpretation of published evidence. Most studies have a limited number of patients, and the absence of a control group of patients is a serious limitation in many of these studies. Cross-sectional studies without a control group fail to take into consideration the prevalence of ocular disease in an age-matched population not exposed to the drug. Ocular alterations due to tamoxifen are not always easily distinguishable from other eye diseases. In a recent small prospective study13 (substudy of a larger randomized controlled trial), pathologic ocular findings were found at baseline ophthalmic examination in 26 of 60 (43.3%) patients aged 50 to 79 years. Another possible explanation lies in different daily doses and treatment duration, because higher cumulative doses have been shown for patients with ocular toxicity in comparison with patients without ocular toxicity.44 Finally, ocular toxicity may have some relation with serum concentration of tamoxifen and its metabolite.58, 59
Our study is probably the largest to assess ocular toxicity after chemoendocrine adjuvant therapy in breast cancer. Its major limitation is its retrospective nature. Absence of a planned ophthalmic evaluation and lack of specific attention to ocular complaints during adjuvant therapy make it very likely that we have underestimated the incidence of ocular toxicity.60 In our study, only 11% of patients had ocular toxicity after adjuvant chemoendocrine therapy, mainly attributable to the phase of treatment, including chemotherapy, which is lower than the 18% recently reported in literature for CMF alone.6 Analysis of Trials IX and 14–93 shows that the majority of ocular toxicity events were Grade 1 or 2, and, in most cases, the first ocular toxicity events were concentrated within the first 2 months of treatment with a plateau at the end of chemotherapy. Some late occurrences of first ocular toxicity event were potentially related to tamoxifen or toremifene (Figs. 1 and 2). The trend is similar in Trial IX and Trial 14–93.
Forty-five of 4948 (0.9%) treated patients had ocular toxicity during tamoxifen or toremifene therapy, but, excluding 15 ocular toxicity cases that occurred during the first 3 months after cessation of chemotherapy (more likely to represent toxicity due to the chemotherapy), only 30 (0.6%) patients had ocular toxicity, possibly because of tamoxifen or toremifene. This incidence is slightly lower than that reported from other experiences in prospective studies of adjuvant therapy,45 and this is probably consistent with the finding that most ocular toxicities due to low dose SERM are probably asymptomatic. Unfortunately, only 15 of these 45 (33.3%) patients had an ophthalmic examination performed, but among these, no cases of confirmed retinopathy were recorded. Twelve patients had impaired visual acuity; 4 patients had cataracts (2 of whom had bilateral cataracts), which is a number probably lower than expected considering the high prevalence of this degenerative disease in a population with a median age of 61 years.52 One patient had optic neuritis; no ophthalmic vessel thrombosis was recorded.
From the current study, it is not possible to evaluate differences in ocular toxicity between tamoxifen and toremifene. Only one patient had ocular toxicity during toremifene therapy after more than 3 months from chemotherapy conclusion. Similarly, no significant differences were reported between these two drugs in patients with metastatic disease12 as well as in the adjuvant setting where a small prospective study included regular ocular examination.13 The small number of patients treated with prednisone and ovarian function suppression treatment makes difficult the assessment of their contribution to observed ocular toxicities.
Despite its limitations, our study has a pragmatic significance. We note that ocular toxicity after chemotherapy is not infrequent, and it may be disturbing for patients, whereas ocular toxicity due to SERMs alone seems rather rare. This may justify secondary preventive measures for patients with ocular toxicity after first-cycle chemotherapy. Otherwise, the apparently modest risk of ocular toxicity during low-dose SERM therapy casts doubt on the need for ophthalmic examination both at base line and during SERM therapy. However, attention should be paid by physicians and nurses to eye disturbances,61 and patients should be given clear instructions about possible visual symptoms caused both by chemotherapy and tamoxifen to facilitate prompt ophthalmic evaluation in case of ocular complaints.
Finally, problems in patients with preexisting mild or severe ocular diseases as well as of those who develop serious ocular toxicity while on tamoxifen therapy raise the question of the best management of these conditions.30 A problem should be evaluated in relation to its severity and breast cancer recurrence risk; however, use of an aromatase inhibitor instead of a SERM may be appropriate.