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Radiation to the Eye

There are risks associated with radiation to the eye, damage to the cornea generally requires a high dose, radiation to the lens can cause a cataract after a dose as low as 2Gy, retinal changes can be seen after 45-60Gy, radiation to the lacrimal gland can cause dryness of the eye, radiation to the optic nerve greater than 60Gy has an 11% risk of vision loss and radiating the optic chasm over 50Gy (of 8Gy single dose) can effect vision (see here and dose section and gamma knife section.) Typical radiation tolerance charts:
Site Damage Dose
lens cataract 600-1200cGy
conrnea keratitis 5000cGy
retina vision loss 4500-5000cGy
optic chiasm vision loss 5000cGy
Late retinal complications of radiation therapy for nasal and paranasal malignancies: relationship between irradiated-dose area and severity. Takeda. IJROBP Volume 44, Issue 3, Pages 599-605 (01 June 1999)


Methods and Materials: Between October 1982 and May 1996, 43 eyes of 25 patients were exposed to fractionated external-beam irradiation for treatment of advanced nasal and paranasal cancer. None of the patients had tumor invasion into the eyes. The patients were followed ophthalmologically for a minimum of 2 years (range 2.0–11, mean 4.5, median 3.3). The radiation dose and area of the retina irradiated were estimated from the dose distribution figures calculated using the portal films and CT scan.

Results: Major late adverse effects of radiotherapy were observed in the retina in 9 of 43 eyes (in 8/25 patients). Radiation retinopathy was observed in 7 eyes, and the cumulative incidence was 25%. The median interval before the onset of symptoms attributable to retinopathy was 32 months (range 16–60). Neovascular glaucoma developed in 3 of the 43 eyes, with a cumulative incidence of 7%. The median period to the onset of symptoms attributable to glaucoma was 22 months (range 16–26). Obstruction of the central retinal artery was observed in 1 eye. The irradiation doses to the retinas that developed late complications ranged between 54–75 Gy (mean 61, median 61). No patients who received less than 50 Gy developed retinal complications. The retina in 21 eyes was exposed to a dose of 50 Gy or more. In 13 of the 21 eyes, 60% or more of the retina was irradiated, and 8 of the eyes (62%) in this group (> 50 Gy, >60%) developed severe retinal complications, whereas such complications only developed in 1 of the 8 eyes (13%) in the other group (>50 Gy, <60%). The results suggest that the radiation dose and area irradiated are the most important factors in the development of severe complications.

Radiation-induced cataract is a well-known adverse effect of radiation therapy to the eye, and a 62–100% incidence of cataract has been described in the literature at dose levels of 40 Gy or more. Recently, however, this is no longer considered a severe complication, because visual acuity can be effectively restored by surgical treatment without significant complications. Late retinal complications such as retinopathy and glaucoma are now considered serious complications of head and neck radiotherapy. We have no effective means of treating these complications when the lesions have progressed; however, we are able to control the progression of retinopathy by photocoagulation, and of glaucoma by proper medication and/or trabeculectomy when they are diagnosed in the early stages.

There have been several reports on radiation-induced retinopathy. Bessell treated 59 orbital lymphoma patients with anterior- and lateral-wedged portals to retinal doses of 25–40 Gy in 2-Gy fractions. None experienced retinopathy during 1–15 years of follow-up. Ten patients who had received 25–30 Gy were examined by fundus fluorescein angiography, and were found to have no retinovascular changes. Peterson  also reported that 311 patients who received 20–30 Gy irradiation for Grave’s disease had not experienced retinopathy. Letschert  treated 22 orbital lymphoma patients with 5-MV X-rays to total doses of 40 Gy in 20 fractions, using anterior portals alone or an anterior-lateral wedged pair without lens shielding. The anterior retina of the patients treated with an anterior portal alone received 44-49 Gy in 20 fractions, and 2 of them (9%) developed radiation retinopathy. Wara  reported 4 patients who developed retinopathy after doses of 46.44, 48.6, 48.6, and 49.23 Gy, administered in fractional doses of 1.8 Gy or more. Parsons  observed no radiation retinopathy at doses below 45 Gy, but saw an increased incidence at doses of 45 Gy. In the dose range 45–50 Gy, 8 of the 15 eyes (53%) developed retinopathy, and there was an increased risk of injury among patients who received fractional doses of 1.9 Gy. They also reported a trend toward increased risk of injury among diabetic patients who had received chemotherapy. Chan and Shukovsky  reported a 4-year actuarial rate of vision loss of 9% (2 of 22 patients) after doses to the entire eye of 60 Gy in 30 fractions over 6 weeks. Only one third of their patients developed significant ocular problems of any kind after irradiation with these doses.

In this study, 46 eyes were irradiated because of advanced nasal and paranasal cancer, and 21 eyes received more than 50 Gy. Seven of the 43 eyes developed retinopathy, and the lowest dose at which retinopathy developed was 54 Gy. Retinopathy occurred between 17 and 60 months after radiotherapy, and the actuarial rates were 26% for all patients, and 56% for patients who received more than 50 Gy. In 6 of the 7 eyes, 60% or more of the area of the retina had been irradiated. These findings suggest that radiation dose and area of retina irradiated are important risk factors for radiation retinopathy. The median period to the onset of retinopathy was 2.7 years (range 1.4–5), and no retinopathy was observed after 5 years in this study.

While previous reports noted that diabetics are particularly susceptible to radiation retinopathy, none of the patients who developed retinopathy in this study had diabetes mellitus.

Concurrent chemotherapy or chemotherapy in close temporal proximity to irradiation are believed to increase the risk of radiation-induced retinopathy. Chan and Shukovsky  noted a 4-fold increase in the actuarial risk of retinopathy in patients who received concurrent intra-arterial 5-fluorouracil compared with patients treated with the same doses of radiation alone for nasal cavity or paranasal sinus cancer. Brown  reported radiation retinopathy in 4 of 7 patients who received chemotherapy compared with 1 of 10 patients who did not receive chemotherapy in addition to irradiation (p = 0.06). In the current series, 18 of the 25 patients (34 eyes) received chemotherapy in conjunction with irradiation, and no severe eye complications were observed in the patients in this group who received irradiation doses under 50 Gy. Among the 14 eyes that received more than 50 Gy and in whom more than 60% of the retinal area was irradiated, 11 eyes were those of patients who received chemotherapy and radiotherapy, and complications developed in 7 of these eyes (64%). On the other hand, 2 of 3 eyes (67%) in patients who did not receive chemotherapy developed complications. Many eyes were those of patients who received chemotherapy; however, the risk associated with chemotherapy was not assessed in this study.

There have been few reports on radiation-induced glaucoma. Letschert et al. reported that 2 patients developed glaucoma secondary to retinopathy . Parsons et al. reported that 7 of 27 eyes with retinopathy developed secondary glaucoma. In these reports, the secondary glaucoma developed a few months after the retinal irradiation. In our patients, however, the glaucoma occurred almost simultaneously with the retinopathy. The time interval between the radiotherapy and development of glaucoma was 1.3–2.2 years. The latent period until the onset of this lesion was shorter than that of retinopathy.

Leonard reported 15 nasal or ethmoid sinus cancer patients who were treated and followed-up. Two of them developed central retinal artery occlusion. They had received 55 Gy and 60 Gy, and developed this complication 9 and 15 months, respectively, after the radiation therapy. They did not have diabetes mellitus or vascular disease. One patient in this study received very high-dose irradiation (75 Gy) to the retina due to hot spot dose formation by anterior open field irradiation, and became blind in that eye as a result of the central retinal artery obstruction. Extremely high-dose irradiation to the retina can result in vascular injury and obstruction of the central retinal artery.

Conclusion: Radiation-induced retinopathy and glaucoma are more serious late complications than cataracts, which are easily treated with surgery. We investigated the risk of late retinal complications of radiotherapy, and our findings suggested that the radiation dose and area irradiated are the most important factors in the development of severe complications. We recommend that the radiation dose and area of the retina irradiated be minimized in patients at risk of eye complications, and the patients should be closely followed by periodic ophthalmologic testing after treatment.

Preventing radiation retinopathy with hyperfractionation

 IJROBP Monroe, IJROBP Volume 61, Issue 3, Pages 856-864 (01 March 2005)
 

Thirty-one eyes in 30 patients developed radiation retinopathy, resulting in monocular blindness in 25, bilateral blindness in 1, and decreased visual acuity in 4. The median time to the diagnosis of retinopathy was 2.6 years (range, 11 months to 5.3 years). The actuarial incidence of developing radiation retinopathy was 20% at both 5 and 10 years. The incidence of developing ipsilateral blindness due to retinopathy was 16% at 5 years and 17% at 10 years. Site-specific incidences varied considerably, with ethmoid sinus (9 of 25, 36%), nasal cavity (13 of 69, 19%), and maxillary sinus (6 of 35, 17%) being the most common sites associated with radiation retinopathy. Three of 72 patients (4%) receiving retinal doses less than 50 Gy developed retinopathy. Higher retinal doses resulted in a steady increase in the incidence of retinopathy, with 25 of the 30 cases occurring after 60 Gy or more. Of the patients receiving more than 50 Gy to the retina, hyperfractionation was associated with a significantly lower incidence of radiation retinopathy (37% vs. 13%; p = 0.0037). On multivariate analysis, retinal dose (p < 0.0001), fractionation schedule (p = 0.0003), age (p = 0.0365), and prolonged overall treatment time (p = 0.0213) were significant predictors of radiation retinopathy.

Conclusion

The incidence of ipsilateral radiation retinopathy after treatment of nasal cavity/paranasal tumors is 20% at 5 and 10 years. Retinal dose and fractionation schedule are the strongest predictors of retinopathy. Hyperfractionated radiotherapy is associated with a significant reduction in the incidence of radiation retinopathy, especially when the retina receives more than 50 Gy.

To our knowledge, this report represents the largest systematic analysis of factors associated with radiation retinopathy after treatment of patients with head-and-neck cancer. Total dose to the retina, age, and dose fractionation were the factors most predictive of retinopathy, with hyperfractionation reducing the incidence by more than half among patients who received more than 50 Gy.

The association between dose and radiation retinopathy is well established; however, a pure threshold dose has been difficult to define. Anecdotal reports of retinopathy developing at low doses must be examined carefully.

In the case of Graves' ophthalmopathy, Kinyoun  initially described three cases of radiation retinopathy after 20 Gy in 10 fractions, only to later qualify that all three cases were probably caused by errors in technique and dose calculations. Despite this ascertation, there are a number of undisputed reports of retinopathy occurring after 20 Gy in patients with Graves' disease  Furthermore, a prospective study recently documented microvascular retinal abnormalities by fluorescein angiography in 2 patients before radiotherapy and 2 after 20 Gy (total of 4 patients), suggesting that the underlying Graves' disease may be sufficient to cause, or at least predispose patients to retinopathy

Moderate doses of radiation typically produce low incidences of retinopathy in patients with orbital lymphoma. Bolek  reported no retinopathy in 38 patients followed for 8.3 years after receiving a median of 25 Gy for orbital lymphoma. Bhatia  described one case of neovascular glaucoma and no retinal injuries after 30 to 40 Gy for orbital lymphoma. Similarly, no cases of radiation retinopathy were reported at the Royal Marsden Hospital in 115 orbital and conjunctival lymphoma patients treated to similar doses. Amoaku  reported three cases of retinopathy in orbital lymphoma patients receiving doses between 34 and 37.5 Gy; however, chemotherapy or diabetes may have been contributing factors in all three cases.

In the current series of 186 mucosal head-and-neck primary tumors, only 3 patients developed retinopathy after receiving less than 50 Gy. As discussed above, 2 had significant pretreatment risk factors and the other was treated with a hypofractionated schedule. Thus, it appears that the risk of radiation retinopathy below 50 Gy with conventional fractionation is low.

Parsons  established a dose response curve for retinopathy characterized by a dramatic increase in incidence between 45 and 55 Gy, such that nearly all patients receiving higher doses developed retinopathy. The dose response data in the current study differs significantly in both methodology and conclusions. Retinal dose was defined by Parsons as the dose received by at least 50% of the retina; whereas, we have defined the retinal dose as the minimum dose to at least 25% of the retina. The definition used in the current study is less sensitive to dose gradients in the region of interest and has more application in the age of conformal treatment planning. A comparison of these definitions reveals that minimum dose to 50% of the retina routinely underestimates the actual dose received by a significant volume of the retina. This difference must be considered when discussing retinal tolerance, as our definition will effectively shift the sigmoid portion of the dose response curve to higher values without changing the shape of the curve.

Above 70 Gy the overall incidence of retinopathy approaches 40%; however, at these high doses the impact of dose fractionation becomes more important. Within the realm of conventional fractionation, a dose per fraction below 1.9 Gy/fraction was previously shown to decrease the incidence of retinopathy. The current study extends this concept to smaller fraction sizes in the context of hyperfractionated radiation. We report more than a 50% reduction in the incidence of retinopathy with hyperfractionation at high doses.

According to the linear-quadratic model, organs with low α/β ratios (normal tissue) are more sensitive to changes in dose fractionation than those with high α/β ratios (tumor). This can be explained in part by their differing repair capacities. Late-responding organs (as the retina is assumed to be) can successfully repair sublethal single-strand DNA damage provided that there is sufficient time between fractions.  Hyperfractionation theoretically allows the retina time to repair single-strand breaks before a second nearby insult can occur. Consequently, late damage is limited to double-strand breaks which manifest as mitotic death months to years later when the slowly dividing organ attempts to proliferate. The findings of this study validate these radiobiologic concepts.

The volume of retina irradiated has also been shown to be a significant predictor of retinopathy. Takeda  found that eyes receiving more than 50 Gy to greater than 60% of the retina were more likely to develop radiation retinopathy. The current study includes patients treated over four decades, with the majority treated before the routine use of three-dimensional conformal treatment planning. Obviously, this limits our conclusions on the effect of volume. Our retinal dose definition corresponds to a two-dimensional approximation of D25, or the dose received by 25% of the retinal volume. In reality, the anterior quarter of the globe is not retinal tissue and was never used for retinal dose calculations. This increases the percentage of retinal volume contained in our D25 approximation to approximately one-third of the total retinal surface area. Prospectively contouring the retina as an organ at risk (OAR) will allow future analysis of dose volume histograms to establish safe radiation/volume parameters.

Conformal avoidance with IMRT offers the ability to elegantly shape dose distributions so that critical structures like the retina can be excluded from high-dose regions. IMRT is routinely used for the treatment of nasopharyngeal tumors and is being investigated for tumors of the paranasal sinuses  Mock recently compared conventional treatment plans for paranasal sinus cancer with three-dimensional conformal radiotherapy (CRT), IMRT, and conformal proton plans. The three-dimensional-CRT and IMRT techniques permitted dose reductions to nontarget tissues, including the retina. Proton therapy further reduced the dose to OAR; however, the reduction was primarily at lower isodose levels (10% to 70%).

Frequently, the planning target volume (PTV) and OAR volumes are in close proximity or may even overlap. In these instances, complex algorithms guide dose delivery to areas of overlap. At the extreme, a decision must be made between underdosing the PTV to spare the retina and ensuring tumor coverage at the expense of normal tissue tolerance. More commonly, a compromise plan is selected which optimizes these goals but attains neither entirely.

Conformal treatment must not ignore radiobiologic principles. Dose inhomogeneity is an inherent feature of IMRT's improved conformality, and as a result, IMRT plans must be scrutinized to ensure that areas of inhomogeneity are minimized within OAR. The radiation oncologist must remember that a 10% hot spot over a critical structure increases both the total dose and the dose per fraction by 10%. This may have practical implications if the resulting biologically effective dose exceeds normal tissue tolerance.

When devising a treatment plan that will include the optic apparatus, the improved conformality of IMRT must be weighed against the findings of this study; namely that hyperfractionation reduces late toxicity to the retina. At this institution, we have reserved IMRT for those cases where the optic apparatus can be completely avoided without compromising tumor coverage. When overlap between the PTV and retina is unavoidable, we treat twice a day with a conventional three-field technique. Although there are logistic barriers to hyperfractionated IMRT, the normal-tissue sparing advantages seen with conformal radiation and hyperfractionation should be complementary. Further studies are warranted to investigate these matters.