Technique
14.2.1 Percutaneous Radiotherapy (External Beam Radiotherapy)
Linear accelerators are used in the main to produce ultrahard photon or electron radiation for percutaneous radiation (external beam radiotherapy, EBRT) Occasionally, X-ray tubes are also used as a source for very soft photon beams (e.g., in the postoperative radiation of pterygium, see Chapter ▶ 14.4.4).
Operating Principle and Use of the Linear Accelerator
High-frequency microwave beam is fed into a vacuum pipe (“waveguide”) and an electron beam is guided onto it. The electrons absorb energy from this and reach a much higher energy than is achievable through direct acceleration between anode and cathode in the classic X-ray tube. This electron beam is then bundled via magnets and directed onto a target of dense material (tungsten), where it is decelerated. The resulting bremsstrahlung is the therapeutically usable photon radiation. This can penetrate the human body easily and is therefore particularly well suited for the radiation of deep-lying structures ( ▶ Fig. 14.1).
Fig. 14.1 Structure of a linear accelerator. A high-frequency microwave is guided into a high-vacuum tube (called a “waveguide”) into which an electron beam is then injected. The electrons are thereby accelerated to high energies, bundled with steering magnets, and fired onto a dense material (e.g., tungsten). This is where the therapeutically useful bremsstrahlung arises as “photon radiation.”
The electron radiation can also be guided directly onto a diffusion foil and then used in treatment. The advantage of this radiation is a prompt build-up of the dose in the body, although it penetrates only a few centimeters in depth. Thus “fast electrons” are ideal for treat target structures close to the body’s surface.
Memorize
High-energy electron and photon beams can be produced with linear accelerators. Electron beams are suitable for the treatment of tumors close to the body’s surface, while photons are good for penetration to depth.
The dose distribution is planned in advance when using therapeutic irradiation so as to ensure sufficient coverage of the target structures while being able to ensure sufficient care is taken of the surrounding normal tissue (so called “organs at risk”).
The simplest form of radiation planning is so-called 2D planning. In this the requisite dose is estimated from the field geometry, the depth of the structure to be irradiated, and the dose prescribed on the basis of sample measurements made previously on an anatomical model. Anatomical characteristics (e.g., influence of bones on the distribution of the dose) are not taken into account here.
3D conformal planning requires planning computed tomography. Through this the electron densities as well as the target structures and organs at risk can be determined individually for the patient. The planning system contains many stored sample measurements with the help of which the computer then calculates a very precise dosage estimate according to specification. In doing this the most accurate systems simulate the irradiation by considering individual photon paths (so-called Monte Carlo simulation).
In classical 3D-planning the radiotherapy physicist specifies not only the direction of the beam and the geometry of the radiation fields to the radiotherapy planning system and then checks the dose distribution in the target structures in order to adjust the field configuration after that if needed. In contrast, with intensity-modulated radiotherapy (IMRT) the dose desired is specified to the planning computer in terms of the target volume and the maximum tolerated exposure of the organs at risk (so-called constraints) ( ▶ Fig. 14.2, Video 14.1). With the assistance of iterative algorithms the computer optimizes the field configuration independently. In doing this, differently shaped fields are irradiated from one gantry angle so that the intensity of the field is modulated (hence the name) in order to reach the planning target. These plans become so complex that they cannot be checked for plausibility with simple software algorithms. The irradiation of such a plan on a dummy for measurement purposes and comparison between what is measured and the dose calculated is the optimum way to verify such planning before the plan is implemented on a patient.
Fig. 14.2 Intensity-modulated irradiation of a carcinoma of the right upper jaw, with extensive destruction of the midfacial bones. The high doses (brown/red) attenuate rapidly in the area of the orbit (green/blue) and this minimizes the side effects of irradiation on the ocular structures.
Imagery-guided radiotherapy (IGRT) requires imagery at the linear accelerator (or at the patient positioning table). Modern equipment uses the high megavoltage photon radiation for imaging. However, these energies are associated with high losses in image quality as this radiation has very poor contrast (only a little radiation is absorbed e.g., in the bone). This is why many accelerators are equipped with a normal X-ray tube as well. Alternatively, X-ray tubes can be directly installed in the radiotherapy bunker that aim at defined angles onto the axis of rotation of the accelerator (the so called “isocenter”). The corresponding image converters are mounted on the other side of the patient table. This way, the anatomy of the patient can be made visible before radiotherapy and, if necessary, corrected by adjustment of the treatment table position.
Ideally, the current position of the tumor is represented by radiopaque markers (e.g., small spirals of gold) and monitored closely during the radiotherapy procedure. The patient can then be adjusted for the respective position of the tumor by automatic movement of the treatment table. This process is designated as image guided radiotherapy (IGRT).
A further example is respiration-gated radiotherapy of a lung carcinoma. In this the respiratory cycle of patients is monitored and the irradiation is administered only in a relatively central position.
Proton and Heavy Ion Radiation (Particle Radiation)
Photons and electrons are classified as “ sparsely ionizing” radiation. In contrast, protons and “heavy” ions (e.g., helium or carbon ions) lose their energy to a lesser extent during most of their trajectory and then transfer most of it in almost the very last part, the so-called “Bragg peak” ( ▶ Fig. 14.3). The position of the Bragg peak depends on the acceleration energy and thus can be determined very precisely. Beyond the Bragg peak only a very minimal radiation survives in the tissue.
Fig. 14.3 Comparison of the energy transmission (linear energy transfer) of photons and of protons. On the horizontal axis the depth (cm) of the surface in a water dummy is given, the vertical axis represents the dose. Tumor tissue, with normal tissue on either side of it, is assumed at a defined depth.
The photons striking the surface of the water only build up their full energy dose in layers lying somewhat deeper (so-called forward scattering) and then penetrate all further tissue equally. The protons exhibit a different characteristic: on the way to the tumor they ionize the surroundings to only a limited extent, and then virtually the whole of the energy is delivered in the tumor; hardly any radiation penetrates behind the tumor. The diameter of the tumor is covered by using protons with different energies whose Bragg peaks then overlap.
As a result of this physical feature, the entire radiotherapy dose required can be deposited in the region of the tumor from one or two irradiation directions. In many cases, therefore, the “crossfire technique” needed for classic 3D-conformal radiotherapy with photons, with its correspondingly higher radiation exposure of neighboring tissue, is not required.
As a result of the high release of energy release in one place in the tissue (linear energy transfer, LET), heavy ion irradiation is biologically more effective than photon irradiation. The relative biological effectiveness (RBE) compares the number of biological effects that are triggered by different types of radiation. Sparsely ionizing photon radiation is rated as 1. Compared with this, proton beams have an RBE of 1.1, helium ions 1.3. 1 As this increases biological effectiveness has an effect not only on the tumor cells but on normal tissue as well, the dose of the heavy ion radiation must be adjusted accordingly. For this, the cobalt gray equivalent (CGE) is a useful concept that also enables comparison with the results of treatment with conventional photon radiation.
Protons are generated from water through hydrolysis and accelerated by a cyclotron to 2/3 of the speed of light. Upon reaching the appropriate speed, the beam is further modulated from its circular path via beam lines, which are formed by electromagnets, and directed to a gantry in the treatment room. Individually prepared compensators can be used to cover the tumor. Alternatively, the equipment can also be fitted with pencil beam scanning. In this the tumor region is “scanned” with the proton beams and thus the treatment session consists of many “single shots.” Although the application of radiation is thereby extended in time, this does mean that no individual collimators have to be produced and disposed of after use (radioactive waste).
A disadvantage of this technique is the extremely high technical effort and thus financial cost necessary for the creation of these types of radiation. For this reason proton radiation is at present only available in a few places.
A further disadvantage is low energy transfer of the particles on their way to the Bragg peak. As the tumor must be covered in its entire depth, particles with the requisite energy differences must be fired into this area and already on the way to the tumor volume the energy emissions overlap. When irradiating tumors in the fundus of the eye, there is therefore significant radiogenic exposure in the anterior parts of the eye. This is why ~35% of patients later develop neovascular glaucomas after proton radiotherapy of uveal melanomas. 1
In summary, so far it has only been clinically demonstrated for a few entities and situations that radiotherapy with particles provides a clinical advantage in the sense of higher tumor control and/or fewer side effects. Among those entities are, for example, the adenoid cystic carcinomas as well as chondrosarcomas of the base of the skull (evaluation of the German Society for Radiooncology at http://www.degro.org/dav/html/download/pdf/Protonen_Stellungnahme_010808.pdf). The aim of the radiooncological research in the abovementioned centers is to examine further indications in clinical studies and to evaluate treatment results.
Memorize
The physical characteristic of proton and heavy-ion irradiation consists in the release of a large part of the energy at a certain point (the so-called Bragg peak). This means that the radiation dose can be applied very precisely. The increased biological effectiveness in comparison with photon irradiation must be taken into account when prescribing the dose.
A disadvantage is the high cost of production so that this form of treatment is only available in a few centers.
Thus far, a clinical advantage for proton irradiation compared with photon radiation has been shown for only a few entities.
Brachytherapy: Contact Radiotherapy
With distance between the radioactive source and the target structure to be irradiated of >10cm the procedure is described as “teletherapy”; with a smaller distance it is known as “brachytherapy.” The advantage of contact radiotherapy in the area of the orbit lies in the possibility of applying high doses of radiation directly in the posterior pole of the eye without having to penetrate the anterior parts of the eye or other areas of the orbit. Various isotopes are used for this that emit radiation by natural mechanisms of decay. A differentiation is made clinically between beta decay (the emission of electrons) and gamma decay (the emission of photons/energy quanta). Alpha emitters do not play a role in this context. One should take account of the fact that, in natural decay series, differing types of decay often occur and also differing energies as well (the so-called natural decay spectrum). The clinically important characteristics are summarized in ▶ Table 14.1. 2
Isotope | Clinically relevant radiation | Energy (mean or spectrum) | HLP | HVLD |
Iodine 125 (125I) | gamma | 0.022–0.031 0.035 | 60 days | 20 |
Palladium 103 (103Pd) | gamma | 0.021 | 17 days | 15 |
Cobalt 60 (60Co) | gamma | 1.17–1.33 | 5.26 years | 108 |
Iridium 192 (192Ir) | gamma | 0.38 | 74 days | 63 |
Ruthenium 106 (106Ru) | beta | 2.07–3.54 | 1 year | 24 |
Strontium 90/yttrium 90 | beta | 90Sr 0.546 | 28 years 64 hours | 1.5 |
Abbreviations: HLP: half-life period HVLD: half-value layer density. | ||||
In general, two different forms of contact radiotherapy in the area of the orbit can be differentiated: episcleral and intraocular brachytherapy. In this, intraocular brachytherapy for the selective radiotherapy of the macula (epimacular brachytherapy) after vitrectomy with strontium-applicators is so far still classed as experimental (see Chapter ▶ 14.4.5). In contrast, the epibulbar application of strontium-applicators of ~1 cm diameter in the treatment of pterygia is well established (see Chapter ▶ 14.4.4). For this, the applicator is held manually directly over the area to be irradiated or is moved slowly in circling movements. With highly active sources, this procedure takes only a few minutes.
In classic episceral brachytherapy during an operative intervention, a cap-shaped applicator is firmly sewn onto the sclera or cornea over the structure to be irradiated. How long it remains in place is dictated by the dose to be administered and the range of the radiation from the isotope deployed.
Due to the high energy of the gamma emission of cobalt 60, the ocular structures are exposed to high doses of radiation; likewise the operating team and nursing staff are also exposed to high radiation doses. For this reason, the use of this isotope has over time become obsolete. Similarly iridium 192—often used for high dose rate contact radiotherapy in other cases—has no part in the treatment of orbital tumors because to its high dose rate and comparatively high energy.
Iodine 125 and palladium 103 are characterized by the emission of gamma radiation with much lower energies. Because of this the surrounding ocular structures can be relatively well protected with gold shields as the rear applicator wall.
This works even better with the beta radiation of ruthenium 106 ( ▶ Fig. 14.4). All of the radiation is absorbed by the 0. 7-mm silver posterior shielding, while a 0.1-mm thin silver foil on the concave side screens out only the low-energy electrons (0.039 MeV) and lets the high-energy electrons at 3.54 MeV exit almost unhindered. The dose gradient is even steeper than with iodine 125 or palladium 103, at a distance of 7 mm from the applicator the dose is reduced to 1/10 of the starting dose. Thus neighboring ocular structures can be well protected. A disadvantage is the unavoidably high dose at the sclera with a tumor apex of >6mm in order to still maintain a sufficient dose in the areas of the tumor lying farthest from the applicator. For this reason, the use of this isotope should remain limited to tumors <5mm in height (+ 1 mm sclera) ( ▶ Fig. 14.4, ▶ Fig. 14.5).
Fig. 14.4 Structure of a ruthenium 106 applicator of the Bebig Company and the depth distribution of a CCA applicator. Left: the rear of the applicator is screened with 0.7 mm silver, while the 0.1 mm-thick silver foil on the inside allows through the beta radiation used in treatment. Right: the emitter is fixed externally to the sclera; at a distance of 0.5 mm 90% of the dose is measured, at 1 mm 75%, at 2 mm more than 50%, and at 4 mm 25% can still be measured. With the kind permission of Eckert & Ziegler BEBIG, Berlin.
Fig. 14.5 Comparison of depth–dose curves between a ruthenium 106 and a iodine 125 applicator on the model of an eye. The clearly steeper dose gradient from the ruthenium 106 is striking. This gives the advantage of lower exposure of the unaffected ocular structures. However, with the irradiation of tumor cells lying >6 mm from the applicator, very high doses are necessarily required at the sclera. With the kind permission of Eckert & Ziegler BEBIG, Berlin.
Memorize
In brachytherapy a natural emitter is placed directly onto the lesion to be treated or the overlying sclera. Episcleral brachytherapy is well established, for example, with iodine 125 and ruthenium 106. As the beta radiation of the ruthenium does not reach as far as the γ gamma radiation of the iodine, ruthenium can only be used to treat tumors at an apical distance of up to 6 mm from the emitter. Tumors up to 10 mm can be treated with iodine applicators; but the surrounding ocular structures will be subject to greater exposure.
14.3 Radiotherapy of Malignant Neoplasias of the Orbit
14.3.1 Metastases in the Area of the Orbit
In principle, any malignant neoplasia of the human body can form metastases in all structures of the orbit. In the course of this the symptoms depend on the particular localization of the metastasis. When the eye muscles are afflicted this is often associated with exophthalmos, pain, and diplopia. Occasionally, however, enophthalmos can also be observed (in particular with cirrhotic adenocarcinomas) if constricting, scarlike infiltrations arise.
Due to the blood flow characteristics and, also probably, due to interactions between surface antigens of the tumor cells with vascular endothelia, most of the secondary metastases are located in the area of the uvea. 3 It is estimated that up to 10% of patients suffering from advanced tumor stages develop metastases in the uvea (literature overview 4); of these, however, ~90% remain asymptomatic and, for that reason, are not detected without ophthalmological examinations. 5
The most frequent originating tumors for uveal metastases are ~80% breast carcinomas in women and the same for bronchial carcinomas in men. 6 The average survival time after diagnosis of such metastases is ~9 months, 7 although the prognosis can differ hugely depending on the primary tumor, previous treatments, and the response of the disease to systemic therapies.
Choroid Metastases
Almost 90% of uveal metastases affect the choroid; metastases rarely occur in the iris, and are even rarer in the ciliary body. 3, 8, 9 In the area of the choroid most of the metastases are localized between the macula and the equator. 9
In up to 50% of choroid metastases they are synchronous or associated with cerebral metastases occurring in the later course of the disease. 6 Multiple choroid metastases are seen in up to 30% of patients. 6 In almost 50% of patients (in particular with breast cancer), bilateral affliction is seen, with half of those afflicted not experiencing any symptoms. 3
The symptoms are dependent on the localization of the metastases. Patients afflicted notice a worsening of their sight or blurred vision; less often they report floaters, photopsia, or scotomas. 3 If it is untreated, there is a danger of complete blindness and a painful, treatment-refractory glaucoma that ultimately will make enucleation unavoidable.
Therapy
Treatment depends on the localization of the metastasis, its size, and the treatment options for the primary tumor.
Small metastases without acute risk to sight in systemically still responsive tumors can be monitored initially within the context of systemic therapies, as the probability of a remission is high. The choroid lies outside the blood–vitreal barrier so that systemic medicaments can flow freely. Very good remission rates have been described for systemic administration of the VEGF-antibody bevacizumab. 10 Astonishingly, intravitreal injections are also effective, probably because of the very high local concentrations, which can sufficiently overpower the blood–vitreal barrier in a reverse direction.
Percutaneous Radiotherapy
Prompt induction of localized therapy is indicated with progression of choroid metastases threatening the ability to see by growing into the macula, subretinal fluid accumulation, or bleeding into the vitreous humor. The aim of such treatment is local control.
In this situation external beam radiotherapy with photons (EBRT) plays a very important role. It is available everywhere, effective, and cheap. The total and single doses of EBRT published since the 1970s vary between 5 × 5 Gy and 25 × 2 Gy (overview 4). Due to variations in irradiation techniques and in the dosages, and the nonstandardized definition of the end point of sight improvement, direct comparison of the study results is difficult. Local control of the tumor was reported in 70 to 90% of patients and stabilization or improvement of the sight in >70%.
In the only prospective phase II study a total dose of 40 Gy with 2 Gy single dose in 65 afflicted eyes (50 patients) was examined with regard to effectiveness and toxicity. 5 The median survival was 7 months. Sonographically, 17% of the tumors exhibited no change as a result of the radiotherapy, 39% a full remission, the others a partial remission. With regard to clinical end points, 85% profited from the therapy: a significant improvement in sight was experienced by 36%, a stabilization by 50% of patients. None of the initially asymptomatic patients experienced a deterioration in their sight. In the further course of the disease, metastases recurred in 14% of the eyes. Half of the patients developed temporary skin erythemas or conjunctivitis during treatment. Severe radiogenic side effects were described in a no more than 5%.
Because of the sensitivity of ocular structures, hypofractionated treatment schedules (e.g., 5 × 5 Gy) are no longer recommended. Instead, as far as clinically possible, a therapy series giving 5 × 2 Gy up to 40 Gy should be followed in accordance with the findings mentioned above.
In clinical practice a dosage of 10 × 3 Gy has also proved to be effective, in particular when concurrent brain metastases are identified and the choroid metastases are to be treated at the same time with whole-brain radiotherapy by widening the radiation fields. Based on radiobiological formulae, comparable effectiveness can be assumed with regard to not only the normal tissue but also the tumor cells. At 10 × 3 Gy, assuming an α/β quotient of 3 for late-reacting normal tissues, the biologically effective dose is 100 Gy3 in comparison to 93.3 Gy3 with a fractionation of 20 × 2 Gy. For tumor cells a distinctly higher α/β quotient (~9) is postulated, the biologically effective dose at 20 × 2 Gy is calculated at 84.3 Gy9 and 93.3 Gy9 at 10 × 3 Gy. No allowance has been made here for the acceleration of the therapy at 10 in comparison to 20 fractions and the thus additionally increased biological effectiveness.
Technique
The EBRT takes place with the patient in a supine position, with the head fixed in a mask positioning system.
The eye structures afflicted, including the orbital optic nerve, are mapped as the CTV (clinical target volume) in the planning CT. The safety margins for the definition of the PTV (planning target volume) only have to cover unsafe positioning of the mask (depending on the system used) and, where necessary, the movement of the eye(s).
If it is anatomically possible, the lenses should be protected. For this, lateral-opposing fields offer good options. The central radiation plane is placed ventrally behind the lenses to avoid divergence of the beam paths in this direction ( ▶ Fig. 14.6).
Fig. 14.6 Radiotherapy of an extensive orbital metastasis, right, with lateral opposing fields. This means both orbits are covered with the same radiation dose homogeneously. Protecting the lenses does not make clinical sense in this example because of the extent of the metastases and therefore has not been attempted.
On the left side of the illustration, the angle and the configuration of both fields are shown schematically; in the center the field aperture is shown in yellow and the configuration of the multileaf collimator (MLC) from the line of sight of the accelerator onto a digitally produced radiograph is shown in green. On the right, the dose distribution is shown in a transversal layer as an example, where the reddish-brown colors correspond to the prescribed dose.
If the metastasis lies in the iris area, the lens cannot be protected by conventional means. Here irradiation with several field angles (“wedge”) is generally unavoidable.
If affliction is unilateral, it is justified not only to irradiate with laterally opposing fields with inclusion of the contralateral ocular fundus (due to the synchronous contralateral metastases found in up to 50% of cases) but also to irradiate unilaterally only on the side afflicted ( ▶ Fig. 14.7). Through the unilateral irradiation only 50 to 70% of the dose will be applied in the area of the contralateral eye. 5 In the above-mentioned prospective study, with this procedure no contralateral choroid metastases recurred. The authors postulated that this dose had effectively prevented the occurrence of contralateral metastases. 11 However, the low number of cases (n = 35 with unilateral occurrence) must be taken into account. Furthermore, so far there have been no further clinical data on dose–effect relationships, either for the elective or for the therapeutic, scenario.
Fig. 14.7 Irradiation of an extensive orbital metastasis, right, unilateral. The aim of this technique is comprehensive protection of the contralateral orbit.
On the left side of the illustration the entry angle and the configuration of the three fields are shown schematically. On the right side, the dose distribution is depicted in a transversal layer as an example, where the reddish-brown colors correspond to the prescribed dose. In comparison to ▶ Fig. 14.6, the temporal right brain is more exposed, but the contralateral orbit has now been taken out of the irradiation fields.
Memorize
EBRT is suitable for treating choroidal metastases with 10 × 3 Gy or 20 × 2 Gy. With this regimen, sight can be improved in 85% of patients or at least stabilized. If the affliction is unilateral both the ipsilateral and the contralateral orbit can be treated. With cerebral metastases the choroid together with the whole cerebrum is irradiated.
Other Radiotherapy Techniques
An alternative to percutaneous irradiation with photons is provided by protons or heavy ions. With this technique very high single doses can be used saving time vis-à-vis EBRT. Furthermore, the eyeball can be sufficiently immobilized through a “light point” technique, so that operative interventions (as in brachytherapy) are not necessary. 12 As there have so far not been any prospective randomized studies comparing it with EBRT, the effectiveness and toxicity of this irradiation technique in comparison with EBRT cannot be assessed. However, the production of these beams is extremely time-consuming, equating to cost-intensive, and thus only possible in a few centers. In the highly palliative situation of the treatment of uveal metastases, the use of this method is mostly not justified.
Alternatively, the deployment of brachytherapy in smaller patient series for the treatment of a single, well-defined choroid metastasis has also been reported. 13 The technique of episcleral treatment is described under “Technical Procedure in Episcleral Brachytherapy” in Chapter ▶ 14.3.3. This does, however, require the operative attachment (and subsequent removal) of an appropriate applicator episclerally on the metastasis. The theoretical advantage vis-à-vis EBRT is the shorter treatment duration and the more precise coverage of the metastasis. As an effective dose, in the largest series a dose of ~68 Gy at the tumor apex and 236 Gy at the base of the tumor metastasis have been reported. 14
Clinical advantages of this more costly therapy over EBRT on a group of patients suffering from an advanced malignant disease have not yet been substantiated. However, the possibility of re-irradiation by brachytherapy is undisputed in the event of a recurrence or renewed progression after EBRT has been given.
Metastases and Tumors of the Eyelid
Systemically far advanced tumors rarely metastasize in the eyelids. Their frequency is assessed at <1% of malignant changes in the eyelids. These lesions grow in a diffusely infiltrating manner as well as locally, 15 so that operative resections can be very complex due to the reconstruction required. As a therapeutic alternative, palliative EBRT can be offered. In a series of seven patients with eyelid metastases, local control with EBRT was reported in four patients. 15
Basaliomas or squamous epithelial carcinomas of the skin can likewise occur in the eyelid area. Here EBRT represents an alternative treatment of equal value to operative procedures, with excellent local control rates.
Therapeutically, either kilovolt-photon irradiation or electron irradiation is used. In order to achieve maximum effect with electron irradiation, a layer of material isodense to water is placed onto the region affected (e.g., a silicone cushion 1 cm in diameter). The radiation builds up in this layer (forward scattering, see ▶ Fig. 14.2) so that 100% of the prescribed dose covers the area of the tumor at skin level. To protect the ocular structures (sclera, lens, retina), before each radiotherapy session a calotte of dense material (gold, lead) is placed onto the sclera under the eyelids after a local anesthetic has been given. Thus these organs at risk (except for the lacrimal gland) can be protected effectively despite the administration of higher doses of radiation.
Technically kilovolt-photon irradiation (if still available) is the easier to use. It is characterized by a smaller half shadow than electron irradiation 16 in the area of the field margin. This must be taken account of in the field definition in order to avoid underdosing in the tumor. Also in favor of the use of kilovolt irradiation is the fact that it can be blocked more easily: eye calottes with lead 2 mm thick with a 0.1-mm gold coating are found to be sufficient for 250 kV ( ▶ Fig. 14.8). 16 For electron irradiation the calottes used must be measured in advance and adjusted appropriately for the energies used as regards the density of the material and the diameter of the calotte. Lead calottes are impractical due to the thickness required at, for example, an electron energy of 9 MeV. Calottes of tungsten or gold have proved to be significantly better suited. 17 The calottes should be coated additionally with 2 mm of acrylic 17 to reduce any backscattering that would give additional exposure to the inside of the eyelids. 17
Fig. 14.8 Example of an eye calotte.
Memorize
With metastases and tumors of the eyelid, EBRT with kilovolt-photon irradiation or with electron irradiation is well suited for achieving local control as an alternative to operative interventions. Eye calottes are placed on the sclera before each administration of radiation to protect unaffected ocular structures.
14.3.2 Orbit Lymphomas
Primary intraocular lymphomas (PIOL) are rare. They belong to the group of extranodal non-Hodgkin’s lymphomas and are mostly derived from the B cell line. T cell lymphomas in this location are a rarity in Europe.
The retina, the vitreous humor, and the optic nerve can be afflicted. 18 In 80% of cases there is CNS involvement within 2 years of diagnosis (so-called oculocerebral lymphoma); in ~20% of primary CNS lymphomas the eye becomes infiltrated in the course of the disease. 19 In this respect, PIOL constitutes one entity of the primary CNS lymphomas (PCSNL). These are mostly diffuse large B-cell lymphomas and accordingly highly malignant lymphomas.
The primary lymphomas of the uvea have to be distinguished from these. These are mostly differentiated as low-malignant B cell lymphomas (extranodal marginal zone lymphomas). 18
With secondary involvement of the orbit within the context of an extraocular lymphoma growth, mostly the uvea or the adnexa are affected.
Due to the radiosensitivity of lymphoma cells, although radiotherapy is associated with high remission rates, it is only for low-malignant lymphomas with long-term tumor control. This is why therapeutically highly malignant lymphomas must be differentiated from low-malignant (indolent) ones.
Memorize
For the treatment of orbit lymphomas it is imperative to differentiate them into low-malignant lymphomas, curable by radiotherapy, and highly malignant ones, curable by chemotherapy. Low-malignant lymphomas mostly afflict the uvea and the orbit adnexa; highly malignant ones afflict the retina, the vitreous humor, and the optic nerve. Of highly malignant lymphomas in the orbit, 80% manifest themselves in the CNS as well over the further course of the disease.
Treatment of Highly Malignant Lymphomas
So far, due to the rarity of the disease, there is no standard procedure. In principle, the condition should be treated locally as long as the disease is restricted to the eye and systemically if the CNS is primarily involved. 20
The polychemotherapy generally deployed for highly malignant lymphoma according to the CHOP protocol (cyclophosphamide, vincristine, doxorubicin, prednisolone) is largely ineffective for eye and CNS involvement as it scarcely overcomes respectively the blood–eye or blood–brain barriers. 20
With the involvement of an eye only, either intravitral methotrexate (MTX) or rituximab is applied or the orbit is irradiated with 30 to 35 Gy. 20 Here it is postulated that the generous covering of both orbits by use of laterally opposing fields without protection of the lenses could be associated with a lower recurrence rate than the strict unilateral irradiation of the afflicted orbit with wedged fields or technical omission of orbital structures (e.g., of the lens), even if there is no prospectively randomized corroboration of this assumption. 21 As so far the superiority of no one treatment modality has been demonstrated, treatment can be according to the patient’s wishes and adjusted for any previous treatments.
When both eyes are afflicted simultaneously, bilateral local therapy can be combined with systemic treatment.
Memorize
Highly malignant lymphomas that are localized only to the eyes are treated locally. For this EBRT and also intravitreal MTX or rituximab can be deployed.
With simultaneous CNS involvement the therapy is orientated on the treatment of PCNSL, where necessary combined with local therapy to compensate for the limited penetration of the chemotherapy and antibodies into the eye chambers.
With PCNSL, the whole cerebrum is treated by radiotherapy (WBRT). After WBRT with 40 Gy and 20 Gy additional boost doses in the regions afflicted, 5-year survival rates of between 10 and 30% are achieved, and ~60% after a combination of ~45 Gy WBRT with high-dose MTX. 22 However, with combination therapy there is a raised risk for chronic neuronal toxicity. This shows itself on the one hand in a reduction of the neurocognitive capabilities, in particular of the executive functions (alertness, learning and reproducing new information) as well as of psychomotor coordination. 23 On the other hand, ~30% of patients develop therapy-associated leukoencephalopathy and brain atrophy after combination therapy, which is associated with dementia, ataxia, and incontinence and can have a lethal progression in one-third of patients. 24
For this reason in phase II studies—at least in patients with complete remission after MTX induction—the dose of the WBRT is successively reduced to 30.6 Gy and 23.4 Gy. 25 In this way the neurotoxicity is indeed distinctly reduced, but in younger patients the oncologic therapy results seemed also to become compromised. Good long-term results have been published for a dose reduction of the WBRT to 23.4 Gy after complete remission with polychemotherapy (MTX, procarbazine, vincristine) including administering rituximab with cytarabine as consolidation. 26 The 3-year survival rate was 87%, in contrast with only 40% in patients who did not exhibit complete remission for the induction therapy and who were irradiated with 45 Gy.
Only one prospective randomized phase III study (G-PCNSL-SG) examined the value of WBRT. In this it was shown that WBRT up to 45 Gy with 1.5 Gy single dose after high-dose MTX or high-dose MTX and ifosfamide significantly improved progression-free survival in some subgroups but not the overall survival of patients. 27 However, a definitive evaluation of the results is not possible as the study was calculated to have a power of 60%, thus being not big enough to substantiate the noninferiority of the chemotherapy alone arm. 25
Nevertheless, in current German therapy studies, when there is complete remission on chemotherapy the cerebrum is not subject to further irradiation. The focus of therapy is on polychemotherapy, with high-dose MTX as a fixed component, flanked by araC, thiotepa, and alkylating agents. With this regimen, 8-year survival rates of 50% are achievable for those under 65 years of age. 28 In addition, rituximab is currently given in the protocols. Although this is poor at penetrating the CNS, nevertheless it is apparently relatively effective in low concentrations in the CNS.
The value of high-dose chemotherapy with autologous stem cell transplantation has still not been definitively established and is being investigated in various randomized studies. 24
The value of whole-brain radiation with optional boost for the regions afflicted with primary or secondary therapy failure after system therapy is undisputed. In this a whole-brain dose of 36 Gy and a single dose of 1.5 Gy should not be exceeded due to the otherwise distinctly raised risk of neurological late toxicity. 29 In patients who are unable to receive chemotherapy, higher overall doses are applied in line with the results described above. When the eyes are affected, the orbits are included in the radiotherapy volume via laterally opposing fields.
Memorize
Highly malignant oculocerebral lymphomas are treated like CNS lymphomas. Here polychemotherapy plays the primary role. In current therapy studies, consolidating irradiation of the CNS still plays a role only in incomplete remission of the lymphomas after chemotherapy. In this, the radiation dose planning must avoid the occurrence of a radiogenic leukoencephalopathy, which proves fatal in 30% of those afflicted.
In patients who for reasons of comorbidity cannot receive chemotherapy, or with recurrences after polychemotherapy, the value of whole- brain radiotherapy is undisputed.
Therapy of Low-Malignant Lymphomas
The role of radiotherapy in these entities is considerably better defined.
Traditionally, indolent lymphomas of all localizations were treated locally with radiation doses between 24 Gy and more than 40 Gy. This reliably gives local control with very high cure rates for MALT lymphomas of the orbit. 30 A SEER analysis on 1111 patients with low-malignant orbit lymphomas who were treated from 1998 to 2010 showed that over the further course none of the patients receiving radiotherapy died as a result of lymphoma, whilst 11.5% 31 of the patients who did not receive radiotherapy died.
The equivalence of 24 Gy and 36 Gy dosage in diverse lymphoma localizations was demonstrated in a randomized prospective study. 32 Various series reported good and long-lasting remission rates after a dose de-escalation to 2 × 2 Gy. This concept too was compared prospectively in a randomized study in diverse localizations with 12 × 2 Gy. 33 However, significantly lower rates of complete remission (44% at 2 × 2 Gy ; 60% at 12 × 2 Gy) were reported and a lower local progression-free survival.
In contrast to the experiences with indolent lymphomas of other localizations, a retrospective series has been published with outstanding results after low-dose radiotherapy in the area of the orbit. This can be attributed to the generally lower tumor burden in the orbit area and its earlier diagnosis with visible or early clinical symptomatic disease in contrast to lymphoma occurring in other locations. Fasola et al report on 20 patients with 27 lymphomas manifesting in the area of the orbit adnexa, which were irradiated with 2 × 2 Gy. 34 After a median follow-up of over 2 years, a complete remission was seen in 85% of the lymphomas treated, a partial remission in 11%. Only one patient experienced an intraorbital recurrence outside the radiotherapy fields. No acute side effects were reported by 80% of the patients; in 20% there were mild, self-limiting toxicities such as periorbital edema, dry eyes, or conjunctivitis. Chronic toxicities did not occur. Although these are retrospective data on a patient group with only 2 years of follow-up monitoring, in several respects these results are normative for radiotherapy of indolent lymphomas of the orbit, as they enable a very gentle treatment option:
Higher doses of radiation are associated with higher risks for acute and chronic toxicities; thus over 50% reported acute complications with doses between 19 and 48 Gy 35; for details see Chapter ▶ 14.5. Even with a local progression after 2 × 2 Gy of previous exposure, re-irradiation is possible with few complications.
Additionally, the target volume definition has been disputed: after selective radiotherapy of the afflicted orbit region, in up to 30% of the patients a recurrence was reported outside the radiation volume, so that initial irradiation of the whole orbit has been considered. 36 Fractionation of 2 × 2 Gy enables partial orbit irradiation since if there is recurrence there can be unproblematic re-irradiation even with fields that overlap previously irradiated structures. On the other hand, a complete orbit irradiation can also be carried out on a primary fractionation schedule with 2 × 2 Gy with minimal toxicity.
Partial orbit irradiation with low-dose radiation does, however, require close follow-up. In so doing, the contralateral orbit is also to be examined as even in this area recurrences have occasionally been described. 34
Memorize
Low-malignant MALT lymphomas of the orbit are curable by EBRT with low doses of radiation (2 × 2 Gy or 12 × 2 Gy). It has not been established whether the whole of the afflicted parts of the orbit have to be treated. With the extremely low radiation doses, treatment of only the afflicted part can be strongly justified.
Technique
The patient is placed in an individually prepared thermoplastic mask. The GTV (gross tumor volume) is determined by the clinical considerations and the imagery. The CTV embraces either the GTV including the afflicted ocular structure (lacrimal gland or conjunctiva), or else the whole orbit (see discussion above). In principle, tumors lying on the surface should be treated with electrons using bolus material (silicone cushion) in order to guarantee an optimal dose build up effect. Volumes lying deeper (e.g., lacrimal gland) are treated with photons after 3D planning ( ▶ Fig. 14.9).
Fig. 14.9 Dose distribution of an irradiation for a low-malignant orbital lymphoma, left. Through the use of three different beam angles, in which one enters cranially via the skull calotte, very good coverage of the target volume is achieved with a sharp dose decay into the surrounding, unaffected structures. The intended dose can be identified as a reddish-brown colors in the transversal section (right) and low radiation doses as green/blue colors.
Whenever appropriate and possible, the lens should be protected with a calotte (see Chapter ▶ 14.3.1).
14.3.3 Uveal Melanomas
The treatment of uveal melanomas has changed fundamentally since the 1980s. Whereas enucleation previously represented the mainstay of treatment, since then—whenever technically possible and desired by the patient—the focus has been on procedures that preserve the eye.
Radiotherapy can control uveal melanomas oncologically and at the same time preserve the sight as well as the eyeball. 2 However, the radiation doses required are above the tolerance doses of the retina, the optic nerve, lenses, eyelids, and lacrimal gland. For this reason, correspondingly adjusted techniques or radiation planning are necessary. The necessary dose distributions can be achieved via episcleral brachytherapy, irradiation with protons/heavy ions, or via radiosurgical techniques. Internationally, brachytherapy is the most frequently used.
Value of Radiotherapy: COMS Studies
The value of radiotherapy was investigated to derive guidance from long-term, prospective, randomized studies by the COMS group. 37 This data is very significant because uveal melanoma is a rare disease 38 with an estimated 1,400 new cases reported per year in the United States. In 1986 three multicenter prospective studies were started at the initiative of the National Eye Institute, into which ~2,500 patients with unilateral choroidal melanomas were recruited.
The melanomas were divided into three categories 39:
Small melanomas: 1.5 to 2.4 mm tumor height, diameter 5 to 16 mm.
Medium-sized melanomas: 2.5 to 10mm tumor height, diameter ≤16 mm (since November, 1990).
Large melanomas: >10 mm tumor height, diameter >16 mm.
Small Melanomas
Patients with small tumors on the criteria above were offered the chance of being included in a prospective monitoring study. With these patients there was the risk of a misdiagnosis by confusion with a benign nevus, so the closely monitored growth process would ultimately provide information about the nature of the tumor. Initially 188 tumors were monitored, of which ~10%, 20%, or 30% were progressing after 1, 2, or 5 years. 40 Although most patients were not treated, only 1% of the patients had died from melanoma within 5 years.
Conclusion
Small uveal melanomas with tumor heights under 2.4 mm and diameters less than 16 mm can often be differentiated from benign nevi only through the long-term growth process. Within 5 years only 30% exhibit progression.
Medium-sized Melanomas
Patients with medium-sized melanomas on the criteria above (no localization peripapillarly or in the ciliary body, cM0) were randomized between episcleral brachytherapy with an iodine 125 applicator or primary enucleation. Over a 12-year period a total of 1,317 patients were treated. 41 The 5-year survival rates did not differ significantly, being 81% after enucleation and 82% after brachytherapy, nor did the tumor-specific survival rates. Long-term data with 10- and 12-year survival rates exhibited no significant differences. 42 Almost half of the patients in the study were still alive after 12 years free of disease. Negative prognostic factors were tumor diameter >11 mm and age >60 years.
The organ-preserving procedure exhibited good oncological effectiveness. In the first 5 years after brachytherapy only ~12.5% of the patients underwent enucleation: 10% for tumor progression (mainly in the first 3 years of primary treatment), 2.5% due to other causes (pain, loss of sight). 43 In 2% of the patients, although a recurrence was documented, enucleation was not done. A recurrence was defined here as an increase in the height of the tumor by 15% in ultrasound or growth of 250 µm in photographs in two consecutive examinations. Age >50 years, tumor height >5 mm, and tumor growth up to the fovea were correlated with the frequency of recurrence.
The mortality of patients after a secondary enucleation might be increased (risk ratio 1.5). After adjustment for other risk factors, however, this finding just failed statistical significance at p = 0.08 and did not affect the survival rates of the whole group (see above). For this reason, brachytherapy can be regarded as a safe alternative in this patient group.
With regard to radiogenic side effects, 532 patients without cataracts before brachytherapy were monitored in follow-up examinations. 44 The first cataract developed a median 2.5 years after primary therapy; the first operation became necessary after a median 3.5 years (with no defined criteria preset for the indication for the operation). After 5 years cataracts had developed in 83% of the affected eyes, but only 12% had to be operated on because of this. After a lens dose of ≥24 Gy, 18% of the patients were operated on; after <12 Gy this was only 4%. Sight improved in most patients after cataract operations or stabilized. Cataract surgery was effective despite the tumor treatment.
Functional limitation in the sense of a substantial loss of sight after brachytherapy was experienced by only 17% of patients after 1 year, by 33% after 2 years, and by >40% after 3 years. 45 The risk was associated with diabetes mellitus, tumor height [≤5 mm vs. >5–7.5 vs. >7.6], distance between tumor and macula, and tumor-associated detachment of the retina (in particular when the macula was involved). The tumor height was directly correlated with the radiation dose required; likewise, the proximity of the tumor to critical structures also determined the dose applied there. Surprisingly, however, they all the patients lost visual acuity, even those with good sight before therapy: approximately 2 lines per year after treatment, to a greater extent in patients with risk factors. 45
The implications of these findings for the quality of life have been examined in an accompanying study on 209 patients at 6 months and then annually after the treatment. 46 Both after brachytherapy and also after enucleation, a significant rise in difficulties was experienced in activities that require visual guidance. The differences in visual function (night-time driving, peripheral vision) between the treatment groups were significantly in favor of brachytherapy, at least during the first 2 years, even if to only a limited extent. After 3 to 5 years, however, the differences leveled out. At the same time, anxious patients suffered more from anxiety symptoms after brachytherapy than did anxious patients after enucleation.
Overall it was demonstrated that enucleation and iodine 125 brachytherapy are equally effective in melanomas with medium-sized tumors regarding survival and tumor control. Although the eye-preserving procedure did favor some functional parameters during the first 2 years after treatment, these differences in functionality and quality of life leveled out in the long-term. In this respect treatment can be selected according to the personal preferences of the individual patient.
