Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

hypoplasia is minimized because of the smaller entrance dose at each of the three fields.

The most serious complication of EBR is an increased risk of second nonocular tumors in children with the genetic form of retinoblastoma (see Sec. III). Because of this risk, there has been a renewed interest in focal treatments such as cryotherapy and photocoagulation for children with intraocular disease.

C.Brachytherapy

1.History

Episcleral brachytherapy was pioneered in 1933 by the British ophthalmologist Henry Stallard [33]. He utilized cobalt applicators that were curved to fit the child’s eye with suture holes built in to attach the plaque to the sclerae. Plaques were left in place for 3–7 days and radiation was delivered at 4000 cGy to the tumor apex. The current technique is similar but refined.

2.Indications

Over the last few years, plaques have been used more commonly as primary therapy due to the increasing awareness among clinicians of the potential for secondary cancer development when EBR is given to certain patients. Relative indications for plaques include tumors that are classified as Reese-Ellsworth Stage IVa or less, tumors that are between 4 and 10 dd in size, and tumors that do not involve the macula. Brachytherapy can also be used as a salvage technique in eyes that have failed other types of therapy including EBR, photocoagulation, or cryotherapy. Relative contraindications to brachytherapy include tumors larger than 10 dd, tumors that involve the macula, and tumors that have produced total vitreous seeding [34].

3.Technique

125I is currently the most commonly used isotope in brachytherapy for retinoblastoma. This isotope is advantageous because the radioactive seeds can be placed into a custom-built plaque designed to match the size of the lesion. The gold shields of 125I plaques also minimize excess radiation exposure for the patient, the patient’s family, and the medical staff [18]. Plaques composed of other isotopes have also been employed with success. These include beta sources such as ruthenium.

Plaque placement is performed in the operating room, typically under general anesthesia. First, the conjunctiva is dissected from the limbus in the quadrant harboring the tumor. If an extraocular muscle overlies the tumor, the muscle is disinserted. The tumor is carefully localized with the indirect ophthalmoscope, and diathermy or ink marks are placed to record the tumor’s position. A dummy plaque of exactly the same size and with identical suture holes as the active plaque is attached to the sclera. The plaque placement is confirmed with the indirect ophthalmoscope and then the active plaque is inserted. The dose is 4000–4500 cGy to the apex of the tumor at a rate of approximately 1000 cGy per day. The plaque is removed in a second operation 3–5 days later, depending on the isotope used and the

size of the tumor. The regression response most commonly seen after removal is a type 4 pattern.

4.Results

A tumor recurrence rate of 12% at 1 year posttreatment has been reported when plaques are used as primary treatment for retinoblastoma [35]. Figures 1 and 2 demonstrate a large retinoblastoma before and after brachytherapy was used as primary treatment. Plaques can even be successful when used as salvage therapy for eyes that have failed other treatment methods. Our group reported a overall success rate for salvage brachytherapy of 50% [36]. Shields et al. recently reported on 148 tumors treated after failure of other methods [35]. Tumor recurrence at 1 year was detected in 8% of tumors previously treated with chemoreduction, 25% of tumors previously treated with external-beam radiotherapy, 34% tumors previously treated with both chemoreduction and external-beam radiotherapy, and 8% of tumors previously treated with laser photocoagulation, thermotherapy, or cryotherapy. Risks for tumor recurrence included the presence of tumor seeds in the vitreous, the presence of subretinal tumor seeds, and increasing patient age. In all cases, visual results depend on the size and location of the tumor(s) initially.

5.Complications

Side effects from brachytherapy for retinoblastoma are rare. Low rates of optic neuropathy and radiation retinopathy arc reported [18]. Cataracts can occur when both cobalt and iodine plaques are placed on anteriorly located tumors. The cataracts can take years to become evident and often do not require surgery. Plaques have not been shown to increase the incidence of second tumors in patients who have also received external-beam radiation [18].

Figure 1 Retinoblastoma in a premature infant prior to placement of a radioactive ruthenium plaque.

Figure 2 Appearance of the same lesion 2 months after treatment with the plaque.

D.Photocoagulation

1.History

Attempts to treat retinoblastoma without removing the eye were attempted as early as 1830, but it was not until the twentieth century that successful focal treatment became feasible. It is only during the past 50 years that retinoblastoma has been managed consistently without enucleation [37]. In 1953, Weve reported on the use of diathermy for the treatment of retinoblastoma tumor foci [38]. Light coagulation with the xenon arc photocoagulator was first described by Meyer-Schwickerath in 1957, initially for the purpose of closing macular holes and then for different diseases including the treatment of retinoblastoma.

2.Mechanism of Action

After passing through the anterior chamber, the laser burns the tiny blood vessels that supply the tumor and the tumor begins to involute within 1 week of treatment. Traditionally, xenon arc photocoagulation (wavelength 250–1500 nm) was used, but currently tumors can be treated with argon lasers in the visible range (wavelength 488–536 nm) or diode/infrared lasers in the invisible range (wavelength 810 nm) with success [6].

3.Indications

Photocoagulation is employed as primary treatment for selected small retinoblastomas. The following tumor features correlate with the success of photocoagulation: small size (less than 3 dd in diameter), anterior location, and low elevation (tumor equal to or less than half the base diameter) [37]. Photocoagulation is not used for tumors that involve the optic disc or fovea, as this technique would result in loss of central vision. In such cases, EBR was commonly employed in the past, and currently either EBR or chemoreduction are typically utilized.

4.Technique

Patients are treated while under general anesthesia with their pupils dilated. The light is aimed through the anterior chamber at the tumor’s feeding vessels. One to three barriers of photocoagulation burns are applied without ever treating the tumor itself. With xenon arc photocoagulation, the light source is inhomogeneous, with a central hot spot that is heated more rapidly. The center of the burn becomes white while the edge becomes gray [37].

5.Results

Our group previously reported on the treatment of 278 retinoblastoma tumors at our center with photocoagulation, more than 70% of which were cured [37]. The mean number of photocoagulation sessions required for the tumors that were cured was 1.3. Of the tumors that failed photocoagulation, 44% went on to develop vitreous seeding and 55% required enucleation. Of eyes that were treated initially with photocoagulation, 50% went on to develop new local tumor foci. In all cases, new tumor foci appeared anterior to the equator. Patients who developed additional tumors in the eye were younger when photocoagulated (mean age, 5.5 months) than those who did not develop additional tumors (mean age, 47.8 months). We currently follow tumors that are treated with photocoagulation for at least 3 years before a cure is considered to be certain.

6.Complications

Potential complications of photocoagulation include cataracts, iris burns, vitreous hemorrhage, and traction effects.

E.Transpupillary Thermotherapy (TTT)

1.History

Transpupillary thermotherapy (TTT) was first used as treatment for retinoblastoma by Lagendijk, although other researchers in the Netherlands had previously studied its use as treatment for choroidal melanoma [39]. In 1982, Lagendijk designed a microwave applicator to deliver whole-eye hyperthermia and administered the treatment to two patients with recurrent retinoblastoma, both of whose disease regressed.

2.Mechanism of Action

The mechanism by which TTT causes tumor cell death is different from the mechanism by which classic laser photocoagulation destroys tumors. With TTT, the temperature is thought to be lower (45–608C), and the thermal effect leads to apoptosis rather than burning. Because the effects of TTT rely on the direct killing of tumor cells, the laser beam is aimed directly at the tumor rather than at the feeding vessels as in photocoagulation.

3.Indications

Indications for TTT have not yet been established. In the largest series to date, patients with viable retinoblastoma within the retina or subretinal space with less than 1.0 mm of overlying subretinal fluid were included [40]. Larger tumors and vitreous seeding from the tumor to be treated with TTT were criteria for exclusion. Our group frequently treats only tumors that are 3 mm or less in base diameter that are not located in the periphery. Unlike the case with photocoagulation, peripapillary tumors can be treated effectively with TTT because the tumors, rather than their vascular beds, are treated directly. With photocoagulation, treatment in this area is often unsuccessful because it requires destruction of the feeding vessels, and the blood supply in the peripapillary area is extremely dense.

4.Technique

Thermal energy is delivered from an 810 mm infrared ophthalmic laser with modifications to the laser’s hardware and software. Three different TTT techniques are utilized for the treatment of retinoblastoma. The first technique, described by Murphree et al. [41] and Murphree and Munier [42], utilizes a pediatric laser gonioscopy lens and an adaptor on the operating room microscope that delivers a transpupillary 3.0-mm spot of radiation. The power is set at 350–1500 mW and treatment typically lasts 1 min. Alternatively, the treatment can be delivered using an adaptor on the indirect ophthalmoscope and a 20 or 28D lens, which delivers a transpupillary 1.6-mm spot of radiation. For this technique, the power is also set at 350–1500 mW and treatment is performed for approximately 1 min. Finally, the radiation can be delivered transconjunctivally via Diopexy probe. For this technique, 1 min of treatment is performed using a handheld adaptor that delivers a 1-mm spot of radiation on a power setting of 500–1500 mW.

5.Results and Complications

In vitro and animal studies [43,44] demonstrating a synergistic effect of TTT and chemotherapy or EBR have prompted several studies exploring the use of TTT with singleor multiple-agent systemic chemotherapy in retinoblastoma patients [41–48]. Our unpublished experience has shown that the majority of retinoblastomas that are 3.0 mm or less in base diameter and not located in the periphery respond to TTT when it is combined with other therapies. Tumors typically regress to flat, pale scars that are less than 2 mm in size. Tumors that are close to the fovea can be treated successfully with no traction effects. Complications include cataracts, scarring/ banding, and visual field defects.

Shields et al. have published the largest series of retinoblastomas treated with chemotherapy to date: 188 retinoblastomas in 80 eyes of 58 patients [40]. A total of 118 tumors were treated simultaneously with systemic chemotherapy and TTT; mean follow-up was 12 months. While 86% of the tumors demonstrated regression, complications were significant and included focal paraxial lens opacity (24%), sector optic disc atrophy (12%), retinal traction (5%), optic disc edema (5%), retinal vascular occlusion (2%), serous retinal detachment (2%), and corneal edema (1%). Focal iris atrophy, the most common complication (36%), was most strongly associated with an increasing number of treatment sessions ( p ¼ 0.001) and an

increasing tumor base diameter ( p ¼ 0.02). Further studies with longer patient follow-up are needed to resolve questions related to tumor recurrence and ocular complications from TTT.

F.Cryotherapy

1.History

Cryotherapy was first introduced by Lincoff in 1967 in a report on one small peripheral retinoblastoma [49]. The use of cryotherapy for intraocular retinoblastoma quickly became widespread in many centers throughout the world. By 1969, Ellsworth noted that cryotherapy was as effective as photocoagulation for the treatment of small tumors [50].

2.Mechanism of Action

The tumor tissue is frozen rapidly ( 908C/min), resulting in intracellular ice crystal formation, protein denaturation, pH changes, and finally cell membrane rupture [51,52]. Cryotherapy also causes cell death by destroying circulation during the freeze via damage to the vascular endothelium and decreased blood flow. Platelet plugs are then formed that induce thrombosis, and the resulting ischemia leads to infarction within minutes or hours [53–55]. Cryotherapy may also influence tumor cell destruction by stimulating an immune reaction [56].

3.Indications

Cryotherapy may be used as the primary treatment for small peripheral retinoblastomas or as secondary treatment for recurrent tumors treated previously with EBR. Retinoblastomas that are successfully treated with cryotherapy include small tumors (less than 3–4 dd) not located at the vitreous base. Tumors with widespread vitreous seeding typically are not best treated with this method [57–59]. However, cryotherapy is uniquely useful for tumors with localized vitreous seeding overlying the tumor apex. In these cases, the freeze is extended in area to include the location of the seeds [58].

4.Technique

Patients are treated under general anesthesia and administered transrectal Tylenol. The tumor is localized via indentation with a cryoprobe and an indirect ophthalmoscope. Tumors anterior to the equator are treated transconjunctivally, while tumors posterior to the equator are treated through a small incision in the conjunctiva. The use of a curved cryotherapy probe aids in the treatment of posterior tumors. Freezing is applied in the center of the tumor until the entire tumor is transformed into a crystalline ball, freezing the overlying vitreous. Tumors are typically treated three times per session for as long as 3 to 4 min per freeze. If necessary, additional cryotherapy is applied until no viable or visible tumor remains, and the patient is left with a white chorioretinal scar.

5.Results

Cryotherapy is an effective method of focal therapy for retinoblastoma. In our center, 90% of tumors less than 3 mm in diameter are cured permanently [58].

6.Complications

The complications associated with cryotherapy for retinoblastoma are few and rarely serious. All patients demonstrate transient conjunctival edema and some experience transient lid edema. Vitreous hemorrhages can be observed in large or previously irradiated tumors [60]. Transient localized retinal detachments (ablation fugax) can occur but usually resolve within a few days to weeks after treatment.

G.Chemoreduction

1.History

Efforts to treat intraocular retinoblastoma with chemotherapy began with Kupfer in the 1950s. In 1953, Kupfer used intravenous nitrogen mustard as a primary treatment for retinoblastoma [61]. Then, in 1955, Reese et al. utilized intracarotid triethylenemelamine (TEM) in combination with EBR in order to decrease the required dose of EBR [62]. Currently chemoreduction is an area of active clinical and basic science research motivated by the desire to avoid enucleation and EBR [6].

2.Indications

The indications for chemoreduction are not yet well established. In general, however, chemoreduction is employed for three purposes. Most commonly, this treatment is used for patients who have visual potential in eyes containing tumors that are too large to treat with focal methods. Chemoreduction is used to shrink these tumors so that focal treatments such as photocoagulation, cryotherapy, thermotherapy, or radioactive plaques can then be administered. It is the focal treatment methods that cause permanent inactivation of the tumors. Chemoreduction is also used for patients below 1 year of age with advanced bilateral disease who require EBR to be cured. When administered to patients below 1 year of age, EBR increases the incidence of second nonocular cancers in these patients (see Sec. III.C). In these cases, chemotherapy is used just to control tumor growth until the patient is 1 year old and can safely undergo EBR. Finally, chemotherapy has also recently been utilized in some studies as a potential single-modality eye-preserving treatment. Permanent responses are rarely observed in these cases.

3.Technique

Most studies of chemoreduction for retinoblastoma have utilized vincristine, carboplatin, and an epipodophyllotoxin, either etoposide or teniposide (Table 2). The addition of cyclosporine as a P-glycoprotein inhibitor has been suggested to decrease the ability of tumor cells to transport antineoplastic drugs from the intracellular space, thereby allowing the cells to develop multidrug resistance [63,64]. Currently, the choice of agents as well as number and frequency of cycles varies at different institutions.

Key: V, vincristine; R, carboplatin; E, etoposide; S, cyclosporine; N, teniposide. a Twenty patients’ results were published in both of these reports.

b This study is not included in Table 3 because the number of eyes in each Reese-Ellsworth group are not specified.

4.Results

The results of recent studies examining chemoreduction followed by focal therapies have been most promising for patients with Reese-Ellsworth stage I–III eyes. For these patients, several authors have demonstrated that enucleation can be successfully avoided almost 100% of the time [41,63–72]. Results for patients with Reese-Ellsworth stage IV and V eyes have been more discouraging. An analysis of all Reese-Ellsworth stage V eyes included in the eight published chemoreduction studies with applicable data is presented in Table 3. In patients treated with chemoreduction, only 30% of eyes avoided both EBR and enucleation. Forty-seven percent of eyes required EBR but avoided enucleation, and 35% of eyes required enucleation (with or without prior EBR). Thus, the goal of utilizing chemoreduction to avoid EBR and enucleation is achieved in only a minority of patients with Reese-Ellsworth stage V eyes.

Shields et al. recently suggested that chemoreduction may prevent trilateral retinoblastoma [73]. The authors retrospectively compared 142 patients treated with chemoreduction and 72 patients treated with nonchemoreduction methods from 1995 to 1999. One of 18 (5.5%) patients at risk for developing trilateral retinoblastoma in the nonchemoreduction group subsequently developed a pineoblastoma, a percentage consistent with a previously published series [74]. In contrast, none of the 99 patients at risk in the chemoreduction group developed trilateral retinoblastoma. The authors conclude that chemoreduction may play a role in preventing pineoblastoma. In this study, however, none of the patients in the chemoreduction group received EBR, which has been shown to be a risk factor for the development of pineoblastoma. The absence of EBR, rather than the addition of

chemoreduction, may, in fact, explain the lack of pineoblastoma development in the chemoreduction arm of this study [75].

5.Complications

Short-term side effects of chemotherapy are common and include fever, nausea, vomiting, and diarrhea. Hematological problems such as leukopenia, thrombocytopenia, and anemia are also common. Serious but uncommon sequelae include neurological and cardiac disturbances. Less serious complications include alopecia and low-grade bacterial infections in an anopthalmic orbit [34].

Several ophthalmic complications have been reported in patients undergoing chemoreduction/local therapy for retinoblastoma. Anagoste et al. reported three cases of rhegmatogenous retinal detachments and active retinoblastoma, with retinal breaks adjacent to cryotherapy scars [76]. Gombos et al. published a case of cholesterosis in the anterior segment of an eye that underwent chemoreduction/local therapy for retinoblastoma [77].

In addition to noncancerous ophthalmic complications, there is evidence that new retinoblastomas can develop in patients while they are being treated with systemic chemotherapy. Scott et al. reported four such cases and theorize that the development of these new tumors could represent primary tumor resistance, selection of a resistant tumor cell line, or inadequate chemotherapeutic levels within small, minimally vascularized tumor cells [78]. Furthermore, our group recently reported on the development of new retinoblastomas in children who were treated with systemic carboplatin as their initial treatment. Children under 6 months of age had a 71% chance of developing new tumors, and children over the age of 6 months had a 25% chance [79].

Another potential complication of chemoreduction is the development of secondary nonocular cancers. Several agents utilized in current chemoreduction studies for retinoblastoma have been demonstrated to increase the risk for secondary cancers either in retinoblastoma patients or in patients treated with these drugs for other primary malignancies. The risk of secondary leukemias in survivors of ovarian cancer treated with platinum-based drugs is well documented [80,81]. One retinoblastoma survivor who received cisplatin developed acute myeloid leukemia (AML) [82]. AML has also been reported in two retinoblastoma patients who received vincristine [83,84]. Furthermore, teniposide has been reported to increase the risk of AML in survivors of childhood cancer, possibly in a pattern related to the schedule of drug delivery [85]. Although the drug is not presently being used in chemoreduction studies for retinoblastoma, cyclophosphamide has also been demonstrated to cause a significant increase in the incidence of second cancers in retinoblastoma patients [86]. The follow-up periods of chemoreduction studies with retinoblastoma patients to date are inadequate to assess the development of second cancers in these patients (Table 3).

6.Periocular Chemotherapy

Ideally, chemotherapy administered for intraocular retinoblastoma would be distributed exclusively to the intraocular space of the affected eye with no systemic exposure to the drug [87]. Based upon this goal, several groups have explored the local delivery of chemotherapeutic agents via intraocular injection. Murray et al. and