Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

worsen a patient’s overall survival and risk for metastasis. In the late 1970s, some researchers presented data suggesting an increased risk of mortality following enucleation [156–159]. The Zimmerman hypothesis maintained that increased pressure associated with surgical intervention, such as an enucleation, disseminated tumor cells, resulting in an increased risk of hematogenous spread. Some clinicians advocated a ‘‘no-touch’’ technique, where gentle manipulation of the eye was combined with freezing of the tumor base [160,161]. However, there were only limited data to suggest that either the hypothesis or the technique was clinically applicable. A number of studies comparing patients treated with brachytherapy versus enucleation failed to show a difference in mortality [83,124,162–165]. The COMS trial addressed this question by randomizing patients with medium-sized tumors to brachytherapy or enucleation [166]; preliminary results have not demonstrated a difference in melanoma-associated mortality between the two groups. Most clinicians no longer advocate enucleation by ‘‘no touch’’ method, although some still adhere to an approach of minimal manipulation.

Today primary enucleations are reserved for eyes with massive tumor involvement (greater than 40–50% tumor volume), no useful vision, total retinal detachment, or neovascular glaucoma (Fig. 12). Ciliary body tumors that are too large for excision or brachytherapy, ring melanomas, and circumpapillary lesions are also treated with this approach. Secondary enucleations are indicated for eyes failing local therapies. Finally, patients with small and medium-sized tumors who, after informed consent, elect not to proceed with eye-sparing techniques may also be considered candidates for organ removal.

Enucleations are usually performed under general anesthesia. Re-examination of the affected eye is recommended intraoperatively prior to the start of the procedure. Following a peritomy, the muscles are disinserted from the globe. The

Figure 12 Histopathology of an enucleated globe containing a large ciliochoroidal melanoma, with a secondary retinal detachment.

optic nerve is transected with scissors using a nasal approach and gentle temporal traction. Following excision, the globe and orbit are carefully inspected for signs of extraocular involvement. If none is appreciated, an orbital implant is inserted. Many surgeons prefer a biointegrated material such as hydroxyapatite. If such a method is used, the implant is first wrapped (with donor tissue or Vicryl mesh) and the rectus muscles are attached in an anatomically correct fashion. Tenon’s capsule is then meticulously closed prior to suturing of the conjunctiva. A pressure patch is applied and the patient is referred for fitting of an ocular prosthesis after postoperative edema has resolved. Cosmetic results are excellent, with good prosthetic motility. The pathology is later reviewed for diagnostic confirmation and complete surgical excision.

Given the concerns raised by the Zimmerman hypothesis, some clinicians have advocated the use of pre-enucleation radiotherapy (PERT). Similar techniques used for other systemic malignancies have been shown to decrease patient morbidity. Yet retrospective studies failed to demonstrate a benefit or improved survival with PERT. The large-tumor COMS group addressed this question in a prospective trial that randomized eyes prior to enucleation. Early results at 5-year follow-up have failed to demonstrate either benefit or harm with PERT [127,130]. As a result, this approach has largely been abandoned.

VIII. EXTRAOCULAR INVOLVEMENT

The management of extraocular melanoma depends largely on the nature and extent of extraocular disease. In this respect, periocular involvement must be distinguished from systemic metastatic disease. Large uveal melanomas, including those with increased basal diameters, are at risk for extrascleral involvement [167]. Tumor cells can spread locally along scleral emissary channels, including vortex veins and ciliary nerves, leaving the sclera grossly intact. These cases are generally treated with surgery, radiotherapy, or a combination of the two [168,169].

Microscopic metastasis is occasionally detected following enucleation of eyes that appeared intact intraoperatively. In such cases postoperative external-beam radiotherapy can be considered [170]. Adjuvant therapy, however, increases the risk of complications, including orbital exposure, extrusion, and socket contracture [171]. Some clinicians prefer to monitor such patients and treat with external-beam radiotherapy only if orbital recurrence occurs.

Unanticipated extrascleral extension is occasionally diagnosed at the time of surgical intervention. If this condition is detected at the time of plaque insertion, management varies based on the size and nature of extraocular disease. One approach is to convert to an enucleation, with local excision of the lesion. If the extraocular component is large and nodular, postoperative radiotherapy should also be considered. Alternatively, in cases with small, flat extrascleral extension (less than 2 mm), one can proceed with brachytherapy following dissection of the tumor from the scleral wall [172].

In proceeding with a planned enucleation, small areas of extrascleral spread can be removed en bloc with the globe and adjacent Tenon’s capsule (tenonectomy) [172–174]. Some reports suggest these cases carry an 8–18% risk of orbital

recurrence. Given these results, adjuvant radiotherapy should be considered in this setting [170,175].

In cases presenting with massive orbital involvement or those following prior enucleation, exenteration may be indicated (Fig. 13) [172,176,177]. There remains debate as to whether this radical procedure actually improves patient survival. Nonetheless, tumor debulking with this approach can be the most cosmetically acceptable option for the patient. Adjuvant external-beam radiotherapy is usually recommended and can be given preoperatively. Many of these patients have systemic disease; therefore a metastatic workup should be considered prior to surgical intervention.

Only a small percentage (approximately 1%) of patients present with both ocular and systemic uveal melanoma. Hepatic involvement is the most common area of organ metastasis, followed by the subcutaneous tissue and lungs. When systemic disease is detected, it is best to refer the patient to a medical oncologist with experience in treating melanomas. Patients with isolated hepatic metastasis have benefited from arterial chemoembolization and local resection [178–181]. A number of systemic chemotherapeutic protocols have been tested, with poor results [182–

Figure 13 Photograph showing prominent orbital extension of melanoma from a ciliochoroidal lesion. The patient refused treatment and died of metastatic disease within 6 months.

185]. Adjuvant therapies with interleukins and interferon have failed to live up to their expectations [186,187]. The EORTC oncology task force recently reported data from a phase II trial of chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and recombinant alpha 2b interferon. The results to date have demonstrated a limited response. Palliative radiotherapy can be effective for patients with painful metastasis to the brain and bones. Generally these patients carry a very poor prognosis [188]. Ocular therapy is therefore deferred for patients with a life expectancy of less that 1 year if the eye is intact, without neovascular changes, and pain free. Should neovascular glaucoma develop in this setting, options include enucleation versus ciliary body ablation.

Given the poor prognosis associated with metastatic disease, a number of centers have considered adjuvant therapies to prevent systemic spread. As discussed elsewhere, pre-enucleation external-beam radiotherapy was advocated by some in an attempt to prevent dissemination of tumor cells at the time of surgery. Preliminary results from the COMS study have not demonstrated any benefit from this approach. Some researchers have vaccinated patients with melanoma antigens [189– 191]. There is a single case report of a choroidal melanoma responding to the administration of a melanoma vaccine [192]. Other studies have investigated the empirical use of systemic agents such as interferon after local therapy. To date, no single method has been shown to significantly alter the course of this disease, prevent metastasis, or lengthen long-term survival.

IX. CONCLUSIONS

Unlike that of many other cancers, diagnosis of the intraocular tumor is often associated with a unique motivation for organ preservation. Today there is a range of therapeutic options available in the management of uveal melanomas. While methods and indications vary, a trend toward eye-sparing techniques whenever possible has clearly emerged. Increasing numbers of patients can be cured and maintain their eyes and vision. Advances in photocoagulation therapies, radiation, and surgical techniques hold great promise for the future.

This optimism is tempered only by the limited progress in the management of systemic disease. Greater understanding is necessary regarding the biological events associated with extraocular and systemic metastasis. Only when these pathways are delineated will the ophthalmologist develop therapies that achieve all the goals of treatment, including (1) curing the intraocular tumor, (2) preventing extraocular disease, and (3) preserving the eye and vision.

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