Malignant choroidal melanoma is the most common primary intraocular neoplasm in adults. For over 100 years, enucleation was the accepted treatment for this disease. The ideal treatment, however, would eradicate the tumor while preserving ocular function. Recent suggestions that enucleation may, in fact, promote the development of distant metastases has led to the use of limited surgical techniques which preserve the eye. Radiation therapy has replaced enucleation as the most common treatment, and is now the subject of a nation-wide clinical trial (Collaborative Ocular Melanoma Study). Unfortunately, the potential advantages of radiation therapy can be negated by the development of chronic radiation- induced complications, particularly in the treatment of tumors grater than 8mm height. The secondary complications eventually impair ocular function and may result in loss of the eye. The use of hyperthermia (42o to 45o C) in combination with radiation has been demonstrated to enhance the effectiveness of radiation therapy in the treatment of human cutaneous melanomas by a factor of two. In an animal model of Greene choroidal melanoma, the combination of these modalities has been demonstrated to allow a reduction of radiation dose while maintaining tumor control. We expect that reducing the radiation dose will lead to fewer secondary complications, thereby preserving useful vision. We have established a new xenograft model of human choroidal melanoma in immuno-suppressed rabbit eyes which we expect to behave more like human choroidal melanoma in situ than the older Greene model. In addition, we have developed a new clinical technique for combining hyperthermia produced by 500 KHz radiofrequency current with I125 irradiation using a gold episcleral plaque. A Phase-1 clinical evaluation of this technique is currently in progress at our institution. We have developed quantitative I125 dosimetry for our plaque delivery system, and preliminary hyperthermia dosimetry in normal rabbit eyes. We have demonstrated that the normal rabbit eye can tolerate temperatures up to 45oC, measured at the plaque- sclera interface, with tolerable acute toxicity. We proposed to: 1) develop quantitative hyperthermia dosimetry for our heating technique in rabbit eyes containing the human uveal melanoma xenograft; 2) determine the dose-response relationship for our xenograft model to I125 irradiation alone; 3) determine the """"""""dose"""""""" temperature response for the xenograft model to hyperthermia alone; 4) determine the dose-response of the xenograft model to the combined modalities, and 5) assess acute chronic toxicity following treatment with irradiation, hyperthermia, or the combined modalities and doses associated with tumor control. Due to the lack of a fovea in the rabbit eye, we further propose to evaluate acute toxicity (from the combined modalities) in a limited number of primate eyes if results using the rabbit model disclose a potential therapeutic gain.
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