Stewart Kroll

Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma : a prospective, randomized, dynamically balanced trial

PURPOSE Optimal radiation therapy for uveal melanoma is uncertain, and the relative efficacies of radioactive plaques and charged particles are unclear. METHODS The authors prospectively studied helium-ion irradiation and iodine 125 (125I) brachytherapy in a randomized, dynamically balanced trial. Of the 184 patients who met the eligibility criteria, 86 were treated with helium ions and 98 with 125I brachytherapy. RESULTS No patients with uveal melanoma had a history of systemic malignancy. Tumors were less than 15 mm in maximum diameter and less than 10 mm in thickness. A minimum tumor dose of 70 GyE was delivered to the tumor apex. There was a significantly higher local recurrence rate after 125I brachytherapy than after helium-ion irradiation. Enucleations occurred more frequently after brachytherapy (relative risk = 1.99; 95% confidence interval, 0.78-5.78). More anterior segment complications occurred after helium-ion irradiation. To date, there has been no measurable impact on survival. CONCLUSIONS Most uveal melanomas can be managed with radiation with retention of the eye. There was better tumor control with helium-ion irradiation; however, there were more anterior segment complications.

Orbital metastases: diagnosis and course

AIMS Three issues were investigated in adult outpatients with orbital metastases. One, how accurate are current diagnostic methods? Two, what is the survival associated with orbital metastases? Three, did any clinical factors correlate with prognosis in this patient cohort? METHODS Retrospective analysis of patients with orbital metastases managed in an ocular oncology unit. RESULTS 11 of 31 (35%) patients had no known primary malignancy at the time of orbital diagnosis. In eight of 31 (26%) computed tomography and/or magnetic resonance imaging data did not yield the diagnosis of metastases. In 15 of 17 (88%) cases a fine needle aspiration biopsy was diagnostic. Several types of therapy were used. The median survival was 1.3 years. CONCLUSION Orbital metastases, even with newer diagnostic techniques can be difficult to diagnose. Management was based on location and extent of both orbital and systemic disease as well as vision. In most cases, orbital symptoms were palliated; however, survival was dismal. No clinical factor correlated with prognosis.

Five-Year Follow-up of Helium Ion Therapy for Uveal Melanoma

One hundred sixty-four patients with uveal melanoma were treated with helium ion irradiation prior to May 1984, and the data were analyzed in June 1989. Most uveal melanomas were large, with a mean tumor thickness of 6.5 mm; approximately 60% of the patients had tumors that extended anterior to the equator. A complete follow-up was obtained for all patients. One hundred twelve patients were alive at the time of this report; 18% of the patients developed clinical and laboratory evidence of metastases and eventually died of widespread tumor. Eighty-four percent of eyes were retained. Data were analyzed with a number of parametric and nonparametric techniques. Larger tumors and those located in close proximity to the optic nerve and fovea had a higher incidence of most complications, especially visual loss.

Radiotherapy for High Grade Clinically Localized Adenocarcinoma of the Prostate

PURPOSE We defined the efficacy of radiotherapy for the treatment of high grade (Gleason scores 8 to 10) adenocarcinoma of the prostate. MATERIALS AND METHODS A total of 50 patients underwent radiotherapy with curative intent for clinically localized prostate cancer with Gleason scores of 8 to 10 at 1 of 4 facilities affiliated with the University of California San Francisco. Patients were considered to have biochemical failure if they had a significant increase in prostate specific antigen (PSA) of 0.5 ng./ml. per year, an increase in PSA to greater than 1.0 ng./ml. or a positive biopsy. RESULTS Among the 50 patients median PSA was 22.7 ng./ml. (range 1.3 to 93.4). Tumors were clinical stage T1 or T2 in 46% of the cases and stage T3 or T4 in 54%. The overall actuarial probability of freedom from biochemical failure at 4 years was 23%. In a multivariate analysis including all patients pretreatment PSA was the only predictor of PSA failure, with 64% free of progression if the pretreatment PSA was 10 ng./ml. or less compared to only 16% at 3 years if PSA was more than 10 ng./ml. (p = 0.01). In a multivariate analysis restricted to patients with PSA less than 20 ng./ml. 83% of those treated to more than 71 Gy. were free of progression compared to 0% for those treated to less than 71 Gy. (p = 0.03). In a multivariate analysis PSA 10 ng./ml. or less (related risk 11.4, p = 0.02), T stage 1 or 2 (relative risk 3.8, p = 0.05) and radiation dose more than 71 Gy. (relative risk 4.0, p = 0.06) were associated with a favorable outcome. CONCLUSIONS At 4 years the freedom from PSA failure following radiotherapy for high grade prostate cancer was comparable to previously reported surgical series. The high failure rate among patients with PSA greater than 20 ng./ml. suggests that these patients should be considered for investigational approaches. The apparent improvement in freedom from progression with the use of higher doses provides reason for optimism.

High intensity 125-Iodine (1251) plaque treatment of uveal melanoma☆

PURPOSE Episcleral 125I plaque therapy of uveal melanoma is an important treatment modality to control tumor, salvage the globe, and potentially preserve vision. We retrospectively analyzed our experience in 239 patients to assess treatment outcome with this technique. METHODS AND MATERIALS Between 1983 and 1990, 239 uveal melanoma patients were treated with 125I plaques at the University of California, San Francisco. High intensity 125I seeds in the range of 3-20 mCi were used to give a minimum tumor dose of 70 Gy in 4 days. Initial mean tumor size was 10.9 mm x 9.2 mm x 5.5 mm with a range in tumor diameter from 4 to 18 mm and tumor height from 1.9 to 11.1 mm. Best corrected pre-treatment visual acuity was 20/200 or better in 92% of patients. RESULTS Local tumor control was maintained in 91.7% of patients with a mean follow-up of 35.9 months; 19 patients had local tumor progression; mean time to progression was 27.3 mo (1.8 to 60.1 mo). Actuarial local control is 82% at 5 years. Multivariate analysis demonstrates significant correlation of local failure with larger maximum tumor diameter (p = 0.0008), closer proximity to the fovea (p = 0.0001), lower radiation dose (p = 0.0437), and smaller ultrasound height (p = 0.0034). The actuarial incidence of distant metastases is 12% at 5 years with multivariate analysis showing significant correlation only with maximum tumor diameter (p = 0.0064). Visual outcome is 20/200 or better in 58% of patients. CONCLUSION While the tumor control rates appear favorable, ocular morbidity is significant. A current randomized trial comparing 125I plaque with Helium ion therapy is in progress with specific comparison of tumor control, survival, and visual outcome.

Randomized Trial of Radiation for Age-related Macular Degeneration

PURPOSE To assess external beam radiation efficacy for subfoveal neovascularization associated with age-related macular degeneration. METHODS All patients were evaluated in the same institution. In this prospective trial, 27 eyes (27 patients) with subfoveal neovascularization associated with age-related macular degeneration were randomized to either single fraction radiation (750 centigray) or observation. Endpoints were assessed by fluorescein angiography and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity. Examiners were masked to patient treatment status. Parametric and nonparametric statistical analyses were performed. RESULTS Twenty-seven patients were entered into the trial with a mean age of 76 years (range, 64 to 89) and a mean follow-up of 17 months (range, 7 to 32). The visual acuity loss was slightly less in the irradiated group, a finding of borderline significance (P < .046). There was no significant difference in fluorescein angiographic evidence of subretinal neovascular membrane change in the control group vs the irradiated group. CONCLUSIONS External beam radiation, at this dose and fractionation, did not appear harmful. There was slightly less visual loss in irradiated eyes. No difference in fluorescein angiographic characteristics of subfoveal neovascularization size or progression in eyes with age-related macular degeneration was noted.

Anterior segment sparing to reduce charged particle radiotherapy complications in uveal melanoma

PURPOSE The purpose of this investigation is to delineate the risk factors in the development of neovascular glaucoma (NVG) after helium-ion irradiation of uveal melanoma patients and to propose treatment technique that may reduce this risk. METHODS AND MATERIALS 347 uveal melanoma patients were treated with helium-ions using a single-port treatment technique. Using univariate and multivariate statistics, the NVG complication rate was analyzed according to the percent of anterior chamber in the radiation field, tumor size, tumor location, sex, age, dose, and other risk factors. Several University of California San Francisco-Lawrence Berkeley National Laboratory (LBNL) patients in each size category (medium, large, and extralarge) were retrospectively replanned using two ports instead of a single port. By using appropriate polar and azimuthal gaze angles or by treating patients with two ports, the maximum dose to the anterior segment of the eye can often be reduced. Although a larger volume of anterior chamber may receive a lower dose by using two ports than a single port treatment. We hypothesize that this could reduce the level of complications that result from the irradiation of the anterior chamber of the eye. Dose-volume histograms were calculated for the lens, and compared for the single and two-port techniques. RESULTS NVG developed in 121 (35%) patients. The risk of NVG peaked between 1 and 2.5 years posttreatment. By univariate and multivariate analysis, the percent of lens in the field was strongly correlated with the development of NVG. Other contributing factors were tumor height, history of diabetes, and vitreous hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques demonstrate that for some patients in the medium and large category tumor groups, a significant decrease in dose to the structures in the anterior segment of the eye could have been achieved with the use of two ports. CONCLUSION The development of NVG after helium-ion irradiation is correlated to the amount of lens, anterior chamber in the treatment field, tumor height, proximity to the fovea, history of diabetes, and the development of vitreous hemorrhage. Although the influence of the higher LET deposition of helium-ions is unclear, this study suggests that by reducing the dose to the anterior segment of the eye may reduce the NVG complications. Based on this retrospective analysis of LBNL patients, we have implemented techniques to reduce the amount of the anterior segment receiving a high dose in our new series of patients treated with protons using the cyclotron at the UC Davis Crocker Nuclear Laboratory (CNL).

Uveal Melanoma Radiation: 125I Brachytherapy Versus Helium Ion Irradiation

The optimum radiation therapy for uveal melanoma is uncertain. Both helium ion irradiation and 125I brachytherapy have been used to treat this neoplasm. This investigation analyzed the control and complication rates of uveal melanomas treated with helium ions of 125I plaques. In both a retrospective and a prospective dynamically balanced study, the control rates appeared to be similar. There were more posterior segment complications after 125I plaques and more anterior segment complications, including neovascular glaucoma, after helium ion irradiation. The follow-up period is too short to draw definitive conclusions on the radiation complications. Overall, approximately 89% of eyes were retained and less than 4% of treated eyes were removed because of failure to control the tumor.

Comparative genomic hybridization analysis of archival formalin-fixed paraffin-embedded uveal melanomas

Comparative genomic hybridization (CGH) was used to analyze seven autologous uveal melanomas with both formalin-fixed, paraffin-embedded and fresh-frozen specimens. In addition, DNA from two archival formalin-fixed tumors more than 45 years old were also analyzed. The most frequent genetic changes were loss of chromosome 3; increase in copy number of 6p and loss of 6q; and increase in copy number of 8q. A comparison of CGH data from the fresh-frozen tumors and their autologous formalin-fixed tumors revealed a correlation coefficient of 0.83. Comparative genomic hybridization (CGH) analysis of 45-year-old specimens identified genetic changes similar to those found in more recent tumors including loss of chromosome 3 and increase in copy numbers of 6p and 8q. The results indicate that there is a good agreement between data obtained from formalin-fixed and fresh-frozen specimens using CGH. Furthermore, the results demonstrate the applicability of this technique in analyzing archival formalin-fixed tumors that were previously not accessible to cytogenetic analysis.

Effect of Various Doses of Radiation for Uveal Melanoma on Regression, Visual Acuity, Complications, and Survival

We reviewed 284 choroidal and ciliary body melanomas treated with 50, 60, 70, or 80 gray equivalents (GyE) of helium ion radiation. Multivariate methods of data analysis were used to adjust for differences between dose groups with respect to the characteristics of patients (and their tumors). Radiation dose level did not affect survival, complications, visual outcome, or tumor regression in this model. The minimum radiation dose necessary to achieve tumor control with charged particles may be less than 50 GyE.