A Prospective, Randomized, Double-blind, Placebo-controlled Study of Orbital Radiotherapy for Graves' Ophthalmopathy.

CONTEXT: Although widely used for more than 85 years, the efficacy of radiotherapy for Graves' ophthalmopathy (GO) has not been established convincingly. OBJECTIVE: To evaluate the efficacy of radiotherapy for GO. DESIGN: Prospective, randomized, internally controlled, double-blind clinical trial in a tertiary care academic medical center. PARTICIPANTS: The patients were ethnically diverse males and females over age 30 seen in a referral practice. The patients had moderate, symptomatic Graves' ophthalmopathy (mean clinical activity score, 6.2) but no optic neuropathy, diabetes, recent steroid treatment, previous decompression, or muscle surgery. Forty-two of 53 consecutive patients were enrolled after giving informed consent and fulfilling study entry criteria. Eleven eligible patients declined to participate because of inconvenience, desire for alternative therapy, or concern about radiation. INTERVENTION: One randomly selected orbit was treated with 20 Gy of external beam therapy; sham therapy was given to the other side. Six months later, the therapies were reversed. MAIN OUTCOME MEASURES: Every 3 months for 1 year, we measured the volume of extraocular muscle and fat, proptosis, range of extraocular muscle motion, area of diplopia fields, and lid fissure width. Effective treatment for GO will modify one or more of these parameters. RESULTS: No clinically or statistically significant difference between the treated and untreated orbit was observed in any of the main outcome measures at 6 months. At 12 months, muscle volume and proptosis improved slightly more in the orbit that was treated first. CONCLUSIONS: In this group of patients, representative of those for whom radiotherapy is frequently recommended, we were unable to demonstrate any beneficial therapeutic effect. The slight improvement noted in both orbits at 12 months may be the result of natural remission or of radiotherapy, but the changes are of marginal clinical significance.

The incidence of cerebrovascular accidents and second brain tumors in patients with pituitary adenoma: a population-based study.

BACKGROUND: To assess the risk of cerebrovascular accidents (CVAs) and second brain tumors (SBTs) in patients with pituitary adenoma after surgery or radiotherapy. METHODS: A cohort of 143 people from Olmsted County, who were diagnosed with pituitary adenoma between 1933 and 2000, was studied. Only patients from Olmsted County were included because of the unique nature of medical care in Olmsted County, which allows the ascertainment of virtually all cases of pituitary adenoma for this community's residents and comparisons to the general population in the county. Surgical resection was performed in 76 patients, 29 patients underwent radiotherapy (with 21 undergoing both surgery and radiotherapy), 5 patients were reirradiated, and 59 patients were managed conservatively and observed. RESULTS: Median follow-up was 15.5 years. There was no difference in CVA-free survival between treatment groups. On univariate analysis age > 60 years (hazard ratio [HR], 11.93; 95% CI, 6.26-23.03; P < .001); male sex (HR, 3.67; 95% CI, 2.03-6.84; P < .001), and reirradiation (HR, 3.41; 95% CI, 1.05-9.68; P = .04) were associated with worse CVA-free survival. In multivariate analysis, only age > 60 years was associated with worse CVA-free survival. Compared with the general population, there was a 4-fold increase in the rate of CVAs in pituitary adenoma patients (HR, 4.2; 95% CI, 2.8-6.1). Two patients developed SBT (an irradiated patient and a surgically managed patient). CONCLUSION: CVA is a significant risk for patients with pituitary tumors, but treatment does not seem to impact the risk. Even with long-term follow-up, SBTs are a rare event regardless of treatment modality.

Factors associated with endocrine deficits after stereotactic radiosurgery of pituitary adenomas.

OBJECTIVE: To analyze the factors associated with anterior pituitary deficits after pituitary adenoma stereotactic radiosurgery (SRS). METHODS: The tumor, pituitary stalk, and pituitary gland were segmented on the dose plans of 82 patients (secreting tumors, n = 53; nonsecreting tumors, n=29) for dose-volume analysis. No patient had undergone prior radiation therapy and all patients had at least 12 months of endocrinological follow-up (median, 63 months; mean, 69 months; range, 13-134). RESULTS: Thirty-four patients (41%) developed new anterior pituitary deficits at a median of 32 months (range, 2-118) after SRS. The risk of developing new anterior pituitary deficits was 16% and 45% at 2 and 5 years, respectively. Multivariate analysis of the entire group showed that poor visualization of the pituitary gland (hazard ratio [HR]=2.63, 95% confidence interval [CI]=1.10-6.25, P=.03) was associated with a higher rate of new anterior pituitary deficits. Dosimetric analysis of 60 patients whose pituitary gland could be clearly identified showed that increasing mean pituitary gland radiation dose correlated with new anterior pituitary deficits (HR=1.11, 95% CI=1.02-1.20, P=.02). New anterior pituitary deficits stratified by mean pituitary gland radiation dose: 19.1 Gy, 83% (5/6). CONCLUSION: New endocrine deficits after pituitary adenoma radiosurgery were correlated with increasing radiation dose to the pituitary gland. Methods that limit the radiation dose to the pituitary gland during SRS may increase the probability of preserving pituitary function.

Radiation complications and tumor control after 125I plaque brachytherapy for ocular melanoma.

PURPOSE: To determine the outcome of 125I plaque brachytherapy at our institution and identify the risk factors associated with the development of radiation complications, tumor recurrence, and metastasis. PATIENTS AND METHODS: From 1986 to 2000, 156 patients underwent 125I episcleral plaque (COMS design) application for the treatment of ocular melanoma. Chart analysis of follow-up ophthalmologic appointments assessed the incidence of ocular side effects after therapy. Statistical analysis assessed outcomes and significant influencing factors. RESULTS: With a median follow-up of 6.2 years, the 5-year overall survival was 83%. The 5-year disease-specific survival was 91%. Initial local control at 5 years was 92%, with 100% ultimate local control after secondary therapy that included 9 enucleations. The risk of metastasis was 10% at 5 years and 27% at 10 years. Vision stayed the same or improved in 25% of patients, and 44% of patients maintained visual acuity better than 20/200. Thirteen percent of patients experienced chronic pain or discomfort in the treated eye. Dose rates to the tumor apex greater than 90 to 100 cGy/h were associated with increased systemic control but worse radiation toxicity. CONCLUSION: Patients in our series experienced excellent local tumor control. Higher dose rates to the tumor apex were associated with reduced rates of distant metastases but worse ocular function.

Leksell Gamma Knife coordinate setting slippage: how often, how much?

OBJECT: The aim of this study was to determine the incidence and magnitude of coordinate setting slippage during gamma knife surgery (GKS). METHODS: Thirty-six consecutive patients undergoing GKS with a Leksell unit between June and December 2000 had their coordinates (right and left x-, y-, and z-coordinates; 1548 coordinates; 258 isocenters) and gamma angles checked after the delivery of treatment to each isocenter to determine whether the coordinate settings had slipped and, if so, which settings and the magnitude of the slippage. CONCLUSIONS: Coordinate setting slippage during GKS with a Leksell unit does occur but is rare. The magnitude of such slippage is typically within the error of the stereotactic system and coordinate reading. The authors noted that coordinate setting slippage is significantly correlated with patient weight.

Selective identification of different brachytherapy sources, ferromagnetic seeds, and fiducials in the prostate using an automated seed sorting algorithm.

PURPOSE: Routine permanent prostate brachytherapy (PPB) includes CT-based postimplant dosimetry (PID). A method of identifying different source types from CT data in the same implant volume is described. METHODS AND MATERIALS: A previously described automatic method for seed localization using CT data is used in this study. Two cases were analyzed: a PPB case with (103)Pd followed by salvage (125)I implantation, both performed at another institution, and a cadaver case where 4 different seed types, including ferromagnetic seeds, and fiducials were implanted. RESULTS: Automatic segregation of different seed types with minimal manual correction is demonstrated using the described localization algorithm. The process is confirmed accurate by comparison of plain film radiographs to CT data and digitally reconstructed radiographs. CONCLUSION: Unique identification of different source types, including PPB seeds, fiducial markers, and ferromagnetic seeds in permanent implants is possible and permits dosimetric analyses that are spatially coincident.

Irradiation of the inguinal lymph nodes in patients of differing body habitus: a comparison of techniques and resulting normal tissue complication probabilities.

The treatment of the inguinal lymph nodes with radiotherapy is strongly influenced by the body habitus of the patient. The effect of 7 radiotherapy techniques on femoral head doses was studied. Three female patients of differing body habitus (ectomorph, mesomorph, endomorph) were selected. Radiation fields included the pelvis and contiguous inguinal regions and were representative of fields used in the treatment of cancers of the lower pelvis. Seven treatment techniques were compared. In the ectomorph and mesomorph, normal tissue complication probability (NTCP) for the femoral heads was lowest with use of anteroposterior (AP) and modified posteroanterior (PA) field with inguinal electron field supplements (technique 1). In the endomorph, NTCP was lowest with use of AP and modified PA field without electron field supplements (technique 2) or a 4-field approach (technique 6). Technique 1 for ectomorphs and mesomorphs and techniques 2 and 6 for endomorphs were optimal techniques for providing relatively homogeneous dose distributions within the target area while minimizing the dose to the femoral heads.

Retinal microvascular abnormalities in patients treated with external radiation for graves ophthalmopathy.

BACKGROUND: A prospective study was conducted to determine if external ionizing radiation could favorably influence the orbital manifestations of Graves ophthalmopathy. Diabetes and untreated systemic hypertension were exclusion criteria. Radiation was directed to the orbits of 42 affected patients using 0.2 rad (20 Gy) delivered in 10 doses of 0.02 rad (2 Gy). Patients were periodically examined during a 3-year interval. OBJECTIVE: To report retinal microvascular abnormalities observed in our study cohort. METHODS: Fundus findings documented with ophthalmoscopy, stereoscopic color photography, and stereoscopic fluorescein angiography prior to radiation were compared with similarly documented findings approximately 3 years following radiation. RESULTS: Prior to orbital radiation, retinal microvascular abnormalities were identified in 2 patients. The abnormalities were present bilaterally in one patient and unilaterally in the other. During the course of the study, microvascular abnormalities developed de novo in the unaffected retina of the latter patient while the retinopathy in the fellow eye progressed. Retinal microvascular abnormalities and their sequelae developed de novo in both eyes in 2 more patients. In addition to the radiation, other confounding factors known to be associated with microvascular retinopathy (uveitis, inadequately controlled systemic hypertension, and borderline blood glucose levels) were identified among the 3 patients whose eyes developed new retinal microvascular abnormalities. CONCLUSIONS: Whether the retinal microvascular abnormalities observed in these patients were caused or aggravated by external beam irradiation cannot be precisely ascertained. However, the observed progression and de novo development of retinal microvascular abnormalities within 3 years of orbital radiation raise concern that 0.2 rad (20 Gy) delivered to the orbit in 10 doses of 0.02 rad (2 Gy) may aggravate existing retinal microvascular abnormalities or cause radiation retinopathy in some patients with Graves disease. These findings and the failure of external beam radiation with 0.2 rad (2000 cGy) to favorably affect Graves ophthalmopathy, as demonstrated in a previous study, have led us to discourage further treatment of Graves ophthalmopathy with radiation.

The aftermath of orbital radiotherapy for graves' ophthalmopathy.

OBJECTIVE: To determine whether long-term improvement could be observed after orbital radiotherapy for Graves' disease; in addition, to evaluate ancillary treatments needed for those who have received radiotherapy, to search for late-emerging adverse consequences of radiotherapy, and to relate orbital changes to serum levels of thyroid-stimulating immunoglobulin (TSI). DESIGN: Three-year follow-up of noncomparative interventional case series. PARTICIPANTS: Forty-two patients. INTERVENTION: All patients had received orbital radiotherapy within 6 months of study entry. Twelve months after study entry, patients were free to select any additional treatment for their ophthalmopathy. MAIN OUTCOME MEASURES: Need for surgery, steroid therapy, volume of extraocular muscles and fat, proptosis, area of diplopia fields and range of extraocular muscle motion, volume changes after decompression and correlations of eye findings with serum TSI levels, retinal status. RESULTS: Half of the patients elected to have a surgical procedure on their eyes or orbits. Among patients who were not decompressed, we found only slight improvement in some of the main outcome measures. TSI did not positively correlate with baseline status or with any observed change in major outcome measures. After orbital decompression, the volumes of both muscle and fat increase, but bony orbital volume increases more and proptosis diminishes. Retinal microvascular abnormalities consistent with radiation retinopathy developed de novo in five eyes of three patients within 3 years of radiation therapy. CONCLUSIONS: In this 3-year uncontrolled follow-up phase, limited evidence for a clinically significant improvement was observed, which may be the result of treatment or of natural remission. In either case, the changes are of little clinical significance. Because it is neither effective nor innocuous, radiotherapy does not seem to be indicated for treatment of mild to moderate ophthalmopathy.

Glomus jugulare tumor: tumor control and complications after stereotactic radiosurgery.

BACKGROUND: We evaluated toxicity and long-term efficacy of stereotactic radiosurgery in patients with symptomatic or progressive glomus jugulare tumors. METHODS: Twenty-five consecutive patients (age, 30-88 years; 17 women, 8 men) who underwent stereotactic radiosurgery with the Leksell Gamma Knife (dose, 12-18 Gy) were prospectively followed. MRI and clinical examinations were performed at 6 months and 1, 2, and 3 years, and then every 2 years. RESULTS: None of the tumors increased in size, 17 were stable, and 8 decreased (median imaging follow-up, 35 months; range, 10-113 months). Symptoms subsided in 15 patients (60%); vertigo occurred in 1, but balance improved with vestibular training (median clinical follow-up, 37 months; range, 11-118 months). No other new or progressive neuropathy of cranial nerves V-XII developed. CONCLUSIONS: Stereotactic radiosurgery can achieve excellent tumor control with low risk of morbidity in the treatment of glomus jugulare tumors. The lower cranial nerves can safely tolerate a radiosurgical dose of 12 to 18 Gy.