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Objectives: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignancy for which the role of radiotherapy is not well-defined. We examine the effect of external beam radiotherapy (EBRT) on cancer-specific survival (CSS) for patients with localized EMC, in a propensity score weighted, population-based analysis., Materials and Methods: The Surveillance, Epidemiology, and End Results database (1973 to 2012) was queried for cases of localized EMC arising from soft connective tissues of the trunk and extremities treated with surgery and/or EBRT. Inverse probability treatment weighting was utilized, with survival analysis by weighted Cox regression and Kaplan-Meier analysis with log-rank testing. The primary endpoint was CSS., Results: One hundred seventy-two patients were identified, diagnosed from 2004 to 2012. Ninety-four percent and 32% of 156 assessable patients underwent surgery and EBRT, respectively. By inverse probability treatment weighting, balancing covariates of age group, sex, race, grade, T stage, N stage, receipt of surgery, and anatomic site, we observed CSS of 97% versus 85% and 94% versus 85% in patients receiving EBRT versus no EBRT, at 3 and 5 years, respectively, at median follow-up of 33 months, P=0.01. A trend toward an overall survival benefit associated with EBRT was noted, P=0.06. Further adjusting for type of resection performed, CSS benefit persisted, 97% versus 85% at 3 years and 94% versus 85% at 5 years, P=0.02, with trend toward an overall survival benefit, P=0.08., Conclusions: The receipt of EBRT is associated with a CSS benefit in localized EMC. Aggressive local therapy, including EBRT, should be considered in these patients.

Purpose: To report an update of our previous experience using stereotactic body radiation therapy (SBRT) for the primary treatment of prostate cancer, risk stratified by the updated National Comprehensive Cancer Network (NCCN) version 2.2014, reporting efficacy and toxicity in a community hospital setting., Methods: From 2007 to 2012, 142 localized prostate cancer patients were treated with SBRT using CyberKnife. NCCN guidelines Version 2.2014 risk groups analyzed included very low (20%), low (23%), intermediate (35%), and high (22%) risk. To further explore group heterogeneity and to comply with new guidelines, we separated our prior intermediate risk group into favorable intermediate and unfavorable intermediate groups depending on how many intermediate risk factors were present (one vs. > one). The unfavorable intermediate group was further analyzed in combination with the high risk group as per NCCN guidelines Version 2.2014. Various dose levels were used over the years of treatment, and have been categorized into low dose (35 Gy, n = 5 or 36.25 Gy, n = 107) and high dose (37.5 Gy, n = 30). All treatments were delivered in five fractions. Toxicity was assessed using radiation therapy oncology group criteria., Results: Five-year actuarial freedom from biochemical failure (FFBF) was 100, 91.7, 95.2, 90.0, and 86.7% for very low, low, intermediate and high risk patients, respectively. A significant difference in 5 year FFBF was noted for patients with Gleason score (GS) ≥8 vs. 7 vs. 5/6 (p = 0.03) and low vs. high dose (p = 0.05). T-stage, pretreatment PSA, age, risk stratification group, and use of ADT did not affect 5-year FFBF. Multivariate analysis revealed GS and dose to be the most predictive factors for 5-year FFBF., Conclusion: Our experience with SBRT for the primary treatment of localized prostate cancer demonstrates favorable efficacy and toxicity comparable to the results reported for IMRT in literature. GS remains the single most important pretreatment predictor of outcome.

Objective: The low alpha/beta ratio of prostate cancer suggests that hypofractionated schemes of dose-escalated radiotherapy should be advantageous. We report our experience using stereotactic body radiation therapy (SBRT) for the primary treatment of prostate cancer to assess efficacy and toxicity., Methods: From 2007 to 2010, 70 patients (51 % low risk, 31 % intermediate risk, and 17 % high risk) with localized prostate cancer were treated with SBRT using the CyberKnife system. One-third of patients received androgen deprivation therapy. Doses of 37.5 Gy ( n  = 29), 36.25 Gy ( n  = 36), and 35 Gy ( n  = 5) were administered in five fractions and analyzed as high dose (37.5 Gy) vs. low dose (36.25 and 35 Gy)., Results: At a median 27 and 37 months follow-up, the low and high dose groups' median PSA nadir to date was 0.3 and 0.2 ng/ml, respectively. The 3-year freedom from biochemical failure (FFBF) was 100 %, 95.0 % and 77.1 % for the low-, intermediate- and high-risk patients. A dose response was observed in intermediate- and high-risk patients with 72 % vs. 100 % 3-year FFBF for the low and high dose groups, respectively ( p  = 0.0363). Grade III genitourinary toxicities included 4 % acute and 3 % late (all high dose). Potency was preserved in 83 % of hormone naïve patients., Conclusion: CyberKnife dose escalated SBRT for low-, intermediate- and high-risk prostate cancer exhibits favorable efficacy with acceptable toxicity.

Purpose: To provide a retrospective analysis of the efficacy of hyperbaric oxygen therapy (HBOT) for treating hemorrhagic cystitis (HC) and proctitis secondary to pelvic- and prostate-only radiotherapy., Methods and Materials: Nineteen patients were treated with HBOT for radiation-induced HC and proctitis. The median age at treatment was 66 years (range, 15-84 years). The range of external-beam radiation delivered was 50.0-75.6 Gy. Bleeding must have been refractory to other therapies. Patients received 100% oxygen at 2.0 atmospheres absolute pressure for 90-120 min per treatment in a monoplace chamber. Symptoms were retrospectively scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale to evaluate short-term efficacy. Recurrence of hematuria/hematochezia was used to assess long-term efficacy., Results: Four of the 19 patients were lost to follow-up. Fifteen patients were evaluated and received a mean of 29.8 dives: 11 developed HC and 4 proctitis. All patients experienced a reduction in their LENT-SOMA score. After completion of HBOT, the mean LENT-SOMA score was reduced from 0.78 to 0.20 in patients with HC and from 0.66 to 0.26 in patients with proctitis. Median follow-up was 39 months (range, 7-70 months). No cases of hematuria were refractory to HBOT. Complete resolution of hematuria was seen in 81% (n = 9) and partial response in 18% (n = 2). Recurrence of hematuria occurred in 36% (n = 4) after a median of 10 months. Complete resolution of hematochezia was seen in 50% (n = 2), partial response in 25% (n = 1), and refractory bleeding in 25% (n = 1)., Conclusions: Hyperbaric oxygen therapy is appropriate for radiation-induced HC once less time-consuming therapies have failed to resolve the bleeding. In these conditions, HBOT is efficacious in the short and long term, with minimal side effects., (Copyright © 2012. Published by Elsevier Inc.)

Objective: To evaluate acute toxicity outcomes of prostate cancer patients treated with CyberKnife-delivered hypofractionated radiotherapy., Methods: This study was a retrospective chart review analysis of the first 50 patients treated with CyberKnife radiotherapy for prostate cancer. Most patients were affected with early to intermediate stage prostate cancer. Two patients had metastatic disease at presentation and were excluded. A total of 37 patients received irradiation at a dose of 35 to 37.5 Gy in 5 fractions of 7 to 7.5 Gy per fraction. Assuming an alpha/beta ratio of 1.5 Gy, this process delivered an equivalent dose of 85 to 96 Gy in 2 Gy fractions (EQD2). A subset of patients (n = 11) received standard linear accelerator-based pelvic radiation treatment either by intensity modulated radiation therapy or tomotherapy and received a boost via the CyberKnife at a dose of 17.6 to 25 Gy in 2 to 5 fractions (EQD2= 46.6-72 Gy). The acute toxicities were recorded using the Common Terminology Criteria for Adverse Events, version 3.0, throughout treatment and at patients' follow-up visits., Results: The median patient age at presentation was 66 years (range, 46-80). The mean pretreatment prostate specific antigen and Gleason scores were 9.16 ng/mL and 7, respectively. Grade 2 acute genitourinary toxicity was reported by 10% of patients (n = 5). Only 3 patients reported grade 3 acute genitourinary toxicity. No gastrointestinal grade 2 or grade 3 toxicities were reported., Conclusions: CyberKnife-delivered hypofractionated radiotherapy for the treatment of prostate cancer has an acceptable acute toxicity profile.

Object: This single-institution Phase II study tests the efficacy of adjuvant radioimmunotherapy with (125)I-labeled anti-epidermal growth factor receptor 425 murine monoclonal antibody ((125)I-mAb 425) in patients with newly diagnosed glioblastoma multiforme (GBM)., Methods: A total of 192 patients with GBM were treated with (125)I-mAb 425 over a course of 3 weekly intravenous injections of 1.8 GBq following surgery and radiation therapy. The primary end point was overall survival, and the secondary end point was toxicity. Additional subgroup analyses were performed comparing treatment with (125)I-mAb 425 (RIT, 132 patients), (125)I-mAb 425 and temozolomide (TMZ+RIT, 60 patients), and a historical control group (CTL, 81 patients)., Results: The median age was 53 years (range 19-78 years), and the median Karnofsky Performance Scale score was 80 (range 60-100). The percentage of patients who underwent debulking surgery was 77.6% and that of those receiving temozolomide was 31.3%. The overall median survival was 15.7 months (95% CI 13.6-17.8 months). The 1- and 2-year survivals were 62.5 and 25.5%, respectively. For subgroups RIT and TMZ+RIT, the median survivals were 14.5 and 20.2 months, respectively. No Grade 3 or 4 toxicity was seen with the administration of (125)I-mAb 425. The CTL patients lacked Karnofsky Performance Scale scores, had poorer survival, were older, and were less likely to receive radiation therapy. On multivariate analysis, the hazard ratios for RIT versus CTL, TMZ+RIT versus CTL, and TMZ+RIT versus RIT were 0.49 (p < 0.001), 0.30 (p < 0.001), and 0.62 (p = 0.008), respectively., Conclusions: In this large Phase II study of 192 patients with GBM treated with anti-epidermal growth factor receptor (125)I-mAb 425 radioimmunotherapy, survival was 15.7 months, and treatment was safe and well tolerated.

Purpose: To define a volume of tissue just outside of the clinical target volume (CTV) or planning target volume (PTV) in stereotactic body radiation therapy (SBRT) that receives doses appreciably above the tolerance level and in which other critical tissue structures must be avoided., Methods and Materials: We define the tissue between the borders of the CTV and PTV as the Inner Red Shell. The tissue surrounding the PTV that receives higher than the local tissue tolerance is defined as the Outer Red Shell. Contributing factors to the volume of the Red Shell include the prescription dose, dose gradient and PTV size, together with the type of tissue and its tolerance are discussed. An illustrative example and two clinical cases are reported., Results: The volume of Red Shell increases with higher prescription dose, slower dose fall-off, larger PTV volume, and higher tissue radiosensitivity. Avoidance of proximal critical serial organs may alter the volume and shape of the Red Shell after repeated, detailed treatment planning., Conclusion: Rather than defining tolerance and toxicity as simply a dose level received by the tissues, the volume of tissue receiving risk levels above tolerance can be quantified as the "cost" of SBRT. This concept may be adopted in other techniques offering ablative and high-dose gradients. Further consideration should be given to collecting clinical data for refining the choice of constraint doses, especially in parts of the brain, lung, liver, and kidney., ((c) 2010 Elsevier Inc. All rights reserved.)

A Phase I/II clinical trial was undertaken between January 29, 1987 and January 25, 1997 to assess the efficacy of (125)I-labeled monoclonal antibody 425 ((125)I-MAb 425) in controlling high-grade brain gliomas. A total of 180 patients diagnosed with glioblastoma multiforme (GBM) and astrocytoma with anaplastic foci (AAF) were administered (125)I-MAb 425 as an adjuvant treatment. All underwent initial surgery followed by postoperative external beam radiation therapy and a cumulative dose of 140 mCi of (125)I-MAb 425. Biodistribution of radioactivity after antibody administration showed increased uptake in brain tumor cells due to enhanced expression of epidermal growth factor receptors. A longer half-life of (125)I-MAb 425 in brain tumor cells compared to blood was observed. All patients were followed up for at least 5 years. Overall actuarial survival range for GBM and AAF patients showed 4-150 and 4-270 months, respectively. GBM and AAF patients under age 40 years with a Karnofsky performance status >70 had an actuarial median survival of 22.5 and 65 months, respectively. This adjuvant therapy demonstrates a significant increase in median survival and should be considered in the management of high-grade brain gliomas.

Purpose: To describe the principles and preliminary results of plaque brachytherapy for selected orbital malignancies., Methods: A custom-designed Iodine-125 plaque, designed to deliver a target dose of 50 Gray, was placed surgically in the region from which an orbital malignancy was partially resected. The mean dose to the target area was 50 Gray. The initial and follow-up patient data were reviewed., Results: Of the 8 patients, the diagnosis was adenoid cystic carcinoma of the lacrimal gland (4 cases), orbital invasion by basal cell carcinoma (2), orbital extension of conjunctival melanoma (1), and metastatic carcinoma (1). Of the 4 with adenoid cystic carcinoma, there was microscopic residual tumor after excision and orbital exenteration was considered. Three have tumor control with follow-up of 1, 3, and 6 years. One patient required exenteration for recurrence separate from the field of brachytherapy and is free of tumor after 10 years. All 4 patients are alive and well with tumor control. Of the 2 patients with orbital extension of basal cell carcinoma, tumor control without recurrence has been achieved in both after 2 years. The patient with orbital metastasis responded to plaque radiotherapy, with no orbital recurrence, but died of systemic metastasis. The patient with orbital melanoma had local orbital recurrence separate from the area of irradiation and is currently being treated for systemic metastasis., Conclusions: Based on preliminary observations, plaque radiotherapy appears to be a reasonable alternative to exenteration and external irradiation for selected orbital malignancies.

The purpose of this study was to investigate the exact dose dependency and time dependency of the radiation-enhancing effect of gemcitabine (2',2'difluoro desoxycytidine [dFdC]) in in vitro experiments (HeLa cells: cancer of the uterine cervix, #4197 cells: oropharyngeal squamous cell carcinoma), and to correlate this effect with the underlying changes in cell cycle distribution. Cell viability was determined fluorometrically after exposure to dFdC (0-20.0 micro mol/l), irradiation (0-37.5 Gy), and both modalities. Combining both therapies, cells were exposed to dFdC (0-10.0 micro mol/l) for 24 hours before further treatment and irradiated (0-30 Gy) immediately afterwards with or without removal of dFdC. For cell cycle analysis by flow cytometry, cells were irradiated (0-40 Gy) or treated with dFdC (0.012-1.0 micro mol/l, 24-48 hours). Additionally, cells were exposed to dFdC (2.0 micro mol/l, 0-4 hours). Cell cycle kinetics were evaluated using bromodeoxyuridine (BrdU) (10 micro mol/l) S-phase labeling, given either 30 minutes before or in the last hour of dFdC treatment (2.0 micro mol/l, 0-6 hours). The fluorometric assay revealed that dFdC enhances radiation-induced cytotoxicity at marginally toxic or nontoxic concentrations (<37 nmol/l). Radiation resulted in the anticipated G2/M arrest already at 2 Gy. DFdC induced concentration and exposure time-dependent cell cycle changes that were better resolved using BrdU, demonstrating a pronounced S-phase arrest already at 12 nmol/l. BrdU-pulse labeling revealed that the cell cycle block occurred at the G1/S boundary. Our data reconfirm the already known radiation enhancement, the S-phase specific activities of dFdC, and the relevance of the synchronized progression of cells through the S-phase with regard to the radiosensitizing properties of low-dose dFdC. However, we could demonstrate that before progressing in the S-phase, cells were blocked and partially synchronized at the more radiosensitive G1/S boundary. Furthermore, cells progressing past the block might accumulate proapoptotic signals caused by both radiation and dFdC, which will also results in cell death.

The present report is the follow-up of patients enrolled in a phase II clinical trial using I-MAb 425 as an adjuvant treatment for high grade gliomas. Patient median survivals support published data from an earlier preliminary report. From January 29, 1987 to January 25, 1997, 180 patients diagnosed with astrocytoma with anaplastic foci (AAF) and glioblastoma multiforme (GBM) were treated as outpatients with an average of three weekly intravenous or intraarterial injections of radiolabeled MAb 425. The mean dose was 140 mCi (5.2 GBq). Only one patient who received a single dose of more than 60 mCi (2.2 GBq) experienced acute toxicity. Patients received prior surgery and radiation therapy, with and without chemotherapy. Overall median survival for patients with GBM and AAF was 13.4 and 50.9 months, respectively, with Karnofsky Performance Status (KPS) ranging from 40 to 100 and age ranging from 11 to 75 years. Prognostic factors (KPS and age) correlated positively with increased survival, with KPS the most important determinant of median survival. Data analysis was performed on patients followed 5 years or longer. We conclude that the administration of I-MAb 425 with intensive medical management demonstrates a significant increase in median survival and should be considered a therapeutic regimen for the management of patients with high grade gliomas.

Objective: To evaluate tumor control and treatment complications following plaque radiotherapy combined with transpupillary thermotherapy for choroidal melanoma., Design: Prospective noncomparative interventional case series., Intervention: All patients received treatment for choroidal melanoma using plaque radiotherapy followed by 3 sessions of transpupillary thermotherapy provided at plaque removal and at 4-month intervals., Participants: Two hundred seventy patients with newly diagnosed choroidal melanoma., Main Outcome Measures: The 2 main outcome measures included local tumor recurrence and treatment-related complications. The clinical data regarding patient features, tumor features, radiotherapy and thermotherapy parameters were analyzed for their effect on the 2 main outcomes using Cox proportional hazards regression models., Results: Prior to treatment, the median base of the tumor was 11 mm (range, 4-21 mm) and the median thickness was 4 mm (range, 2-9 mm). Most tumors were located in the posterior pole with a median proximity of 2 mm to the foveola and 2 mm to the optic disc. The median radiotherapy dose to the tumor apex was 9000 rad. Transpupillary thermotherapy was applied in 3 sessions at 4-month intervals for a median of 700 mW. The tumor decreased in thickness to a median of 2.3 mm by 1 year and 2.1 mm by 2 years' follow-up with stable findings thereafter. Using Kaplan-Meier estimates, tumor recurrence was 2% at 2 years and 3% at 5 years. Risk factors for tumor recurrence included macular location of the tumor epicenter (P =.03), diffuse tumor configuration (P =.005), and tumor margin extending underneath the foveola (P =.001). Using Kaplan-Meier estimates, treatment-related complications at 5 years included maculopathy in 18% of the participants, papillopathy in 38%, macular retinal vascular obstruction in 18%, vitreous hemorrhage in 18%, rhegmatogenous retinal detachment in 2%, cataract in 6%, and neovascular glaucoma in 7%. Enucleation for radiation complications was necessary in 3 cases (1%)., Conclusion: Plaque radiotherapy combined with transpupillary thermotherapy provides excellent local tumor control with only 3% recurrence at 5 years' follow-up.

Background: In experimental studies the nucleoside analog Gemcitabine (2',2' difluorodesoxycytidine) clearly demonstrates radiation enhancing properties. After describing the pharmacological Gemcitabine-related data and the clinical studies regarding combined radiochemotherapy and taking under consideration the in-vitro data and the results provided by animal models, this overview is aimed to draw clinically relevant conclusions, resulting in the improvement of treatment approaches., Materials and Methods: The available literature data regarding the metabolism and the mechanism of action, the evaluation of possible schedules of administration, and combined radiochemotherapy including Gemcitabine has been reviewed. Publications reporting experimental data in vitro and in vivo as well as our own experimental results have been incorporated., Results: In clinical phase I and II studies, the favorable tumor response is accompanied by a high incidence of grade III-IV toxicities whereby the maximum-tolerated dose (MTD) of the various schedules of administration used is always lower compared to the MTD of single-agent treatment. In in-vitro and in-vivo data addressing the description and the evaluation of the radiation enhancing mechanism (especially influence on cell cycle, depletion of the dATP pool, induction of apoptosis, inhibition of DNA synthesis, reduction of DNA repair) this effect is already observed with non and moderately toxic Gemcitabine concentrations and depends on drug concentration and exposure time. Independent of the fractionation effect of radiotherapy, the radiation enhancement is persistent for at most 72 hours after the end of drug exposure. Taking under consideration the single dose per day and the target volume, a prolonged infusion and/or a twice-weekly administration of Gemcitabine at low concentration each and simultaneous radiotherapy are presumably considered to resemble the experimental data., Conclusion: It is without doubt that data provided by clinical studies are of highest relevance for the evaluation of an optimized radiochemotherapy with Gemcitabine. However, although it is often difficult to transfer experimental data into the clinical situation, these data offer the possibility to develop an improved schedule of administration in patient treatment based on rational evidence in tumor biology.

The advancements in radiation oncology in the past 50 years in the United States were probably more dramatic than those in the first half of the 20th century. Not only were there major technical achievements, but there was also an associated increase in the overall cure rates of cancer, from 20% at 5 years 50 years ago to now nearly 60% at 5 years. The cure rates in selected tumor sites at 5 years in 1950 and in 2000, respectively, were as follows: breast, 50% and 80%; colon and rectum, 40% and 85%; lung, 5% and 15%-20%; prostate, 40% and 80%; Hodgkin disease, 50% and more than 90%; cervix, 40% and 70%-80%; uterus (endometrium), 80% and more than 90%; bladder, 30% and 50%; head and neck, 30% and 60%; and esophagus, 2% and 15%. Much of this has been due to a broader array of techniques in radiation therapy available for treatment but also because of new emphasis on combined integrated modalitities (surgery, radiation therapy, and chemotherapy). New imaging techniques have contributed substantially, allowing better selection of patients for treatment and better selections of treatment modalities.

Carcinoma of the bladder (CaB) is a common and important tumor in North America and Western Europe. There has been a steady increase in the incidence of CaB during the past 25 years in both of these regions with a simultaneous decrease in the mortality rates. The decrease in mortality is primarily due to an earlier diagnosis and the availability of more effective therapeutic interventions resulting from major advances in surgery and a wide use of multimodality bladder preservation therapy.The use of radiotherapy in the management of muscle-invasive CaB has undergone a major evolution. External beam radiotherapy alone is used infrequently in carefully selected patients. The same applies to the use of preoperative irradiation. Brachytherapy alone or combined with external beam radiotherapy has been used successfully in Europe but is used infrequently in North America. External beam radiotherapy is an essential component of a multimodality therapy consisting of cytoreductive surgery via transurethral resection of a bladder tumor followed by a planned combination of radiotherapy and chemotherapy. The outcomes of this bladder preservation therapy are similar to those reported in a like patient population treated with radical cystectomy. The main benefit of conservatively treated patients is functioning bladder in about 50% of those receiving conservative therapy. Radiotherapy alone or in a combination with chemotherapy remains an important and effective palliative therapy for patients with recurrent and/or metastatic CaB. Current research efforts are directed toward a better identification of important pretreatment risk factors predicting failure thus helping in a more optimal selection of patients who would benefit most from radical cystectomy or from the application of bladder preservation therapy.

The purpose of this symposium was to provide a forum for discussion on current information on the etiology and diagnosis of, and therapy for, tumors of the kidney, testis, and several uncommon malignancies of the genitourinary tract. The most recent contributions in epidemiology and molecular genetics were discussed with specific reference to their importance for clinical practice. Contemporary treatment approaches with the emphasis on multidisciplinary patient management of tumors commonly seen in the clinic as well as those that are only rarely diagnosed by urooncologists were presented. Major stress was given to the management optimization as it pertains to short- and long-term quality of life issues of patients treated for these tumors. Methods to reduce treatment toxicity including carcinogenic potential of chemotherapy, radiotherapy, or their combination were found to be of nearly equal importance to patient survival. Symposium participants reached consensus on a number of important points: 1) The management of patients with several malignancies discussed requires the presence of a multidisciplinary team of specialist who are interested in diagnosis and treatment of genitourinary tumors; 2) Patients managed in such an environment are expected to have optimal survival and the best possible quality of life; 3) Real advances in the management of patients can be best obtained through well-designed prospective clinical trials; and 4) There is a need for timely introduction of relevant advances in epidemiology and molecular genetics to clinics.

Objective: To identify clinical predictive factors for visual outcome in a large series of patients who underwent plaque radiotherapy for uveal melanoma., Design: Clinical factors, including patient data, tumor features, and radiation variables, were analyzed for their impact on visual acuity using Cox proportional hazards regression models., Participants: Patients with uveal melanoma and initial visual acuity of 20/100 or better in the affected eye who were treated with plaque radiotherapy between July 1976 and June 1992., Main Outcome Measures: Two end points were used to evaluate posttreatment visual acuity: (1) final visual acuity (good [20/20-20/100] vs poor [20/200 to no light perception]) and (2) loss of visual acuity (minimal [<5 lines Snellen visual acuity] vs moderate [> or = 5 lines Snellen visual acuity])., Results: Of 1300 consecutive patients with uveal melanoma treated by plaque radiotherapy, 1106 had a visual acuity of 20/100 or better at the time of treatment. In this group, poor visual acuity was found in 34% at 5 years and 68% at 10 years of follow-up. From multivariable analysis, clinical factors that best predicted poor visual acuity were increasing tumor thickness, proximity to foveola of less than 5 mm, notched plaque shape, tumor recurrence, patient age 60 years or older, subretinal fluid, cobalt isotope, anterior tumor margin posterior to equator, and worse initial visual acuity. Moderate loss of visual acuity of 5 Snellen lines or more was found in 33% at 5 years and 69% at 10 years of follow-up. From multivariable analysis, clinical factors that best predicted moderate visual acuity loss included increasing tumor thickness, worse initial visual acuity, notched plaque shape, tumor recurrence, proximity to foveola of less than 5 mm, patient age of 60 years or older, subretinal fluid, and diabetes mellitus or hypertension. When analyzing visual outcome with regard to tumor thickness, ultimate poor visual acuity of 20/200 or worse at 5 years was found in 24% with a small melanoma (< or = 3.0 mm), 30% with a medium melanoma (3.1-8.0 mm), and 64% with a large melanoma (>8.0 mm). When analyzing visual outcome with regard to tumor proximity to visually important structures, tumors less than 5 mm from the optic disc or foveola demonstrated poor visual acuity in 35% at 5 years, whereas those 5 mm or more from the optic disc and foveola showed poor visual acuity in 25% at 5 years., Conclusions: Ultimate visual acuity after plaque radiotherapy for uveal melanoma depends on many factors, including patient age and general health, initial visual acuity, tumor location and size, subretinal fluid, radioactive isotope, and final tumor control. At 10 years' follow-up, 68% of patients demonstrate poor visual acuity. Visual acuity is most effectively preserved in eyes with small tumors outside a radius of 5 mm from the optic disc and foveola. Arch Ophthalmol. 2000;118:1219-1228

Major changes have occurred in the last 25 years which have impacted significantly on the practice of radiation oncology. Twenty-five years ago, less than 40% of all patients had radiation therapy as a part of their management either for cure, palliation or in combination with surgery and/or chemotherapy. In 1998, about 60% of all patients had radiation therapy as a part of their treatment program either initially or at some time during the course of their disease process. Clearly, randomized clinical trials have made their contribution in cancer management but probably the most significant impact has been improving the standards of care relative to cancer treatment through better education and more cooperative efforts. It is extraordinarily difficult to predict the future for radiation oncology in the third millennium primarily because of the major changes in technology as well as the financial limitations with regards to treatment.

Background: The relative effectiveness of plaque radiotherapy and enucleation in patients with choroidal or ciliochoroidal melanoma remains controversial. Most published comparative survival studies have evaluated clearly biased groups, short-term follow-up, or both., Methods: The authors performed a retrospective, non-randomized, comparative survival study on 734 patients with a choroidal or ciliochoroidal melanoma treated by enucleation (n=237) or plaque radiotherapy (n=497) between July 1980 and June 1985, and on a residual group of 448 patients, 103 treated by enucleation and 345 treated by plaque radiotherapy, identified by variable-by-variable range matching. Melanoma-specific mortality and all-cause mortality were evaluated by the life-table method., Results: The melanoma-specific mortality rate was substantially worse in the original enucleation subgroup throughout available post-treatment follow-up; however, differences in baseline prognostic factors between the subgroups are likely to explain much of the survival differential. After eliminating patients with nonoverlapping values of individual clinical variables to adjust for recognized intergroup differences at baseline, there was no significant difference in the mortality curves of the residual subgroups. The cumulative 15-year survival based on deaths from metastatic melanoma in the enucleation subgroup was 57.1% (standard error=6.4%), while that in the plaque radiotherapy subgroup was 61.8% (standard error=3.3%)., Conclusion: On the basis of these results, we conclude that a large difference in survival between equivalent groups of patients with primary choroidal or ciliary body melanoma treated by enucleation or by plaque radiotherapy appears unlikely.

Objective: To identify the risk factors that lead to the development of radiation retinopathy following plaque radiotherapy for posterior uveal melanoma. Radiation retinopathy is a slowly progressive, occlusive vasculopathy characterized by radiation-induced endothelial damage., Methods: Review of the medical records of patients with posterior uveal melanoma treated with plaque radiotherapy., Results: Of 1300 patients with posterior uveal melanoma treated with plaque radiotherapy from July 1, 1976, through June 30, 1992, radiation retinopathy developed in 560 (43.1%). By using Kaplan-Meier survival estimates, we found that 5% of the patients had nonproliferative radiation retinopathy at 1 year (95% confidence interval [CI], 3%-6%) and 42% at 5 years (95% CI, 38%-45%). The proportion of patients with proliferative retinopathy was 1% at 1 year (95% CI, 0.2%-1.5%) and 8% at 5 years (95% CI, 5%-10%). Multivariate analyses showed that the subset of clinical variables best related to the development of nonproliferative radiation retinopathy were tumor margin of less than 4 mm from foveola (P<.001), tumor limited to the choroid (P = .002), and radiation dose rate of greater than 260 cGy/h to the tumor base (P = .02). The best subset of independent variables related to the development of radiation maculopathy were tumor of less than 4 mm to foveola (P<.001) and the use of radioisotope iridium 192 (192Ir) (P = .02) compared with iodine 125 (125I). From a multivariate model, the most important factors for the development of proliferative radiation retinopathy included diabetes mellitus (P = .01), radioisotope 192Ir (P = .01) compared with 125I, and tumor base of greater than 10 mm (P = .02)., Conclusions: Radiation retinopathy is a common finding after plaque radiotherapy for choroidal melanoma, occurring in 42% of patients at 5 years. The main predictors of radiation retinopathy are posterior tumor location with margin near the foveola and high radiation dose rate to the tumor base.

Purpose: To determine the outcome of plaque radiotherapy in the treatment of macular choroidal melanoma and to identify the risk factors associated with the development of radiation complications, tumor recurrence, and metastasis., Methods: Chart analysis of 630 consecutive patients (630 eyes) with macular choroidal melanoma managed by plaque radiotherapy between July 1976 and June 1992., Results: The median largest basal tumor diameter was 10 mm, and the median tumor thickness was 4 mm. By means of Kaplan-Meier estimates, visually significant maculopathy developed at 5 years in 40% of the patients, cataract in 32%, papillopathy in 13%, and tumor recurrence in 9%. Vision decrease by 3 or more Snellen lines was found in 40% of the patients at 5 years. Sixty-nine eyes (11%) were enucleated because of radiation complications and recurrence. Twelve percent of the patients developed metastasis by 5 years and 22% by 10 years. Results of multivariate Cox proportional hazards analyses showed that the significant predictors for tumor recurrence were a distance of tumor margin from the optic disk of less than 2 mm (P = .003) and retinal invasion (P = .009). The significant variables that were predictive of metastasis included tumor thickness greater than 4 mm (P = .02) and largest basal tumor diameter greater than 10 mm (P = .03)., Conclusions: Plaque radiotherapy offers a 91% 5-year local tumor control rate for macular choroidal melanoma. Despite good local tumor control, the risk for metastasis is 12% at 5 years and 22% at 10 years. In 11% of the patients, enucleation eventually became necessary because of radiation complications and tumor recurrence.

Background: There are several options for management of ciliary body melanoma, including plaque radiotherapy, charged particle irradiation, local resection, and enucleation. The choice of therapy depends on many factors, and plaque radiotherapy is often used., Objectives: To determine the outcome of plaque radiotherapy in the management of ciliary body melanoma and to identify the risk factors associated with the development of radiation complications, tumor recurrence, metastasis, and melanoma-related death after plaque radiotherapy of ciliary body melanoma., Methods: We analyzed the clinical records of 136 patients with ciliary body melanoma who were treated with plaque radiotherapy between July 1976 and June 1992., Results: The median follow-up period was 70 months. Using Kaplan-Meier survival estimates, the most frequent radiation complication at 5 years' follow-up was cataract, developing in 48% of the patients, followed by neovascular glaucoma (21%), retinopathy (20%), scleral necrosis (12%), and vitreous hemorrhage (11%). Visual acuity decrease (by > or =3 Snellen lines) was noted in 40% of the patients at 5 years. Kaplan-Meier estimates showed that 8% of the patients developed recurrence, 28% had metastasis, and 22% died of melanoma-related causes by 5 years. Univariate analysis demonstrated that the factors predictive of radiation cataract were superonasal (P = .003) and inferior tumor meridian (P = .02) compared with inferonasal meridian and apex dose rate greater than 57 cGy/h (P = .05). The development of neovascular glaucoma was significantly related to iris involvement with the ciliary body tumor (P<.001). The factors predictive of development of radiation retinopathy were base dose rate greater than 230 cGy/h (P = .03) and the presence of diabetes mellitus (P = .05). The only predictor of metastasis was tumor thickness greater than 7 mm (P = .02). The risk factors for melanoma-related death were the presence of metastasis (P<.001), tumor thickness greater than 7 mm (P = .02), and recurrence (P = .02). Multivariate analyses showed that the most significant variables predictive of the development of scleral necrosis were intraocular pressure greater than 15 mm Hg (P<.001) and tumor thickness greater than 7 mm (P = .007). The most significant predictive factors for vitreous hemorrhage were visual acuity of 20/40 to 20/200 (P = .02) and intraocular pressure greater than 15 mm Hg (P = .02). The best subset of independent predictors of vision decrease were mushroom tumor shape (P = .002), age older than 61 years (P = .006), and superonasal meridian (P = .04). The risks for melanoma-related death were presence of metastasis (P<.001) and tumor thickness greater than 7 mm (P = .01). There was no group of significant variables predictive for radiation cataract, neovascular glaucoma, retinopathy, tumor recurrence, and metastasis in multivariate analysis., Conclusions: Plaque radiotherapy offers 92% 5-year local control rate for ciliary body melanoma. Metastasis occurs in 28% of the patients treated with this method by 5 years. Patients with tumors greater than 7 mm in thickness are at greater risk than patients with thinner tumors for metastatic disease and melanoma-related death. Major radiation complications include radiation cataract, neovascular glaucoma, retinopathy, and scleral necrosis.

Objective: This study aimed to determine whether the long-term melanoma-specific mortality rate of patients with a primary choroidal or ciliary body melanoma treated by enucleation is appreciably lower than that of similar patients treated by plaque radiation therapy., Design: Retrospective, nonrandomized, comparative clinical trial., Participants: A previously reported group of 237 patients, 140 treated by enucleation and 97 treated by cobalt-60 (Co-60) plaque between May 1976 and June 1980, and a residual group of 122 patients, 51 treated by enucleation and 71 treated by Co-60 plaque, were identified by variable-by-variable range matching., Intervention: Primary treatment by enucleation or Co-60 plaque radiation therapy was performed., Main Outcome Measures: Melanoma-specific mortality and duration of post-treatment survival were measured., Results: The melanoma-specific mortality rate was substantially worse in the original enucleation subgroup over the entire 15-year follow-up interval; however, differences in baseline prognostic factors between the subgroups are likely to explain the difference in survival curves. After elimination of patients with nonoverlapping values of individual clinical variables to adjust for recognized intergroup differences at baseline, there was no significant or clinically important difference in the 15-year mortality curves of the residual subgroups. The relative rate ratio for the treatment effect in the residual patients was 0.97 (95% confidence interval, 0.51-1.86). There was no late downturn in the survival curve of the plaque-treated patients or late crossing of the curves., Conclusion: A large difference in survival between equivalent groups of patients with primary choroidal or ciliary body melanoma treated by enucleation versus plaque radiation therapy appears to be unlikely.

Carcinoma of the bladder (CaB) is a common tumor of the genitourinary tract. In the United States in 1997, CaB was second in frequency of occurrence and third in mortality among genitourinary tumors. This tumor has a well-documented history of environmental and industrial causative factors. The strongest etiologic risk factors include the use of tobacco, which is thought to be responsible for half of the CaB diagnosed in men in the United States, and some arylamines. In the past 30 years, there has been major improvement in the survival of patients with this disease. Multiple factors were responsible for this accomplishment and they include: 1) better understanding of the natural history of CaB, 2) development of immunohistochemical analysis helpful in defining prognostic factors, 3) improved imaging and nonimaging diagnostic modalities helpful in making earlier diagnosis and better defining the true anatomical extent of the tumor, 4) development of more effective therapy for carcinoma in situ, 5) major improvement in surgical techniques resulting in better treatment outcomes, and 6) the wide use of adjuvant chemotherapy. Major stress has been placed on the quality of life of patients treated for CaB. Quality of life was improved by optimizing surgical, radiation, and medical treatment techniques. The two most important factors producing this quality-of-life improvement include: 1) the use of organ-preserving therapy in properly selected patients that involves the use of a multimodality therapeutic approach with transurethral resection, radiation therapy, and chemotherapy; and 2) the ability to treat selected men and women with radical cystectomy followed by orthotopic reconstruction that allows patients nearly physiologic voiding. Current research efforts are directed toward better patient selection for appropriate therapy which is expected to increase patient survival and improve quality of life. Of particular importance in the selection of this optimal therapy in patients with CaB is a wide application in the clinical practice of important recent advances in molecular genetics.

Twenty-two patients who had failed conventional treatment for advanced colorectal carcinoma metastatic to the liver were entered in this study. Survival from the date the hepatic disease was documented and ranged from 3 to 62 months, with an average of 20 months. Notably, 8 of the 22, or 36%, lived 24 months or more. Four patients, or 18%, survived 3 to 5 years after diagnosis of hepatic metastasis.

Purpose: This study was undertaken to assess the toxicity and possible benefits from the administration of low-dose external-beam irradiation for Age-Related Macular Degeneration (ARMD). The premise of the treatment is that radiation induces regression and/or promotes inactivation of the subretinal neo-vasculature, resulting in reabsorption of fluid and blood thus reducing the risk for further leakage or bleeding, as well as subretinal fibrosis. Clinically, the beneficial effect could be translated into stabilization of visual acuity and prevention of progression of the wet type of ARMD with the possibility for some visual improvement., Methods and Materials: Allegheny University Hospitals, Hahnemann, Department of Radiation Oncology, treated 278 patients prospectively beginning in January 1995 with low-dose irradiation for wet-type macular degeneration. Two hundred forty-nine patients were treated with a total dose of 14.40 Gy in eight fractions of 1.80 Gy over 10-13 elapsed days, and 27 patients with 20 Gy at 2 Gy per fraction over 12-15 days. The first two patients were treated to a total dose of 10.00 Gy in five fractions of 2.00 Gy. Patients were evaluated at 2-3 weeks and 2-3 months. A percentage (36.7%) of the patients had previously received laser treatments in the study eye, 21.9% once, 5% twice, 9.7% three or more. Subjective visual acuity and toxicity data was collected on all patients., Results: At 2-3 weeks after treatment 195 patients (70%) retained their visual acuity without change, 68 patients (24.5%) stated they had improved vision, and 15 patients (4.8%) stated their vision continued to decrease. Two to 3 months after treatment, 183 patients (65.8%) had no change in their vision, 75 patients (27%) had an improvement in their vision, and 20 patients (7.2%) had a decrease in visual acuity. Transient acute reactions occurred in 14 of the 278 patients treated., Conclusion: Our observations in this group of 278 patients support the conclusion that many patients will have improved or stable vision after treatment with low-dose irradiation for age related wet type macular degeneration.

Local control of unresectable esophageal carcinomas remains a significant problem in spite of aggressive treatments. External beam radiation therapy, chemotherapy, and combined modality treatment have all been employed with limited success. Here we review the existing literature and our own experience with external beam radiation followed by low-dose-rate or high-dose-rate intracavitary radiation for carcinoma of esophagus. The addition of intracavitary brachytherapy to external beam irradiation is well tolerated, causes no significant toxicity, and improves local control. Low-dose-rate intracavitary boost compared to high-dose-rate intracavitary boost has the advantage of a greater margin of safety, requires a single application, does not require highly sophisticated computerized technology, and is accompanied with fewer high-grade toxicities. Combined modality therapy consisting of concomitant infusional chemotherapy, external beam irradiation, and low-dose-rate intracavitary boost needs to be investigated.

Enhanced accumulation of monoclonal antibodies in tumor tissue has been observed as a result of external beam irradiation (EBR). This effect was mainly attributed to increased vascular leakage due to unspecific radiation damage of vascular endothelial cells. The aim of this study was to investigate the effects of EBR on expression and antibody-binding of epidermal growth-factor receptor (EGF-R) in human glioma cells in-vitro. High-grade glioma cells were irradiated with conventional x-rays (0-3600 Rad) and surface binding, internalization and radiocytotoxicity of 125I-labeled monoclonal antibody (MAb) 425, specific for human EGF-R, was tested. EBR showed a short-term dose and time dependent increase of specific MAb 425 binding and internalization in receptor positive cell lines U87-MG and A1207. This effect was probably due to a mitotic block and an increase in cellular volume. Combination of EBR and 125I-425 showed additive effects on cell vitality/survival and was more pronounced in contact inhibited cells as compared to cells growing in a log-phase. We assume that cells exposed to 125I-labeled MAb 425 are only able to accumulate a critical number of DNA double-strand breaks when the doubling-time is prolonged e.g. under contact-inhibition or radiation induced mitotic blockade. We conclude that EBR has no negative effects on EGF-R expression, MAb-binding and internalization. The combination of EBR and 125I-MAb 425 enhances cytotoxic efficacy and thus supports adjuvant use in the clinical management of high-grade glioma.

Carcinoma of the female urethra is uncommon. The review of literature and our own experience indicates that early distal urethral cancers (squamous and adenocarcinoma) can be treated either with surgery (70-80% 5-year survival) or with radiotherapy (brachytherapy) with excellent results (75% 5-year survival). Early proximal or entire urethral cancers (squamous and adenocarcinoma), if treated surgically, will require exenterative procedures. Alternatively, these cancers can be treated with a combination of external beam and brachytherapy with or without chemotherapy with good results and preservation of organs. Surgery can be used for failures or persistent tumors. Advanced cancers require a multimodality approach, and a combination of radiation and chemotherapy appears to be the optimal way to treat these patients-with surgery to be used for biopsy-proven persistent tumors or recurrences.

Patients with primary ocular tumors are seen infrequently in the medical profession, and most of these patients are referred to specialty centers which has resulted in a good study population. In the past, ocular tumors were treated with enucleation, but the current emphasis is now on organ preservation with sparing of all or partial visual acuity. In the management of these tumors, plaque brachytherapy and particle beam therapy have been used more frequently as an alternative to enucleation. A multi-institutional study, the Collaborative Ocular Melanoma Study (COMS), is currently underway, organized by the National Eye Institute. The COMS isotope of choice is Iodine-125 (I-125). Recurrence after plaque therapy is approximately 15%, although it may be as high as 37% at 15 years for metastatic disease. In one study, nondiffuse iris melanoma has been controlled in 93% of patients by custom plaques utilizing I-125. Plaque brachytherapy also utilizes I-125 for the treatment of retinoblastoma tumors either as primary therapy or following external beam radiation. Currently, through the utilization of plaque radiation therapy, enucleation may be avoided in the majority of patients, and many patients may retrieve some visual acuity. We will review plaque brachytherapy techniques, diagnosis, staging, and some of the pertinent literature of the two most frequently encountered primary ocular tumors: choroidal melanoma, sometimes referred to as uveal melanoma, with an incidence of approximately 1,500 new cases per year in the adult population; and retinoblastoma, the most common intraocular primary malignancy found in childhood, with a frequency of approximately 250 [corrected] new cases per year.

Adenocarcinoma of the prostate (CaP) in the Western world has become the most common noncutaneous human tumor. CaP is also the second most important cause of cancer deaths among the male population in the United States. Major progress was made in the past decade in better understanding this disease process, as well as in improved diagnostic accuracy. This improved diagnostic accuracy was due to wide application of prostate-specific antigen (PSA), use of transrectal ultrasound (TRUS), and greater awareness among clinicians of CaP. The use of PSA in clinical practice has resulted in a sharp increase in the number of patients diagnosed with capsule-confined tumors. The optimal treatment for capsule-confined CaP is in the process of being defined. Radical prostatectomy in the United States is currently the most commonly applied treatment for younger patients. Excellent treatment results with a 10-year actuarial survival > 80% are readily obtainable in properly selected patients. Nerve-sparing procedures helped reduce the high incidence of impotence that occurs in patients after radical retropubic prostatectomy. Radiotherapy remains the other curative treatment method in the management of CaP patients, with long-term survival rates similar to those reported in surgical series. Due to the problem of frequent preoperative tumor understaging, a routine use of postoperative irradiation to the prostatic fossa produces an excellent (> 95%) incidence of local tumor control. Management of patients with metastatic disease has undergone a considerable evolution with the development of modern hormonal management and treatment with strontium-89 to control intractable bone pain. Newer treatment methods such as hyperthermia are currently being investigated. Major efforts are directed toward the reduction of short- and long-term treatment toxicity associated with surgery, radiotherapy, and hormonal management, thus improving patient quality of life.

Disseminated carcinoma of the prostate (CaP) is a common manifestation of this disease. Metastatic CaP in the United States is seen in about 45,000 patients each year at diagnosis. At least the same number of patients who have had prior definitive treatment with surgery or radiotherapy develop evidence of metastatic disease. Hormonal management is the most important and well established treatment for patients with prostatic metastases. Orchiectomy remains the most efficient and most cost effective therapy in a rapid ablation of testicular androgens. Due to a well known psychological reaction to castration which is seen in many patients, diethylstilbestrol (DES) is a good alternative and cost effective therapy. The mode of action of DES is to suppress LH production and to slowly, indirectly, decrease serum testosterone level. In recent years, total androgen blockade (TAB) has become a widely accepted treatment option. This treatment has been shown in several clinical trials to be effective and well tolerated by the patients. A major problem with a routine use of TAB is a relatively high cost of this therapy. In a European prospective randomized trial, goserelin acetate-flutamide combination significantly increased time to progression when compared with orchiectomy alone. Patients with localized and symptomatic metastases are best treated with radiotherapy. Those with multiple sites of involvement are best treated with strontium-89 which results in a good palliation in a majority of patients. Nearly all hormonally treated patients, with metastatic CaP, eventually show tumor progression. Presently available chemotherapy is of a low effectiveness and should not be used for these patients outside of controlled clinical trials. Current research is directed to identify effective therapy for hormone refractory patients. Immunotherapy and gene therapy may be useful future therapeutic options.

Background: Radiotherapy is effective for the management of most uveal metastases, and standard external beam radiotherapy is generally administered during a 3-to 4-week period. For those patients in whom external beam radiotherapy or other methods fail or those patients with solitary uveal metastases, plaque radiotherapy may be an alternative method., Objective: To determine the effectiveness of plaque radiotherapy for the management of uveal metastasis., Methods: A retrospective review of 36 patients with uveal metastases who were examined at the Oncology Service at Wills Eye Hospital, Philadelphia, Pa, and treated with plaque radiotherapy. The clinical findings and follow-up data of the primary tumor and the uveal metastasis were analyzed., Results: Of the 36 patients, 27 (75%) received plaque treatment as primary therapy for the uveal metastasis and 9 (25%) received plaque treatment as secondary therapy after failure of the uveal tumor to respond to external beam radiotherapy, chemotherapy, or hormonal therapy. During treatment, 22 patients (61%) had no other systemic metastasis and 14 (39%) had controlled systemic metastasis. No patients had active metastasis elsewhere. The uveal metastasis was solitary and well circumscribed in all but 1 patient; it measured a mean of 11 mm in basal dimension and 4 mm in thickness. The mean time for treatment was 86 hours, and the mean therapeutic dose was 68.80 Gy to the tumor apex and 235.64 Gy to the tumor base. Regression of the uveal metastasis was documented in 34 patients (94%) during a mean follow-up of 11 months. As early as 3 months after treatment, the mean tumor thickness had decreased to 2 mm. Plaque radiotherapy salvaged 5 of the 6 eyes that had failed prior external beam radiotherapy. Radiation retinopathy, radiation papillopathy, or both were found in 3 patients (8%) and occurred at a mean of 8 months after treatment. At the last examination, 18 patients (50%) were alive (11 with and 7 without active systemic metastasis) and 18 (50%) were dead from systemic metastasis., Conclusions: Plaque radiotherapy is an effective method for treating selected solitary uveal metastasis. It offers a high degree of tumor control, especially for those eyes in which other methods have failed. Plaque treatment is provided during a short period, minimizing the time demand for these patients with a limited life expectancy.