Benefit of Radiotherapy in Extraskeletal Myxoid Chondrosarcoma: A Propensity Score Weighted Population-based Analysis of the SEER Database.

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.

SBRT for the Primary Treatment of Localized Prostate Cancer: The Effect of Gleason Score, Dose and Heterogeneity of Intermediate Risk on Outcome Utilizing 2.2014 NCCN Risk Stratification Guidelines.

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.

Stereotactic body radiation therapy for the primary treatment of localized prostate cancer.

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.

Hyperbaric oxygen therapy for radiation-induced cystitis and proctitis.

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.

Acute toxicity after cyberknife-delivered hypofractionated radiotherapy for treatment of prostate cancer.

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.

Radiotherapy in the treatment of gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) are uncommon mesenchymal tumors of the gastrointestinal tract. Up to one-third of GISTs are malignant with a high rate of metastasis. Surgical resection is the mainstay of care for patients with resectable disease. Imatinib mesylate, a selective tyrosine kinase inhibitor, is the current standard of care for GISTs that cannot be completely resected or in cases of metastatic GIST. Although often overlooked, radiation therapy is a viable option for select patients with GIST. We report the case of a patient with unresectable GIST who was treated with local radiotherapy and achieved long-term response. We also present a review of the literature regarding the use of radiotherapy in the treatment of GIST. GIST has been shown to be a radiosensitive tumor. Radiotherapy can offer long-term local control and should be considered in the adjuvant or palliative setting. The role of radiotherapy delivered concurrently with imatinib in the treatment of GIST may warrant further investigation.

Red shell: defining a high-risk zone of normal tissue damage in stereotactic body radiation therapy.

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.

A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme.

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.

Radioimmunotherapy as a novel treatment regimen: 125I-labeled monoclonal antibody 425 in the treatment of high-grade brain gliomas.

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.

Plaque radiotherapy for selected orbital malignancies: preliminary observations: the 2002 Montgomery Lecture, part 2.

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.

Radiation enhancement by gemcitabine-mediated cell cycle modulations.

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.

Radioiodinated (I-125) monoclonal antibody 425 in the treatment of high grade glioma patients: ten-year synopsis of a novel treatment.

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.

Combined plaque radiotherapy and transpupillary thermotherapy for choroidal melanoma: tumor control and treatment complications in 270 consecutive patients.

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.

[Combined radiotherapy and gemcitabine. Evaluation of clinical data based on experimental knowledge]. / Kombination von Radiotherapie und Gemcitabine. Bewertung der klinischen Daten auf der Basis experimenteller Erkenntnisse.

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.