American College of Radiology-American Brachytherapy Society practice parameter for electronically generated low-energy radiation sources.

BACKGROUND: This collaborative practice parameter technical standard has been created between the American College of Radiology and American Brachytherapy Society to guide the usage of electronically generated low energy radiation sources (ELSs). It refers to the use of electronic X-ray sources with peak voltages up to 120 kVp to deliver therapeutic radiation therapy. MAIN FINDINGS: The parameter provides a guideline for utilizing ELS, including patient selection and consent, treatment planning, and delivery processes. The parameter reviews the published clinical data with regard to ELS results in skin, breast, and other cancers. CONCLUSIONS: This technical standard recommends appropriate qualifications of the involved personnel. The parameter reviews the technical issues relating to equipment specifications as well as patient and personnel safety. Regarding suggestions for educational programs with regard to this parameter,it is suggested that the training level for clinicians be equivalent to that for other radiation therapies. It also suggests that ELS must be done using the same standards of quality and safety as those in place for other forms of radiation therapy.

Bicalutamide alone prior to brachytherapy achieves cytoreduction that is similar to luteinizing hormone-releasing hormone analogues with less patient-reported morbidity.

OBJECTIVES: To compare the impact of bicalutamide (B) vs. luteinizing hormone-releasing hormone analogues (LHRHa) on prostate volume, patient-reported side effects, and postimplant urinary toxicity in the setting of interstitial brachytherapy for early-stage prostate cancer. METHODS: Between May 1998 and January 2004, 81 patients received androgen-deprivation therapy (ADT) for cytoreduction prior to interstitial brachytherapy alone. Fifty-six patients received LHRHa and 25 patients received B. Prostate volumes were measured prospectively prior to initiating therapy, and then intraoperatively at the time of implant by a single, blinded ultrasonographer. Patient-reported quality of life data were obtained prospectively, and postimplant urinary toxicity (catheter dependency and need for surgical intervention) was recorded during follow-up. Median follow-up was 53 (range 23-78) months. RESULTS: The median percentage prostate volume reductions of 26% for B and 32% for LHRHa were not statistically different (P = 0.61). Decrements in libido (92% vs. 44%, P < 0.001) and erectile function (79% vs. 20%) were reported in more respondents treated with LHRHa than B. The incidence of recatheterization (28% vs. 24%, P = 0.34), and the need for subsequent surgical intervention (11% vs. 4%, P = 0.16) were similar for patients treated with LHRHa and B. CONCLUSIONS: The degree of prostate downsizing with B is similar to that achieved with LHRHa. B was associated with fewer patient-reported sexual side effects and similar urinary morbidity. A randomized trial is needed to establish whether LHRHa or B should be the standard of care for prostate downsizing before interstitial brachytherapy.

Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas.

CONTEXT: Radiation therapy is a potentially curative treatment for corticotroph adenomas refractory to surgery. Protons have an advantage over photons (x-rays) by depositing energy at the target with no exit dose, providing a lower dose to adjacent normal tissues. Until recently, proton stereotactic radiotherapy (PSR) was available at only two U.S. centers; use will increase as proton facilities are under development. OBJECTIVE: Our objective was to evaluate the efficacy and safety of PSR for persistent Cushing's disease (CD) and Nelson's syndrome (NS). DESIGN: This was a retrospective review of 38 patients (33 with CD and five with NS) treated between 1992 and 2005. PARTICIPANTS: All patients had transsphenoidal surgery without biochemical cure. Four had previous irradiation with photons. The patients with NS underwent bilateral adrenalectomy 29-228 months (median 40) before PSR. INTERVENTION: Single-fraction PSR was delivered at a median dose of 20 Cobalt Gray Equivalents (range 15-20) on 1 treatment day. MAIN OUTCOME MEASURES: Complete response (CR) was defined as sustained (> or =3 months) normalization of urinary free cortisol off medical therapy. CR in NS was based on normalization of plasma corticotropin. RESULTS: At a median follow-up of 62 months (range 20-136), CR was achieved in five patients (100%) with NS and 17 (52%) patients with CD. Among all patients with CR, median time to CR was 18 months (range 5-49). No secondary tumors were noted on follow-up magnetic resonance imaging scans, and there was no clinical evidence of optic nerve damage, seizure, or brain injury. There were 17 patients (52%) who developed new pituitary deficits. CONCLUSIONS: PSR is effective for patients with persistent corticotroph adenomas with low morbidity after a median follow-up of 62 months; longer follow-up is warranted for late radiation-related sequelae.

Androgen deprivation-mediated cytoreduction before interstitial brachytherapy for prostate cancer does not abrogate the elevated risk of urinary morbidity associated with larger initial prostate volume.

PURPOSE: We examined whether prostate volume reduction after a short course of androgen deprivation (AD) lowered the risks of acute and chronic urinary morbidity related to radioactive seed implantation for low-risk prostate cancer. METHODS AND MATERIALS: Eighty-one patients received AD for cytoreduction before interstitial brachytherapy alone. Urinary morbidity was carefully assessed for all patients during a median followup of 53 (range, 23-78) months after treatment. Outcomes were then compared with those of a control group of 81 patients who were matched 1:1 based on identical prostate volume measured at the time of radioactive seed implant, but who had not received AD. RESULTS: Despite effective cytoreduction (median, 30% prostate volume reduction) with AD, prolonged catheterization was required significantly more often for patients who had received AD when compared with the control group of patients who were implanted at identical prostate volumes but who had not received AD (27% vs. 9%, p = 0.02). This finding remained statistically significant on multivariate analysis (p = 0.04). Surgical intervention (9% vs. 4%, p = 0.09) and subsequent urinary incontinence (4% vs. 1%, p = 0.16) were also more frequent among patients who had received AD when compared with implant volume-matched controls. CONCLUSIONS: Patients who achieved smaller prostate volumes through the use of AD maintained a significantly elevated risk (threefold) for urinary complications, commensurate with their initially large prostate volume, when compared with a control group of patients who were implanted at identical prostate volumes but who had not received AD. Therefore, patients presenting with larger prostate glands that would warrant a short course of AD before implant should be counseled accordingly when discussing options for local therapy.

Proton stereotactic radiosurgery in management of persistent acromegaly.

OBJECTIVE: To evaluate the efficacy and safety of proton stereotactic radiosurgery (PSRS) for acromegaly that is refractory to surgical treatment and medication. METHODS: From 1992 to 2003, 22 patients were treated at our institution for persistent acromegaly with use of PSRS. All patients had undergone at least one transsphenoidal surgical procedure without biochemical cure. The median treatment dose delivered during PSRS was 20 (range, 15 to 24) cobalt gray equivalents. RESULTS: Follow-up was available for all patients at a median of 6.3 (range, 2.5 to 14.2) years after PSRS. A response to PSRS was observed in 21 of 22 patients (95%). A complete response (CR), defined as sustained (> or =3 months) normalization of insulinlike growth factor-I without medical suppression, was attained in 13 patients (59%). Among patients with CR, the median time to CR was 42 (range, 6 to 62) months. No visual complications, seizures, clinical evidence of brain injury, or secondary tumors were noted on regular magnetic resonance imaging scans. One patient had complete pituitary dysfunction before PSRS and was therefore excluded from evaluation for failure. Of the other 21 patients, 8 (38%) had new pituitary deficits. CONCLUSION: These results demonstrate that PSRS is effective for persistent acromegaly, with 59% of patients attaining normal insulinlike growth factor-I levels without use of any medication after a median of 6.3 years. Our findings indicate that radiosurgery results in an expeditious biochemical response with low morbidity.

Prostate-specific antigen recurrence and mortality after conventional dose radiation therapy in select men with low-risk prostate cancer.

BACKGROUND: Prostate-specific antigen (PSA) recurrence, prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM) were evaluated for men age >70 years receiving conventional dose external beam radiation therapy (RT). METHODS: Between January 1, 1989, and December 1, 2002, 358 men were treated with RT for localized prostate cancer at a Harvard Medical School Affiliate in Fall River, MA. Median age was 71.2 (range, 43.2-83.5) years and patients were followed for a median of 4.0 (range, 0.2-13.5) years. RESULTS: Univariable analysis demonstrated that increasing pretreatment PSA velocity was significantly associated with increasing pretreatment PSA (P < .0001), Gleason score (P = .0002), and shorter post-RT PSA doubling time (P = .0007) but not with clinical T-category (P = .09) or percent positive biopsies (P = .08). For the select cohort of men age >70 years with low-risk disease and a pretreatment PSA velocity < or =1.0 ng/mL per year, all deaths observed to date have been from nonprostate cancer etiologies. Whereas PSA recurrence in this group reached 43.3% by 7 years, due to the advanced age of the cohort and less aggressive biology, competing causes of mortality predominated as the cause of death despite PSA failure. CONCLUSIONS: In men age >70 years with low-risk prostate cancer and pretreatment PSA velocity < or =1.0 ng/mL/year, prostate cancer death was not observed despite a modest PSA recurrence rate.

Long-term survival after gamma knife radiosurgery for primary and metastatic brain tumors.

In this paper, we studied factors related to long-term survival after gamma knife radiosurgery (GKS) for primary and metastatic brain tumors. We examined all cases of brain metastases and malignant glioma treated with GKS between September 1994 and December 1998. All patients with survival exceeding 2 years were studied retrospectively using prospectively acquired data. A total of 22 patients, with an average age of 56, were identified, which accounts for 11% of the total patients treated during this time interval. Seventeen of 22 are still alive with a mean follow-up of 48 months. Sixteen patients had metastatic tumors, whereas 6 had a malignant glioma. Thirteen of 15 patients with metastases had a controlled primary site, and the other 2 patients did not have a primary site identified. These 2 patients were among the 3 that died during the follow-up period. Fourteen patients developed symptomatic radiation necrosis by MRI criteria with 4 confirmed by biopsy. Quality-of-life factors were assessed in 20 of 22 patients using a modified Spitzer scale, which showed a high level of functioning in all of the long-term survivors (mean score 8.65 of 10), and only 1 patient had a Karnofsky Performance Score of less than 70. We conclude that radiosurgery provides a noninvasive and effective way of controlling brain tumors, while preserving quality of life.

Gamma knife surgery for trigeminal neuralgia: outcome, imaging, and brainstem correlates.

PURPOSE: To review our results with gamma knife surgery (GKS) in the treatment of trigeminal neuralgia (TN), and to determine whether pain relief, medication usage, and the development of facial numbness are affected by trigeminal nerve compression, MRI imaging quality, or brainstem radiation dose. METHODS AND MATERIALS: One hundred twelve patients with TN refractory to medical or surgical management were treated at the University of Maryland Gamma Knife Center between June 1996 and July 2001. Patients were treated using a 4-mm shot to the trigeminal nerve, at a point 2-4 mm anterior to the root entry zone of the nerve into the pons. The median dose prescribed was 75 Gy (range, 60-80 Gy). T1- and T2-weighted, axial, 1.5-mm-thick MRI images were obtained using three-dimensional gradient echo acquisition after contrast injection for treatment planning. MRI images were evaluated for imaging quality (i.e., the adequacy of visualization of the affected prepontine trigeminal nerve), the presence of trigeminal nerve compression, and the brainstem dose. Follow-up data were obtained via telephone interviews, and patients were asked to rate their pre-GKS and post-GKS pain using the Barrow Neurological Institute (BNI) Pain Intensity Scale. Patients were also asked about side effects from GKS and were asked to rate any facial numbness on the BNI Facial Numbness Scale. Medication use, time to pain response, and duration of relief were also evaluated. RESULTS: Ninety-six patients who had follow-up data were included in the analysis. Eighty-six patients (89.6%) responded to GKS with an improvement in BNI pain class. Ten patients (10.4%) were found to have an MRI of poor quality, 30 (31.3%) fair quality, and 56 (58.3%) good quality. Forty-two (43.8%) received 10% of the maximal dose to the brainstem edge, whereas 54 (56.2%) received 20%. Eleven (11.5%) patients were found to have obvious nerve compression by MRI. Imaging quality (p = 0.1863), presence of compression (p = 0.1147), and brainstem dose (p = 0.3168) did not correlate with treatment response. There was also no correlation between these variables (MRI quality, compression, and brainstem dose) and medication use (p = 0.5372, p = 0.0913, p = 0.6832, respectively). Facial numbness was the only side effect experienced. Thirteen patients reported varying degrees of facial numbness, but there was no correlation between imaging quality (p = 0.0600), brainstem dose (p = 0.6773), and presence of compression (p = 0.5785) with the development of facial numbness. CONCLUSIONS: Gamma knife surgery is effective in the treatment of TN and has a favorable side effect profile. Treatment response and the development of facial numbness do not correlate with MRI imaging quality, presence of nerve compression, or radiation dose to the brainstem.

Repeat gamma knife radiosurgery for refractory or recurrent trigeminal neuralgia: treatment outcomes and quality-of-life assessment.

PURPOSE: Stereotactic radiosurgery (SRS) has become a minimally invasive treatment modality for patients with refractory trigeminal neuralgia. It is unclear, however, how best to treat patients with pain that is refractory or recurrent after initial SRS. We report on treatment outcomes and quality of life for patients treated with repeated SRS for refractory or recurrent trigeminal neuralgia. METHODS AND MATERIALS: Between June 1996 and June 2001, 112 patients with trigeminal neuralgia were treated with SRS at the University of Maryland Medical Center. Eighteen patients underwent repeat SRS 3-42 months (median, 8 months) after initial radiosurgery because of unsatisfactory or unsustained pain relief. Patients received a median prescription dose of 75 and 70 Gy, respectively, for the first and second treatments. Self-reports of pain control were assessed with a standard questionnaire containing the complete Barrow Neurologic Institute Pain Scale. RESULTS: The median follow-up was 37.5 months (range, 12-68 months) after initial SRS and 24.5 months (range, 6-65 months) after repeat SRS. For the 18 patients in this series, the percentage of patients reporting excellent, good, fair, and poor responses after the initial and repeat SRS was 50%, 28%, 6%, and 16% and 45%, 33%, 0%, and 22%, respectively. None of the 3 patients with pain refractory to initial SRS responded to repeat SRS. Among those with recurrent pain after initial SRS, 14 patients (93%) achieved excellent or good pain outcomes after repeat SRS. The actuarial analysis revealed a 1-year recurrence rate of 22%, with no patients reporting recurrent pain after 9 months of follow-up. Two patients (11%) reported new or increased facial numbness after retreatment, which was described as bothersome by one. Repeat SRS resulted in a median 60% improvement in quality of life, and 56% of patients believed that the procedure was successful. CONCLUSION: Despite a modest dose reduction, repeat SRS provided similar rates of complete pain control as the initial procedure, but was not effective for patients with no response to initial treatment. Repeat SRS was more efficacious for those patients who experienced longer periods of pain relief after the initial SRS. The incidence of complications was not significantly different from that observed for initial SRS. In this series, most patients had significant improvements in quality of life.

Radiosurgical treatment of trigeminal neuralgia: evaluating quality of life and treatment outcomes.

PURPOSE: To assess the safety, efficacy, and quality of life (QOL) associated with radiosurgical treatment for trigeminal neuralgia (TN). METHODS AND MATERIALS: Between June 1996 and June 2001, 112 patients with TN refractory to medical or surgical management were treated with gamma knife radiosurgery (GKRS) at the University of Maryland Medical Center. A median prescription dose of 75 Gy (range: 70-80 Gy) was delivered to the involved trigeminal nerve root entry zone. Treatment outcomes were assessed through patient self-reports of pain control and medication usage during follow-up visits. In addition, patients responded to a standard questionnaire containing the Barrow Neurologic Institute Pain Scale (BNI) and selected sections of the McGill Pain Scale. Treatment outcomes and objective quality of life measures were also addressed. RESULTS: Ninety-six patients (86%) completed questionnaires for a median follow-up of 30 months (range: 8-66 months). Seventy-four patients (77%) reported pain relief occurring after a median of 3 weeks (range: 0-24 weeks) after GKRS. A decrease in medication usage was noted in 66% of patients. Actuarial analysis demonstrated 1-year, 2-year, and 3-year recurrence rates of 23%, 33%, and 39%, respectively. Response to treatment was associated with lack of prior surgical treatment (p = 0.03) and less than 50 months' pain duration before GKRS (p = 0.04). Patients who described their TN pain as more severe than their worst non-TN headache pain (McGill Pain Scale IV-V vs. I-III) were also more likely to respond to treatment (p < 0.001). Seven (7.3%) patients reported new or increased trigeminal dysfunction; however, only 3.1% reported these symptoms as bothersome (BNI III-IV). Patients with sustained pain relief reported an average of 100% improvement in their QOL as a direct result of pain relief after GKRS, and 100% believed that the procedure was successful. Furthermore, among those patients with temporary pain relief and subsequent recurrence, 65% felt their treatment was a success with an average of 80% improvement in their QOL. CONCLUSIONS: GKRS provides significant pain relief and improves QOL in the majority of patients treated for TN, with few bothersome side effects. Patients with both temporary and sustained responses to treatment realized significant improvements in QOL after GKRS, and considered their treatment successful. Longer follow-up of these patients may reveal additional recurrences highlighting the importance of studies evaluating repeat GKRS and optimization of current treatment techniques and patient selection.

Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in established and primary glioma cell lines.

OBJECT: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF cytokine family, which mediates programmed cell death (apoptosis) selectively in tumor cells. The selective tumoricidal activity of TRAIL is believed to be modulated by agonistic (DR4 and DR5) and antagonistic receptors (DcR1 and DcR2), which appear to compete for ligand binding. Because TRAIL is expressed in a wide range of tissues, including brain, kidney, and spleen, and seems consistently to induce cell death in tumor cells, the cytokine has been identified as a promising approach for selectively inducing tumor cell death. In this study, the authors examine the importance of TRAIL's receptors in both its selectivity for tumor cells and its ability to induce apoptosis. METHODS: The authors first examined sensitivity to TRAIL and expression of TRAIL receptors in four established and four primary cultured glioma cell lines by using viability and fluorescent apoptosis assays. They then evaluated DR5 expression and JNK, caspase 3, and caspase 7 activation by conducting immunoblot analyses. Reverse transcriptase-polymerase chain reaction (RTPCR) was performed to study expression of DR4, DR5, DcR1, and DcR2. The DR5 transcripts from one TRAIL-sensitive, one partially TRAIL-resistant, and one TRAIL-resistant cell line were subsequently sequenced. The expression of TRAIL receptors in normal and glial brain tumor pathological specimens were then compared using immunohistochemistry. Finally, to study the direct effects of DR5 on glioma cells, the authors conducted transient and stable transfections of the full-length DR5 transcript into glioma cells with and without preestablished overexpression of the antiapoptotic gene bcl-2. The established glioma cell lines T98G and U87MG, and all primary cell lines, were apoptotic at greater than or equal to 100 ng/ml TRAIL. The A172 cells, by contrast, were susceptible only with cycloheximide, whereas U373MG cells were not susceptible to TRAIL. The JNK, caspase 3, and caspase 7 activity evaluated after treatment with TRAIL showed that TRAIL-sensitive cell lines exhibited downstream caspase activation, whereas TRAIL-resistant cells did not. The DR5 sequences in T98G, A172, and U373MG cell lines were identical to published sequences despite these differences in sensitivity to TRAIL. The RT-PCR performed on extracts from the eight glioma cell lines showed that all expressed DR5. Immunohistochemistry revealed ubiquitous expression of DR5 in glioma specimens, with an associated lack of decoy receptor expression. Normal brain specimens, by contrast, stained positive for both DR5 and DcR1. Overexpression of DR5 under both transfection conditions resulted in cell death in all three cell lines. The previously seen resistance of U373 cells to TRAIL was not observed. Apoptotic cell death was confirmed using DNA fragmentation in T98G cell lines and fluorescent miscroscopy in all cell lines. The T98G cells stably transfected with bcl-2 before DR5 overexpression were protected from cell death. CONCLUSIONS: The authors conclude that DR5 represents a promising new approach to directly activating the intrinsic caspase pathway in glioma cells. The fact that TRAIL-resistant gliomas do not express decoy receptors suggests a mechanism of resistance unique from that proposed for normal tissues. The overexpression of DR5 induced apoptotic cell death in glioma cells without TRAIL and was able to overcome the resistance to TRAIL demonstrated in U373 cells. The Bcl-2 protects cells from DR5 by acting downstream of the receptor, most likely at the level of caspase activation.