Survival and Radiation Dose Differences Between Single Versus Multi-Session Gamma Knife Stereotactic Radiosurgery in Patients Treated for Multiple (≥10) Brain Metastases.

OBJECTIVE:  To explore whether treatment with multiple Gamma Knife sessions (mGK) resulted in different survival outcomes or cumulative radiation doses compared to single session Gamma Knife (sGK) in patients who have been treated for ≥10 brain metastases (BMs). METHODS:  Thirty-five patients with ≥10 BMs treated with Gamma Knife stereotactic radiosurgery (GK SRS) were identified and separated into sGK vs. mGK cohorts. Survival outcomes and dosimetry data were compared between the two groups. Recursive partitioning analysis (RPA) classes were used to further stratify patients. RESULTS:  mGK patients survived longer from the first GK treatment (p<0.009). By RPA class, patients with class 1 had a prolonged survival from BM diagnosis than those in classes 2 and 3 (p=0.004). However, survival was not significantly different between the classes from the first GK treatment (p=0.089). Stratified by mGK vs. sGK and RPA classes, sGK patients in RPA class 1 had the longest survival from BM diagnosis but the worst survival from GK treatment. mGK patients in any RPA class had the best survival from the first GK treatment. For patients with RPA class 2+3, mGK was associated with longer survival from both BM diagnosis and first treatment. Statistical but not clinical differences between the mGK vs. sGK groups were observed in the max dose to the targets and cochlea, and the V40Gy whole brain dose. CONCLUSIONS:  mGK may be beneficial if GK is initiated early at first BM diagnosis vs. sGK initiated late. Future research is required to confirm these findings and explore additional areas of interest, such as quality-of-life and economic considerations.

BEDVH-A method for evaluating biologically effective dose volume histograms: application to eye plaque brachytherapy implants.

PURPOSE: A method is introduced to examine the influence of implant duration T, radionuclide, and radiobiological parameters on the biologically effective dose (BED) throughout the entire volume of regions of interest for episcleral brachytherapy using available radionuclides. This method is employed to evaluate a particular eye plaque brachytherapy implant in a radiobiological context. METHODS: A reference eye geometry and 16 mm COMS eye plaque loaded with (103)Pd, (125)I, or (131)Cs sources were examined with dose distributions accounting for plaque heterogeneities. For a standardized 7 day implant, doses to 90% of the tumor volume ( (TUMOR)D(90)) and 10% of the organ at risk volumes ( (OAR)D(10)) were calculated. The BED equation from Dale and Jones and published α/ß and µ parameters were incorporated with dose volume histograms (DVHs) for various T values such as T = 7 days (i.e., (TUMOR) (7)BED(10) and (OAR) (7)BED(10)). By calculating BED throughout the volumes, biologically effective dose volume histograms (BEDVHs) were developed for tumor and OARs. Influence of T, radionuclide choice, and radiobiological parameters on (TUMOR)BEDVH and (OAR)BEDVH were examined. The nominal dose was scaled for shorter implants to achieve biological equivalence. RESULTS: (TUMOR)D(90) values were 102, 112, and 110 Gy for (103)Pd, (125)I, and (131)Cs, respectively. Corresponding (TUMOR) (7)BED(10) values were 124, 140, and 138 Gy, respectively. As T decreased from 7 to 0.01 days, the isobiologically effective prescription dose decreased by a factor of three. As expected, (TUMOR) (7)BEDVH did not significantly change as a function of radionuclide half-life but varied by 10% due to radionuclide dose distribution. Variations in reported radiobiological parameters caused (TUMOR) (7)BED(10) to deviate by up to 46%. Over the range of (OAR)α/ß values, (OAR) (7)BED(10) varied by up to 41%, 3.1%, and 1.4% for the lens, optic nerve, and lacrimal gland, respectively. CONCLUSIONS: BEDVH permits evaluation of the relative biological effectiveness for brachytherapy implants. For eye plaques, (TUMOR)BEDVH and (OAR)BEDVH were sensitive to implant duration, which may be manipulated to affect outcomes.

Relationship between gene expression profile class and tumor thickness regression after plaque brachytherapy for choroidal melanoma.

BACKGROUND AND OBJECTIVE: To examine the relationship between gene expression profile class and tumor thickness reduction as measured by ultrasonography in response to plaque brachytherapy using a single-center, retrospective cohort study. METHODS: A total of 15 patients with choroidal melanoma who underwent biopsy for gene expression profiling and were treated with plaque brachytherapy from a single institution from 12/8/14 through 12/19/19 were retrospectively reviewed for clinical characteristics and rate of tumor regression. Ultrasonographic B-scan tumor height was recorded just prior to plaque placement and following plaque removal in the patient's chart to assess percent reduction in tumor thickness from baseline. RESULTS: A total of 15 patients met inclusion criteria and were analyzed in this study. Minimum follow-up was 6 months after plaque removal. The percent regression in tumor thickness from baseline as measured by ultrasonography was greater for class 2 tumors than for class 1 tumors at 12-month follow up after treatment, and this difference was statistically significant (P = 0.012). There was no statistical significance in reduction at 3 months (P = 0.46) and 9 months (P = 0.10) after plaque brachytherapy. Although not statistically significant, class 2 tumors appeared to regress more rapidly than class 1 tumors in response to radiation. CONCLUSIONS: In this study, class 2 choroidal melanoma tumors show a more rapid anatomic response to treatment than class 1 tumors at 12 months post plaque brachytherapy.

Retreatment of trigeminal neuralgia with Gamma Knife radiosurgery: is there an appropriate cumulative dose? Clinical article.

OBJECT: Trigeminal neuralgia (TN) is a disorder of the trigeminal nerve that results in intense episodic pain. Primary treatment with Gamma Knife surgery (GKS) is well established; however, a significant number of patients experience recurrence of TN over time. Repeat GKS can be performed, but the retreatment dose has not been well established. In this study, the authors present their institutional retreatment results and compare them with other series. METHODS: Between December 2003 and January 2006, 28 patients were treated at Tufts Medical Center with repeat GKS for recurrence of TN. All patients had been initially treated with GKS at this institution, and only those with significant pain improvement were offered retreatment. The maximum dose was prescribed using a single isocenter; the 4-mm collimator was used. The initial median GKS dose was 80 Gy, the median retreatment dose was 45 Gy, and the median cumulative dose was 125 Gy. The median time between GKS procedures was 18.1 months. Facial pain outcomes were defined using the Marseille scale. Excellent outcome was defined as no pain (with or without medications), and good outcome was defined as > 50% pain relief. Toxicity was categorized as none, mild, or bothersome. The median clinical follow-up after the second GKS was 19.7 months. Our clinical outcomes were compared with 8 previously reported retreatment series (including 1 abstract), both for rate of pain control and for rate of complications. RESULTS: Outcomes after the second GKS were excellent in 29% (8 patients), good in 32% (9), and poor in 39% (11). Four patients (14%) experienced no improvement after repeat GKS. Eight patients (29%) experienced new trigeminal nerve dysfunction, including numbness (11%), paresthesia (14%), dysesthesia (4%), taste alteration (11%), and bite weakness (4%). None of these were bothersome. No patient developed corneal numbness. Univariate analysis failed to reveal any significant predictors of pain control or complications. Seven published peer-reviewed retreatment series and the authors' data (total 215 patients) were analyzed. There was a cumulative dose-response relationship for both pain control (p = 0.04) and new trigeminal dysfunction (p = 0.08). Successful pain control was strongly correlated with development of new dysfunction (p = 0.02). A cumulative dose > 130 Gy was more likely to result in successful (> 50%) pain control, but was also more likely (> 20%) to result in development of new dysfunction. CONCLUSIONS: Successful retreatment of patients in whom the initial GKS treatment fails is feasible. Patients who respond initially may be at a higher risk of retreatment-related complications. There appears to be a dose-response relationship for both pain control and development of new side effects. It is important to counsel and treat patients individually based on this dose-response relationship.

Intracardiac chloroma.

Chloromas are not frequently seen in patients with acute myelogenous leukemia and chloromas involving cardiac structures have only been rarely reported in the literature. We report a complete radiographic response to low-dose fractionated radiotherapy in a patient with an intracardiac chloroma.

Gamma Knife radiosurgery for locally recurrent choroidal melanoma following plaque radiotherapy.

BACKGROUND: For the majority of eyes with choroidal melanoma, radiation therapy is the treatment of choice. Local recurrence after radiation therapy can occur, however, and when it does, salvaging the globe with useful vision is atypical. CASE PRESENTATION: We report a case of late, local failure 7 years following previous brachytherapy successfully managed with Gamma Knife radiosurgery (GKR). With 3 years of follow up after GKR, the visual acuity is 20/20 and there is no evidence of systemic metastases. CONCLUSION: To our knowledge, this is the first report of successful salvage GKR therapy after brachytherapy failure in an eye with choroidal melanoma. GKR is an option for select cases of local recurrence after radiation plaque brachytherapy.

Brachytherapy vs. external beam radiotherapy for choroidal melanoma: Survival and patterns-of-care analyses.

PURPOSE: No modern randomized trials exist comparing external beam radiotherapy (EBRT) and plaque brachytherapy (BT) for choroidal melanoma, and the optimal treatment modality is currently unknown. This study compares the patterns of care and efficacy of EBRT vs. BT based on data in the Surveillance, Epidemiology, and End Results database. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was queried for patients aged 20-79 diagnosed with choroidal melanoma from 2004 to 2011, treated with EBRT or BT; included patients were clinically T1-T4, N0, and M0. Overall survival and cause-specific survival curves were calculated by the Kaplan-Meier method. Univariate and multivariate analyses were performed in the survival and patterns-of-care analyses. RESULTS: A total of 1004 cases (380 EBRT and 624 BT) were included in the survival analysis. There was no difference in the 5-year overall survival (83.3% EBRT vs. 82.5% BT, p = 0.69) and 5-year cause-specific survival (88.3% EBRT vs. 88.3% BT, p = 0.92). In the survival analysis, older age and advanced tumor stage were predictors of increased risk of death. In the patterns-of-care analysis, later year of diagnosis and smaller tumor stage were predictors of BT use. CONCLUSIONS: Advanced tumor stage and older age seem to be independent predictors for risk of death from choroidal melanoma. The use of BT favors smaller tumors and later year of diagnosis. There is no difference in survival between those treated with EBRT or BT, and the utilization of BT is increasing.

Analysis of dose conformity and normal-tissue sparing using two different IMRT prescription methodologies for irregularly shaped CNS lesions irradiated with the Beak and 1-cm MIMiC collimators.

PURPOSE: To determine whether intensity modulated sequential tomotherapy using the NOMOS Beak provides superior dose conformity and organ sparing to the MIMiC "1-cm" mode, and if so, to identify a subset of patients most likely to benefit from Beak intensity modulated sequential tomotherapy. METHODS AND MATERIALS: Twelve patients with irregularly shaped central nervous system tumors were selected for intensity modulated radiation therapy planning. Two treatment plans, one using the Beak collimator and the other using the 1-cm MIMiC collimator, were generated for each patient with identical anatomic contouring, prescriptions, and optimization algorithms. The Beak attaches to the MIMiC collimator and truncates the 1-cm MIMiC mode beamlet size from 1.00 x 0.85 cm(2) to 1.00 x 0.39 cm(2) at isocenter. Conformity indexes were calculated for each lesion using two different prescription methodologies, and mean doses to critical structures were recorded. RESULTS: For the first prescription methodology using uniform prescribed isodose, mean conformity index was 2.19 (range, 1.33-3.90) for the Beak compared to 2.67 (range, 1.64-4.75) for the 1-cm mode (p = 0.0003). Mean doses to the brainstem, right orbit, and left optic nerve were significantly lower with the Beak than with the 1-cm mode (p = 0.0150, 0.0068, and 0.0284, respectively). For the second prescription methodology using uniform target volume coverage prescription, mean conformity index was 2.04 (range, 1.56-2.70) for the Beak compared to 2.73 (range, 1.70-8.58) for the 1-cm mode (p = 0.07). Mean doses to the brain, brainstem, optic chiasm, right optic nerve, left optic nerve, and left orbit were significantly lower with the Beak than with the 1-cm mode (p = <0.0001, <0.0026, <0.0016, <0.0076, <0.0007, and <0.046, respectively). CONCLUSION: Beak intensity modulated sequential tomotherapy is superior to the 1-cm MIMiC mode for irregularly shaped central nervous system tumors, because it provides better conformity and critical organ sparing. These differences may allow for safer dose escalation and retreatment, so the method presents an alternative to gamma knife stereotactic radiosurgery.

Determination of the 4 mm Gamma Knife helmet relative output factor using a variety of detectors.

Though the 4 mm Gamma Knife helmet is used routinely, there is disagreement in the Gamma Knife users community on the value of the 4 mm helmet relative output factor. A range of relative output factors is used, and this variation may impair observations of dose response and optimization of prescribed dose. To study this variation, measurements were performed using the following radiation detectors: silicon diode, diamond detector, radiographic film, radiochromic film, and TLD cubes. To facilitate positioning of the silicon diode and diamond detector, a three-dimensional translation micrometer was used to iteratively determine the position of maximum detector response. Positioning of the films and TLDs was accomplished by manufacturing custom holders for each technique. Results from all five measurement techniques indicate that the 4 mm helmet relative output factor is 0.868 +/- 0.014. Within the experimental uncertainties, this value is in good agreement with results obtained by other investigators using diverse techniques.

Intravascular brachytherapy using 90Sr for saphenous vein grafts having diameters ranging from 2.0-5.0 mm.

PURPOSE: Symptomatic coronary artery disease is routinely treated with angioplasty and stenting. Unfortunately, treatment failure in the form of in-stent restenosis (ISR) occurs relatively frequently. Intravascular brachytherapy (IVBT) is a safe and effective method proven to markedly reduce the rate of ISR in native coronary arteries. The commercially available devices for IVBT are not FDA-approved for treatment of saphenous vein grafts (SVG). This article presents calculated dosimetry for treatment of a wide range of SVG, in addition to further evaluating the dose homogeneity for native coronary arteries. METHODS AND MATERIALS: AAPM Task Group 43 and 60 formalisms permitted dose calculations for a wide range of vessel internal diameters (phi) in both native coronary arteries and SVG. Doses were analytically calculated for the Novoste Beta-Cath 5.0 French (F) treatment devices (30, 40, and 60 mm sourcetrains) when employed for the treatment of native vessels with 2.7

Treatment of in-stent restenosis for saphenous vein grafts using intravascular brachytherapy: regulatory challenges and clinical application.

Treatment of in-stent restenosis using intravascular brachytherapy (IVBT) has been demonstrated to be successful and has become the standard of care for native coronary artery disease. Based on the current Food and Drug Administration (FDA) indications for use and the clinical demand to increase the scope of this form of therapy to include saphenous vein grafts for the Beta-Cath System (Novoste Corporation, Norcross, Georgia), we set out to obtain institutional approval for off-label use. Identification of institutional regulatory bodies and related procedures for obtaining off-label device use was performed. Additionally, the IVBT written directive proscription and patient informed consent forms were revised to accurately administer radiation dose and to disclose the regulatory status of using IVBT for this anatomic site. While the specifics are outlined in this report, this process and the resources needed to obtain institutional approval for off-label use are indicative of that to be expected at similar institutions.

Salvage Gamma Knife Radiosurgery after failed management of bilateral trigeminal neuralgia.

BACKGROUND: The incidence of bilateral trigeminal neuralgia (TN) is 1-6% of total number of TN cases. Gamma Knife Radiosurgery (GKRS) is effective in treating unilateral TN; however, outcomes of bilateral TN treated by GKRS have not been well evaluated. The purpose of this study is to evaluate the long-term GKRS outcomes of bilateral TN at our institution and compare with our published treatment outcomes of unilateral TN. METHODS: Between 2000 and 2006, eight patients with bilateral TN were treated with GKRS. Data available on seven patients were collected. Facial pain outcomes were defined using the Barrow Neurological Institute pain intensity scale. Outcomes and toxicities were compared to published outcomes of unilateral TN patients treated with GKRS at our institution. RESULTS: The incidence of bilateral TN in our series is 2.3%. Treatment outcomes were excellent in 5/14, good in 1/14, and poor in 8/14. Median follow-up time was 58 months. Median time-to-failure was 38 months. Pain control rate was 80% at 12 months and 65% at 36 months. Bothersome side effects were seen in 4/14 nerves treated. Compared with our long-term unilateral TN cohort, there was no statistically significant difference in outcome, time-to-failure, or rate of toxicity. CONCLUSION: Bilateral TN is rare, and effective treatment is crucial to improve the quality of life of those afflicted. Salvage GKRS is a reasonable treatment modality for individuals with bilateral TN.

Use of cone-beam computed tomography angiography in planning for gamma knife radiosurgery for arteriovenous malformations: a case series and early report.

BACKGROUND: The effectiveness of Gamma Knife radiosurgery (GKR) for cerebral arteriovenous malformations (AVMs) is predicated on inclusion of the entire nidus while excluding normal tissue. As such, GKR may be limited by the resolution and accuracy of the imaging modality used in targeting. OBJECTIVE: We present the first case series to demonstrate the feasibility of using ultrahigh-resolution C-arm cone-beam computed tomography angiography (CBCT-A) in AVM targeting. METHODS: From June 2009 to June 2013, CBCT-A was used for targeting of all patients with AVMs treated with GKR at our institution. Patients underwent Leksell stereotactic head frame placement followed by catheter-based biplane 2-dimensional digital subtraction angiography, 3-dimensional rotational angiography, as well as CBCT-A. The CBCT-A dataset was used for stereotactic planning for GKR. Patients were followed at 1, 3, 6, and 12 months and then annually thereafter. RESULTS: CBCT-A-based targeting was used in 22 consecutive patients. CBCT-A provided detailed spatial resolution and sensitivity of nidal angioarchitecture enabling treatment. The average radiation dose to the margin of the AVM nidus corresponding to the 50% isodose line was 15.6 Gy. No patient had treatment-associated hemorrhage. At early follow-up (mean, 16 months), 84% of patients had a decreasing or obliterated AVM nidus. CONCLUSION: CBCT-A-guided radiosurgery is feasible and useful because it provides sufficient detailed resolution and sensitivity for imaging brain AVMs.

Local control and results of Leksell Gamma Knife therapy for the treatment of uveal melanoma.

BACKGROUND AND OBJECTIVE: To evaluate the effectiveness of Leksell Gamma Knife stereotactic radio-surgery (Elekta, Stockholm, Sweden) with respect to local tumor control, visual acuity, and radiation side effects for uveal melanoma. PATIENTS AND METHODS: Retrospective, non-comparative case series of 23 patients with uveal melanoma treated with Gamma Knife stereotactic radiosurgery at Tufts Medical Center from 2000 to 2012. Patients received single-fraction stereotactic radiation therapy of 20-25 gray (Gy) (mean: 21.7 Gy), primarily at the 50% isodose line. Follow-up was 4 to 121 months (median: 41.5 months). Main outcome measures included local tumor control, metastasis, visual acuity, and complications of therapy. RESULTS: In 21 of 23 patients (91%), local control was achieved with a single session of Gamma Knife therapy. Both patients who did not have local control, as well as a third patient (three of 23, 13%) developed liver metastases. Visual acuity was 20/200 or better in eight of 23 patients (35%) at last follow-up. Radiation side effects severe enough to cause vision loss were present in 14 of 23 patients (61%). CONCLUSION: Gamma Knife therapy may be an effective alternative to enucleation in patients with uveal melanoma who are deemed less satisfactory candidates for brachytherapy or wish to avoid surgery.

Analysis of visual toxicity after gamma knife radiosurgery for treatment of choroidal melanoma: identification of multiple targets and mechanisms of toxicity.

OBJECTIVES: Identification of the targets of radiation damage after radiosurgical treatment of ocular melanoma will potentially allow for sparing of vision with improved treatment planning. MATERIALS AND METHODS: Six patients with ocular melanoma, who had useful vision before therapy, were treated with gamma knife stereotactic radiosurgery with curative intent. Dosimetric analysis of functional targets of radiation damage including the fovea, optic nerve, lens, and iris was carried out. Serial testing of visual acuity and fundoscopic examination were carried out after treatment. RESULTS: Visual sparing was achieved in 3 of 6 patients at last followup with a median follow-up of 2 years. The causes of loss of vision in those patients who lost useful vision were retinal detachment, neovascular glaucoma, and optic neuropathy. CONCLUSIONS: Preradiosurgical size and location are likely predictors of posttreatment visual outcomes.

A 17-year retrospective study of institutional results for eye plaque brachytherapy of uveal melanoma using (125)I, (103)Pd, and (131)Cs and historical perspective.

PURPOSE: To compare overall survival, local and distant failure rates, ocular toxicity, and vision preservation in patients treated with eye plaque brachytherapy at Tufts Medical Center with those in the published literature. METHODS AND MATERIALS: Records were reviewed for 53 patients with the diagnosis of uveal melanoma treated with plaque brachytherapy at Tufts Medical Center over the past 17 years. American Joint Committee on Cancer staging (T1, T2, or T3) were 4, 39, and 10 patients, respectively. All the patients were treated using (125)I (n=37), (103)Pd (n=5), or (131)Cs (n=11) to a dose of 85Gy (documented as 100Gy before 1996 for the same physical dose). RESULTS: With a mean followup of 75 months, 38 of 53 patients were still alive. Five patients (all (125)I) developed liver metastases (9%) with no evidence of local failure. There were 10 definitive local failures and four additional transpupillary thermo-therapy procedures performed to ensure local control for lesions slow to respond. Twelve patients (23%) required enucleation. At most recent followup, 32 patients (71%) maintained 20/200 vision or better in the treated eye. In this first report of (131)Cs plaque therapy with a mean followup of 20 months, there were two transpupillary thermo-therapy procedures and one definitive failure requiring enucleation after 10 months. CONCLUSIONS: Our disease control and ocular results were comparable to those in the literature given the extended followup. We are developing a multi-institutional, prospective clinical protocol for considering radionuclide selection and other prescriptive criteria.

Local recurrence after mastectomy in patients with T3pN0 breast carcinoma treated without postoperative radiation therapy.

OBJECTIVE: The need for comprehensive adjuvant radiotherapy in patients with T3pN0 breast cancer is controversial. This retrospective analysis was performed to assess the frequency of local and distant recurrence in patients treated with mastectomy without postoperative radiation. MATERIALS AND METHODS: A single institution database of 2362 patients with breast carcinoma treated from 1974 to 1994 yielded 101 patients who had T3pN0 disease and did not receive chest wall or nodal irradiation. The median follow-up time was 93 months (range, 10-256 months). Sites of first failure were categorized as isolated chest wall (CWF), regional lymph nodes (RNF, which in this case were considered to be either axillary or supraclavicular), or distant sites (DF). CWF and/or RNF were considered local recurrences. Patients with simultaneous CWF and DF or RNF and DF were scored as DF. A comparison was made to 286 T2pN0 patients, also treated between 1974 and 1994. RESULTS: Twenty-two T3N0 patients developed recurrent disease. Site of first recurrence was isolated local recurrence in 11 patients and distant in 11 patients. Four patients had simultaneous local and distant recurrences. Site of isolated local recurrence was CWF in 5 patients and RNF in 6 patients. Median tumor size was 6 cm (range, 5-10.5 cm). There was no difference in local recurrence for tumor sizes < or =7 cm versus >7 cm (P = 0.07). The crude recurrence rate for T3pN0 patients treated by mastectomy was similar to T2pN0 patients treated in similar fashion (P = 0.3). CONCLUSION: The risk of isolated local recurrence in patients with T3pN0 breast cancer and negative margins is moderately low and similar to T2pN0 patients. These results suggest that routine use of postoperative chest wall and nodal irradiation in all T3pN0 patients may not be required.