Faculty Bibliography

The SRS/SBRT Scientific Meeting 2014, Minneapolis, MN, USA, 7-10 May 2014. The Radiosurgery Society(®), a professional medical society dedicated to advancing the field of stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), held the international Radiosurgery Society Scientific Meeting, from 7-10 May 2014 in Minneapolis (MN, USA). This year's conference attracted over 400 attendants from around the world and featured over 100 presentations (46 oral) describing the role of SRS/SBRT for the treatment of intracranial and extracranial malignant and nonmalignant lesions. This article summarizes the meeting highlights for SRS/SBRT treatments, both intracranial and extracranial, in a concise review.

BACKGROUND:Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as "radioresistant," the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). METHODS:We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. RESULTS:WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). CONCLUSIONS:Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials.

OBJECTIVE:To determine if concomitant CT-guided biopsy and percutaneous fiducial seed placement in the lung can be performed in a selective patient population without increased complication or decreased success rates compared to either procedure alone. MATERIALS AND METHODS/METHODS:An IRB approved retrospective analysis of 285 consecutive patients that underwent CT-guided placement of fiducial seeds in the lung alone (N=63), with concomitant core biopsy (N=53) or only core biopsy (N=169) was performed. Variables compared included: patient demographics, lesion size, depth from pleura, needle size, number of passes through pleura, number and size of core biopsies, number of seeds placed and technical success rates. Statistical analysis was performed using univariate and multivariate pair-wise comparisons. RESULTS:A pathologic diagnosis of malignancy was confirmed in all cases undergoing seed placement alone and seed placement with concurrent biopsy, and in 144 of the biopsy alone lesions. On univariate analysis, major complication rates were similar for all three groups as were lesion size, depth, number of pleural passes, and technical success. Pair-wise comparisons of the remaining variables demonstrated a significant younger age and smaller needle size in the biopsy only group, and less minor complications in the fiducial only group. Overall there were 80/285 (28.1%) minor and 29/285 (10.2%) major complications. All major complications leading to admission consisted of either pneumothorax or hemothorax, while minor complications included asymptomatic stable or resolving pneumothoraces, transient hemoptysis or small hemothoraces. CONCLUSIONS:A combined procedure of percutaneous pulmonary core biopsy and stereotactic seed placement can be performed without additional risk of a major complication when compared to performing these separately.

BACKGROUND:The RSSearch™ Registry is a multi-institutional, observational, ongoing registry established to standardize data collection from patients treated with stereotactic radiosurgery (SRS) and/or stereotactic body radiotherapy (SBRT). This report describes the design, patient demographics, lesion characteristics, and SRS/SBRT treatment patterns in RSSearch™. Illustrative patient-related outcomes are also presented for two common treatment sites--brain metastases and liver metastases. MATERIALS AND METHODS/METHODS:Thirty-nine US centers participated in RSSearch™. Patients screened for SRS/SBRT were eligible to be enrolled. Descriptive analyses were performed to assess patient characteristics, physician treatment practices, and clinical outcomes. Kaplan-Meier analysis was used to determine overall survival (OS), local progression-free (LPFS), and distant disease-free survival (DDFS). RESULTS:From January, 2008-January, 2013, 11,457 patients were enrolled. The median age was 67 years (range 7-100 years); 51% male and 49% female. Forty-six percent had no prior treatment, 22% had received chemotherapy, 19% radiation therapy and 17% surgery. There were 11,820 lesions from 65 treatment locations; 54% extracranial and 46% intracranial. The most common treatment locations were brain/cranial nerve/spinal cord, lung, prostate and liver. Metastatic lesions accounted for the majority of cases (41.6%), followed by primary malignant (32.9%), benign (10.9%), recurrent (9.4%), and functional diseases (4.3%). SRS/SBRT was used with a curative intent in 39.8% and palliative care in 44.8% of cases. The median dose for all lesions was 30 Gy (range < 1-96.7 Gy) delivered in a median number of 3 fractions. The median dose for lesions in the brain/cranial nerve/spinal cord, lung, liver, pancreas and prostate was 24, 54, 45, 29 and 36.25 Gy, respectively. In a subset analysis of 799 patients with 952 brain metastases, median OS was 8 months. For patients with a Karnofsky performance score (KPS) > 70, OS was 11 months vs. 4 months for KPS ≤ 70. Six-month and 12-month local control was 79% and 61%, respectively for patients with KPS ≤ 70, and 85% and 74%, respectively for patients with KPS > 70. In a second subset analysis including 174 patients with 204 liver metastases, median OS was 22 months. At 1-year, LPFS and DDFS rates were 74% and 53%, respectively. LPFS CONCLUSION/UNASSIGNED:This study demonstrates that collective patterns of care and outcomes research for SRS/SBRT can be performed and reported from data entered by users in a common database. The RSSearch™ dataset represents SRS/SBRT practices in a real world setting, providing a useful resource for expanding knowledge of SRS/SBRT treatment patterns and outcomes and generating robust hypotheses for randomized clinical studies.

Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1-8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59-92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.

OBJECTIVE:Image-guided radiation therapy allows precise tumor targeting using real-time tracking of radiopaque fiducial markers. To enable appropriate tracking, it is recommended to place fiducials with "ideal fiducial geometry" (IFG). Our objectives were to determine the proportion of patients in whom IFG can be achieved when fiducials are placed by endoscopic ultrasound (EUS) and surgery and to determine if attaining IFG is necessary for delivering radiation. METHODS:This single-center retrospective cohort study included 77 patients with biopsy-proven advanced pancreatic cancer who underwent either EUS-guided or laparotomy/laparoscopy-assisted fiducial placement between September 2005 and July 2009. RESULTS:Gold fiducials were implanted by EUS in 39 patients (51%) and by surgery in 38 patients (49%). The proportion of patients with IFG was significantly higher for surgical placement [18/38, 47%; 95% confidence interval (CI), 32%-63%] compared with EUS-guided placement (7/39, 18%; 95% CI, 8%-32%), P = 0.0011. However, fiducial tracking was successfully used for Cyberknife therapy in 35 (90%) of 39 (95% CI, 77%-97%) patients in the EUS group compared with 31 (82%) of 38 (95% CI, 67%-92%) patients in the surgery group. There were 5 procedure-related complications in the EUS group. CONCLUSIONS:Achieving IFG appears unnecessary for successful tracking and delivery of radiation.

The high rate of brain metastasis in patients with advanced melanoma has been a clinical challenge for oncologists. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive. This is due to the high incidence of CNS metastases, which progress relentlessly and which are only anecdotally responsive to systemic therapies. Surgery, stereotactic radiosurgery and whole-brain radiotherapy with or without cytotoxic chemotherapy remain the mainstay of treatment. However, new drugs have been developed based on our improved understanding of the molecular signaling mechanisms responsible for host immune tolerance and for melanoma growth. In 2011, the US FDA approved two agents, one antagonizing each of these processes, for the treatment of advanced melanoma. The first is ipilimumab, an anti-CTLA-4 monoclonal antibody that enhances cellular immunity and reduces tolerance to tumor-associated antigens. The second is vemurafenib, an inhibitor that blocks the abnormal signaling for melanoma cellular growth in tumors that carry the BRAF(V600E) mutation. Both drugs have anecdotal clinical activity for brain metastasis and are being evaluated in clinical trial settings. Additional clinical trials of newer agents involving these pathways are also showing promise. Therefore, targeted therapies must be incorporated into the multimodality management of melanoma brain metastasis.

PURPOSE/OBJECTIVE:Stereotactic radiosurgery (SRS) is an effective alternative to microsurgical resection or embolization for definitive treatment of arteriovenous malformations (AVMs). Digital subtraction angiography (DSA) is the gold standard for pretreatment diagnosis and characterization of vascular anatomy, but requires rigid frame (skull) immobilization when used in combination with SRS. With the advent of advanced proton and image-guided photon delivery systems, SRS treatment is increasingly migrating to frameless platforms, which are incompatible with frame-based DSA. Without DSA as the primary image, target definition may be less than optimal, in some cases precluding the ability to treat with a frameless system. This article reports a novel solution. METHODS AND MATERIALS/METHODS:Fiducial markers are implanted into the patient's skull before angiography. Angiography is performed according to the standard clinical protocol, but, in contrast to the previous practice, without the rigid frame. Separate images of a specially designed localizer box are subsequently obtained. A target volume projected on DSA can be transferred to the localizer system in three dimensions, and in turn be transferred to multiple CT slices using the implanted fiducials. Combined with other imaging modalities, this "virtual frame" approach yields a highly precise treatment plan that can be delivered by frameless SRS technologies. RESULTS:Phantom measurements for point and volume targets have been performed. The overall uncertainty of placing a point target to CT is 0.4 mm. For volume targets, deviation of the transformed contour from the target CT image is within 0.6 mm. The algorithm and software are robust. The method has been applied clinically, with reliable results. CONCLUSIONS:A novel and reproducible method for frameless SRS of AVMs has been developed that enables the use of DSA without the requirement for rigid immobilization. Multiple pairs of DSA can be used for better conformality. Further improvement, including using nonimplanted fiducials, is potentially feasible.

PURPOSE/OBJECTIVE:To evaluate spectral computed tomography (CT) with metal artifacts reduction software (MARS) for reduction of metal artifacts associated with gold fiducial seeds. MATERIALS AND METHODS/METHODS:Thirteen consecutive patients with 37 fiducial seeds implanted for radiation therapy of abdominal lesions were included in this HIPAA-compliant, institutional review board-approved prospective study. Six patients were women (46%) and seven were men (54%). The mean age was 61.1 years (median, 58 years; range, 29-78 years). Spectral imaging was used for arterial phase CT. Images were reconstructed with and without MARS in axial, coronal, and sagittal planes. Two radiologists independently reviewed reconstructions and selected the best image, graded the visibility of the tumor, and assessed the amount of artifacts in all planes. A linear-weighted κ statistic and Wilcoxon signed-rank test were used to assess interobserver variability. Histogram analysis with the Kolmogorov-Smirnov test was used for objective evaluation of artifacts reduction. RESULTS:Fiducial seeds were placed in pancreas (n = 5), liver (n = 7), periportal lymph nodes (n = 1), and gallbladder bed (n = 1). MARS-reconstructed images received a better grade than those with standard reconstruction in 60% and 65% of patients by the first and second radiologist, respectively. Tumor visibility was graded higher with standard versus MARS reconstruction (grade, 3.7 ± 1.0 vs 2.8 ± 1.1; P = .001). Reduction of blooming was noted on MARS-reconstructed images (P = .01). Amount of artifacts, for both any and near field, was significantly smaller on sagittal and coronal MARS-reconstructed images than on standard reconstructions (P < .001 for all comparisons). Far-field artifacts were more prominent on axial MARS-reconstructed images than on standard reconstructions (P < .01). Linear-weighted κ statistic showed moderate to perfect agreement between radiologists. CT number distribution was narrower with MARS than with standard reconstruction in 35 of 37 patients (P < .001). CONCLUSION/CONCLUSIONS:Spectral CT with use of MARS improved tumor visibility in the vicinity of gold fiducial seeds.