Amol J. Ghia

Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial

SUMMARY Background After brain metastasis resection, whole-brain radiation therapy (WBRT) decreases local recurrence but may cause cognitive decline. We performed this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved local tumor tumor-free recurrence rates compared to surgical resection alone as an alternative to the need for immediate WBRT. Methods The main entry criteria for the study included patients >3 years of age, with a Karnofsky Performance Score ≥ 70, who were able to undergo an MRI scan and who had a complete resection of 1–3 brain metastases (the maximum diameter of the resection cavity had to be ≤4cm). Patients were assigned randomly to either SRS treatment of the resection cavity (within 30 days of surgery) or observation (OBS). Patients were stratified by histology, tumor size, and number of metastases. Patients were recruited at a single tertiary cancer center. The primary endpoint was time to local recurrence in the resection cavity assessed by blinded central review of brain MRI scans in the intention-to-treat population. The trial was registered at clinicaltrials.gov (Trial NCT00950001, status: closed to new participants). Findings Between 8/13/2009 and 2/16/2016, 132 patients were randomized to OBS (N=68) or SRS (N=64), with 128 patients available for analysis. We stratified by metastasis size (maximum diameter of ≥3 cm vs. <3 cm), histology (melanoma vs. other), and number of metastases (one vs. two or three). The 12-month local tumor recurrence-free rate was 43% (OBS) (95% CI 31%–59%) and 72% (SRS) (95% CI 60%–87%) (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.24–0.88, p=0.015). Interpretation This prospective randomized trial of patients undergoing surgical resection for 1–3 brain metastases indicates that SRS administered to the resection cavity significantly lowers local recurrence compared to observation alone. Thus, the use of SRS after brain metastasis resection is an alternative to WBRT.BACKGROUND After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone. METHODS In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants. FINDINGS Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8-20·4). 12-month freedom from local recurrence was 43% (95% CI 31-59) in the observation group and 72% (60-87) in the SRS group (hazard ratio 0·46 [95% CI 0·24-0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group. INTERPRETATION SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy. FUNDING National Institutes of Health.

Intracranial hemangiopericytoma and the role of radiation therapy: A population based analysis

BACKGROUND Intracranial hemangiopericytoma (HPC) is a rare malignancy for which treatment recommendations vary. OBJECTIVE We sought to characterize outcomes of HPC patients treated with postoperative external beam radiotherapy (PORT). METHODS A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Program of the US National Cancer Institute. We identified patients with intracranial hemangiopericytoma who underwent surgery alone or PORT. RESULTS We identified 88 patients with a diagnosis of HPC between 1982 and 2009 treated with surgery alone or PORT. The majority of patients were female (53%) and white (84%) with a median age of 50.5 years (range, 0-92 years). Gross total resection (GTR) was achieved in 55%, and PORT was delivered to 48% of the entire cohort. The median overall survival (OS) and cause-specific survival (CSS) were 111 months and 161 months, respectively. On univariate analysis, age older than 50 years correlated with poor OS (hazard ratio [HR]: 3.43; 95% confidence interval [CI]: 1.70-6.95; P = .001) and CSS (HR: 2.77; 95% CI: 1.18-6.48; P = .019). On multivariate analysis (MVA), age >50 years correlated with poor OS (HR: 3.69; 95% CI: 1.72-7.93; P = .001) and CSS (HR: 2.67; 95% CI: 1.08-6.59; P = .034). On MVA, GTR correlated with improved OS (HR: 0.28; 95% CI: 0.11-0.71; P = .007) and CSS (HR: 0.23; 95% CI: 0.07-0.76; P = .016). In addition, PORT correlated with improved OS (MVA HR: 0.02; 95% CI: 0.00-0.31; P = .005) and CSS (MVA HR: 0.02; 95% CI: 0.00-0.45; P = .015). Patients undergoing STR with PORT compared favorably with those undergoing GTR alone with respect to OS (HR: 0.43; 95% CI: 0.15-1.26; P = .13) and CSS (HR: 0.51; 95% CI: 0.15-1.78; P = .29). CONCLUSION In intracranial HPC, both PORT and GTR independently correlate with improved OS and CSS.

Utilization of laser interstitial thermotherapy guided by real-time thermal MRI as an alternative to separation surgery in the management of spinal metastasis.

OBJECT High-grade malignant spinal cord compression is commonly managed with a combination of surgery aimed at removing the epidural tumor, followed by spinal stereotactic radiosurgery (SSRS) aimed at local tumor control. The authors here introduce the use of spinal laser interstitial thermotherapy (SLITT) as an alternative to surgery prior to SSRS. METHODS Patients with a high degree of epidural malignant compression due to radioresistant tumors were selected for study. Visual analog scale (VAS) scores for pain and quality of life were obtained before and within 30 and 60 days after treatment. A laser probe was percutaneously placed in the epidural space. Real-time thermal MRI was used to monitor tissue damage in the region of interest. All patients received postoperative SSRS. The maximum thickness of the epidural tumor was measured, and the degree of epidural spinal cord compression (ESCC) was scored in pre- and postprocedure MRI. RESULTS In the 11 patients eligible for study, the mean VAS score for pain decreased from 6.18 in the preoperative period to 4.27 within 30 days and 2.8 within 60 days after the procedure. A similar VAS interrogating the percentage of quality of life demonstrated improvement from 60% preoperatively to 70% within both 30 and 60 days after treatment. Imaging follow-up 2 months after the procedure demonstrated a significant reduction in the mean thickness of the epidural tumor from 8.82 mm (95% CI 7.38-10.25) before treatment to 6.36 mm (95% CI 4.65-8.07) after SLITT and SSRS (p = 0.0001). The median preoperative ESCC Grade 2 was scored as 4, which was significantly higher than the score of 2 for Grade 1b (p = 0.04) on imaging follow-up 2 months after the procedure. CONCLUTIONS The authors present the first report on an innovative minimally invasive alternative to surgery in the management of spinal metastasis. In their early experience, SLITT has provided local control with low morbidity and improvement in both pain and the quality of life of patients.

Intracranial hemangiopericytoma: Patterns of failure and the role of radiation therapy

BACKGROUND Meningeal hemangiopericytoma (M-HPC) is a rare entity. OBJECTIVE To characterize our institutional experience in treating M-HPC. METHODS We reviewed the medical records of patients with M-HPC evaluated at The University of Texas M.D. Anderson Cancer Center between 1979 and 2009. RESULTS We identified 63 patients diagnosed between 1979 and 2009 with M-HPC treated with surgery alone or with postoperative radiotherapy (PORT). The majority were male (59%) and with a median age of 40.9 years (range, 0-71). Gross total resection (GTR) predominated (n = 31, 49%) followed by subtotal resection (n = 23, 37%) and unknown status (n = 9, 14.3%). PORT was delivered to 39 of the 63 patients (62%). The 5-, 10-, and 15-year overall survival were 90%, 68%, and 28%, respectively. The 5-, 10-, and 15-year local control (LC) were 70%, 37%, and 20%, respectively. The 5-, 10-, and 15-year metastasis-free survival were 85%, 39%, and 7%. PORT resulted in improved LC (hazard ratio [HR] 0.38, P = .008). Radiotherapy (RT) dose ≥60 Gy correlated with improved LC relative to <60 Gy (HR 0.12, P = .045). GTR correlated with improved LC (HR 0.40, P = .03). On multivariate analysis, PORT (HR 0.33, P = .003), GTR (HR = 0.33, P = .008), and RT dose ≥60 Gy (HR 0.33, P = .003) correlated with improved LC. Among those with GTR, PORT resulted in improved LC (HR 0.18, P = .027). Extent of resection and PORT did not correlate with improved overall survival. CONCLUSION In M-HPC, both PORT and GTR independently correlate with improved LC. PORT improves LC following GTR. We recommend RT dose ≥60 Gy to optimize LC.

Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials.

OBJECTIVE The objective of this study was to compare fractionation schemes and outcomes of patients with renal cell carcinoma (RCC) treated in institutional prospective spinal stereotactic radiosurgery (SSRS) trials who did not previously undergo radiation treatment at the site of the SSRS. METHODS Patients enrolled in 2 separate institutional prospective protocols and treated with SSRS between 2002 and 2011 were included. A secondary analysis was performed on patients with previously nonirradiated RCC spinal metastases treated with either single-fraction (SF) or multifraction (MF) SSRS. RESULTS SSRS was performed in 47 spinal sites on 43 patients. The median age of the patients was 62 years (range 38-75 years). The most common histological subtype was clear cell (n = 30). Fifteen sites underwent surgery prior to the SSRS, with laminectomy the most common procedure performed (n = 10). All SF SSRS was delivered to a dose of 24 Gy (n = 21) while MF regiments were either 27 Gy in 3 fractions (n = 20) or 30 Gy in 5 fractions (n = 6). The median overall survival duration for the entire cohort was 22.8 months. The median local control (LC) for the entire cohort was 80.6 months with 1-year and 2-year actuarial LC rates of 82% and 68%, respectively. Single-fraction SSRS correlated with improved 1- and 2-year actuarial LC relative to MF SSRS (95% vs 71% and 86% vs 55%, respectively; p = 0.009). On competing risk analysis, SF SSRS showed superior LC to MF SSRS (subhazard ratio [SHR] 6.57, p = 0.014). On multivariate analysis for LC with tumor volume (p = 0.272), number of treated levels (p = 0.819), gross tumor volume (GTV) coverage (p = 0.225), and GTV minimum point dose (p = 0.97) as covariates, MF SSRS remained inferior to SF SSRS (SHR 5.26, p = 0.033) CONCLUSIONS SSRS offers durable LC for spinal metastases from RCC. Single-fraction SSRS is associated with improved LC over MF SSRS for previously nonirradiated RCC spinal metastases.

Astroblastomas: A Surveillance, Epidemiology, and End Results (SEER)-Based Patterns of Care Analysis

OBJECTIVE This study sought to report patient characteristics, risk factors, and trends in management for astroblastoma patients. METHODS A retrospective analysis was conducted utilizing the Surveillance, Epidemiology and End Results Program of the National Cancer Institute. RESULTS Two hundred and thirty-nine patients were identified, with 206 patients receiving treatment. The median age at diagnosis was 35 years (range 0 to 84 years). Tumor location was available for 177 patients, and the majority were supratentorial (n = 144, 81.3%). The median overall survival and cause-specific survival for the cohort receiving treatment was 55 and 65 months, respectively. On univariate analysis, patients receiving surgery alone compared to only radiotherapy displayed improved overall survival (OS) and cause-specific survival (CSS) with a 5-year OS of 62.2% vs. 27.3%, P < .001, and CSS of 67.3% vs. 31.9%, P = .003. Supratentorial tumor location was associated with worse survival, with an estimated 5-year OS of 44.9% for supratentorial tumors compared to 75% for infratentorial tumors (hazard ratio 3.41 [95% CI, 1.76 to 6.62]; P < .001) and CSS of 47.5% (supratentorial) to 82% (infratentorial) (hazard ratio 3.95 [95% CI, 1.81 to 8.62]; P = .001). Age >60 years at diagnosis and treatment before 1990 were correlated with decreased survival on both the univariate and the multivariate analyses. CONCLUSIONS To our knowledge, this is the largest report of astroblastoma patients described in the literature. Supratentorial tumor location, older age, and treatment prior to 1990 were poor prognostic factors.

Impact of tumor size on survival in cancer of the cervix and validation of stage IIA1 and IIA2 subdivisions

OBJECTIVE A change has recently been made to the Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer to account for size within stage IIA cancers. This study was designed to investigate the impact of size within stage I-IIIB cervical carcinoma, and to validate these changes. METHODS The Surveillance, Epidemiology, and End Results Program database was used to extract data on patients from 1988 to 2008. Patients were included who had information recorded regarding stage, size, and type of treatment received. They were then stratified by stage and size, and analyzed for cause-specific survival (CSS) using Kaplan Meier estimates, as well as hazard ratios using Cox proportional hazards regression modeling. RESULTS A total of 18,649 cases were evaluated. All stages evaluated demonstrated improved CSS on Kaplan Meier estimates for smaller tumor sizes (largest p=0.0003). Hazard ratios were significantly worse for larger tumor sizes on both univariate and multivariate modeling. Specifically, stage IIA cancers demonstrated a hazard ratio of 2.0 on univariate, and 1.69 on multivariate analysis (C.I. 1.46-2.75, p<0.0001 and C.I. 1.20-2.38, p=0.0025, respectively). Further size subdivisions of 2 and 4cm for stage I, 4cm for stage IIB, and 4 and 6cm for stage IIIB also maintained prognostic significance. On multivariate analysis within each stage, size was the only variable to maintain independent significance in all stages evaluated. CONCLUSIONS Size is independently prognostic within each stage in cervical cancer, validating the recent changes to the FIGO staging system.

Creation of a Prognostic Index for Spine Metastasis to Stratify Survival in Patients Treated With Spinal Stereotactic Radiosurgery: Secondary Analysis of Mature Prospective Trials.

PURPOSE There exists uncertainty in the prognosis of patients following spinal metastasis treatment. We sought to create a scoring system that stratifies patients based on overall survival. METHODS AND MATERIALS Patients enrolled in 2 prospective trials investigating stereotactic spine radiation surgery (SSRS) for spinal metastasis with ≥ 3-year follow-up were analyzed. A multivariate Cox regression model was used to create a survival model. Pretreatment variables included were race, sex, age, performance status, tumor histology, extent of vertebrae involvement, previous therapy at the SSRS site, disease burden, and timing of diagnosis and metastasis. Four survival groups were generated based on the model-derived survival score. RESULTS Median follow-up in the 206 patients included in this analysis was 70 months (range: 37-133 months). Seven variables were selected: female sex (hazard ratio [HR] = 0.7, P=.02), Karnofsky performance score (HR = 0.8 per 10-point increase above 60, P = .007), previous surgery at the SSRS site (HR = 0.7, P=.02), previous radiation at the SSRS site (HR = 1.8, P=.001), the SSRS site as the only site of metastatic disease (HR = 0.5, P=.01), number of organ systems involved outside of bone (HR = 1.4 per involved system, P<.001), and >5 year interval from initial diagnosis to detection of spine metastasis (HR = 0.5, P < .001). The median survival among all patients was 25.5 months and was significantly different among survival groups (in group 1 [excellent prognosis], median survival was not reached; group 2 reached 32.4 months; group 3 reached 22.2 months; and group 4 [poor prognosis] reached 9.1 months; P < .001). Pretreatment symptom burden was significantly higher in the patient group with poor survival than in the group with excellent survival (all metrics, P < .05). CONCLUSIONS We developed the prognostic index for spinal metastases (PRISM) model, a new model that identified patient subgroups with poor and excellent prognoses.

Clinical outcomes and patterns of failure in pineoblastoma: A 30-year, single-institution retrospective review

OBJECTIVE To update outcomes and assess prognostic factors in the modern, multimodality treatment of patients with pineoblastoma. METHODS The medical records of patients with pineoblastoma evaluated at the M.D. Anderson Cancer Center between 1982 and 2012 were reviewed retrospectively. RESULTS Thirty-one patients with medical records suitable for review were identified. The majority of patients were female (67.7%) with a median age at diagnosis of 18.2 years (range, 0.3-52.8 years). Twenty-one patients underwent surgical resection, recorded as gross total (n = 9) or subtotal (n = 12) resections. Thirty patients received radiation with photon-based therapy (n = 16), proton-based therapy (n = 13), or radiosurgery (n = 1) to a median craniospinal irradiation dose of 36 Gy (range, 23.4-40 Gy) and a median focal dose of 54 Gy (range, 40-58.4 Gy). Twenty-eight patients received chemotherapy before (n = 10), during (n = 10), and after (n = 22) radiation. Median overall survival was 8.7 years for the entire cohort, with 2-, 5-, and 10- year actuarial rates of 89.5%, 69.4%, and 48.6%, respectively. Median disease-free survival was 10 years with 2-, 5-, and 10- year actuarial rates of 84.3%, 62.6%, and 55.7%, respectively. Univariate analysis failed to correlate age, sex, or extent of surgical resection with disease-free or overall survival. CONCLUSIONS Modern, multimodality treatment of pineoblastoma yields a high rate of overall survival, with acceptable short- and long-term toxicity. A greater M-stage at presentation and development of disease recurrence correlate with worse overall survival. Patients who received focal radiation initially experienced a greater rate of disease recurrence compared with those treated to the craniospinal axis.

Primary vaginal cancer and chemoradiotherapy: A patterns-of-care analysis

Introduction: No prospective randomized trials exist to delineate the role of combined chemoradiotherapy (CRT) in the treatment of vaginal cancer (VC). We sought to describe the utilization rate of CRT and evaluate the potential survival benefit of CRT over radiotherapy alone in VC. Methods: A retrospective analysis of the SEER-Medicare-linked database was performed analyzing women with VC treated with external beam radiation and/or brachytherapy and diagnosed between 1991 and 2005. Results: Of the 1709 primary VC patients in the SEER-Medicare database, 326 met inclusion criteria. Most were white (80.1%) and in the 70- to 74-year age group (42.1%). Squamous cell carcinoma was the most predominant histologic diagnosis (80.4%). Brachytherapy was used in 34% of patients, whereas cisplatin was the chemotherapy of choice in 59% of CRT patients. Median follow-up was 21.5 months. Kaplan-Meier estimated that 5-year cause-specific survival (CSS) and overall survival (OS) was 67.6% and 27.1%, respectively. Before 1999, CRT was used in 7.5% of patients compared with 36.1% of patients thereafter (P < 0.001). Chemoradiotherapy was less likely to be used in patients older than 80 years (P < 0.001) but was otherwise balanced in race, stage, grade, histologic diagnosis, comorbidities, and brachytherapy use. Chemoradiotherapy did not correlate with CSS (hazard ratio [HR], 0.91; P = 0.84) or OS (HR, 1.34; P = 0.21) by multivariate analysis. Factors associated with worse CSS include stage IVA disease (HR, 4.2; P = 0.003) and 2 or more comorbidities (HR, 2.89; P = 0.03). Factors associated with worse OS include age older than 80 years (HR, 1.78; P = 0.04), stage IVA disease (HR, 3.35; P < 0.0001), and 2 or more comorbidities (HR, 2.58; P = 0.001). Conclusions: Chemoradiotherapy utilization for VC has increased since 1999. We failed to delineate a CSS or OS benefit for CRT in this cohort.