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Results of a pilot/phase II study of gamma knife radiosurgery for brain metastases and implications for future prospective clinical trials

Authors:
James B Yu at St. Francis Hospital
James B Yu
Charu Singh at Yale-New Haven Hospital
Charu Singh
Ranjit S. Bindra
Ranjit S. Bindra
Ranjit S. Bindra
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Joseph N. Contessa
Joseph N. Contessa
Joseph N. Contessa
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Introduction Gamma knife radiosurgery is a well established method of treating intracranial metastases. We created a dose algorithm based on our standard clinical practice, taking into account tumor volume, number of metastases, radiosensitivity, and prior whole brain radiation treatment. We performed a phase 2 study to validate this algorithm and to investigate the feasibility of a larger clinical trial. Methods A total of 39 patients were prospectively enrolled at Yale New Haven Hospital (YNHH) between April 3, 2014 and November 21, 2016. There were 114 evaluable brain metastases. The pre-defined primary endpoint of this study was the control of all irradiated lesions for each patient. Survival was estimated using the method of Kaplan-Meier. Cox proportional hazard regression was performed to identify factors associated with survival and local control. Results The median patient age of enrolled patients was 64 years (range, 34–88). Of the 114 evaluable lesions, 58 (50.9%) had complete response, 16 (14.0%) had partial response, 33 (28.9%) had stable disease, and 7 (6.1%) had progression at last imaging follow-up. Therefore, there was a per-lesion local control rate of 93.9%. Six (15.3%) patients developed symptomatic radiation necrosis requiring steroids or surgery, with median time to occurrence of 6 months. Median survival after gamma knife was 11.4 months (95% CI 4.9–15.7). Age was the only significant variable in univariate and multivariate analysis. Having a bladder primary (vs. lung) was associated with a higher risk of death, although this was based on only two patients and therefore is of unclear significance. Conclusion In this pilot/phase II study, we learned: (1) radiosurgery using radiation doses based on our algorithm provides good local control with low toxicity. (2) Despite the relative commonality of brain metastases, patients with brain metastases are difficult to enroll on clinical trials. (3) A prospective study that encompasses all potentially important clinical variables that go into radiosurgery dose selection will require large amounts of patients. Our findings have important implications for future clinical trials of radiosurgery for brain metastases.
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ORIGINAL RESEARCH
Results of a pilot/phase II study of gamma knife radiosurgery for brain
metastases and implications for future prospective clinical trials
James B. Yu
1,2
&Charu Singh
1,3
&Ranjit S. Bindra
1,2
&Joseph N. Contessa
1,2
&Zain Husain
1,2
&James E. Hansen
1,2
&
Henry S. Park
1,2
&Kenneth B. Roberts
1,2
&James E. Bond
1
&Christopher J. Tien
1
&Fanqing Guo
1
&Rovel J. Colaco
4
&
Nadine Housri
1,2
&William J. Magnuson
5
&Amit Mahajan
2,6
&Sacit B. Omay
2,3
&Veronica L. S. Chiang
2,3
Received: 31 October 2018 / Accepted: 14 December 2018 / Published online: 14 January 2019
#Springer-Verlag GmbH Germany, part of Springer Nature 2019
Abstract
Introduction Gamma knife radiosurgery is a well established method of treating intracranial metastases. We created a dose
algorithm based on our standard clinical practice, taking into account tumor volume, number of metastases, radiosensitivity,
and prior whole brain radiation treatment. We performed a phase 2 study to validate this algorithm and to investigate the
feasibility of a larger clinical trial.
Methods A total of 39 patients were prospectively enrolled at Yale New Haven Hospital (YNHH) between April 3, 2014 and
November 21, 2016. There were 114 evaluable brain metastases. The pre-defined primary endpoint of this study was the control
of all irradiated lesions for each patient. Survival was estimated using the method of Kaplan-Meier. Cox proportional hazard
regression was performed to identify factors associated with survival and local control.
Results The median patient age of enrolled patients was 64 years (range, 34–88). Of the 114 evaluable lesions, 58 (50.9%) had
complete response, 16 (14.0%) had partial response, 33 (28.9%) had stable disease, and 7 (6.1%) had progression at last imaging
follow-up. Therefore, there was a per-lesion local control rate of 93.9%. Six (15.3%) patients developed symptomatic radiation necrosis
requiring steroids or surgery, with median time to occurrence of 6 months. Median survival after gamma knife was 11.4 months (95%
CI 4.9–15.7). Age was the only significant variable in univariate and multivariate analysis. Having a bladder primary (vs. lung) was
associated with a higher risk of death, although this was based on only two patients and therefore is of unclear significance.
Conclusion In this pilot/phase II study, we learned: (1) radiosurgery using radiation doses based on our algorithm provides good
local control with low toxicity. (2) Despite the relative commonality of brain metastases, patients with brain metastases are
difficult to enroll on clinical trials. (3) A prospective study that encompasses all potentially important clinical variables that go
into radiosurgery dose selection will require large amounts of patients. Our findings have important implications for future
clinical trials of radiosurgery for brain metastases.
Keywords Gamma Knife .Brain metastases .Radiotherapy
Introduction
Gamma knife radiosurgery is a well-established method of
treating intracranial metastases. However, the selection of radio-
surgery dose has not been standardized for use in clinical trials.
The RTOG 9005 trial [7] was a single phase I dose escalation
study that reported safety and toxicity data for single dose
radiosurgical treatment of recurrent primary brain tumors and
brain metastases after prior irradiation. Stratification for dose
was done by largest lesion diameter, and based on this study,
doses of 24, 18, and 15 Gy were determined to be safe for treat-
ment of tumors of < 20 mm, 21–30 mm, and 31–40 mm in
maximum diameter, respectively.
*James B. Yu
james.b.yu@yale.edu
1
Yale Department of Therapeutic Radiology, HRT 138, 333 Cedar St.,
New Haven, CT 06520, USA
2
Yale Cancer Center, New Haven, CT, USA
3
Yale Department of Neurosurgery, New Haven, CT, USA
4
Radiation Oncology, The Christie NHS Foundation Trust,
Manchester, UK
5
Peninsula Radiation Oncology Center, Soldotna, AK, USA
6
Yale Department of Diagnostic Radiology, New Haven, CT, USA
Journal of Radiation Oncology (2019) 8:39–46
https://doi.org/10.1007/s13566-018-0370-7
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
ResearchGate has not been able to resolve any citations for this publication.
Predicting treatment related imaging changes (TRICs) after radiosurgery for brain metastases using treatment dose and conformality metrics
Article
Full-text available
  • Jan 2016
Purpose: Treatment-related imaging changes (TRICs) after stereotactic radiosurgery (SRS) involves the benign transient enlargement of radiographic lesions after treatment. Identifying the radiation dose volumes and conformality metrics associated with TRICs for different post-treatment periods would be helpful and improve clinical decision making. Methods: 367 metastases in 113 patients were treated using Gamma Knife SRS between 1/1/2007-12/31/2009. Each metastasis was measured at each imaging follow-up to detect TRICs (defined as ≥ 20% increase in volume). Fluctuations in small volume lesions (less than 108 mm3) were ignored given widely variable conformity indices (CI) for small volumes. The Karolinska Adverse Radiation Effect (KARE) factor, Paddick's CI, Shaw's CI, tumor volume (TV), 10 Gy (V10) and 12 Gy (V12) volumes, and prescription isodose volume (PIV) were calculated. Results: From 0-6 months, all measures correlated with the incidence of TRICs (p<.001), except KARE, which was inversely correlated. During the 6-12 month period all measures except KARE were still correlated. Beyond 12 months, no correlation was found between any of the measures and the development of TRICs. Conclusions: All metrics except KARE were associated with TRICs from 0-12 months only. Additional patient and treatment factors may become dominant at greater times after SRS.
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Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial
Article
Full-text available
  • Jun 2004
  • LANCET
Brain metastases occur in up to 40% of all patients with systemic cancer. We aimed to assess whether stereotactic radiosurgery provided any therapeutic benefit in a randomised multi-institutional trial directed by the Radiation Therapy Oncology Group (RTOG). Patients with one to three newly diagnosed brain metastases were randomly allocated either whole brain radiation therapy (WBRT) or WBRT followed by stereotactic radiosurgery boost. Patients were stratified by number of metastases and status of extracranial disease. Primary outcome was survival; secondary outcomes were tumour response and local rates, overall intracranial recurrence rates, cause of death, and performance measurements. From January, 1996, to June, 2001, we enrolled 333 patients from 55 participating RTOG institutions--167 were assigned WBRT and stereotactic radiosurgery and 164 were allocated WBRT alone. Univariate analysis showed that there was a survival advantage in the WBRT and stereotactic radiosurgery group for patients with a single brain metastasis (median survival time 6.5 vs 4.9 months, p=0.0393). Patients in the stereotactic surgery group were more likely to have a stable or improved Karnofsky Performance Status (KPS) score at 6 months' follow-up than were patients allocated WBRT alone (43% vs 27%, respectively; p=0.03). By multivariate analysis, survival improved in patients with an RPA class 1 (p<0.0001) or a favourable histological status (p=0.0121). WBRT and stereotactic boost treatment improved functional autonomy (KPS) for all patients and survival for patients with a single unresectable brain metastasis. WBRT and stereotactic radiosurgery should, therefore, be standard treatment for patients with a single unresectable brain metastasis and considered for patients with two or three brain metastases.
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Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases
Article
Full-text available
  • Jul 2006
  • J Am Med Assoc
In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. umin.ac.jp/ctr Identifier: C000000412.
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A contemporary dose selection algorithm for stereotactic radiosurgery in the treatment of brain metastases - An initial report
Article
  • Jan 2016
Indications and treatment goals for SRS have changed since the publication of RTOG 90-05. We present initial retrospective outcomes from a new dose selection algorithm in use at our institution felt to be more contemporary with doses being used in the radiosurgery community today and report our local control and toxicity outcomes. This dose selection algorithm will be subject to a forthcoming prospective phase 2 trial. Introduction: To evaluate safety and efficacy of an institutional dose selection algorithm in the treatment of brain metastases (BM) with single fraction radio-surgery (SRS). Methods and materials: The medical records of 65 patients with ≤10 BM treated with GK at our institution between April 2012 and October 2012 were reviewed retrospectively. The prescription doses used in this study ranged from 16-22Gy and were based upon RTOG 90-05 guideline doses subsequently modified at our institution depending on lesion number, lesion volume, institutional experience and prior history of whole brain radiation therapy (WBRT). Primary endpoint was local recurrence (LR) with additional outcomes measured including distant intracranial recurrence (DIR), death without local recurrence (DWLR) and alive and disease free (ADF). Fine Gray competing risk analysis was used to examine factors affecting local recurrence. Results: Median follow up was 8.9 months (range 1.0-29.6months) and 12 month overall survival was 37% (95% CI 24.9-49.1%). Overall local recurrence rate was 7.7%. On competing risks regression analysis, no variable was significantly associated with local recurrence, including previous whole brain radiotherapy (WBRT), (SHR 1.21 [95%CI 0.13-11.5], p=0.87 and radioresistant versus radiosensitive histology (SHR 0.51 [95% CI 0.06-7.73], p=0.55). No patient developed grade 3 or higher neurotoxicity at 12 months following GK. Conclusions: Initial local control and toxicity results from our institutional dose selection algorithm are reported here. Comparison of our results with RTOG 90-05 is difficult due to significant differences in the patient population and their treatments. The applicability of this algorithm merits further investigation across multiple centers for the purpose of treatment and clinical trial standardization in single fraction SRS and will be the subject of a forthcoming phase 2 prospective study within our own institution.
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Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control
Article
  • Sep 2017
  • RADIOTHER ONCOL
Background: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. Material and methods: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). Results: The median follow-up time was 15.5months. In the MD Anderson cohort, patients who received SRS after 5.5months (n=20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5months (n=51) (median 3.63 vs. 8.09months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03-4.16, p=0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/µL had reduced risk of intracranial recurrence compared with those with ≤1000/µL (HR 0.46, 95% CI 0.0.23-0.94, p=0.03). Conclusions: In this multi-institutional study, patients who received SRS for new brain metastases within 5.5months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control.
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Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: Early analysis of a non-randomised, open-label, phase 2 trial
Article
  • Jun 2016
  • LANCET ONCOL
Background: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). Methods: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. Findings: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. Interpretation: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. Funding: Merck and the Yale Cancer Center.
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Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases?
Article
  • Nov 2015
OBJECT Radiation necrosis (RN), or its imaging equivalent, treatment-related imaging changes (TRIC), is an inflammatory reaction to high-dose radiation in the brain. The authors sought to investigate the hypothesis that immunotherapy increases the risk of developing RN/TRIC after stereotactic Gamma Knife (GK) radiosurgery for brain metastases. METHODS A total of 180 patients who underwent GK surgery for brain metastases between 2006 and 2012 were studied. The systemic therapy they received was classified as cytotoxic chemotherapy (CT), targeted therapy (TT), or immunotherapy (IT). The timing of systemic therapy in relation to GK treatment was also recorded. Logistic regression was used to calculate the odds of developing RN according to type of systemic therapy received. RESULTS The median follow-up time was 11.7 months. Of 180 patients, 39 (21.7%) developed RN/TRIC. RN/TRIC rates were 37.5% (12 of 32) in patients who received IT alone, 16.9% (14 of 83) in those who received CT only, and 25.0% (5 of 20) in those who received TT only. Median overall survival was significantly longer in patients who developed RN/TRIC (23.7 vs 9.9 months, respectively). The RN/TRIC rate was increased significantly in patients who received IT alone (OR 2.40 [95% CI 1.06–5.44]; p = 0.03), whereas receipt of any CT was associated with a lower risk of RN/TRIC (OR 0.38 [95% CI 0.18–0.78]; p = 0.01). The timing of development of RN/TRIC was not different between patients who received IT and those who received CT. CONCLUSIONS Patients who receive IT alone may have an increased rate of RN/TRIC compared with those who receive CT or TT alone after stereotactic radiosurgery, whereas receiving any CT may in fact be protective against RN/TRIC. As the use of immunotherapies increases, the rate of RN/TRIC may be expected to increase compared with rates in the chemotherapy era.
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Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: Final report of RTOG protocol 90- 05
Article
  • May 2000
  • INT J RADIAT ONCOL
To determine the maximum tolerated dose of single fraction radiosurgery in patients with recurrent previously irradiated primary brain tumors and brain metastases. Adults with cerebral or cerebellar solitary non-brainstem tumors </= 40 mm in maximum diameter were eligible. Initial radiosurgical doses were 18 Gy for tumors </= 20 mm, 15 Gy for those 21-30 mm, and 12 Gy for those 31-40 mm in maximum diameter. Dose was prescribed to the 50-90% isodose line. Doses were escalated in 3 Gy increments providing the incidence of irreversible grade 3 (severe) or any grade 4 (life threatening) or grade 5 (fatal) Radiation Therapy Oncology Group (RTOG) central nervous system (CNS) toxicity (unacceptable CNS toxicity) was < 20% within 3 months of radiosurgery. Chronic CNS toxicity was also assessed. Between 1990-1994, 156 analyzable patients were entered, 36% of whom had recurrent primary brain tumors (median prior dose 60 Gy) and 64% recurrent brain metastases (median prior dose 30 Gy). The maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm in maximum diameter, respectively. However, for tumors < 20 mm, investigators' reluctance to escalate to 27 Gy, rather than excessive toxicity, determined the maximum tolerated dose. In a multivariate analysis, maximum tumor diameter was one variable associated with a significantly increased risk of grade 3, 4, or 5 neurotoxicity. Tumors 21-40 mm were 7.3 to 16 times more likely to develop grade 3-5 neurotoxicity compared to tumors < 20 mm. Other variables significantly associated with grade 3-5 neurotoxicity were tumor dose and Karnofsky Performance Status. The actuarial incidence of radionecrosis was 5%, 8%, 9%, and 11% at 6, 12, 18, and 24 months following radiosurgery, respectively. Forty-eight percent of patients developed tumor progression within the radiosurgical target volume. A multivariate analysis revealed two variables that were significantly associated with an increased risk of local progression, i.e. progression in the radiosurgical target volume. Patients with primary brain tumors (versus brain metastases) had a 2.85 greater risk of local progression. Those treated on a linear accelerator (versus the Gamma Knife) had a 2.84 greater risk of local progression. Of note, 61 % of Gamma Knife treated patients had recurrent primary brain tumors compared to 30% of patients treated with a linear accelerator. The maximum tolerated doses of single fraction radiosurgery were defined for this population of patients as 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm in maximum diameter. Unacceptable CNS toxicity was more likely in patients with larger tumors, whereas local tumor control was most dependent on the type of recurrent tumor and the treatment unit.
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Local control of brain metastases by stereotactic radiosurgery in relation to dose to the tumor margin
Article
  • Jul 2006
  • J NEUROSURG
The maximal tolerated dose (MTD) for stereotactic radiosurgery (SRS) for brain tumors was established by the Radiation Therapy Oncology Group (RTOG) in protocol 90-05, which defined three dose groups based on the maximal tumor diameter. The goal in this retrospective study was to determine whether differences in doses to the margins of brain metastases affect the ability of SRS to achieve local control. Between 1997 and 2003, 202 patients harboring 375 tumors that met study entry criteria underwent SRS for treatment of one or multiple brain metastases. The median overall follow-up duration was 10.7 months (range 3-83 months). A dose of 24 Gy to the tumor margin had a significantly lower risk of local failure than 15 or 18 Gy (p = 0.0005; hazard ratio 0.277, confidence interval [CI] 0.134-0.573), whereas the 15- and 18-Gy groups were not significantly different from each other (p = 0.82) in this regard. The 1-year local control rate was 85% (95% CI 78-92%) in tumors treated with 24 Gy, compared with 49% (CI 30-68%) in tumors treated with 18 Gy and 45% (CI 23-67%) in tumors treated with 15 Gy. Overall patient survival was independent of dose to the tumor margin. Use of the RTOG 90-05 dosing scheme for brain metastases is associated with a variable local control rate. Tumors larger than 2 cm are less effectively controlled than smaller lesions, which can be safely treated with 24 Gy. Prospective evaluations of the relationship between dose to the tumor margin and local control should be performed to confirm these observations.
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