Veronica L. S. Chiang and Jonathan P. S. Knisely
Jonathan P. S. Knisely, Rohan Ramakrishna, and Theodore H. Schwartz
Jonathan P. S. Knisely, Masaaki Yamamoto, Cary P. Gross, William A. Castrucci, Hidefumi Jokura, and Veronica L. S. Chiang
Oligometastatic brain metastases may be treated with stereotactic radiosurgery (SRS) alone, but no consensus exists as to when SRS alone would be appropriate. A survey was conducted at 2 radiosurgery meetings to determine which factors SRS practitioners emphasize in recommending SRS alone, and what physician characteristics are associated with recommending SRS alone for ≥ 5 metastases.
All physicians attending the 8th Biennial Congress and Exhibition of the International Stereotactic Radiosurgery Society in June 2007 and the 18th Annual Meeting of the Japanese Society of Stereotactic Radiosurgery in July 2009 were asked to complete a questionnaire ranking 14 clinical factors on a 5-point Likert-type scale (ranging from 1 = not important to 5 = very important) to determine how much each factor might influence a decision to recommend SRS alone for brain metastases. Results were condensed into a single dichotomous outcome variable of “influential” (4–5) versus “not influential” (1–3). Respondents were also asked to complete the statement: “In general, a reasonable number of brain metastases treatable by SRS alone would be, at most, ___.” The characteristics of physicians willing to recommend SRS alone for ≥ 5 metastases were assessed. Chi-square was used for univariate analysis, and logistic regression for multivariate analysis.
The final study sample included 95 Gamma Knife and LINAC-using respondents (54% Gamma Knife users) in San Francisco and 54 in Sendai (48% Gamma Knife users). More than 70% at each meeting had ≥ 5 years experience with SRS. Sixty-five percent in San Francisco and 83% in Sendai treated ≥ 30 cases annually with SRS. The highest number of metastases considered reasonable to treat with SRS alone in both surveys was 50. In San Francisco, the mean and median numbers of metastases considered reasonable to treat with SRS alone were 6.7 and 5, while in Sendai they were 11 and 10. In the San Francisco sample, the clinical factors identified to be most influential in decision making were Karnofsky Performance Scale score (78%), presence/absence of mass effect (76%), and systemic disease control (63%). In Sendai, the most influential factors were the size of the metastases (78%), the Karnofsky Performance Scale score (70%), and metastasis location (68%). In San Francisco, 55% of respondents considered treating ≥ 5 metastases and 22% considered treating ≥ 10 metastases “reasonable.” In Sendai, 83% of respondents considered treating ≥ 5 metastases and 57% considered treating ≥ 10 metastases “reasonable.” In both groups, private practitioners, neurosurgeons, and Gamma Knife users were statistically significantly more likely to treat ≥ 5 metastases with SRS alone.
Although there is no clear consensus for how many metastases are reasonable to treat with SRS alone, more than half of the radiosurgeons at 2 international meetings were willing to extend the use of SRS as an initial treatment for ≥ 5 brain metastases. Given the substantial variation in clinicians' approaches to SRS use, further research is required to identify patient characteristics associated with optimal SRS outcomes.
Jonathan P. S. Knisely, James B. Yu, Jaclyn Flanigan, Mario Sznol, Harriet M. Kluger, and Veronica L. S. Chiang
A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival.
The authors conducted an institutional review board–approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated.
Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03).
The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4–6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2-year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT.
Marina Kushnirsky, Vinh Nguyen, Joel S. Katz, Jared Steinklein, Lisa Rosen, Craig Warshall, Michael Schulder, and Jonathan P. S. Knisely
Contrast-enhanced MRI is the preeminent diagnostic test for brain metastasis (BM). Detection of BMs for stereotactic radiosurgery (SRS) planning may improve with a time delay following administration of a high-relaxivity agent for 1.5-T and 3-T imaging systems. Metastasis detection with time-delayed MRI was evaluated in this study.
Fifty-three volumetric MRI studies from 38 patients undergoing SRS for BMs were evaluated. All studies used 0.1-mmol/kg gadobenate dimeglumine (MultiHance; Bracco Diagnostics) immediately after injection, followed by 2 more axial T1-weighted sequences after 5-minute intervals (final image acquisition commenced 15 minutes after contrast injection). Two studies were motion limited and excluded. Two hundred eighty-seven BMs were identified. The studies were randomized and examined separately by 3 radiologists, who were blinded to the temporal sequence. Each radiologist recorded the number of BMs detected per scan. A Wilcoxon signed-rank test compared BM numbers between scans. One radiologist determined the scan on which BMs were best defined. All confirmed, visible tumors were contoured using iPlan RT treatment planning software on each of the 3 MRI data sets. A linear mixed model was used to analyze volume changes.
The interclass correlations for Scans 1, 2, and 3 were 0.7392, 0.7951, and 0.7290, respectively, demonstrating excellent interrater reliability. At least 1 new lesion was detected in the second scan as compared with the first in 35.3% of subjects (95% CI 22.4%–49.9%). The increase in BM numbers between Scans 1 and 2 ranged from 1 to 10. At least 1 new lesion was detected in the third scan as compared with the second in 21.6% of subjects (95% CI 11.3%–35.3%). The increase in BM numbers between Scans 2 and 3 ranged from 1 to 9. Between Scans 1 and 3, additional tumors were seen on 43.1% of scans (increase ranged from 1 to 14). The median increase in tumor number for all comparisons was 1. There was a significant increase in number of BMs detected from Scan 1 to Scan 2 (p < 0.0367) and from Scan 1 to Scan 3 (p < 0.0264). In 34 of the 51 subjects (66.7%), the radiologist selected the third scan as the one providing the clearest tumor definition. There was an average 25.4% increase in BM volume between Scans 1 and 2 (p < 0.0001) and a 9% increase in BM volume between Scans 2 and 3 (p = 0.0001).
In patients who are being prepared for SRS of BMs, delayed MRI after contrast injection revealed more targets that needed treatment. In addition, apparent treatment volumes increased with a time delay. To avoid missing tumors that could be treated at the time of planned SRS and resultant "treatment failures," the authors recommend that postcontrast MR images be acquired between 10 and 15 minutes after injection in patients undergoing SRS for treatment of BMs.
Andy J. Redmond, Michael L. DiLuna, Ryan Hebert, Jennifer A. Moliterno, Rani Desai, Jonathan P. S. Knisely, and Veronica L. Chiang
Gamma Knife surgery (GKS) improves overall survival in patients with malignant melanoma metastatic to the brain. In this study the authors investigated which patient- or treatment-specific factors influence survival of patients with melanoma brain metastases; they pay particular interest to pre- and post-GKS hemorrhage.
Demographic, treatment, and survival data on 59 patients with a total of 208 intracranial metastases who underwent GKS between 1998 and 2007 were abstracted from treatment records and from the Connecticut Tumor Registry. Multivariate analysis was used to identify factors that independently affected survival.
Survival was significantly better in patients with solitary metastasis (p = 0.04), lesions without evidence of pre-GKS hemorrhage (p = 0.004), and in patients with total tumor volume treated < 4 cm3 (p = 0.02). Intratumoral bleeding occurred in 23.7% of patients pre-GKS. Intratumoral bleeding occurred at a mean of 1.8 months post-GKS at a rate of 15.2%. Unlike the marked effect of pretreatment bleeding, posttreatment bleeding did not independently affect survival. Sex, systemic control, race, metastases location, whole-brain radiation therapy, chemotherapy, history of antithrombotic medications, and cranial surgery had no independent association with survival.
These data corroborate previous findings that tumor burden (either as increased number or total volume of lesions) at the time of GKS is associated with diminished patient survival in those with intracerebral melanoma metastases. Patients who were noted to have hemorrhagic melanoma metastases prior to GKS appear to have a worse prognosis following GKS compared with patients with nonhemorrhagic metastases, despite similar rates of bleeding pre- and post-GKS treatment. Gamma Knife surgery itself does not appear to increase the rate of hemorrhage.
Paul Porensky and E. Antonio Chiocca
Leland Rogers, Peixin Zhang, Michael A. Vogelbaum, Arie Perry, Lynn S. Ashby, Jignesh M. Modi, Anthony M. Alleman, James Galvin, David Brachman, Joseph M. Jenrette, John De Groot, Joseph A. Bovi, Maria Werner-Wasik, Jonathan P. S. Knisely, and Minesh P. Mehta
This is the first clinical outcomes report of NRG Oncology RTOG 0539, detailing the primary endpoint, 3-year progression-free survival (PFS), compared with a predefined historical control for intermediate-risk meningioma, and secondarily evaluating overall survival (OS), local failure, and prospectively scored adverse events (AEs).
NRG Oncology RTOG 0539 was a Phase II clinical trial allocating meningioma patients to 1 of 3 prognostic groups and management strategies according to WHO grade, recurrence status, and resection extent. For the intermediate-risk group (Group 2), eligible patients had either newly diagnosed WHO Grade II meningioma that had been treated with gross-total resection (GTR; Simpson Grades I–III) or recurrent WHO Grade I meningioma with any resection extent. Pathology and imaging were centrally reviewed. Patients were treated with radiation therapy (RT), either intensity modulated (IMRT) or 3D conformal (3DCRT), 54 Gy in 30 fractions. The RT target volume was defined as the tumor bed and any nodular enhancement (e.g., in patients with recurrent WHO Grade I tumors) with a minimum 8-mm and maximum 15-mm margin, depending on tumor location and setup reproducibility of the RT method. The primary endpoint was 3-year PFS. Results were compared with historical controls (3-year PFS: 70% following GTR alone and 90% with GTR + RT). AEs were scored using NCI Common Toxicity Criteria.
Fifty-six patients enrolled in the intermediate-risk group, of whom 3 were ineligible and 1 did not receive RT. Of the 52 patients who received protocol therapy, 4 withdrew without a recurrence before 3 years leaving 48 patients evaluable for the primary endpoint, 3-year PFS, which was actuarially 93.8% (p = 0.0003). Within 3 years, 3 patients experienced events affecting PFS: 1 patient with a WHO Grade II tumor died of the disease, 1 patient with a WHO Grade II tumor had disease progression but remained alive, and 1 patient with recurrent WHO Grade I meningioma died of undetermined cause without tumor progression. The 3-year actuarial local failure rate was 4.1%, and the 3-year OS rate was 96%. After 3 years, progression occurred in 2 additional patients: 1 patient with recurrent WHO Grade I meningioma and 1 patient with WHO Grade II disease; both remain alive. Among 52 evaluable patients who received protocol treatment, 36 (69.2%) had WHO Grade II tumors and underwent GTR, and 16 (30.8%) had recurrent WHO Grade I tumors. There was no significant difference in PFS between these subgroups (p = 0.52, HR 0.56, 95% CI 0.09–3.35), validating their consolidation. Of the 52 evaluable patients, 44 (84.6%) received IMRT, and 50 (96.2%) were treated per protocol or with acceptable variation. AEs (definitely, probably, or possibly related to protocol treatment) were limited to Grade 1 or 2, with no reported Grade 3 events.
This is the first clinical outcomes report from NRG Oncology RTOG 0539. Patients with intermediate-risk meningioma treated with RT had excellent 3-year PFS, with a low rate of local failure and a low risk of AEs. These results support the use of postoperative RT for newly diagnosed gross-totally resected WHO Grade II or recurrent WHO Grade I meningioma irrespective of resection extent. They also document minimal toxicity and high rates of tumor control with IMRT.
Clinical trial registration no.: NCT00895622 (clinicaltrials.gov).
Diana A. Roth O’Brien, Sydney M. Kaye, Phillip J. Poppas, Sean S. Mahase, Anjile An, Paul J. Christos, Benjamin Liechty, David Pisapia, Rohan Ramakrishna, AG Wernicke, Jonathan P. S. Knisely, Susan C. Pannullo, and Theodore H. Schwartz
Publications on adjuvant stereotactic radiosurgery (SRS) are largely limited to patients completing SRS within a specified time frame. The authors assessed real-world local recurrence (LR) for all brain metastasis (BM) patients referred for SRS and identified predictors of SRS timing.
The authors retrospectively identified BM patients undergoing resection and referred for SRS between 2012 and 2018. Patients were categorized by time to SRS, as follows: 1) ≤ 4 weeks, 2) > 4–8 weeks, 3) > 8 weeks, and 4) never completed. The relationships between timing of SRS and LR, LR-free survival (LRFS), and survival were investigated, as well as predictors of and reasons for specific SRS timing.
In a cohort of 159 patients, the median age at resection was 64.0 years, 56.5% of patients were female, and 57.2% were in recursive partitioning analysis (RPA) class II. The median preoperative tumor diameter was 2.9 cm, and gross-total resection was achieved in 83.0% of patients. All patients were referred for SRS, but 20 (12.6%) did not receive it. The LR rate was 22.6%, and the time to SRS was correlated with the LR rate: 2.3% for patients receiving SRS at ≤ 4 weeks postoperatively, 14.5% for SRS at > 4–8 weeks (p = 0.03), and 48.5% for SRS at > 8 weeks (p < 0.001). No LR difference was seen between patients whose SRS was delayed by > 8 weeks and those who never completed SRS (48.5% vs 50.0%; p = 0.91). A similar relationship emerged between time to SRS and LRFS (p < 0.01). Non–small cell lung cancer pathology (p = 0.04), earlier year of treatment (p < 0.01), and interval from brain MRI to SRS (p < 0.01) were associated with longer intervals to SRS. The rates of receipt of systemic therapy also differed significantly between patients by category of time to SRS (p = 0.02). The most common reasons for intervals of > 4–8 weeks were logistic, whereas longer delays or no SRS were caused by management of systemic disease or comorbidities.
Available data on LR rates after adjuvant SRS are often obtained from carefully preselected patients receiving timely treatment, whereas significantly less information is available on the efficacy of adjuvant SRS in patients treated under “real-world” conditions. Management of these patients may merit reconsideration, particularly when SRS is not delivered within ≤ 4 weeks of resection. The results of this study indicate that a substantial number of patients referred for SRS either never receive it or are treated > 8 weeks postoperatively, at which time the SRS-treated patients have an LR risk equivalent to that of patients who never received SRS. Increased attention to the reasons for prolonged intervals from surgery to SRS and strategies for reducing them is needed to optimize treatment. For patients likely to experience delays, other radiotherapy techniques may be considered.
Douglas Kondziolka, Phillip V. Parry, L. Dade Lunsford, Hideyuki Kano, John C. Flickinger, Susan Rakfal, Yoshio Arai, Jay S. Loeffler, Stephen Rush, Jonathan P. S. Knisely, Jason Sheehan, William Friedman, Ahmad A. Tarhini, Lanie Francis, Frank Lieberman, Manmeet S. Ahluwalia, Mark E. Linskey, Michael McDermott, Paul Sperduto, and Roger Stupp
Estimating survival time in cancer patients is crucial for clinicians, patients, families, and payers. To provide appropriate and cost-effective care, various data sources are used to provide rational, reliable, and reproducible estimates. The accuracy of such estimates is unknown.
The authors prospectively estimated survival in 150 consecutive cancer patients (median age 62 years) with brain metastases undergoing radiosurgery. They recorded cancer type, number of brain metastases, neurological presentation, extracranial disease status, Karnofsky Performance Scale score, Recursive Partitioning Analysis class, prior whole-brain radiotherapy, and synchronous or metachronous presentation. Finally, the authors asked 18 medical, radiation, or surgical oncologists to predict survival from the time of treatment.
The actual median patient survival was 10.3 months (95% CI 6.4–14). The median physician-predicted survival was 9.7 months (neurosurgeons = 11.8 months, radiation oncologists = 11.0 months, and medical oncologist = 7.2 months). For patients who died before 10 months, both neurosurgeons and radiation oncologists generally predicted survivals that were more optimistic and medical oncologists that were less so, although no group could accurately predict survivors alive at 14 months. All physicians had individual patient survival predictions that were incorrect by as much as 12–18 months, and 14 of 18 physicians had individual predictions that were in error by more than 18 months. Of the 2700 predictions, 1226 (45%) were off by more than 6 months and 488 (18%) were off by more than 12 months.
Although crucial, predicting the survival of cancer patients is difficult. In this study all physicians were unable to accurately predict longer-term survivors. Despite valuable clinical data and predictive scoring techniques, brain and systemic management often led to patient survivals well beyond estimated survivals.