Leptomeningeal disease after surgical resection and radiosurgery for brain metastases and neurologic death: A multi-institutional analysis.

2524 Background: Postoperative radiosurgery (SRS) has been associated with up to 30% risk of subsequent leptomeningeal disease (LMD). We previously demonstrated that radiographic pattern of LMD (classical “sugarcoating” [cLMD] vs. nodular [nLMD]) in this setting is prognostic. The association between radiographic pattern of LMD, type of salvage treatment (tx), and neurologic death (ND) has not been well described. Methods: The records of patients (pts) with brain metastases (BM), of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. Pts with classically radiosensitive tumors or prior or planned whole brain radiotherapy (WBRT) were excluded. ND was defined as symptomatic CNS progression around the time of death without life threatening systemic symptoms or progression. Salvage radiotherapy (RT) for LMD was categorized according to use of WBRT vs. focal cranial RT. Results: The study cohort consisted of 147 pts, of which 125 had died with known cause, 107 also received LMD salvage tx, and 82 also had cranial MRI follow-up. The ND rate in the 125 pts who died with known cause was 79%; the rate in pts who underwent LMD salvage tx (n = 107) was 76%. Univariate logistic regression demonstrated radiographic pattern of LMD (cLMD vs. nLMD, odds ratio [OR] 2.9, p = 0.04) and 2nd LMD failure after salvage tx (OR 3.9, p = 0.02) as significantly associated with ND. The ND rate was 86% for cLMD vs. 68% for nLMD pattern. WBRT was used in 95% of pts with cLMD vs. 52% of pts with nLMD. In the nLMD cohort (n = 58), there was no difference in ND rate based on type of salvage RT (WBRT: 67% vs. focal cranial RT: 68%, p = 0.92). Second LMD failure (vs. not) was associated with higher ND in the nLMD cohort (77% vs. 52%, p = 0.02). Of the 26 pts with nLMD who experienced 2nd LMD failure, 7 had classical 2nd LMD, of which 100% experienced ND, and 19 had nodular 2nd LMD, of which 68% experienced ND (p = 0.09). Conclusions: LMD after surgery and SRS for brain metastases is a clinically significant event with high rates of neurologic death. Classical LMD pattern (vs. nodular) and 2nd LMD failure after salvage tx were significantly associated with higher risk of neurologic death. In the nodular LMD cohort, radiographic pattern of 2nd LMD may be associated with risk of subsequent neurologic death. Pts with nodular LMD treated with salvage focal cranial RT or WBRT had similar risk of neurologic death. Methods to decrease LMD and the subsequent high risk of neurologic death in this setting warrant investigation.

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A multi-institutional analysis of presentation and outcomes for leptomeningeal disease recurrence after surgical resection and radiosurgery for brain metastases

Neuro-Oncology ◽

10.1093/neuonc/noz049 ◽

2019 ◽

Vol 21 (8) ◽

pp. 1049-1059 ◽

Cited By ~ 12

Author(s):

Roshan S Prabhu ◽

Brandon E Turner ◽

Anthony L Asher ◽

Samuel R Marcrom ◽

John B Fiveash ◽

...

Keyword(s):

Brain Metastases ◽

Tertiary Care ◽

Multivariable Analysis ◽

Whole Brain Radiotherapy ◽

Disease Recurrence ◽

Distinct Pattern ◽

Leptomeningeal Disease ◽

Study Cohort ◽

Brain Radiotherapy ◽

Tertiary Care Centers

Abstract Background Radiographic leptomeningeal disease (LMD) develops in up to 30% of patients following postoperative stereotactic radiosurgery (SRS) for brain metastases. However, the clinical relevancy of this finding and outcomes after various salvage treatments are not known. Methods Patients with brain metastases, of which 1 was resected and treated with adjunctive SRS, and who subsequently developed LMD were combined from 7 tertiary care centers. LMD pattern was categorized as nodular (nLMD) or classical (“sugarcoating,” cLMD). Results The study cohort was 147 patients. Most patients (60%) were symptomatic at LMD presentation, with cLMD more likely to be symptomatic than nLMD (71% vs. 51%, P = 0.01). Salvage therapy was whole brain radiotherapy (WBRT) alone (47%), SRS (27%), craniospinal radiotherapy (RT) (10%), and other (16%), with 58% receiving a WBRT-containing regimen. WBRT was associated with lower second LMD recurrence compared with focal RT (40% vs 68%, P = 0.02). Patients with nLMD had longer median overall survival (OS) than those with cLMD (8.2 vs 3.3 mo, P < 0.001). On multivariable analysis for OS, pattern of initial LMD (nodular vs classical) was significant, but type of salvage RT (WBRT vs focal) was not. Conclusions Nodular LMD is a distinct pattern of LMD associated with postoperative SRS that is less likely to be symptomatic and has better OS outcomes than classical “sugarcoating” LMD. Although focal RT demonstrated increased second LMD recurrence compared with WBRT, there was no associated OS detriment. Focal cranial RT for nLMD recurrence after surgery and SRS for brain metastases may be a reasonable alternative to WBRT.

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Tumor Progression in Patients Receiving Adjuvant Whole-Brain Radiotherapy vs Localized Radiotherapy After Surgical Resection of Brain Metastases

Neurosurgery ◽

10.1227/neu.0000000000000626 ◽

2015 ◽

Vol 76 (4) ◽

pp. 411-420 ◽

Cited By ~ 17

Author(s):

Jason Hsieh ◽

Paul Elson ◽

Balint Otvos ◽

Jonathan Rose ◽

Christopher Loftus ◽

...

Keyword(s):

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Surgical Resection ◽

Multivariable Analysis ◽

Intraoperative Radiotherapy ◽

Whole Brain Radiotherapy ◽

Leptomeningeal Disease ◽

Whole Brain ◽

Brain Radiotherapy ◽

Significant Difference

Abstract BACKGROUND: Surgery followed by adjuvant radiotherapy is a well-established treatment paradigm for brain metastases. OBJECTIVE: To examine the effect of postsurgical whole-brain radiotherapy (WBRT) or localized radiotherapy (LRT), including stereotactic radiosurgery and intraoperative radiotherapy, on the rate of recurrence both local and distal to the resection site in the treatment of brain metastases. METHODS: We retrospectively identified patients who underwent surgery for brain metastasis at the Cleveland Clinic between 2004 and 2012. Institutional review board-approved chart review was conducted, and patients who had radiation before surgery, who had nonmetastatic lesions, or who lacked postadjuvant imaging were excluded. RESULTS: The final analysis included 212 patients. One hundred fifty-six patients received WBRT, 37 received stereotactic radiosurgery only, and 19 received intraoperative radiotherapy. One hundred forty-six patients were deceased, of whom 60 (41%) died with no evidence of recurrence. Competing risks methodology was used to test the association between adjuvant modality and progression. Multivariable analysis revealed no significant difference in the rate of recurrence at the resection site (hazard ratio [HR] 1.46, P = .26) or of unresected, radiotherapy-treated lesions (HR 1.70, P = .41) for LRT vs WBRT. Patients treated with LRT had an increased hazard of the development of new lesions (HR 2.41, P < .001) and leptomeningeal disease (HR 2.45, P = .04). Median survival was 16.5 months and was not significantly different between groups. CONCLUSION: LRT as adjuvant treatment to surgical resection of brain metastases is associated with an increased rate of development of new distant metastases and leptomeningeal disease compared with WBRT, but not with recurrence at the resection site or of unresected lesions treated with radiation.

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Preoperative stereotactic radiosurgery before planned resection of brain metastases: updated analysis of efficacy and toxicity of a novel treatment paradigm

Journal of Neurosurgery ◽

10.3171/2018.7.jns181293 ◽

2019 ◽

Vol 131 (5) ◽

pp. 1387-1394 ◽

Cited By ~ 7

Author(s):

Roshan S. Prabhu ◽

Katherine R. Miller ◽

Anthony L. Asher ◽

John H. Heinzerling ◽

Benjamin J. Moeller ◽

...

Keyword(s):

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Prospective Trial ◽

Whole Brain Radiotherapy ◽

Subtotal Resection ◽

Leptomeningeal Disease ◽

Study Cohort ◽

Single Fraction ◽

Increased Risk ◽

Reduced Risk

OBJECTIVEPreoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS and may lower the risk of radiation necrosis (RN) and leptomeningeal disease (LMD) recurrence. The study goal was to report the efficacy and toxicity of preoperative SRS in an expanded patient cohort with longer follow-up period relative to prior reports.METHODSThe records for patients with brain metastases treated with preoperative SRS and planned resection were reviewed. Patients with classically radiosensitive tumors, planned adjuvant whole brain radiotherapy, or no cranial imaging at least 1 month after surgery were excluded. Preoperative SRS dose was based on lesion size and was reduced approximately 10–20% from standard dosing. Surgery generally followed within 48 hours.RESULTSThe study cohort consisted of 117 patients with 125 lesions treated with single-fraction preoperative SRS and planned resection. Of the 117 patients, 24 patients were enrolled in an initial prospective trial; the remaining 93 cases were consecutively treated patients who were retrospectively reviewed. Most patients had a single brain metastasis (70.1%); 42.7% had non–small cell lung cancer, 18.8% had breast cancer, 15.4% had melanoma, and 11.1% had renal cell carcinoma. Gross total resection was performed in 95.2% of lesions. The median time from SRS to surgery was 2 days, the median SRS dose was 15 Gy, and the median gross tumor volume was 8.3 cm3. Event cumulative incidence at 2 years was as follows: cavity local recurrence (LR), 25.1%; distant brain failure, 60.2%; LMD, 4.3%; and symptomatic RN, 4.8%. The median overall survival (OS) and 2-year OS rate were 17.2 months and 36.7%, respectively. Subtotal resection (STR, n = 6) was significantly associated with increased risk of cavity LR (hazard ratio [HR] 6.67, p = 0.008) and worsened OS (HR 2.63, p = 0.05) in multivariable analyses.CONCLUSIONSThis expanded and updated analysis confirms that single-fraction preoperative SRS confers excellent cavity local control with very low risk of RN or LMD. Preoperative SRS has several potential advantages compared to postoperative SRS, including reduced risk of RN due to smaller irradiated volume without need for cavity margin expansion and reduced risk of LMD due to sterilization of tumor cells prior to spillage at the time of surgery. Subtotal resection, though infrequent, is associated with significantly worse cavity LR and OS. Based on these results, a randomized trial of preoperative versus postoperative SRS is being designed.

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Whole brain radiotherapy after local treatment of brain metastases in melanoma patients - a randomised phase III trial

BMC Cancer ◽

10.1186/1471-2407-11-142 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 46

Author(s):

Gerald Fogarty ◽

Rachael L Morton ◽

Janette Vardy ◽

Anna K Nowak ◽

Catherine Mandel ◽

...

Keyword(s):

New Zealand ◽

Brain Metastases ◽

Local Treatment ◽

Whole Brain Radiotherapy ◽

Neurocognitive Function ◽

Cerebral Metastases ◽

Phase Iii ◽

Leptomeningeal Disease ◽

Whole Brain ◽

Brain Radiotherapy

Abstract Background Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete. Methods/Design This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function. Discussion Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000512426

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Faculty Opinions recommendation of A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717969214.793469111 ◽

2013 ◽

Author(s):

Marc Chamberlain

Keyword(s):

Quality Of Life ◽

Brain Metastases ◽

Solid Tumors ◽

Surgical Resection ◽

Whole Brain Radiotherapy ◽

Phase Iii ◽

Phase Iii Trial ◽

European Organisation ◽

Brain Radiotherapy

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Prognostic factors and survival after whole-brain radiotherapy for initial brain metastases arising from non-small cell lung cancer

Journal of Radiotherapy in Practice ◽

10.1017/s1460396921000030 ◽

2021 ◽

pp. 1-6

Author(s):

Yukinori Okada ◽

Mariko Kobayashi ◽

Mio Shinozaki ◽

Tatsuyuki Abe ◽

Naoki Nakamura

Keyword(s):

Prognostic Factors ◽

Brain Metastasis ◽

Brain Metastases ◽

Gene Mutation ◽

Stage Iv ◽

Whole Brain Radiotherapy ◽

Hazard Ratio ◽

Small Cell Lung ◽

Mutation Status ◽

Brain Radiotherapy

Abstract Aim: To identify prognostic factors and investigate patient survival after whole-brain radiotherapy (WBRT) for initial brain metastases arising from non-small cell lung cancer (NSCLC). Methods: Patients diagnosed with NSCLC between 1 January 2010 and 30 September 2019, and who received WBRT upon first developing a brain metastasis, were investigated. Overall survival was determined as related to age, sex, duration between initial examination and brain metastasis detection, stage at the first examination, presence of metastases outside the brain, blood analysis findings, brain metastasis symptoms, radiotherapy dose and completion, imaging findings, therapeutic course of chemotherapy and/or radiation therapy, histological type, and gene mutation status. Results: Thirty-one consecutive patients (20 men and 11 women) with a mean age of 63·8 years and median survival of 129 days were included. Multivariate analysis with stepwise testing was performed to investigate differences in survival according to gene mutation status, lactate dehydrogenase (LDH) level, irradiation dose, WBRT completion and Stage status. Of these, a statistically significant difference in survival was observed in patients with gene mutation status (hazard ratio: 0·31, 95% CI: 0·11–0·86, p = 0·025), LDH levels <230 vs. ≥230 IU/L (hazard ratio: 4·08, 95% CI: 1·45–11·5, p < 0·01) received 30 Gy, 30 Gy/10 fractions to 35 Gy/14 fractions, and 37·5 Gy/15 fractions (hazard ratio: 0·26, 95% CI: 0·09–0·71, p < 0·01), and stage IV versus non-stage IV (hazard ratio: 0·13, 95 CI:0·02–0·64, p < 0·01) Findings: Gene mutation, LDH, radiation dose and Stage are prognostic factors for patients with initial brain metastases who are treated with WBRT.

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A Dutch phase III randomized multicenter trial: whole brain radiotherapy vs. stereotactic radiotherapy for 4-10 brain metastases

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab021 ◽

2021 ◽

Author(s):

Dianne Hartgerink ◽

Anna Bruynzeel ◽

Danielle Eekers ◽

Ans Swinnen ◽

Coen Hurkmans ◽

...

Keyword(s):

Quality Of Life ◽

Side Effects ◽

Brain Metastases ◽

Survival Rates ◽

Whole Brain Radiotherapy ◽

Phase Iii ◽

Whole Brain ◽

Brain Radiotherapy ◽

One Year

Abstract Background The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. Methods Patients with 4 to 10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at three months post-treatment. Results The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range, 4-9) and the median total treatment volume was 13.0 cc 3 (range, 1.8-25.9 cc 3). QOL at three months decreased in the SRS group by 0.1 (SD=0.2), compared to 0.2 (SD=0.2) in the WBRT group (p=0.23). The actuarial one-year survival rates were 57% (SRS) and 31% (WBRT) (p=0.52). The actuarial one-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (p=0.22). Conclusion In patients with 4 to 10 BM, SRS alone resulted in one-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

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