Concurrent Whole Brain Radiotherapy Research Articles

Anlotinib combined with whole-brain radiotherapy in non-small cell lung cancer with multiple brain metastases that progressed or developed after at least one lines of prior treatment.

Intracranial metastasis that failed standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with whole-brain radiotherapy (WBRT) for NSCLC with brain metastases (BMs) that progressed or developed after at least one line of prior treatment and compare the outcomes with that of the contemporary institutional control. NSCLC patients with multiple BMs that progressed or developed after at least one line of prior systematic treatment and treated with WBRT subsequently between 2019 and 2021 were selected retrospectively for analysis. Based on whether concurrent anlotinib had been used in combination with WBRT, the cases were divided into the anlotinib group and control group. The primary endpoints were intracranial progression-free survival (iPFS) and safety. A total of 76 patients met the inclusion criteria of the study. Of the 76 patients, 34 received concurrent WBRT and anlotinib followed by anlotinib maintenance and 42 were treated with WBRT alone or in combination with other systemic agents at the physicians' discretion. The median follow-up for the entire cohort was 21 months. The median iPFS for the anlotinib and control group was 6.7 months (95% CI, 4.6-9.9) and 5.3 months (95% CI, 4.0-6.5), respectively (log-rank P = 0.04). There was no difference in overall survival between the two groups (log-rank P = 0.38). In the anlotinib group, treatment-related adverse events were reported in 15 patients (44.1%), with acute or late grade 3-5 adverse events identified in 14.7% of patients (n = 5). WBRT plus anlotinib, as a convenient chemo-free regimen, may represent an overall safe and effective procedure in advanced NSCLC with multiple BMs that progressed or developed after standard systematic treatment.

Anti-PD1 Therapy Plus Whole-Brain Radiation Therapy May Prolong PFS in Selected Non-Small Cell Lung Cancer Patients with Brain Metastases: A Retrospective Study.

BackgroundWhole-brain radiotherapy (WBRT) remains an essential modality of treatment for brain metastases (BMs) derived from non-small cell lung cancer (NSCLC) patients and anti-PD-1 therapy has demonstrated intracranial responses in these patients. We aimed to evaluate if the combination of the two treatments could yield additive efficacy.MethodsA retrospective review of our institution’s database was carried out to identify NSCLC patients with BMs who had been treated with anti-PD1 therapy and/or WBRT between 2015 and 2020. Patient characteristics, main outcomes, including progression-free survival (PFS) and overall survival (OS), and factors affecting these outcomes were analyzed. SPSS 24 was used for statistical analysis. Appropriate statistical tests were employed according to the type of data.ResultsOverall, 21 NSCLC BM patients were identified that had received WBRT. Of these, ten had been additionally treated with anti-PD1 therapy within 30 days of WBRT initiation. Median PFS was 3 (95% CI 0.8–5.1) months with WBRT alone versus 11 (95% CI 6.3–15.6) months with combined treatment. Risk of disease progression was 71% lower with the combined approach (HR 0.29, 95% CI 0.11–0.80; p=0.016). A trend toward improved OS was also observed with the combined approach (HR 0.33, 95% CI 0.08–1.12; p=0.107). Concurrent treatment (p=0.028) and male sex (p=0.052) were associated with improved PFS, while OS was associated only with age (p=0.02).ConclusionConcurrent WBRT and anti-PD1 therapy may delay progression and improve survival in BM patients with confirmed EGFR- and ALK-negative NSCLC histology. Prospective studies are warranted to validate and elucidate on the additive effect of the two modalities.

Anlotinib in Combination With Whole Brain Radiotherapy for Advanced Non-Small-Cell Lung Cancer With Brain Metastases Progressive or Developed After at Least One Lines of Prior Treatment

Intracranial metastasis failed to standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. Post Hoc analysis of a phase III randomized control trial (ALTER0303) has demonstrated that anlotinib can benefit patients with advanced NSCLC with brain metastases (BM) and is highly potent in the management of intracranial lesions. Here we report results of a comparative analysis of survival in patients with NSCLC with BM receiving whole brain radiotherapy (WBRT) with and without anlotinib, for whom intracranial disease had progressed or developed after at least one lines of prior systematic therapy.From 2019 to 2020, a total of 96 patients of NSCLC in our institution with BM failed to at least one lines of systematic treatment met inclusion criteria for the study. Patients were treated with concurrent anlotinib and WBRT followed by anlotinib consolidation (an-WBRT group) or WBRT with other regimens at the discretion of the treating physician (WBRT group) at intracranial progression. Overall survival (OS) and intracranial progression-free survival (iPFS) were measured from the date of brain progression.The median lines of prior therapy are both 2 for an-WBRT and WBRT groups. The median OS for the an-WBRT (n = 26) and WBRT (n = 70) cohorts was 12.8 and 14.3 months, respectively (P = 0.82). The an-WBRT group has a longer iPFS than WBRT group (HR, 0.33; 95% CI, 0.21-0.65), with median iPFS of 8.1 months and 4.0 months respectively.This retrospective analysis demonstrated that the combination of anlotinib and WBRT is associated with better iPFS than WBRT in NSCLC patients with intracranial metastasis failed to standard systematic treatment. Randomized, prospective studies are needed to further validate these findings.C. Kong: None. X. Zhu: None. M. Jiang: None. X. Song: None. P. Qian: None. J. Zhu: None. J. Xu: None. X. He: None.

Stereotactic Radiosurgery to More Than 10 Brain Metastases: Evidence to Support the Role of Radiosurgery for Ideal Hippocampal Sparing in the Treatment of Multiple Brain Metastases

Brain metastases are a common occurrence, with literature supporting the treatment of a limited number of brain metastases with stereotactic radiosurgery (SRS), as opposed to whole brain radiotherapy (WBRT). Less well understood is the role of SRS in patients with ≥10 brain metastases. Patients treated with SRS to ≥10 brain metastases without concurrent WBRT between March 1999 and December 2016 were reviewed. Analysis was performed for overall survival, treated lesion freedom from progression (FFP), freedom from new metastases (FFNMs), and adverse radiation effect. Hippocampal volumes were retrospectively generated in patients treated with up-front SRS for evaluation of dose volume metrics. A total of 143 patients were identified with 75 patients having up-front SRS and 68 patients being treated as salvage therapy after prior WBRT. The median number of lesions per patient was 13 (interquartile range [IQR], 11-17). Median total volume of treatment was 4.1 cm3 (IQR, 2.0-9.9 cm3). The median 12-month FFP for up-front and salvage treatment was 96.8% (95% confidence interval [CI], 95.5-98.1) and 83.6% (95% CI, 79.9-87.5), respectively (P < 0.001). Twelve-month FFNMs for up-front and salvage SRS was 18.8% (95% CI, 10.9-32.3) versus 19.2% (95% CI, 9.7-37.8), respectively (P= 0.90). The mean hippocampal dose was 150 cGy (IQR, 100-202 cGy). Excellent rates of local control can be achieved when treating patients with >10 intracranial metastases either in the up-front or salvage setting. Hippocampal sparing is readily achievable with expected high rates of new metastatic lesions in treated patients.

CMET-08. CEREBROSPINAL FLUID CARCINOEMBRYONIC ANTIGEN PREDICT PROGNOSIS IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicopathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.

1563P - Carcinoembryonic antigen of cerebrospinal fluid predict prognosis of leptomeningeal metastasis from non-small cell lung cancer

BackgroundLeptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. MethodsSeventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. ResultsMedian KPS at diagnosis of LM were 60 (range, 20-90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (>50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. ConclusionsMedian overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Phase I Study of Trametinib in Combination with Whole-Brain Radiation Therapy for Brain Metastases

Trametinib is an oral reversible, highly selective inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and 2, and preclinical data suggests that trametinib can radiosensitize tumor cells. We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of trametinib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases (BM). After confirmation of intracranial BM, patients were treated with trametinib and WBRT to a dose of 37.5 Gy in 15 fractions. Trametinib was given starting day -6 (7 total doses), followed by WBRT starting on day 1, and trametinib was given concurrently with radiation (7 days per week). The starting dose of trametinib was 1 mg and was escalated in a standard 3+3 fashion, to 1.5 mg and 2 mg. The primary endpoint was to determine the MTD of trametinib to be used in combination with WBRT. Secondary objectives included evaluation of tolerability and feasibility of WBRT + trametinib, objective response (RECIST criteria), neurologic progression-free survival (nPFS), and overall survival (OS). Characteristics of the 10 patients enrolled 2014-2016 were: mean age, 55 yrs; median BM, 5 (range 1 to >10); histologies were melanoma (n=5), breast (n=2), colorectal (n=1), esophageal adenocarcinoma (n=1) and eccrine carcinoma (n=1). Treatment involved WBRT 37.5 Gy in 10 fractions (n=9) and 30 Gy in 10 fractions (n=1). Dose level 1 was trametinib 1 mg (n=3), and level 2 was trametinib 1.5 mg (n=7). 1 patient withdrew consent in dose level 2. There were 39 Grade 1-2 toxicities and there were 13 Grade 3-4 toxicities. 1 patient experienced a grade 2 seizure during treatment, but no other reported neurotoxicities. 2 patients in dose level 2 experienced a DLT: grade 4 thrombocytopenia and grade 3 diarrhea. 1 patient experienced grade 4 elevation of hepatic enzymes, which was not a pre-defined DLT. 5 patients experienced ten grade 3 toxicities: lymphopenia, thrombocytopenia, diarrhea, fatigue, dehydration, nausea/vomiting, hyperglycemia, dyspnea, hyponatremia, and elevated troponin. The trial failed to accrue the 3 additional patients in dose level 1 and was closed early due to slow accrual. Median follow-up time from on treatment date to off-study date was 2.2 months. Median OS was 2.2 months. The median nPFS was 1.5 months. Objective response was measured in 6 patients as 4 did not live to complete follow up imaging. Of these 6, only 2 demonstrated a partial response to treatment. Trametinib failed to show a signal for response with concurrent WBRT, but survival in our cohort was worse than expected. The MTD is less than 1.5 mg. Concurrent use of WBRT with 1 mg of trametinib demonstrated safety in 3 patients; however, the trial was closed early due to slow accrual. Shifting patterns of practice contributed to slow accrual, particularly increased utilization of stereotactic radiosurgery (SRS). Future studies may attempt to ascertain the MTD in healthier individuals using SRS.

MLTI-02. A PHASE I TRIAL OF SORAFENIB WITH WHOLE BRAIN RADIOTHERAPY (WBRT) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES AND A CORRELATIVE FLT-PET BRAIN IMAGING STUDY IN PATIENTS RECEIVING WBRT +/- SORAFENIB

BACKGROUND: Sorafenib has demonstrated anti-tumor efficacy in breast cancer and radiosensitizing activity preclinically. [18F] 3’deoxy-3’-fluorothymidine (FLT) is a PET tracer which correlates with cellular proliferation and may improve response assessment. METHODS: A phase I trial of whole brain radiotherapy (WBRT)+sorafenib was conducted using a 3 + 3 design. Sorafenib was given daily at the start of WBRT for 21 days (dose levels: 200mg, 400mg, and 600mg). The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment. A correlative serial FLT-PET imaging study was conducted to assess radiographic changes among pts receiving WBRT +/- sorafenib, in parallel with MRI. RESULTS:13 pts in the dose escalation were evaluable for dose-limiting toxicity (DLT). DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was 200mg. Six additional pts were treated in an expansion cohort without additional DLT. 14 pts were evaluable for response. The overall response rate was 71%: 4 complete + 6 partial responses. Median follow up was 14 months (range: 3–44). Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT+sorafenib and 5 WBRT) were enrolled in the FLT-PET study: all had baseline FLT-PET, 14 with follow up at 7–10 days post WBRT (FU1), and 9 with followup at 12 weeks post WBRT (FU2). 55 baseline lesions were observed and analyzed: 38 at FU1 and 15 at FU2. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib pts and 2/4 (50%) of WBRT only pts at FU1. CONCLUSIONS: Concurrent WBRT+sorafenib appears safe at 200mg daily dose with clinical activity. This combination should be considered for further efficacy evaluation. NCT01724606 and NCT01621906.

LPTO-07. CARCINOEMBRYONIC ANTIGEN OF CEREBROSPINAL FLUID PREDICT PROGNOSIS OF LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER

BACKGROUND: Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS: Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS: Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION: Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.

Comparing the efficacy of concurrent EGFR-TKI and whole-brain radiotherapy vs EGFR-TKI alone as a first-line therapy for advanced EGFR-mutated non-small-cell lung cancer with brain metastases: a retrospective cohort study.

BackgroundNon-small-cell lung cancer (NSCLC) is a global public health problem, and brain is a common metastatic site in advanced NSCLC. Currently, whole-brain radiotherapy (WBRT) remains a major treatment for brain metastases, while EGFR-tyrosine kinase inhibitor (TKI) is the standard treatment for advanced NSCLC harboring EGFR mutations, which is also effective for brain metastases. However, whether EGFR-TKIs plus radiotherapy is superior to EGFR-TKIs alone for the treatment of advanced EGFR-mutant NSCLS with brain metastases remains controversial. This study aimed to compare the efficacy of concurrent EGFR-TKIs and WBRT vs EGFR-TKI alone in a retrospective cohort of advanced EGFR-mutant NSCLS with brain metastases.Patients and methodsThe medical records of 104 treatment-naïve, advanced EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed, and there were 56 patients undergoing concurrent EGFR-TKI and WBRT, and 48 patients given EGFR-TKI alone, including 20 cases with salvage WBRT upon brain metastasis progression. The survival prognosis was compared between the two cohorts.ResultsThe baseline clinicopathologic factors were balanced between the two cohorts. After a median follow-up of 23 months, 35.6% of the study subjects survived. Concurrent EGFR-TKI and WBRT significantly improved the median intracranial PFS (iPFS) compared with EGFR-TKI alone (17.7 vs 11.0 months, P=0.015); however, no significant difference was seen in median overall survival between the two cohorts (28.1 vs 24.0 months, P=0.756). In addition, the median iPFS was found to significantly vary in the number of brain metastases (≤3 vs>3 metastases: 18.0 vs 12.5 months, P=0.044). Subgroup analysis showed that concurrent EGFR-TKI and WBRT improved median iPFS compared with EGFR-TKI alone in patients with more than three brain metastases (P=0.001); however, no significant difference was observed between the two regimens in patients with three or less brain metastases (P=0.526).ConclusionOur data demonstrate that concurrent EGFR-TKI and WBRT achieves longer iPFS than EGFR-TKI alone in advanced EGFR-mutant NSCLC with brain metastases. In advanced EGFR-mutant NSCLC with three or less brain metastases, EGFR-TKI alone may be an option as a first-line therapy.

Abstract P1-19-03: A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib

Abstract Background: WBRT is a standard therapy for metastatic breast cancer (MBC) patients (pts) with brain metastases (BM), but disease progression in the brain is common. Sorafenib, a tyrosine kinase inhibitor with anti-VEGF activity, has demonstrated anti-tumor efficacy in MBC and radiosensitizing activity preclinically. [18F] 3'deoxy-3'-fluorothymidine (FLT) is a new PET tracer which correlates with cellular proliferation and may improve response assessment in the brain. Methods: A phase I trial of sorafenib with WBRT in MBC pts with BM was conducted using a 3+3 design. Sorafenib was given orally daily at the start of WBRT for a total of 21 days with 3 doses levels: 200mg, 400mg, and 600mg. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was central nervous system progression-free survival (CNS-PFS). Macdonald Criteria were used for response assessment with serial MRI brain imaging. Key eligibility criteria include MBC with new or progressive ≥ 1cm BM, ECOG PS 0-2, non-escalating corticosteroid dose, and no other concurrent anti-tumor therapy except trastuzumab. In parallel, we conducted a correlative FLT-PET imaging study (baseline, 7-10 days (FU1), and 10-12 weeks (FU2) after the WBRT) to assess radiographic changes among pts receiving WBRT + sorafenib and in a separate WBRT only cohort. FLT standard uptake value (SUV) and kinetic parameter data were obtained. Results: 13 pts were treated in the dose escalation phase and evaluable for dose-limiting toxicity (DLT). The median age was 56 years (range: 43-77). There were 4 HER2 positive (31%) and 3 triple negative (23%) pts. 2 pts had prior stereotactic radiosurgery. DLTs were: Grade (G) 4 increased lipase at 200mg (1 pt) and G3 rash at 400mg (3 pts) level. MTD was determined to be 200mg. 10 pts were evaluable for response (at least 1 follow up brain imaging). The overall response rate was 70%: 4 complete responses (CR) + 3 partial responses. All 13 pts were evaluated for CNS PFS with a median follow up of 29.7 months (min 19.6, max 57.4mo). Median CNS-PFS was 8.2 months (95%CI: 3.4-31.8). Median OS was 15.4 months (95% CI: 3.4-NR). A total of 10 pts with WBRT and sorafenib and 5 pts with WBRT only were enrolled in the FLT-PET study: all 15 pts had baseline FLT PET, 14 with FU1, and 9 with FU2. 55 baseline lesions, 38 at FU1 and 15 at FU2 were observed and analyzed. All lesions with FLT uptake had MRI correlates. Decline in average SUVmax of ≥25% was seen in 9/10 (90%) of WBRT+sorafenib and 2/4(50%) of WBRT only pts at FU1. A complete disappearance of FLT uptake was noted in 1 pt at FU1 and 2 more pts at FU2. Conclusions: Concurrent WBRT with sorafenib appears safe at 200mg daily dose with a higher rate of CR compared to historical WBRT data. We are currently enrolling patients in the safety-expansion cohort. This combination should be considered for further efficacy evaluation. Additional analysis of FLT-PET as a complementary imaging modality to MRI is currently ongoing. Clinical trial registry: NCT01724606 and NCT01621906. Support: Bayer, Susan G Komen, ASCO Gianni Bonadonna Breast Cancer Award Citation Format: Morikawa A, Jhaveri K, Grkovski M, Tang K, Humm JL, Holodny A, Beal K, Schoder H, Seidman AD. A phase I trial of sorafenib with whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases and a correlative study of FLT-PET brain imaging in patients receiving WBRT with or without sorafenib [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-03.

Clinical efficacy of erlotinib combined with concurrent whole brain radiotherapy in treatment of multiple brain metastases from EGFR-mutant lung adenocarcinoma

Objective To investigate the clinical efficacy and safety of erlotinib combined with concurrent whole brain radiotherapy (WBRT) in the treatment of multiple brain metastases from lung adenocarcinoma, and to provide objective evidence for improving the prognosis of patients. Methods Eighty-nine patients with brain metastases from epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who were admitted to our hospital were divided into experimental group (n=45) and control group (n=44) according to the different treatment methods. The experimental group received erlotinib combined with concurrent WBRT. The control group received oral administration of erlotinib alone for 28 d and then received concurrent WBRT. The survival rates were calculated using the Kaplan-Meier method and analyzed using the log-rank test. The other data were analyzed by the chi-square test. Results The objective response rate was significantly higher in the experimental group than in the control group (78% vs. 55%, P=0.000). The median progression-free survival (PFS) time in the experimental group and the control group were 9.1 months (95% confidence interval[CI]: 5.18-12.47) and 5.6 months (95%CI: 3.46-9.12), respectively (P=0.078). The median overall survival (OS) time in the experimental group and the control group were 14.3 months (95%CI: 9.51-17.82) and 9.7 months (95%CI: 4.59-16.74), respectively (P=0.032). The incidence rates of headache and dizziness were significantly higher in the experimental group than in the control group (38% vs. 14%, P=0.029; 33% vs. 9%, P=0.020). Conclusions In the treatment of multiple brain metastases from EGFR-mutant lung adenocarcinoma, erlotinib combined with concurrent WBRT is superior to erlotinib alone. The combination therapy increases PFS and OS time of the nervous system in patients. Key words: Neoplasms metastasis, brain/radiotherapy; Neoplasms metastasis, brain/targeted therapy; Treatment outcome

Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: a systematic review and meta-analysis.

Brain metastasis is the leading cause of death among advanced non-small cell lung cancer (NSCLC) and breast cancer patients. The standard treatment for brain metastases is radiotherapy. The combination of radiotherapy and chemotherapy has been tested. However, the management of brain metastases has yet to be successful. Here, we aimed to determine the efficacy and safety of whole brain radiotherapy (WBRT) alone or in combination with temozolomide (TMZ) in NSCLC and breast cancer patients with brain metastases. A systematic review of PubMed, CNKI (China National Knowledge Infrastructure) and WANFANG (WANGFANG data) involving 870 patients were conducted. Fourteen randomized controlled trials (RCTs) were independently identified by two reviewers. The primary outcome measures were objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity. The ORR was better with combination therapy of WBRT and TMZ than with WBRT alone (RR = 1.34, p < 0.00001) and subgroup analysis showed a significantly superior ORR in NSCLC patients (RR = 1.38, p < 0.00001), but not in breast cancer patients (RR = 1.03, p = 0.86). OS and PFS did not significantly differ between combination therapy and WBRT alone. A higher rate of toxicity was observed in combination therapy than in WBRT alone (RR = 1.83, p = 0.0006). No advantages of concurrent WBRT and TMZ were observed in breast cancer patients with brain metastases. Combination therapy was associated with improved ORR in NSCLC patients, especially in Chinese patients. As a "surrogate endpoint" for OS, ORR may allow a conclusion to be made about the management of NSCLC with brain metastases with the combination of WBRT and TMZ. However, it needs to be validated to show that improved ORR predicts the treatment effects on the clinical benefit. The ORR may be valid for a particular indication such as status of MGMT promoter methylation.

Radiotherapy for cranial and brain metastases from prostate cancer: a systematic review.

Intracranial metastasis from prostate cancer is rare. As treatment of castration-resistant prostate cancer improves, the incidence of men with intracranial metastasis from prostate cancer is increasing. Radiation therapy for treatment of intracranial metastasis from prostate cancer is systematically reviewed. A comprehensive review examining peer-reviewed, English language articles from 1990 to 2015 was performed on multiple databases, yielding 1274 articles. These articles were reviewed and selected for studies that met the following inclusion criteria: (1) patients with intracranial metastases from prostate cancer; (2) patients underwent radiation therapy as primary or adjuvant therapy; (3) the sample size of patients was larger than 2. All studies that met inclusion criteria utilized whole-brain radiation therapy (WBRT) in at least one patient. Other treatment regimens included stereotactic radiosurgery (SRS), surgical resection followed by WBRT, as well as concurrent cabazitaxel and WBRT. The range of average time from initial diagnosis of prostate cancer to diagnosis of brain metastasis was 29-45 months. The range of reported median survival time after WBRT was 4-9 months, whereas median survivals after SRS ranged from 9 to 13 months. Intracranial metastases from prostate cancer occur late in the disease process, and are increasing as novel therapies for metastatic disease prolong survival. The reviewed literature suggests that outcomes of patients with prostate cancer intracranial metastases appear similar to those of intracranial metastases from other histologies. Prospective examinations of systemic therapies that cross the blood-brain barrier in conjunction with targeted radiotherapy appear warranted for this increasingly common clinical problem.

P2.05-030 WBRT Prior EGFR TKIs is Effective Treatment Option for NSCLC Patients with CNS Metastases Harboring EGFR Mutation: Topic: Multimodality Treatment

Central nervous system (CNS) metastases are considered as a common cause of morbidity and mortality in advanced non-small-cell lung cancer (NSCLC). It is estimated that 20–40% of NSCLC develop CNS metastases during their disease course. Sensitivity of chemotherapy is limited in CNS metastases of NSCLC, because of restrict transit function of blood-brain barrier. The main treatment options based on whole brain radiation therapy (WBRT), stereotactic radiosurgery, neurosurgery or combination of them. Median overall survival (mOS) achieved in NSCLC with CNS metastases treated with irradiation methods is 6.5-7.5 months. Introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) – gefitinib, erlotinib, afatinib – improved the treatment possibilities in selected group of NSCLC patients harboring EGFR gene mutations. Also CNS metastatic lesions of NSCLC showed sensitivity to EGFR-TKIs (mOS to 15-17 months). Moreover, concurrent EGFR TKIs and WBRT may be used synergistic because potentially improve survival and delays intracranial progression. The main aim of the study was evaluation weather implementation of WBRT prior EGFR TKIs in NSCLC patients with CNS metastases might influence on their survival in comparison to patients without CNS metastases treated with EGFR TKIs monotherapy. The studied group included 178 NSCLC patients harboring EGFR gene mutation. 160 (110 female, 50 male; median age 67 years) patients with primary NSCLC received EGFR TKIs in first or second line of treatment. 18 patients (16 female, 2 male; median age 69 years), who had diagnosed CNS metastases, received WBRT prior administration of EGFR TKIs. The treatment response was showed in both studied group. We did not observe a significant difference in survival in both studied groups. The progression free survival (PFS) in patients with primary NSCLC treated with EGFR TKIs and in patients with CNS lesions treated with WBRT prior EGFR TKIs was 10 vs. 9 months (p=0.785; HR=1.07; 95% CI=0,618-1.866), respectively. Also mOS did not show significance discrepancies in both studied group (26 vs. 32 months, respectively; p=0.32; HR=0.639; 95% CI=0.301-1.356). Implementation of WBRT prior TKIs did not lead to additional neurotoxicity. The following study showed that combination of WBRT prior TKIs in NSCLC patients with CNS metastases achieves similar benefit like treatment of primary NSCLC (without CNS metastases) with EGFR TKIs monotherapy. Based on overall data, patients with CNS metastases achieved better response rate when EGFR TKIs are administrated prior WBRT. It may be caused by EGFR TKIs feature which possess CNS penetrability for radiation.

Role of Gamma Knife® Radiosurgery for the Treatment of Brain Metastases from Gynecological Cancers.

Objective: Gamma Knife® (GK) (Elekta Instruments, Stockholm, Sweden) radiosurgery is well established for treatment of brain metastases. There are limited data on patients treated with GK from gynecological cancers. The authors sought to determine the effectiveness of the GK in patients with brain metastases from gynecological cancers.Methods: An IRB-approved database was queried for patients with gynecologic cancers treated with GK between June 1996 and May 2016. Imaging studies were reviewed post-SRS (stereotactic radiosurgery) to evaluate local control (LC) and distant brain control (DC). Overall survival (OS), local control, and distant brain control were calculated using the Kaplan-Meier (KM) method and log-rank test. Results: Thirty-three patients underwent SRS for 73 separate cranial lesions. The median age was ­58.5 years, and 17 (52%) also had extracranial metastases. Ten (30%) patients had previously received whole brain radiotherapy (WBRT), and 11 (33%) underwent concurrent WBRT. The median tumor volume was 0.96 cm3. Median radiographic follow-up was 11 months. At the time of treatment, 39% of patients were categorized as recursive partitioning analysis (RPA) Class I, 55% as RPA Class II, and 6% as RPA Class III. The local failure rate was 8%. Five patients (15%) developed new brain lesions outside the radiation field with a median progression-free survival (PFS) of seven (range: 3-9) months. Median OS was 15 months from GK treatment. One-year OS was 72.9% from GK treatment. Primary cancer histology was a significant predictor of OS, favoring ovarian and endometrial cancer (p = 0.03).Conclusions: Gamma Knife stereotactic radiosurgery for gynecologic brain metastases leads to excellent control rates of treated lesions. Primary histology may have a significant impact on OS following GK, with improved survival seen with ovarian and cervical cancer following Gamma Knife radiosurgery (p = 0.03).

Erlotinib plus concurrent whole-brain radiation therapy for non-small cell lung cancers patients with multiple brain metastases.

Sequencing of the epidermal growth factor receptor (EGFR) gene to identify mutations in lung adenocarcinomas is routine in clinical practice. The use of tyrosine kinase inhibitors (TKIs) has transformed the management of patients with brain metastases harboring EGFR mutations, with improved response rates (RR) and survival. We evaluate the role of concurrent TKI therapy and radiotherapy in this group of patients, considering this data in the context of emerging concepts in this advancing field.

Clinical research on systemic chemotherapy concurrent whole brain radiotherapy for brain metastases from non-small cell lung cancer

Objective To explore the feasibility and safety of systemic chemotherapy concurrent whole brain radiotherapy (WBRT) for non-small cell lung cancer (NSCLC) with brain metastases. Methods Eighty cases of NSCLC patients with brain metastases were divided into observation group (40 cases) and the control group (40 cases) according to random number table. Patients were given systemic chemotherapy synchronous WBRT or sequential WBRT. Results The Ⅰ-Ⅳ degree leukocytopenia incidences of the two groups were 12.5%, 25.0%, 25.0%, 0.0 and 30.0%, 25.0%, 12.5%, 15.0%, and there was statistical significance (χ2=12.12, P 0.05). The median progression free survival of the observation group and of the control group were (3.5±2.3) months and (3.6±1.1) months, respec-tively, with no significant difference (t=5.23, P>0.05). But the 1-years survival rate in the observation group was 37.5% (15/40), significantly higher than that in the control group (17.5%, 7/40), which had statistical significance (χ2=9.11, P<0.05). Conclusion The safety of systemic chemotherapy synchronous WBRT for NSCLC patients with brain metastases is higher, with good curative effect and strong application feasibility. Key words: Carcinoma, non-small-cell lung; Neoplasm metastasis; Drug therapy; Whole brain radiotherapy

Whole brain radiotherapy plus concurrent chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis.

ObjectiveThe aim of the present meta-analysis is to evaluate the response rate, median survival time (MST) and toxicity in patients with brain metastases (BM) originating from non-small cell lung cancer (NSCLC) and who were treated using either whole brain radiotherapy (WBRT) plus concurrent chemotherapy or WBRT alone.MethodsPubMed, EMBASE, Web of Science, The Cochrane Library, clinical trials and current controlled trials were searched to identify any relevant publications. After screening the literature and undertaking quality assessment and data extraction, the meta-analysis was performed using Stata11.0 software.ResultsIn total, six randomized controlled trials (RCT) involving 910 participants were included in the meta-analysis. The results of the analysis indicate that WBRT plus concurrent chemotherapy was more effective at improving response rate (RR = 2.06, 95% CI [1.13, 3.77]; P = 0.019) than WBRT alone. However, WBRT plus concurrent chemotherapy did not improve median survival time (MST) (HR = 1.09, 95%CI [0.94, 1.26]; P = 0.233) or time of neurological progression (CNS-TTP) (HR = 0.93, 95%CI [0.75, 1.16]; P = 0.543), and increased adverse events (Grade≥3) (RR = 2.59, 95% CI [1.88, 3.58]; P = 0.000). There were no significant differences in Grade 3–5 neurological or hematological toxicity between two patient groups (RR = 1.08, 95%CI [0.23, 5.1]; P = 0.92).ConclusionThe combination of chemotherapy plus WBRT in patients with BM originating from NSCLC may increase treatment response rates of brain metastases with limited toxicity. Although the therapy schedule did not prolong MST or CNS-TTP, further assessment is warranted.

Ipilimumab and whole brain radiation therapy for melanoma brain metastases.

Brain metastases (BM) frequently develop in patients with melanoma and are associated with a poor prognosis. Whole brain radiation therapy (WBRT) is a standard intervention for intracranial disease, particularly in patients with multiple BM. Ipilimumab improves survival in patients with advanced melanoma. The purpose of this study is to investigate the safety and efficacy of concurrent WBRT and ipilimumab. A retrospective analysis was conducted of 13 consecutive patients treated with WBRT within 30 days of ipilimumab administration. Radiographic response, as measured by serial magnetic resonance imaging scans post-treatment, was graded by modified World Health Organization (mWHO) and immune-related response criteria (irRC) in the 9 patients with follow-up imaging. Treatment-related toxicity was prospectively assessed during treatment. Four of nine patients (44 %) experienced partial response or stable central nervous system (CNS) disease as measured by mWHO criteria. This number increased to 5 patients (56 %) when irRC criteria were used. Rates of treatment-related neurologic toxicity were low with only one patient experiencing grade 3-4 neurologic toxicity. There was a high rate of intratumoral hemorrhage in this patient population, with 10 of 10 patients with post-treatment imaging demonstrating new or increased intratumoral bleeding after WBRT. This retrospective study demonstrates that the primary pattern of CNS response to WBRT and ipilimumab is stable disease and not regression of BM. Furthermore, while the combination of WBRT and ipilimumab may offer promising efficacy, prospective studies are needed to further assess efficacy and toxicity.