Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer

Cao, Kim; Lebas, N; Gerber, Sophie; Lévy, Christelle; Scodan, Romuald Le; Bourgier, C.; Pierga, Jean‐Yves; Gobillion, A.; Savignoni, Alexia; Kirova, Y.

doi:10.1093/annonc/mdu488

Cited by 49 publications

(31 citation statements)

References 18 publications

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“…Randomized data have demonstrated that the addition of systemic therapy to WBRT increases both extracranial and CNS toxicity [28][29][30]. In a phase III trial, patients with NSCLC brain metastases were randomized to SRS + WBRT with or without temozolomide or erlotinib [31].…”

Section: Whole-brain Radiation Therapymentioning

confidence: 99%

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies

et al. 2017

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To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS at a single tertiary-care institution from 1997 to 2015 were eligible for inclusion. The class and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1650 patients presented with 2843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6 and 5.3%, respectively (p = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7 vs. 3.7%, p = 0.04). In particular, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8 vs. 5.3%, p < 0.01). Among these therapies, significantly increased rates of RN were observed with VEGFR tyrosine kinase inhibitors (TKIs) (14.3 vs. 6.6%, p = 0.04) and EGFR TKIs (15.6 vs. 6.0%, p = 0.04). Most classes of systemic therapies may be safely delivered concurrently with SRS in the management of newly-diagnosed brain metastases. However, the rate of radiographic RN is significantly increased with the addition of concurrent systemic therapies to SRS and WBRT.

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Section: Whole-brain Radiation Therapymentioning

confidence: 99%

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies

et al. 2017

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“…69 Increased GM-CSF content of orthotopic glioma bearing murine brain is immunosuppressive by increasing MDSC 31 in a parallel fashion as liver metastases generate local MDSC accretions by GM-CSF oversecretion. 76 Radiation of breast cancer brain metastases lowers lymphocyte count 77 but it has never been clear how. Concomitant radiation and temozolomide after GB resection induce decreased circulating lymphocytes.…”

Section: Elevated G(m)-csf Is Immunosuppressive In Gbmentioning

confidence: 99%

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Kast¹,

Hill

Wion

et al. 2017

Tumour Biol.

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Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain-be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation-increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration-and European Medicines Agency-approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

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“…However, individually, only one out of 7 randomized controlled trials RCTs included in this meta-analysis showed a some survival improvement following the addition of temozolomide to radiotherapy, with median survival times of 7and 8.6 months in the RT arm and TMZ plus RT arm, respectively (15). In four randomized controlled trials that compare radiotherapy to concomitant TMZ and RT, the OS was lower in patients who were treated with combination TMZ and RT (11,(19)(20)(21) It is hard to compare the results of our study, that was performed on a homogenous group of patients ;with the previously mentioned studies which included more heterogeneous groups of patients and with different treatment regimens.…”

Section: Discussion:-mentioning

confidence: 89%

Concurrent Whole Brain Irradiation With or Without Temozolomide in Treatment of Brain Metastases From Breast Cancer.

Abdelgawad¹,

Ismail²,

Sarhan³

2017

IJAR

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Background : to evaluate the response rate , survival and safety of the combination of temozolamide and whole brain radiotherapy in breast cancer patients with previously untreated brain metastases Patients and Methods:40 patients with brain metastases were divided in two groups Control arm(A): patients received whole brain radiotherapy(WBRT) at a dose of 30 Gy in 10 daily fractions over 2 weeks. TMZ plus WBI arm (B): patients treated with (WBRT) at a dose of 30 Gy in 10 daily fractions over 2 weeks concomitant with temozolamide. The primary endpoint was overall response (OR) Secondary endpoints were progression free survival (PFS) and overall survival ( OS) Results: Patients who received WBI and TMZ had an overall response of 45% compared with 40% in WBI alone with no statistically significant difference. Brain metastasis progression was observed in 45% in the control group(A) versus 15% in group B with a statistically significant difference (p=0.038) . Median progression free survival ( PFS) was 6 months in group A but 9.5 in group B with non significant difference. One year progression free survival was 37.5% in group A versus 45% in group B . One year overall survival was 33.3% in group A versus 47.8% in group B . Median overall survival was 7 months in group A versus 11 months in group B with non-significant difference. Most of patients had tolerable side effects and recovered eventually. Conclusion: Although, the combination of WBRT and TMZ was safe and appeared to improve local control , OS and PFS of BMs from breast cancer in this study, this improvement was non-significant, and further studies with larger number of patients are needed to get significant results.

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Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer

Abstract: WBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer. CLINICALTRIALS.GOV: NCT00875355.

Cited by 49 publications

References 18 publications

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies

Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Concurrent Whole Brain Irradiation With or Without Temozolomide in Treatment of Brain Metastases From Breast Cancer.

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