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Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.

ABSTRACT: Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS).Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment of any single lesion were considered concurrent if SRS was administered within 4 weeks of immunotherapy. The impact of the timing and type of immunotherapy on the lesional response was determined with the Wilcoxon rank-sum test, which was used to compare the median percent lesion volume change 1.5, 3, and 6 months after SRS treatment, with significance determined by P?=?.0167 according to the Bonferroni correction for multiple comparisons.Concurrent use of immunotherapy and SRS resulted in a significantly greater median percent reduction in the lesion volume at 1.5 (-63.1% vs -43.2%, P?

SUBMITTER: Qian JM

PROVIDER: S-EPMC5030143 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.

Qian Jack M JM Yu James B JB Kluger Harriet M HM Chiang Veronica L S VL

Cancer 20160610 19

<h4>Background</h4>Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS).<h4>Methods</h4>Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single ...[more]

PMID: 27285122

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Project description:Introduction:Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials:All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ?4 BM were included in this institutional review board-approved, retrospective, single-institution study. Patients were treated with linear accelerator-based image guided SRS. Results:A total of 59 patients with ?4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8?cc (range, 0.7-28.8?cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20?Gy. The median of the mean dose to the total PTV was 19.5?Gy. Although the number of treated lesions (4-5 vs ?6) did not influence survival, better survival was noted for a total PTV <10?cc versus ?10?cc (7.1 vs 4.2 months, respectively; P?=?.0001). A mean dose of ?19?Gy to the entire PTV was also associated with increased survival (6.6 vs 5.0 months, respectively; P?=?.0172). Patients receiving a dose of >12?Gy to ?10?cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P?=?.0028). Conclusion:In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12?Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.

Project description:BackgroundUntil 50% of patients with renal cancer or melanoma, develop brain metastases during the course of their disease. Stereotactic radiotherapy has become a standard of care for patients with a limited number of brain metastases. Given the radioresistant nature of melanoma and renal cancer, optimization of the fractionation of stereotactic radiotherapy is needed. The purpose of this retrospective study was to elucidate if hypofractionated stereotactic radiotherapy (HFSRT) impacts local control of brain metastases from radioresistant tumors such as melanoma and renal cancer, in comparison with radiosurgery (SRS).MethodsBetween 2012 and 2016, 193 metastases, smaller than 3 cm, from patients suffering from radioresistant primaries (melanoma and renal cancer) were treated with HFSRT or SRS. The primary outcome was local progression free survival (LPFS) at 6, 12 and 18 months. Overall survival (OS) and cerebral progression free survival (CPFS) were secondary outcomes, and were evaluated per patient. Objective response rate and radionecrosis incidence were also reported. The statistical analysis included a supplementary propensity score analysis to deal with bias induced by non-randomized data.ResultsAfter a median follow-up of 7.4 months, LPFS rates at 6, 12 and 18 months for the whole population were 83, 74 and 70%, respectively. With respect to fractionation, LPFS rates at 6, 12 and 18 months were 89, 79 and 73% for the SRS group and 80, 72 and 68% for the HFSRT group. The fractionation schedule was not statistically associated with LPFS (HR = 1.39, CI95% [0.65-2.96], p = 0.38). Time from planning MRI to first irradiation session longer than 14 days was associated with a poorer local control rate. Over this time, LPFS at 12 months was reduced from 86 to 70% (p = 0.009). Radionecrosis occurred in 7.1% for HFSRT treated metastases to 9.6% to SRS treated metastases, without any difference according to fractionation (p = 0.55). The median OS was 9.6 months. Six, 12 and 18 months CPFS rates were 54, 24 and 17%, respectively.ConclusionFractionation does not decrease LPFS. Even for small radioresistant brain metastases (< 3 cm), HFSRT, with 3 or 6 fractions, leads to an excellent local control rate of 72% at 1 year with a rate of 7.1% of radionecrosis. HFSRT is a safe and efficient alternative treatment to SRS.

Project description:BackgroundStereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases.MethodsPatients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life.DiscussionCurrently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure.Trial registrationClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Project description:Abstract Background Brain metastases (BM) are the most frequent neoplasm in the central nervous system (CNS) and primary tumors frequently involved are melanoma, lung cancer and breast cancer. CNS localisation is associated with poor prognosis, and stereotactic radiosurgery (SRS) represents a treatment option for patients with a good performance status. Glutamate (Glu) is a neurotransmitter which plays a facilitating role in carcinogenesis and progression of malignant tumors, as well as in excitotoxicity. Glu efflux from the brain is regulated by scavengers glutamic oxaloacetic transaminase (GOT), glutamate-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH), with aspartate and lactate as catabolites. Glu efflux from the brain seems to be impaired in advanced-stage cancers, resulting in increased blood Glu levels where scavengers exert a protective role. Our hypothesis is that serum Glu and scavengers’ levels are related to neuroinvasion and treatment response in patients with BM and may represent potential biomarkers for BM course and prognosis. Material and Methods Serum Glu scavengers (GOT1, GPT and LDH), serum Glu, aspartate and lactate levels are collected in included patients treated and grouped in A) BM group of patients affected by BM from lung or breast cancer or melanoma, treated with SRS; B) Control-1 group of patients affected by lung cancer, breast cancer or melanoma but without BM and C) Control-2 group of patients with benign intracranial lesions (meningiomas, acoustic schwannomas) treated with SRS.In A) and C) serum metabolites and scavengers will be analyzed before and after SRS treatment (at 3, 6, 9 months) while in B) analyzed once. Blood levels in A) and C) help in identifying differences related to malignancy, the role of SRS and the association with disease control, while blood levels in A) and B) help in detecting differences related to BMs. Exclusion criteria are surgical or previous radiosurgical treatment for BM. This study has received Institutional Ethical Committee approval on 3rd August 2020 (Project NCH04-2020, Clinicaltrials.gov identifier: NCT04785521). Preliminary results Comparison between BM group (n = 32) and Control-1 (n=18) revealed a significant difference in LDH (271.93 vs 217.56 U/L; p 0.041) and lactate (1.86 vs 1.34 mmol/L, p = 0.022) and a trend towards significance in glutamate (103.43 vs 73.74 µmol/L, p = 0.07). Comparison between BM group (n=32) and Control-2 (n = 37) revealed a difference in LDH (271.93 vs 210.89 U/L; p < 0.001), lactate (1.86 vs 1.24 mmol/L; p < 0.001), aspartate (16.36 vs 10.22 µmol/L, p 0.006) and glutamate levels (123 vs 103 µmol/L, p = 0.052). Conclusion The present study is the first one addressing serum glutamate and scavenger levels in patients with BM. If the hypothesis will be confirmed, new targets in glutamate signalling pathway could be identified to define new therapeutic strategies in this challenging disease.

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Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.

Publications

Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.

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