Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes

doi:10.1016/j.radonc.2018.06.017

Radiotherapy and Oncology

Volume 128, Issue 2, August 2018, Pages 266-273

https://doi.org/10.1016/j.radonc.2018.06.017 Get rights and content

Abstract

Purpose

Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM).

Materials and methods

Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan–Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT + immunotherapy groups. Significance was defined as a P value ≤ 0.05.

Results

A total of 1104 patients were identified: 912 received RT alone and 192 received RT plus immunotherapy. The median follow-up time was 6.4 (0.1–56.8) months. Patients with extracranial disease (OR 1.603, 95% CI 1.146–2.243, P = 0.006), and patients receiving SRS (OR 1.955, 95% CI 1.410–2.711, P < 0.001) as compared to WBRT, had a higher likelihood of being treated with immunotherapy. The utilization of immunotherapy had nearly doubled between 2011 and 2013 (12.9–22.8%). On multivariable analysis, factors associated with superior OS were younger age, lower medical comorbidities, lack of extracranial disease, and treatment with immunotherapy and SRS. The median OS was 11.1 (8.9–13.4) months in RT plus immunotherapy vs. 6.2 (5.6–6.8) months in RT alone (P < 0.001), which remained significant after propensity score matching.

Conclusions

An increase in trend for the use of immunotherapy was noted, however, an overwhelming majority of the patients with this disease are still treated without immunotherapy. Addition of immunotherapy to RT is associated with improved OS in MBM. Given the selection biases that are inherent in this analysis, prospective trials investigating the combination of RT, especially SRS and immunotherapy are warranted.

Section snippets

Materials and methods

The NCDB is a joint project of the American Cancer Society and the American College of Surgeons Commission on Cancer. The American College of Surgeons has executed a Business Associate Agreement that includes a data use agreement with each of its Commission on Cancer accredited hospitals. The NCDB, established in 1989, is a nationwide, facility-based, comprehensive clinical surveillance resource oncology data set that currently captures 70% of all newly diagnosed malignancies in the US

Patterns of care

A total of 1104 patients were identified and used for analysis based on the previously mentioned selection criteria: 192 patients (17.4%) received RT + immunotherapy and 912 (82.6%) received RT alone (Table 1). The use of immunotherapy in this patient population has nearly doubled from 12.9% in 2011 to 22.8% in 2013 (Fig. 2A). In regard to RT technique, the majority (67.1%) patients were treated with WBRT. The rate of WBRT was found to be slowly declining while the rate of SRS was slowly

Discussion

Using the NCDB, this study shows an increasing trend in the use of immunotherapy and combination of RT + immunotherapy for the treatment of melanoma brain metastases in the modern treatment era. However, the majority of the patients are still being treated without immunotherapy or SRS. In an unselected patient population, it is observed that the addition of immunotherapy to RT for melanoma brain metastasis is associated with improved OS as compared to RT alone. Furthermore, the addition of

Conclusion

In conclusion, in this population based analysis, an increase in trend for the use of immunotherapy and specifically, SRS + immunotherapy was noted, however, an overwhelming majority of the patients with this disease were treated with WBRT and without immunotherapy. Despite the study limitations, in this large observational study, it is demonstrated that addition of immunotherapy to RT is associated with improved OS in melanoma brain metastases. This observation is even more pronounced when

Funding

None.

Conflict of interest

We have no conflict of interests to disclose for this work.

Acknowledgements

The Authors wish to acknowledge the Commission on Cancer of the American College of Surgeons and the American Cancer Society for making public data available through the National Cancer Data Base (NCDB). The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoC NCDB are the source of the de-identified data used herein; they have not verified and are not responsible

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A total of 7 therapeutic modalities for MBM were studied. Retrieval was conducted through Embase, PubMed, Cochrane Library and Web of science databases and the quality of the included literature was evaluated. Meta-analysis and Bayesian network meta-analysis were performed using Review Manager and R language.
A total of 10 articles were included with 836 MBM patients. Direct comparison showed that stereotactic radiotherapy combined with immunotherapy (SRS + IT) was superior to IT (HR = 0.66, 95%CI = 0.52–0.84) or SRS (HR = 0.81, 95%CI = 0.63–1.03) alone in improving intracranial progression-free survival (PFS). In terms of overall survival (OS), SRS + IT was superior to SRS alone (HR = 0.64, 95%CI = 0.49–0.83), or IT (HR = 0.59, 95%CI = 0.29–1.21). Rank probability and surface under the cumulative ranking curve (SUCRA) by indirect comparison showed that SRS + IT had the best effect on improving intracranial PFS (0.88) and OS (0.98). Additionally, various combination therapies, especially SRS + IT (0.72), increased the incidence of radiation necrosis (RN). In direct comparisons, SRS + IT (RR = 0.93, 95%CI = 0.47–1.83) and SRS + TT (targeted therapy) (RR = 0.24, 95%CI = 0.10–0.56) did not increase intracranial hemorrhage (ICH) compared with SRS.
SRS + IT treatment was the best choice for MBM patients in both intracranial PFS and OS, even though it also led to an increased probability of RN.
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Citation Excerpt :
Among the included publications, five13–17 scored 6 and three articles18–20 scored 7. Eight articles21–28 scored 8, and the left29 scored 9. All the studies we included except one were retrospective.
Many studies have reported the combination of radiosurgery and immune checkpoint inhibitors (ICI) in the treatment of brain metastasis, but these studies have not reached a consistent conclusion. Therefore, we conducted this systematic review and meta-analysis to evaluate the effect of combination therapy compared with radiosurgery alone on the prognosis of patients with brain metastasis. The Pubmed-MEDLINE and Ovid-EMBASE databases were comprehensively searched to identify relevant articles until May 5, 2022. The search results were filtered by the inclusion and exclusion criteria described in this paper. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were presented as estimates effect to reflect the effect of combined therapy on each outcome. A total of 17 eligible studies covering 2079 patients were included in this meta-analysis. The pooled results showed that the use of targeted drugs could significantly improve the overall survival (HR = 0.62, 95%CI: 0.51–0.76; P<0.01), reduce the risk of local recurrence (HR = 0.48, 95%CI: 0.38–0.62; P<0.01) and distant brain recurrence (HR = 0.70, 95%CI: 0.50–0.97; P<0.05). Overall, SRS combined with ICIs could significantly improve overall survival, local control, and distant brain control of patients with brain metastasis compared to SRS alone, but the effect varies for different pathological types. Our results verified the rationality of the current treatment strategy for brain metastasis which emphasizes the combination of local and systematic therapy.
Radiotherapy and Immunotherapy in Melanoma Brain Metastases
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This meta-analysis included 2498 patients from 44 studies published up to August 1, 2021 (Fig. 1). Data included patients’ demographics, treatment characteristics, OS and 1-y OS, 1-y LC, 1-y RBC, ORR, and AEs (Tables 1–3) [7,15,32-73]. A total 25 studies used SRS, 1 study employed WBRT, and 18 studies included both treatments.
Melanoma brain metastasis (MBM) generally portends a dismal prognosis. Simultaneous use of radiotherapy (RT) and immune checkpoint inhibitor (ICI) therapy demonstrated tremendous promise and emerged as the new standard. This meta-analysis was conducted to evaluate survival outcomes and toxicities of this combination in patients with MBM. Data analyses were performed using Comprehensive Meta-Analysis software (version 2) and IBM SPSS software (version 27).
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A total 44 studies involving 2498 patients were reviewed. The pooled effect size (ES) for overall survival (OS) to compare the ICI + RT arm and ICI alone arm (HR: 0.693 [0.526–0.913, p = .001]), and compare the ICI + RT arm and brain RT alone (HR: 0.595 [0.489–0.723, p < .001)] indicated better survival outcomes in ICI + RT versus RT alone and ICI alone arms. Comparing central nervous system toxicity in the ICI + RT arm and RT alone arm, the pooled ES Grade ≥ 3 neurologic adverse events (NAEs) risk ratio ([RR] = 1.425; 95% confidence interval [CI]: 0.485–4.183; p = .519) indicated that ICI + RT nonsignificantly increased Grade 3–4 NAEs. Comparing Grade ≥ 3 radiation necrosis in the ICI + RT arm and RT alone arm, the pooled ES RR (RR = 2.73; 95% CI: 0.59–12.59; p = .199) indicated that ICI + RT nonsignificantly increased Grade ≥ 3 radiation necrosis.
Concurrent administration of RT and ICI evinced favorable OS outcomes and acceptable safety profile in MBM patients. Planned prospective trials are required to demonstrate the issue.
Radiation therapy for extensive-stage small-cell lung cancer in the era of immunotherapy
2022, Cancer Letters
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Unfortunately, there is a lack of data on BRT-immunotherapy as of yet. Studies of melanoma have suggested that the addition of immunotherapy to BRT is associated with improved survival [71–73]. Retrospective studies have suggested that combining SRS with immunotherapy is safe and is associated with better intracranial disease control and favorable survival in NSCLC, melanoma, and renal cell carcinoma [74,75].
Unlike non-small-cell lung cancer (NSCLC), the progression of small-cell lung cancer (SCLC) is slow. Extensive-stage SCLC (ES-SCLC) is a serious threat to human health, with a 5-year survival rate of <7%. Chemotherapy has been the first-line treatment for the past 30 years. The anti-PD-L1 checkpoint blockades durvalumab and atezolizumab have greatly prolonged overall survival and have become the standard first-line therapy for ES-SCLC since the CASPIAN and IMpower133 trials. In the era of chemotherapy, radiation therapy (RT), including thoracic radiation therapy (TRT) and brain radiation therapy (BRT), has shown clinical effects in randomized and retrospective studies on ES-SCLC. RT-immunotherapy has shown exciting synergistic effects in NSCLC. For ES-SCLC, the clinical effects of combining TRT/BRT with immunotherapy have not yet been systematically explored. In this review, we found that studies on RT-immunotherapy in ES-SCLC are relatively few and limited to early phase studies focusing on toxicity. The efficacy and safety profiles of early phase studies encourage prospective clinical trials. In this review, we discuss the best population, optimum TRT dose, proper TRT time, and strategies for reducing radiation-induced neurotoxicity. Furthermore, we suggest that biomarkers and patient performance status should be fully assessed before RT-immunotherapy treatment. Prospective trials are needed to provide more evidence for RT-immunotherapy applications in ES-SCLC.
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View all citing articles on Scopus

View full text

ImmunoradiotherapyStereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes

Abstract

Purpose

Materials and methods

Results

Conclusions

Section snippets

Materials and methods

Patterns of care

Discussion

Conclusion

Funding

Conflict of interest

Acknowledgements

Lancet Oncol

Lancet Oncol

Lancet Oncol

Lancet Oncol

Adv Radiat Oncol

Radiother Oncol

Lancet Oncol

J Clin Epidemiol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Cell

Survival rates of patients with metastatic malignant melanoma

J Med Life

Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial

JAMA

Radiosurgery for brain metastases: changing practice patterns and disparities in the United States

J Natl Compr Canc Netw

Combined nivolumab and ipilimumab or monotherapy in untreated melanoma

N Engl J Med

Nivolumab and ipilimumab versus ipilimumab in untreated melanoma

N Engl J Med

Immunoradiotherapy
Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes