Role of stereotactic radiosurgery for the treatment of brain metastasis in the era of immunotherapy: A systematic review on current evidences and predicting factors

https://doi.org/10.1016/j.critrevonc.2021.103431Get rights and content

Highlights

  • SRS and IT are increasingly used in melanoma and non-small cell lung cancer (NSCLC) brain metastases (BM).

  • A systematic review on current evidences up to December 2020 was performed.

  • SRS-IT combination resulted in a significant improvement in survival and lesion response.

  • SRS-IT combination did not lead to increase in radionecrosis, hemorrhage or other complications.

  • SRS-IT combination is safe and effective in providing a significant improvement in relevant clinical and radiological outcomes.

Abstract

Stereotactic radiosurgery (SRS) in combination with immunotherapy (IT) is increasingly used in the setting of melanoma and non-small cell lung cancer (NSCLC) brain metastases (BM). The synergistic properties of this treatment combination are still not deeply understood. IT-SRS appropriate combination has been envisioned as a strategic point in patients’ management.

Authors performed a systematic review on current evidences up to December 2020. The impact of SRS-IT and different IT schedules on survival, local/distant intracranial control and toxicity, as well as predictive factors for relevant oncological and radiological outcomes has been analyzed.

Authors retrieved 23 pertinent studies. Combining SRS with IT resulted in a significant improvement in OS and lesion response with no increase in radionecrosis, hemorrhage or other complications.

The present review suggests that combining IT to SRS is safe and effective in providing a significant improvement in relevant clinical and radiological outcomes in melanoma and NSCLC BMs patients.

Introduction

Brain metastases (BMs) are the most frequent malignancies of the central nervous system, representing a common complication of solid tumors (Pekmezci and Perry, 2013). Lung cancer and melanoma, together with breast cancer, are indeed the most frequent primary tumors that metastasize to the brain, accounting for 67–80% of BM (Nayak et al., 2012).

Historically, before the “era of immunotherapy”, specific BMs management mainly involved neurosurgeons and radiation oncologists; classical therapeutic strategies included whole brain radiation therapy (WBRT), surgery and stereotactic radiosurgery (SRS) alone or combined, at the expense of systemic strategies.

Currently, SRS has become a well-established treatment option and represents to date the standard of care for patients with a good performance status and limited brain disease (Soliman et al., 2016).

The advent of immunotherapy agents (anti-CTLA4, anti-PDL1 and anti-PD1 antibodies) has dramatically changed patients’ prognosis, mainly for melanoma and non-small cell lung cancer (NSCLC) (Aquilanti and Brastianos, 2020). For this reason, management of BMs has become even more complex requiring a multidisciplinary approach.

The synergistic properties of this kind of treatment combination are still not deeply understood and literature on the topic is still extremely limited (Pin et al., 2020). In the last decade, the appropriate combination of IT and SRS in patients with melanoma and NSCLC BM has been envisioned as a strategic point in patients’ management.

In the present paper, authors systematically reviewed the most relevant evidences from nowadays available clinical studies, comparing SRS alone and combined to IT, focusing on the impact of SRS-IT combination on survival, local and overall oncological control, as well as mortality and complications. Predicting factors have been systematically evaluated and analyzed according to statistical significance and clinical relevance.

Section snippets

Materials and methods

Records were searched for pertinent studies from different international databases (MEDLINE via PubMed, Science Direct, Cochrane Wiley and Embase) up to December 2020 by two independent investigators. The search strategy string can be found in the supplementary material file.

We designed a systematic review to assess relevant oncologic and radiologic outcomes in solid cancer brain metastasis treated by SRT alone vs combination therapy of SRS and IT (SRS-IT).

For this purpose, we used the

Results

Out search in different international databases yielded to 703 reference. After removal of 33 duplicates, we selected 69 records on a title/abstract excluding irrelevant articles. The search process including selection and exclusion reasons is illustrated in Fig. 1.

A total of 16 papers were retained after full text review. By checking the references of these articles, 7 additional papers were considered eligible. One recent article from Hadi et al., (Hadi et al. (2020)) was eventually excluded

Overall survival

There is still a great debate on the real advantage in combining IT and SRS compared to SRS alone in improving survival of patients with brain metastasis from melanoma and NSCLC. Four (Stokes et al., 2017; Diao et al., 2018; Knisely et al., 2012; Lanier et al., 2019) out of 13 studies (Patel et al., 2017; Yusuf et al., 2017; Stokes et al., 2017; Enright et al., 2020; Diao et al., 2018; Knisely et al., 2012; Lanier et al., 2019; Acharya et al., 2017; Colaco et al., 2016; Mathew et al., 2013;

Conclusions

This systematic review gathered and synthetized the available evidences on relevant outcomes of SRS associated to IT compared to SRS as well as different IT timing in the treatment of melanoma and NSCLC BM. It represents the largest and most comprehensive systematic review on this topic, comprising more than 3000 BM patients.

The results arising from the 22 included studies demonstrate that combining stereotactic radiosurgery with IT can dramatically impact median OS (particularly in melanoma

Role of funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

  • The main field of activity of GF is translational research in neuro-oncology, with special emphasis on cancer immunology and immunotherapy and genetics and genomics of gliomas and other brain tumors.

  • He pioneered the use of viral vectors for gene therapy of brain tumors (Benedetti et al, Nature Medicine 2000) and was the first to introduce in Italy immunotherapy strategies

Declaration of Competing Interest

The authors report no declarations of interest.

Dr. Filippo Gagliardi has completed the Medical School at the University of Verona (2006) and has accomplished the Residency Program in Neurosurgery at the University Vita-Salute San Raffaele University in Milan (2013). Currently, as neurosurgeon, he works as a Member of the Staff at the Department of Neurosurgery and Gamma Knife Radiosurgery of the San Raffaele Hospital in Milan. He has completed a PhD in Neuroscience at the International PhD Program in Molecular Medicine at the University

References (28)

  • K. Diao

    Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity

    J. Neurooncol.

    (2018)
  • T.L. Enright

    Combined immunotherapy and stereotactic radiotherapy improves neurologic outcomes in patients with non-small-cell lung cancer brain metastases

    Clin. Lung Cancer

    (2020)
  • I. Hadi

    Stereotactic radiosurgery combined with targeted/ immunotherapy in patients with melanoma brain metastasis

    Radiat. Oncol.

    (2020)
  • J.P. Knisely

    Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival

    J. Neurosurg.

    (2012)
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    Dr. Filippo Gagliardi has completed the Medical School at the University of Verona (2006) and has accomplished the Residency Program in Neurosurgery at the University Vita-Salute San Raffaele University in Milan (2013). Currently, as neurosurgeon, he works as a Member of the Staff at the Department of Neurosurgery and Gamma Knife Radiosurgery of the San Raffaele Hospital in Milan. He has completed a PhD in Neuroscience at the International PhD Program in Molecular Medicine at the University Vita-Salute, San Raffaele Scientific Institute in Milan (2016), where he currently works on the research on stem cells in brain tumors. He has obtained the national scientific qualification for associate professor in neurosurgery (2017). In 2012 he won the international award "Karl Storz" due to a research project on skull-base surgery. He has been "Research Fellow" at the Department of Neurosurgery of the George Washington University (Washington DC, USA), where he currently continues to work on research projects, keeping periodical internships in place.He has been invited as “Faculty Member” at numerous international courses all over the world. He is author and co-author of more than 70 peer-reviewed articles published on international journals, and book chapters edited by international publishers and e-journals. In 2019 he published as editor a book of neurosurgical technique titled “Operative cranial neurosurgical anatomy” printed by Thieme. He has given lectures as “Invited lecturer” at the University of Verona (Verona, Italia), Macquarie University (Sydney, NSW, Australia), and at the George Washington University (Washington DC, USA). His interests include surgery and multimodal treatment of brain tumors, skull base surgery and preclinical research on central nervous system tumors.

    Dr. Pierfrancesco De Domenico has completed the Medical School at the University of Messina (2016) and is currently enrolled in the Residency Program in Neurosurgery at the University Vita-Salute San Raffaele University in Milan (since 2019). He works in the Department of Neurosurgery and Gamma Knife Radiosurgery of the San Raffaele Hospital in Milan. He has completed a Research Fellowship in Neuroscience at Virginia Commonwealth University (Richmond, VA, USA) in 2014 and a Research Fellowship in Perioperative Medicine and Intensive Care at San Raffaele Hospital, Milan in 2018. He conducted, coordinated and contributed to the ideation and funding of several international clinical trials. Moreover, he was appointed Study Coordinator of a large trial investigating the effect of continuous vs intermittent infusion of meropenem in septic shock patients, granted by AIFA (Italian Medicines Agency). His interests include surgery and multimodal treatment of brain tumors, clinical and preclinical and clinical research on central nervous system tumors.

    Dr Silvia Snider has completed the Medical School at the University Vita-Salute San Raffaele University in Milan (2003), discussing the final thesis entitled ‘Role of stereotactic radiosurgery in the treatment of brain metastases’. In 2008 has accomplished the Residency Program in Neurosurgery at the University Vita-Salute San Raffaele University in Milan. She discussed the final thesis entitled ‘Role of stereotactic radiosurgery in the treatment of cerebral arteriovenous malformation’. In 2016 has completed a PhD Program in Molecular Medicine, Experimental Neurology section, at the University Vita-Salute, San Raffaele Scientific Institute in Milan, discussing the final thesis entitled: ‘Biomaterial- and Cell-based approaches to promote regeneration after spinal cord injury’. Since 2012, she works as neurosurgeon, as Member of the Staff at the Department of Neurosurgery and Gamma Knife Radiosurgery of the San Raffaele Hospital in Milan. Her interests include surgery, radiosurgery and multimodal treatment of brain tumors.

    Dr. Francesca Roncelli has completed the Medical School at the Vita-Salute San Raffaele University in Milan (2016) with a final thesis about cognitive outcome in meningiomas treated with Gamma-Knife Radiosurgery in which she presented the results of a clinical trial developed in her internship during the last two years of medical school. She is currently attending the fourth year of the Residency Program in Neurosurgery at the University Vita-Salute San Raffaele University in Milan. She is also currently attending the European Association of Neurosurgical Societies (EANS) training course lasting four years. Her interests include surgery and multimodal treatment of brain tumors and research on central nervous system tumors. She is involved in a few research protocols in Neurosurgery Unit about glutamate metabolism in brain tumors (primary brain tumors and metastases) and a multicentric study regarding grade II and III meningiomas. She is co-author of 3 peer-reviewed articles published on international journals.

    Dr. Edoardo Pompeo has graduated with full grades from Vita-Salute San Raffaele University in 2017 with a thesis about Gamma Knife Radiosurgery for the treatment of skull base meningiomas. Since 2018, he has been attending the Residency Program in Neurosurgery at the Vita-Salute San Raffaele University in Milan. He is currently working as a resident in the Department of Neurosurgery and Gamma Knife Radiosurgery of the San Raffaele Hospital in Milan. He is actively participating in multiple clinical and preclinical researches, mainly regarding primary and secondary malignant brain tumors. His main interests include Gamma Knife Radiosurgery and surgical treatment of malignant brain tumors.

    Dr. Lina Raffaella Barzaghi has completed the Medical School at the University of Milan (1998) and has accomplished the Residency Program in Neurosurgery at the Vita-Salute San Raffaele University in Milan (2003). Since 2002 she works as a Member of the Staff at the Department of Neurosurgery and Gamma Knife Radiosurgery of the San Raffaele Scientific Institute in Milan, where actually she is the Chief of Stereotactic Neurosurgery. The surgical experience covers the main areas of neurosurgery, mainly brain tumors and functional neurosurgery: particular areas of interest are neuro-navigation, brain mapping, intra-operative ultra-sound, stereotaxy and gamma knife radiosurgery. In 2109 she obtained the Stereotactic & Functional Neurosurgery Diploma, awarded by the Educational Committee of the European Society of Stereotactic and Functional Neurosurgery. She is author and co-author of 50 peer-reviewed articles published on international journals, and book chapters edited by international publishers (Scopus h index 17). She is resident member to the European Society of Stereotactic and Functional Neurosurgery (ESSFN), International Stereotactic Radiosurgery (ISRS) and European Leksell Gamma Knife Society.

    Dr. Alessandra Bulotta has completed the Medical School in 2004 and the Postgraduate Degree Specialty in Oncology in 2009 at the University Magna Graecia of Catanzaro. Since 2009, she is Medical Oncologist, involved in Thoracic Oncology, Head and Neck and Melanoma Unit of the Department of Medical Oncology at San Raffaele Hospital in Milan. She performs in-patient and outpatient clinical practice and she is a member of the multidisciplinary teams involved in the management of melanoma and lung cancer patients. Since the years of her Academic Education, she has been involved in preclinical in vitro and in vivo studies on experimental treatment of human tumors at the Department of Experimental and Clinical Medicine of Laboratory of Medical Oncology, University Magna Graecia of Catanzaro. During the last years, she has been interested in clinical and translational cancer research, manly focused on the role of the oncogenic pathways, responsible for drug resistance in patients with non small cell lung cancer. With regards to clinical research, she was sub-investigator in almost 50 Phase I, II and III clinical trials, involving the development of first and second generation ALK inhibitors (crizotinib, alectinib, ceritinib, brigatinib), the third generation EGFR-TKi osimertinib and the PD-1 and PDL-1 inhibitors nivolumab, pembrolizumab and atezolizumab. She is a member of the Italian Association Of Medical Oncology (AIOM) and the European Society for Medical Oncology (ESMO). She is author and co-author of more than 20 peer-reviewed articles published on international journals (Lancet Oncology, Lung Cancer, Journal of Clinical Oncology, Clinical Cancer Research, Cancer, etc.).

    Dr. Vanesa Gregorc has completed the Medical School in 1997 and the Postgraduate Degree Specialty in Oncology in 2002 at the University of Perugia. Currently, she is the Director of Thoracic Oncology, Head and Neck and Melanoma Unit of the Department of Medical Oncology at Scientific Institute San Raffaele Hospital and contract Professor for the Chair of Oncology at the MD International Program of Vita-Salute San Raffaele University. She performs clinical and research activities on thoracic neoplasms with a focus on identifying biomarkers to choose targeted therapies tailored to the need of a patient. She has been contributing, for more than 20 years in the development of various innovative treatments such as antitumor drugs today available in clinical practices, for the treatment of solid tumors, specifically lung and pleural mesothelioma tumors. She is also coordinator and initiator of various research projects not associated with the pharmaceutical sector: studies on experimental treatments, new diagnostic-therapeutic approaches for pulmonary carcinoma and malignant pleural mesothelioma. In collaboration with Vanderbilt University, Colorado Cancer Center and the Biocompany Biodesix, she promoted and completed a study on advanced stage lung cancer on the role of a method of predicting the response to treatment using proteomic. In 2013 her project was selected to be presented at the American congress ASCO (American Society of Clinical Oncology) and published in the renowned magazine JNCI (Journal of the National Cancer Institute) and inserted in the NCI (National Cancer Institute) guidelines for the choice of line II treatment for pulmonary carcinoma. In collaboration with Molmed, she significantly contributed to the study of the anti-tumor drug NGR-TNFalfa in the treatment of pleural mesothelioma. The drug is currently being evaluated by EMA (European Medicines Agency) to be registered in Europe, and studied to treat small cell lung cancer in association with anthracyclines. Since 2016 she was appointed Secretary of the Working Group Lung within the Alliance Against Cancer, the largest Italian organization for cancer research, established by the Ministry of Health. As secretary, she contributed to the development of a National Lung cancer Program that has the aim to introduce Next Generation Sequencing analysis in routine clinical practice. During the last 10 years she has been principal investigator e sub-investigator for over 100 profit and no profit, national and international clinical studies. She has also won different Grants for research projects from AIRC (the Italian Research Association against Cancer), the Ministry of Health and the Umbra association “Lotta Contro il Cancro”.

    Dr. Chiara Lazzari has completed the Medical School at Vita-Salute University in 2009 and the Residency Program in Oncology at the University of Milano in 2016. Since the years of her Academic Education, she has been been involved in translational cancer research, manly focused on the role of immunotherapy and the oncogenenic pathways, responsible for drug resistance in patients with non small cell lung cancer (NSCLC). In collaboration with Vanderbilt University, Colorado Cancer Center and the Biocompany Biodesix, she contributed to the development and validation of a serum proteomic algorithm (VeriStrat), able to guide physicians for second line treatment choice in patients with NSCLC. The algorithm is useful in those patients with no molecular alterations, in which second line therapy is based on chemotherapy, erlotinib or compounds targeting programmed cell death-1 or its ligand PD-L1. From September 2015 to June 2016 she was fellow at the Catalan Institute of Oncology under the supervision of Dr Rafael Rosell, where she carried out a research program aimed to provide preclinical evidence on how to improve treatment strategies in patients with KRAS mutated NSCLC. On December 2019 she concluded her PhD program in molecular medicine with a project focused on the validation of a sequencing panel for the detection of genomic alterations in patients with NSCLC. The study aims to provide a strategy at a national level to introduce the use of next generation sequencing in routinely clinical practice, increase the number of NSCLC patients with a molecular classification, develop infrastructures and improve competences in order to make the Italian research Institutes autonomous for genomic profiling services. With regards to clinical activity, since September 2016 she has been working as a medical oncologist at the department of oncology, at IRCCS San Raffaele Hospital. During the last five years, she has been sub-investigator in more than 60 Phase I, II and III clinical trials, involving the development of first and second generation ALK inhibitors (crizotinib, alectinib, ceritinib, brigatinib), the third generation EGFR-TKI osimertinib and the PD-1 and PDL-1 inhibitors nivolumab, pembrolizumab and atezolizumab.

    Stefano Cascinu is a Full Professor of Medical Oncology and Head of the Department of Oncology at the University “Vita-Salute” and IRCCS San Raffaele Hospital, Milan, Italy. After receiving his medical degree from Ancona University in 1985, he completed his specialty training in Medical Oncology at Ancona University in 1988. He also completed a fellowship in Radiation Therapy at the Bologna University in 1992. Prof. Cascinu is a member of several societies including the Italian Association of Medical Oncology (AIOM). He served as President (2011–2014) and previously on its Board of Directors, twice (1995–1999) and as General Secretary (2005–2007); the European Society of Medical Oncology (ESMO), serving from 1997 to 2002 in the Educational Committee and now as a member of the Gastrointestinal Faculty; the American Association of Clinical Oncology and the American Association of Cancer Research. He is co-author of more than 500 papers in peer review journals and has been involved in more than 400 GCP clinical trials as Principal Investigator. Prof. Cascinu’s major areas of interest are GI cancers and tumor biology.

    Gaetano Finocchiaro, MD, Born in Milan, Italy on October 30, 1952. Present position: Coordinator, Functional Unit of Neuro-Oncology, Department of Neurology, San Raffaele Scientific Institute, Milano, Italy Education. Milan University, Board in Biochemistry and Clinical Chemistry 1984–1987 Yale University Post-doctoral fellow in Human Genetics. Milan University, Board in Neurology. Milan University, degree in Medicine and Surgery

    Pietro Mortini is full Professor of Neurosurgery at Vita-Salute San Raffaele University (Milan, Italy). Since 2008 he is Chairman of the Department of Neurosurgery and Gamma Knife Radiosurgery at San Raffaele Hospital in Milan (Italy). He has completed the Residency in Neurosurgery at the University of Verona (Italy) and in ENT surgery at the University of Brescia. He has attended an international fellowship at The George Washington University (Washington DC, USA). He has performed more than 7000 surgical procedures for skull base, brain and spine tumors as well as cerebrovascular disorders. He is Director of the Unit of Experimental Neurosurgery. His major research interests lie in pre-clinical study on olfactory cell transplantation in spinal cord injuries and pre-clinical study on use of collagen scaffold in spinal cord and peripheral nerves injuries. He leads both clinical and basic research projects with many international foreign institutes. He has published more than 200 papers in refereed journals and he is scientific reviewer of “Pituitary” and editor of “Journal of Neurosurgical Sciences”. Professor Mortini is full-time professor at Vita-Salute San Raffaele University and, from 2014, Director at the International University Master in Radiosurgery. Since 2002, he is clinical professor of neurosurgery at The George Washington University (Washington D.C. - USA). He has been invited as lecturer to more than 70 international meetings and he has been the organizer of many post-graduated international courses in several fields of neurosurgery.

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