Brain metastases treatment

Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, Stereotactic radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population ¹⁾.

Liu et al. systematically reviewed the English language literature up to March 2020 to compare the efficacy of brain metastases surgery and stereotactic radiosurgery for brain metastases.

They identified cohort studies from the Cochrane Library, PubMed, and EMBASE databases and conducted a meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Twenty cohort studies involving 1,809 patients were included. Local control did not significantly differ between the SR and SRS groups overall (hazard ratio [HR] 1.02, 95% confidence interval (CI) 0.64-1.64, p = 0.92; I2 = 54%, p = 0.03) or in subgroup analyses of SR plus SRS vs. SRS alone, SR plus whole brain radiation therapy (WBRT) versus SRS plus WBRT, or SR plus WBRT versus SRS alone. Distant intracranial control did not significantly differ between the SR and SRS groups overall (HR 0.78, 95% CI 0.38-1.60, p = 0.49; I2 = 61%, p = 0.03) or in subgroup analyses of SR plus SRS versus SRS alone or SR plus WBRT versus SRS alone. In addition, overall survival (OS) did not significantly differ in the SR and SRS groups (HR 0.91, 95% CI 0.65-1.27, p = 0.57; I2 = 47%, p = 0.09) or in subgroup analyses of SR plus SRS versus SRS alone, SR plus WBRT versus SRS alone or SR plus WBRT versus SRS plus WBRT

Initial treatment of BM with SRS may offer comparable local and distant intracranial control to SR in patients with single or solitary BM. OS did not significantly differ between the SR and SRS groups in people with single or solitary BM ²⁾.

Brain metastases treatment guidelines.

Recursive partitioning analysis class decision

With the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed ³⁾.

Historically, overall survival after diagnosis is poor; however, since the 1980s, improved systemic disease therapies and multimodality brain metastasis treatment have substantially increased survival. This increase in the quantity of life after diagnosis allows clinicians to minimize morbidity and focus on the patient’s quality of life. Choosing an appropriate personalized treatment plan for patients with brain metastasis maximizes survival and minimizes morbidity from unnecessary or futile treatments. The wide variety of tumor types, treatment strategies, and constant innovations within the field requires close collaboration among neurosurgeons, medical oncologists, radiation oncologists, and other specialists. Current treatment paradigms for brain metastases employ several treatment modalities, including open surgical resection, Gamma Knife or CyberKnife stereotactic radiosurgery, focused external beam radiotherapy, whole-brain radiotherapy (WBRT), traditional chemotherapy, and newer targeted biological agents personalized for tumor type.

Advances in intraoperative surgical technology (i.e., fluorescence, confocal microscopy, and brachytherapy) hold promise for improved outcomes for brain metastasis resection. The future of brain metastasis management is predicated on personalized therapy targeted to specific tumor molecular pathways, such as those involved in the blood–brain barrier transgression, cell–cell adhesion, and angiogenesis. Brain metastases are often biologically distinct lesions compared to the primary tumor. Personalized therapies should therefore be chosen on the basis of brain metastasis tissue whenever available. The multidisciplinary management of patients with brain metastases by neurosurgeons, medical oncologists, and radiation oncologists is essential as therapies become increasingly complex and individualized ⁴⁾.

That means that the treatment of brain metastases is multidisciplinary with radiation forming the cornerstone ⁵⁾ ⁶⁾.

Neurosurgical resection and whole brain radiation therapy (WBRT) are accepted treatments for single and oligometastatic cancer to the brain.

The combination of radiotherapy and chemotherapy improves response rate and/or progression-free survival in some studies, but not overall survival ⁷⁾. ⁸⁾ ⁹⁾.

Local radiotherapy as adjuvant treatment to surgical resection of brain metastases is associated with an increased rate of development of new distant metastases and leptomeningeal disease compared with WBRT, but not with recurrence at the resection site or of unresected lesions treated with radiation ¹⁰⁾.

The neurosurgical treatment of patients with metastatic cancer is an integral component of multimodality therapy for brain and spinal metastases. Survival benefit has been demonstrated for the addition of open surgery as well as the use of stereotactic radiosurgery (SRS) to whole-brain radiation therapy for treatment of patients with isolated cranial metastases compared with whole-brain radiation therapy alone. New clinical trials that directly compare open surgical procedures with SRS are underway ¹¹⁾.

see Brain metastases surgery

To avoid the decline in neurocognitive function (NCF) linked to WBRT, the authors conducted a prospective, multicenter, phase 2 study to determine whether surgery and carmustine wafers (CW), while deferring WBRT, could preserve NCF and achieve local control (LC).

NCF and LC were measured in 59 patients who underwent resection and received CW for a single (83%) or dominant (oligometastatic, 2 to 3 lesions) metastasis and received stereotactic radiosurgery (SRS) for tiny nodules not treated with resection plus CW. Preservation of NCF was defined as an improvement or a decline ≤ 1 standard deviation from baseline in 3 domains: memory, executive function, and fine motor skills, evaluated at 2-month intervals.

Significant improvements in executive function and memory occurred throughout the 1-year follow-up. Preservation or improvement of NCF occurred in all 3 domains for the majority of patients at each of the 2-month intervals. NCF declined in only 1 patient. The chemowafers were well tolerated, and serious adverse events were reversible. There was local recurrence in 28% of the patients at 1-year follow-up.

The rate of LC (78%) was comparable to historic rates of surgery with WBRT and superior to reports of WBRT alone. For patients who undergo resection for symptomatic or large-volume metastasis or for tissue diagnosis, the addition of CW can be considered as an option ¹²⁾.

see Radiotherapy for brain metastases.

see Stereotactic radiosurgery for brain metastases.

CyberKnife Radiosurgery for brain metastases.

see Melanoma brain metastases treatment.

¹⁾

Brown PD, Ballman KV, Cerhan JH, Anderson SK, Carrero XW, Whitton AC, Greenspoon J, Parney IF, Laack NNI, Ashman JB, Bahary JP, Hadjipanayis CG, Urbanic JJ, Barker FG 2nd, Farace E, Khuntia D, Giannini C, Buckner JC, Galanis E, Roberge D. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1049-1060. doi: 10.1016/S1470-2045(17)30441-2. Epub 2017 Jul 4. PMID: 28687377; PMCID: PMC5568757.

²⁾

Liu Z, He S, Li L. Comparison of Surgical Resection and Stereotactic Radiosurgery in the Initial Treatment of Brain Metastasis [published online ahead of print, 2020 Sep 8]. Stereotact Funct Neurosurg. 2020;1-12. doi:10.1159/000509319

³⁾

Shen CJ, Lim M, Kleinberg LR. Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship. Curr Treat Options Oncol. 2016 Sep;17(9):46. Review. PubMed PMID: 27447703.

⁴⁾

Hardesty DA, Nakaji P. The Current and Future Treatment of Brain Metastases. Front Surg. 2016 May 25;3:30. doi: 10.3389/fsurg.2016.00030. eCollection 2016. Review. PubMed PMID: 27252942; PubMed Central PMCID: PMC4879329.

⁵⁾

Chang JE, Robins HI, Mehta MP. Therapeutic advances in the treatment of brain metastases. Clin Adv Hematol Oncol. 2007;5:54–64.

⁶⁾

Mintz A, Perry J, Spithoff K, Chambers A, Laperriere N. Management of single brain metastasis: a practice guideline. Curr Oncol. 2007 Aug;14(4):131-43. PubMed PMID: 17710205; PubMed Central PMCID: PMC1948870.

⁷⁾

Antonadou D, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002;20:3644–3650.

⁸⁾

Robinet G, et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Francais de Pneumo-Cancerologie (GFPC) Protocol 95–1. Ann Oncol. 2001;12:59–67.

⁹⁾

Verger E, et al. Temozolomide and concomitant whole brain radiotherapy in patients with brain metastases: a phase II randomized trial. Int J Radiat Oncol Biol Phys. 2005;61:185–191.

¹⁰⁾

Hsieh J, Elson P, Otvos B, Rose J, Loftus C, Rahmathulla G, Angelov L, Barnett GH, Weil RJ, Vogelbaum MA. Tumor Progression in Patients Receiving Adjuvant Whole-Brain Radiotherapy vs Localized Radiotherapy After Surgical Resection of Brain Metastases. Neurosurgery. 2015 Apr;76(4):411-20. doi: 10.1227/NEU.0000000000000626. PubMed PMID: 25599198.

¹¹⁾

Claus EB. Neurosurgical management of metastases in the central nervous system. Nat Rev Clin Oncol. 2011 Dec 6;9(2):79-86. doi: 10.1038/nrclinonc.2011.179. Review. PubMed PMID: 22143137.

¹²⁾

Brem S, Meyers CA, Palmer G, Booth-Jones M, Jain S, Ewend MG. Preservation of neurocognitive function and local control of 1 to 3 brain metastases treated with surgery and carmustine wafers. Cancer. 2013 Nov 1;119(21):3830-8. doi: 10.1002/cncr.28307. Epub 2013 Aug 23. PubMed PMID: 24037801.