Non small cell lung cancer intracranial metastases radiosurgery

Non small cell lung cancer intracranial metastases radiosurgery

Multisession radiosurgery (M-GKS) may be an effective alternative for large brain metastases from Non small cell lung cancer (NSCLC). Specifically, severe radiation induced toxicity (≥ grade 3) did not occur in M-GKS for large-volume metastases. Although the long-term effects and results from larger samples remain unclear, M-GKS may be a suitable palliative treatment for preserving neurological function 1).

Traditionally, whole brain radiotherapy (WBRT) has been the cornerstone of Non small cell lung cancer intracranial metastases treatment, but its indication is a matter of debate. A randomized trial has shown that for patients with a poor prognosis, WBRT does not add quality of life (QoL) nor survival over the best supportive care. In recent decades, stereotactic radiosurgery (SRS) has become an attractive non-invasive treatment for patients with BM. Only the BM is irradiated to an ablative dose, sparing healthy brain tissue. Intracranial recurrence rates decrease when WBRT is administered following SRS or resection but does not improve overall survival and comes at the expense of neurocognitive function and QoL. The downside of SRS compared with WBRT is a risk of radionecrosis (RN) and a higher risk of developing new BM during follow-up. Currently, SRS is an established treatment for patients with a maximum of four BM. Several promising strategies are currently being investigated to further improve the indication and outcome of SRS for patients with BM: the effectivity and safety of SRS in patients with more than four BM, combining SRS with systemic therapy such as targeted agents or immunotherapy, shared decision-making with SRS as a treatment option, and individualized isotoxic dose prescription to mitigate the risk of RN and further enhance local control probability of SRS.

The review of Hartgerink et al., discusses the current indications of SRS and future directions of treatment for patients with BM of NSCLC with focus on the value of SRS 2).


Radiosurgery for multiple BMs is controversial, yet patients with EGFR Non small cell lung cancer intracranial metastases and Anaplastic lymphoma kinase non small cell lung cancer may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene-addicted NSCLC with four or more BMs 3).

References

1)

Park K, Kim JW, Chung HT, Paek SH, Kim DG. Single-Session versus Multisession Gamma Knife Radiosurgery for Large Brain Metastases from Non-Small Cell Lung Cancer: A Retrospective Analysis. Stereotact Funct Neurosurg. 2019 May 22:1-7. doi: 10.1159/000496154. [Epub ahead of print] PubMed PMID: 31117101.
2)

Hartgerink D, van der Heijden B, De Ruysscher D, Postma A, Ackermans L, Hoeben A, Anten M, Lambin P, Terhaag K, Jochems A, Dekker A, Schoenmaekers J, Hendriks L, Zindler J. Stereotactic Radiosurgery in the Management of Patients With Brain Metastases of Non-Small Cell Lung Cancer: Indications, Decision Tools and Future Directions. Front Oncol. 2018 May 9;8:154. doi: 10.3389/fonc.2018.00154. eCollection 2018. Review. PubMed PMID: 29868476; PubMed Central PMCID: PMC5954030.
3)

Robin TP, Camidge DR, Stuhr K, Nath SK, Breeze RE, Pacheco JM, Liu AK, Gaspar LE, Purcell WT, Doebele RC, Kavanagh BD, Rusthoven CG. Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non-Small Cell Lung Cancer. J Thorac Oncol. 2018 May;13(5):715-720. doi: 10.1016/j.jtho.2017.12.006. Epub 2017 Dec 19. PubMed PMID: 29269007.

EGFR Non small cell lung cancer intracranial metastases

EGFR Non small cell lung cancer intracranial metastases

Advances in our understanding of genomic alterations in lung cancer have led to the discovery of several driver mutations in non small cell lung cancer 1). The most common are the EGFR activating mutations, which are present in 50% of patients of Asian descent and in 10%–15% of white patients with NSCLC of adenocarcinoma histology 2).

Huang et al., investigated whether tumor mutation status (EGFRKRASALKROS1BRAF) and treatment history were associated with survivalafter neurosurgery.

They reviewed the electronic health records of 104 non small cell lung cancer (NSCLC) patients with genomic profiling who underwent neurosurgical resection for symptomatic brain metastases at an academic institution between January 2000 and January 2018.

They used multivariate Cox proportional hazards models to evaluate the association between overall survival (OS) after neurosurgery and clinico-pathological factors including mutation status.

Mean age of patients in this study was 61 (±12) years, and 44% were men. The median OS after neurosurgery was 24 months (95% confidence interval: 18-34). Our multivariate analysis showed that the presence of an EGFR mutation in the tumor was significantly associated with improved OS (hazard ratio [HR] 0.214 p = 0.029), independent of tyrosine kinase inhibitor (TKI) use. Presence of KRAS, ALK, ROS1 and BRAF alterations were not associated with survival (all p > 0.05). Conversely, older age (HR: 1.039; p=0.029), a history of multiple brain irradiation procedures (HR 9.197; p < 0.001) and presence of extracranial metastasis (HR 2.556; p = 0.016) resulted in increased risk of mortality.

Patients requiring surgical resection of an EGFR mutated NSCLC brain metastasis had an associated improved survival compared to patients without this mutation, independent of TKI use. Decreased survival was associated with older age, multiple prior brain radiation therapies and extracranial metastasis 3).


Activating mutations in the epidermal growth factor receptor (EGFR) predict for prolonged progression-free survival in patients with advanced non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy.


A group of patients with non-small cell lung cancer (NSCLC) have tumors that contain an inversion in chromosome 2 that juxtaposes the 5′ end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3′ end of the anaplastic lymphoma kinase (ALK) gene, resulting in the novel fusion oncogene EML4-ALK


Multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed 4).

References

1)

Zer A, Leighl N. Promising targets and current clinical trials in metastatic non-squamous nsclc. Front Oncol. 2014;4:329. doi: 10.3389/fonc.2014.00329.
2)

Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4:36–54.
3)

Huang Y, Chow KKH, Aredo JV, Padda SK, Han SS, Kakusa BW, Gephart MH. EGFR mutation status confers survival benefit in non-small cell lung cancer patients undergoing surgical resection of brain metastases: a retrospective cohort study. World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30210-4. doi: 10.1016/j.wneu.2019.01.112. [Epub ahead of print] PubMed PMID: 30710723.
4)

Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK, Beal K, Amini A, Patil T, Kavanagh BD, Camidge DR, Braunstein SE, Boreta LC, Balasubramanian SK, Ahluwalia MS, Rana NG, Attia A, Gettinger SN, Contessa JN, Yu JB, Chiang VL. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol. 2017 Apr 1;35(10):1070-1077. doi: 10.1200/JCO.2016.69.7144. Epub 2017 Jan 23. PubMed PMID: 28113019.

Small intracranial aneurysm

Small intracranial aneurysm

Definition

Small intracranial aneurysm size: 3-4 mm.

Of 26 studies, 5, 10, and 8 described the growth rate of aneurysms 3 mm and smaller, 5 mm and smaller, and 7 mm and smaller, respectively, whereas rupture rates were reported in 7, 11, and 13 studies for aneurysms 3 mm and smaller, 5 mm and smaller, and 7 mm and smaller, respectively. The annualized growth rate was less than 3% in all but 1 study for all 3 size categories. The annualized rupture rate was 0%, less than 0.5%, and less than 1% for the 3 size categories, respectively. Strength of evidence was very low quality for growth rates and low quality for rupture rates.

Poor-quality evidence suggests that small UIAs have low growth and rupture rates and very small UIAs have little or no risk for rupture 1).


The annual rupture rate of small (3-4 mm) unruptured intracranial aneurysms (UIA) is 0.36% per year, however, the proportion of small ruptured aneurysms < 5 mm is 35%. This discrepancy is explained by the hypothesis that most acute subarachnoid hemorrhage (SAH) is from recently formed, unscreened aneurysms, but this hypothesis is without definitive proof.

Ikawa et al., aimed to clarify the actual number of screened, ruptured small aneurysms and risk factors for rupture.

The Unruptured Cerebral Aneurysm Study Japan, a project of the Japan Neurosurgical Society, was designed to clarify the natural course of UIAs. From January 2001 through March 2004, 6697 UIAs among 5720 patients were prospectively registered. At registration, 2839 patients (49.6%) had 3132 (46.8%) small UCAs of 3-4 mm. The registered, treated, and rupture numbers of these small aneurysms and the annual rupture rate were investigated. The rate was assessed per aneurysm. The characteristics of patients and aneurysms were compared to those of larger unruptured aneurysms (≥ 5 mm). Cumulative rates of SAH were estimated per aneurysm. Risk factors underwent univariate and multivariate analysis.

Treatment and rupture numbers of small UCAs were 1132 (37.1% of all treated aneurysms) and 23 (20.7% of all ruptured aneurysms), respectively. The registered, treated, rupture number, and annual rupture rates were 1658 (24.8%), 495 (16.2%), 11 (9.9%), and 0.30%, respectively, among 3-mm aneurysms, and 1474 (22.0%), 637 (20.9%), 12 (10.8%), and 0.45%, respectively, among 4-mm aneurysms. Multivariate risk-factor analysis revealed that a screening brain checkup (hazard ratio [HR] 4.1, 95% confidence interval [CI] 1.2-14.4), history of SAH (HR 10.8, 95% CI 2.3-51.1), uncontrolled hypertension (HR 5.2, 95% CI 1.8-15.3), and location on the anterior communicating artery (ACoA; HR 5.0, 95% CI 1.6-15.5) were independent predictors of rupture.

Although the annual rupture rate of small aneurysms was low, the actual number of ruptures was not low. Small aneurysms that ruptured during follow-up could be detected, screened, and managed based on each risk factor. Possible selection criteria for treating small UCAs include a history of SAH, uncontrolled hypertension, location on the ACoA, and young patients. Further large prospective and longitudinal trials are needed.Clinical trial registration no.: C000000418 (https://www.umin.ac.jp/ctr2).


From September 2000 to January, 2004, 540 aneurysms (446 patients) were registered. Four hundred forty-eight unruptured aneurysms <5 mm in size (374 patients) have been followed up for a mean of 41.0 months (1306.5 person-years) to date.

Sonobe et al., calculated the average annual rupture rate of small unruptured aneurysms and also investigated risk factors that contribute to rupture and enlargement of these aneurysms.

The average annual risks of rupture associated with small unruptured aneurysms were 0.54% overall, 0.34% for single aneurysms, and 0.95% for multiple aneurysms. Patient <50 years of age (P=0.046; hazard ratio, 5.23; 95% CI, 1.03 to 26.52), aneurysm diameter of >or=4.0 mm (P=0.023; hazard ratio, 5.86; 95% CI, 1.27 to 26.95), hypertension (P=0.023; hazard ratio, 7.93; 95% CI, 1.33 to 47.42), and aneurysm multiplicity (P=0.0048; hazard ratio, 4.87; 95% CI, 1.62 to 14.65) were found to be significant predictive factors for rupture of small aneurysms.

The annual rupture rate associated with small unruptured aneurysms is quite low. Careful attention should be paid to the treatment indications for single-type unruptured aneurysms <5 mm. If the patient is <50 years of age, has hypertension, and multiple aneurysms with diameters of >or=4 mm, treatment should be considered to prevent future aneurysmal rupture 3).

Treatment

Endovascular treatment of small intracranial aneurysms has historically been technically challenging and has been associated with high rates of complications and intraprocedural rupture.

A retrospective cohort study was performed to include all patients who underwent coiling of an intracranial aneurysm between 2005 and 2012. Small aneurysms were defined as any aneurysm 4.0 mm or smaller in all dimensions. The primary outcome was a composite outcome of the occurrence of an intraoperative aneurysm rupture or a perioperative thromboembolic event. The secondary outcome of interest was aneurysm recurrence.

483 patients were treated using endovascular techniques; 85 (17.6%) of these patients had small aneurysms. In the small aneurysm group, there was only one (1.2%) intraoperative rupture, three (3.5%) perioperative thromboembolic events, and 11 (12.9%) incidents of aneurysm recurrence. Both the primary and secondary outcomes of interest were similar in patients presenting with small or large aneurysms. Small aneurysm size was not a risk factor for either the composite primary outcome or aneurysm recurrence in multivariate analysis.

Treatment of small intracranial aneurysms via conventional endovascular coiling techniques is not inferior to endovascular treatment of larger aneurysms based on this single institution experience. While technically challenging, such aneurysms may be treated safely and effectively with acceptable rates of complications and recurrence 4).

References

1)

Malhotra A, Wu X, Forman HP, Grossetta Nardini HK, Matouk CC, Gandhi D, Moore C, Sanelli P. Growth and Rupture Risk of Small Unruptured Intracranial Aneurysms: A Systematic Review. Ann Intern Med. 2017 Jul 4;167(1):26-33. doi: 10.7326/M17-0246. Epub 2017 Jun 6. Review. PubMed PMID: 28586893.
2)

Ikawa F, Morita A, Tominari S, Nakayama T, Shiokawa Y, Date I, Nozaki K, Miyamoto S, Kayama T, Arai H; Japan Neurosurgical Society for UCAS Japan Investigators. Rupture risk of small unruptured cerebral aneurysms. J Neurosurg. 2019 Jan 25:1-10. doi: 10.3171/2018.9.JNS181736. [Epub ahead of print] PubMed PMID: 30684948.
3)

Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke. 2010 Sep;41(9):1969-77. doi: 10.1161/STROKEAHA.110.585059. Epub 2010 Jul 29. PubMed PMID: 20671254.
4)

Stetler WR Jr, Wilson TJ, Al-Holou WN, Chaudhary N, Gemmete JJ, Thompson BG, Pandey AS. Conventional endovascular treatment of small intracranial aneurysms is not associated with additional risks compared with treatment of larger aneurysms. J Neurointerv Surg. 2014 Mar 12. doi: 10.1136/neurintsurg-2014-011133. [Epub ahead of print] PubMed PMID: 24623836.
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