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.

Brain metastases outcome

Brain metastases outcome

Overall prognosis depends on ageextent and activity of the systemic disease, number of brain metastases and performance status. In about half of the patients, especially those with widespread and uncontrolled systemic malignancy, death is heavily related to extra-neural lesions, and treatment of cerebral disease doesn’t significantly improve survival.

In such patients the aim is to improve or stabilize the neurological deficit and maintain quality of lifeCorticosteroids and whole brain radiotherapy usually fulfill this purpose. By contrast, patients with limited number of brain metastases, good performance status and controlled or limited systemic disease, may benefit from aggressive treatment as both quality of life and survival are primarily related to treatment of brain lesions.

Strong positive prognostic factors include good functional status, age <65 years, no sites of metastasis outside of the central nervous system (CNS), controlled primary tumor 1), the presence of a single metastasis in the brain, long interval from primary diagnosis to brain relapse, and certain cancer subtypes such as HER2 positive breast cancer brain metastasesand EGFR Non small cell lung cancer intracranial metastases (NSCLC) 2) 3) 4)

Recursive partitioning analysis class

http://rcalc.ccf.org, under the category “Brain Cancer” 5).

In a study of the Royal North Shore Hospital, on univariate analysis, number of metastases (P = 0.04), symptomatic extracranial disease (P = 0.04) and early CNS relapse within 6 months (P < 0.01) had worse survival. No grade 3-4 toxicityevents were noted in 129 patients undergoing RT 6).


It is presently unknown whether patients with brain metastases from heavily pre-treated cancers have a significantly different prognosis than those with less pre-treatment 7).

References

1)

Gaspar L, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–751.
2)

Melisko ME, Moore DH, Sneed PK, De Franco J, Rugo HS. Brain metastases in breast cancer: clinical and pathologic characteristics associated with improvements in survival. J Neurooncol. 2008;88:359–365.
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Eichler AF, et al. Survival in patients with brain metastases from breast cancer: the importance of HER-2 status. Cancer. 2008;112:2359–2367.
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Eichler AF, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010;12:1193–1199.
5)

Barnholtz-Sloan JS, Yu C, Sloan AE, Vengoechea J, Wang M, Dignam JJ, Vogelbaum MA, Sperduto PW, Mehta MP, Machtay M, Kattan MW. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol. 2012 Jul;14(7):910-8. doi: 10.1093/neuonc/nos087. Epub 2012 Apr 27. PubMed PMID: 22544733; PubMed Central PMCID: PMC3379797.
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Or M, Jayamanne D, Guo L, Stevens M, Parkinson J, Cook R, Little N, Back M. Focal radiation therapy for limited brain metastases is associated with high rates of local control and low subsequent whole brain radiation therapy. ANZ J Surg. 2019 Mar 5. doi: 10.1111/ans.15040. [Epub ahead of print] PubMed PMID: 30836451.
7)

Lanier CM, McTyre E, LeCompte M, Cramer CK, Hughes R, Watabe K, Lo HW, O’Neill S, Munley MT, Laxton AW, Tatter SB, Ruiz J, Chan MD. The number of prior lines of systemic therapy as a prognostic factor for patients with brain metastases treated with stereotactic radiosurgery: Results of a large single institution retrospective analysis. Clin Neurol Neurosurg. 2017 Dec 27;165:24-28. doi: 10.1016/j.clineuro.2017.12.021. [Epub ahead of print] PubMed PMID: 29289917.

Stereotactic radiosurgery for brain metastases

Stereotactic radiosurgery for brain metastases

Management of brain metastases typically includes radiotherapy (RT) with conventional fractionation and/or stereotactic radiosurgery (SRS). However, optimal indications and practice patterns for SRS remain unclear.

Significant heterogeneity exists in target volumes for postoperative stereotactic radiosurgery.

The use of radiosurgery as a first-line or salvage treatment for brain metastases continues to expand. As a focal, highly precise treatment option, stereotactic radiosurgery (SRS) provides many benefits, including a short treatment timeline, a low probability of normal tissue complication, and a high probability of treated lesion control 1).


Kann et al. sought to evaluate national practice patterns for patients with metastatic disease receiving brain RT. They queried the National Cancer Data Base (NCDB) for patients diagnosed with metastatic non-small cell lung cancer, breast cancer, colorectal cancer, or melanoma from 2004 to 2014 who received upfront brain RT. Patients were divided into SRS and non-SRS cohorts. Patient and facility-level SRS predictors were analyzed with chi-square tests and logistic regression, and uptake trends were approximated with linear regression. Survival by diagnosis year was analyzed with the Kaplan-Meier method. Results: Of 75,953 patients, 12,250 (16.1%) received SRS and 63,703 (83.9%) received non-SRS. From 2004 to 2014, the proportion of patients receiving SRS annually increased (from 9.8% to 25.6%; P<.001), and the proportion of facilities using SRS annually increased (from 31.2% to 50.4%; P<.001). On multivariable analysis, nonwhite race, nonprivate insurance, and residence in lower-income or less-educated regions predicted lower SRS use (P<.05 for each). During the study period, SRS use increased disproportionally among patients with private insurance or who resided in higher-income or higher-educated regions. From 2004 to 2013, 1-year actuarial survival improved from 24.1% to 49.6% for patients selected for SRS and from 21.0% to 26.3% for non-SRS patients (P<.001). Conclusions: This NCDB analysis demonstrates steadily increasing-although modest overall-brain SRS use for patients with metastatic disease in the United States and identifies several progressively widening sociodemographic disparities in the adoption of SRS. Further research is needed to determine the reasons for these worsening disparities and their clinical implications on intracranial control, neurocognitive toxicities, quality of life, and survival for patients with brain metastases 2).

Complications

With increased adoption of this approach also comes an increase in incidence of treatment failure. Radiosurgical failure, either due to tumor regrowth or radiation necrosis, can occur in about 10% to 15% of patients still alive at 1 yr 3).

Radiation necrosis (RN) may occur after treatment and is challenging to distinguish from local recurrence (LR).

PET is superior to computed tomography and magnetic resonance imaging in the differentiation between recurrence and radiation reaction/necrosis. However, temporary radiation effects may mask remaining tumor tissue, and repeat PET studies may sometimes be necessary 4).


There are a variety of salvage options available for patients with brain metastases who experience local failure after stereotactic radiosurgery (SRS). These options include resection,whole brain radiation therapy, laser interstitial thermotherapy, and repeat SRS. There is little data on the safety and efficacy of repeat SRS following local failure of a prior radiosurgical procedure.

Systematic Reviews

2017

Using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was conducted using PubMed and Medline up to November 2016. A separate search was conducted for SRS for larger brain metastases.

Twenty-seven prospective study, critical reviews, metaanalysis, and published consensus guidelines were reviewed. Four key points came from these studies. First, there is no detriment to survival by withholding whole brain radiation (WBRT) in the upfront management of brain metastases with SRS. Second, while SRS on its own provides a high rate of local control (LC), WBRT may provide further increase in LC. Next, WBRT does provide distant brain control with less need for salvage therapy. Finally, the addition of WBRT does affect neurocognitive function and quality of life more than SRS alone. For larger brain metastases, surgical resection should be considered, especially when factoring lower LC with single-session radiosurgery. There is emerging data showing good LC and/or decreased toxicity with multisession radiosurgery.

A number of well-conducted prospective and meta-analyses studies demonstrate good LC, without compromising survival, using SRS alone for patients with a limited number of brain metastases. Some also demonstrated less impact on neurocognitive function with SRS alone. Practice guidelines were developed using these data with International Stereotactic Radiosurgery Society consensus 5).


Stereotactic radiosurgery (SRS) offers excellent local control for brain metastases (BM) with low rates of toxicity.

It avoids whole brain radiotherapy (WBRT)-associated morbidity.

Studies have clearly established the safety and efficacy of single-dose SRS. However, as patient survival has increased, the recurrence of tumors and the development of metastases to new sites within the brain have made it desirable to repeat treatments over time. The cumulative toxicity of multi-isocenter, multiple treatments has not been well defined.

Postoperative stereotactic radiosurgery to the resection cavity safely and effectively augments local control of large brain metastases. Patients with <4 metastases and controlled systemic disease have significantly lower rates of distant brain failure (DBF) and are ideal treatment candidates 6).

In patients with limited brain metastases from non small cell lung cancer (NSCLC), SRS is an effective treatment associated with high local control rate with low morbidity. When performed in isolation, close follow-up is mandatory and radiosurgery can be renewed as salvage treatment for distant brain progression, limiting the use of WBRT 7).

Significant tumor volume reduction by 6 or 12 weeks post-SRS was associated with long-term local control.

For patients at low risk of distant intracranial failure (such as those with systemic disease control) with early, robust volumetric response, it may reasonable to lengthen imaging intervals to maximize clinical utility.

Although it is necessary to validate the findings in a larger, prospective series, the results are encouraging that a robust early volumetric response is associated with sustained local control for metastatic brain lesions 8).

Gamma Knife radiosurgery (GKRS) offers a high rate of tumor control and good survival benefits in both new and recurrent patients with MBT. Thus, GKRS is an effective treatment option for new patients with MBT, as well as an adjuvant therapy in patients with recurrent MBT. 9) 10).


There appears to be no consensus regarding the optimal treatment strategy among patients with >3 brain metastases, and practice patterns are heterogeneous. Radiation oncologists, especially high-volume CNS specialists, are treating significantly more brain metastases with SRS than what currently is recommended by published consensus guidelines. Providers struggle with patients with a moderate intracranial disease burden. Further prospective studies are needed to support these practice patterns and guide decision making 11).

Case series

Patients (n = 41) undergoing single-fraction Gamma Knife SRS following surgical resection of brain metastases from 2011 to 2017 were retrospectively reviewed. SRS included the entire contrast-enhancing cavity with heterogeneity in inclusion of the surgical tract and no routine margin along the dura or clinical target volume margin. Follow-up MR imaging was fused with SRS plans to assess patterns of failure.

The median follow-up was 11.1 months with a median prescription of 18 Gy. There were 5 local failures: infield (n = 3, 60%), surgical tract (n = 1, 20%), and marginal > 5 mm from the resection cavity (n = 1, 20%). No marginal failures < 5 mm or dural margin failures were noted. For deep lesions (n = 13), 62% (n = 8) had the entire tract covered. The only tract recurrence was in a deep lesion without coverage of the surgical tract (n = 1/5).

In this small preliminary experience, despite no routine inclusion of the dural tract or bone flap, no failures were noted in these locations. Omission of the surgical tract in deep lesions may increase failure rates 12).

References

1)

Nieder C, Grosu AL, Gaspar LE. Stereotactic radiosurgery (SRS) for brain metastases: a systematic review. Radiat Oncol. 2014 Jul 12;9:155. doi: 10.1186/1748-717X-9-155. Review. PubMed PMID: 25016309; PubMed Central PMCID: PMC4107473.
2)

Kann BH, Park HS, Johnson SB, Chiang VL, Yu JB. Radiosurgery for Brain Metastases: Changing Practice Patterns and Disparities in the United States. J Natl Compr Canc Netw. 2017 Dec;15(12):1494-1502. doi: 10.6004/jnccn.2017.7003. PubMed PMID: 29223987.
3)

Sneed PK, Mendez J, Vemer-van den Hoek JG, Seymour ZA, Ma L, Molinaro AM, Fogh SE, Nakamura JL, McDermott MW. Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors. J Neurosurg. 2015 Aug;123(2):373-86. doi: 10.3171/2014.10.JNS141610. Epub 2015 May 15. PubMed PMID: 25978710.
4)

Ericson K, Kihlström L, Mogard J, Karlsson B, Lindquist C, Widén L, Collins VP, Stone-Elander S. Positron emission tomography using 18F-fluorodeoxyglucose in patients with stereotactically irradiated brain metastases. Stereotact Funct Neurosurg. 1996;66 Suppl 1:214-24. PubMed PMID: 9032864.
5)

Chao ST, De Salles A, Hayashi M, Levivier M, Ma L, Martinez R, Paddick I, Régis J, Ryu S, Slotman BJ, Sahgal A. Stereotactic Radiosurgery in the Management of Limited (1-4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline. Neurosurgery. 2017 Nov 3. doi: 10.1093/neuros/nyx522. [Epub ahead of print] PubMed PMID: 29126142.
6)

Ling DC, Vargo JA, Wegner RE, Flickinger JC, Burton SA, Engh J, Amankulor N, Quinn AE, Ozhasoglu C, Heron DE. Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection. Neurosurgery. 2015 Feb;76(2):150-7. doi: 10.1227/NEU.0000000000000584. PubMed PMID: 25549189.
7)

Zairi F, Ouammou Y, Le Rhun E, Aboukais R, Blond S, Vermandel M, Deken V, Devos P, Reyns N. Relevance of gamma knife radiosurgery alone for the treatment of non-small cell lung cancer brain metastases. Clin Neurol Neurosurg. 2014 Oct;125:87-93. doi: 10.1016/j.clineuro.2014.07.030. Epub 2014 Jul 27. PubMed PMID: 25108698.
8)

Sharpton SR, Oermann EK, Moore DT, Schreiber E, Hoffman R, Morris DE, Ewend MG. The Volumetric Response of Brain Metastases After Stereotactic Radiosurgery and Its Post-treatment Implications. Neurosurgery. 2014 Jan;74(1):9-16. doi: 10.1227/NEU.0000000000000190. PubMed PMID: 24077581.
9)

Bir SC, Ambekar S, Nanda A. Long term outcome of Gamma Knife radiosurgery for metastatic brain tumors. J Clin Neurosci. 2014 Dec;21(12):2122-8. doi: 10.1016/j.jocn.2014.05.015. Epub 2014 Jul 25. PubMed PMID: 25065951.
10)

Bir SC, Ambekar S, Bollam P, Nanda A. Long-term outcome of gamma knife radiosurgery for metastatic brain tumors originating from lung cancer. Surg Neurol Int. 2014 Sep 5;5(Suppl 8):S396-403. doi: 10.4103/2152-7806.140197. eCollection 2014. PubMed PMID: 25289169; PubMed Central PMCID: PMC4173307.
11)

Sandler KA, Shaverdian N, Cook RR, Kishan AU, King CR, Yang I, Steinberg ML, Lee P. Treatment trends for patients with brain metastases: Does practice reflect the data? Cancer. 2017 Feb 8. doi: 10.1002/cncr.30607. [Epub ahead of print] PubMed PMID: 28178376.
12)

McDermott DM, Hack JD, Cifarelli CP, Vargo JA. Tumor Cavity Recurrence after Stereotactic Radiosurgery of Surgically Resected Brain Metastases: Implication of Deviations from Contouring Guidelines. Stereotact Funct Neurosurg. 2019 Feb 14:1-7. doi: 10.1159/000496156. [Epub ahead of print] PubMed PMID: 30763944.
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