Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization
- Departments of Neurosurgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Bezmialem Vakif University Medical School, Istanbul, Turkey,
- Department of Oncology, Royal Berkshire NHS Foundation Trust, Reading, United Kingdom.
- Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden,
- Departments of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
- Department of Oncology-Pathology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
Department of Oncology-Pathology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
DOI:10.25259/SNI_275_2019Copyright: © 2020 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Georges Sinclair, M. Stenman, H. Benmakhlouf, P. Johnstone, P. Wersäll, M. Lindskog, M. A. Hatiboglu, U. Harmenberg. Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization. 14-Feb-2020;11:21
How to cite this URL: Georges Sinclair, M. Stenman, H. Benmakhlouf, P. Johnstone, P. Wersäll, M. Lindskog, M. A. Hatiboglu, U. Harmenberg. Adaptive radiosurgery based on two simultaneous dose prescriptions in the management of large renal cell carcinoma brain metastases in critical areas: Towards customization. 14-Feb-2020;11:21. Available from: https://surgicalneurologyint.com/surgicalint-articles/9872/
Background: The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario.
Case Description: A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (
Results: Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR.
Conclusion: Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.
Keywords: Brain metastases, Engel score, Hypofractionated gamma knife radiosurgery, Karnofsky performance status, Metastatic renal cell carcinoma, Recursive partitioning analysis, Single-dose gamma knife radiosurgery
Despite promising advances in the fields of neurosurgery and radiotherapy in the era of targeted therapy and immunotherapy, the prognosis of metastatic renal cell carcinoma (mRCC) remains poor. The overall benefits of systemic treatment can significantly be precluded by the presence of brain metastases. Microsurgery is not always feasible due to preexisting regional physioanatomical constraints and/or the extent of intra- and extra-cranial metastatic activity. Due to the radioresistant nature of renal cell tumors, the clinician is often obliged to deliver focal high dose radiation, such as single fraction gamma knife radiosurgery (SF-GKRS). However, SF-GKRS may lead to severe toxicity in lesions >8–10 cc, especially in the eloquent brain. We present the case of a patient with mRCC and two large, critically located, brain metastases treated in next to emergency setting with a gamma knife based dose-volume adaptive technique coined rapid rescue radiosurgery (RRR). To the best of our knowledge, this is the first reported case of mRCC brain lesions treated with a staged dose-volume adaptive procedure structured on two concurrent prescription doses, at least in Scandinavia.
A previously healthy 56-year-old man developed gradual left- side hemiparesis, more accentuated in the lower limb (July 2016). A brain computerized tomography (CT)-scan and complementary magnetic resonance imaging (MRI) showed a solitary metastatic lesion (Met 1) in the right central sulcus (11.95 cc) with extensive perilesional edema [
Follow-up MRI at 1, 3, and 6 months confirmed subsequent tumor volume reduction of Met 1 with ensuing significant improvement of the patient’s motor function [
Met 2 decreased in volume by 15% between GKRS 1 and GKRS 3. Follow-up MRI at 14 months after RRR-treatment of Met 1 (=2 months after RRR-treatment of Met 2) showed further tumor volume reduction of Met 2 while Met 1 and Met 3 remained unchanged [
Brain metastases occur in approximately 3.5–17% of patients with mRCC and are associated with significant morbidity and poor survival (median overall survival <11 months).[
Aiming to decrease the risk of SF-GKRS associated ARE, different groups have explored alternative schedules with the aim of reducing toxicity whilst optimising local control; in this framework, volume-staged hypofractionation has become a vivid subject of discussion.[
Modulation of two concurrent prescription doses at each fraction: RRR
RRR is a ‘double blade’ staged technique based on the concurrent adaption of two different dose prescriptions:
A BED (biological effective dose) plotted peripheral dose conceived to control dose dissipation to the circumscribing healthy tissues while ensuring steep intratumoural dose escalation A 10Gy baseline ablative prescription set to cover 70% to 90% of the tumor bed (previously coined baseline ablative isodose line or BAIL).[
A BED (biological effective dose) plotted peripheral dose conceived to control dose dissipation to the circumscribing healthy tissues while ensuring steep intratumoural dose escalation
A 10Gy baseline ablative prescription set to cover 70% to 90% of the tumor bed (previously coined baseline ablative isodose line or BAIL).[
Both prescriptions are surrogate to tumor volume dynamics and change concurrently at each fraction; the Leksell GammaPlanÒ software plays a fundamental role in that respect.
The inclusion of underlying radiobiological parameters and inherent physio-mathematical variables are quintessential for triggering key microenvironmental events involving vascular damage and antitumor immunity. The rationale of the procedure can be found elsewhere.[
In this particular case, the positive clinical and radiographic evolution of Met 1 and Met 2 post-RRR were similar to previous reports from other authors and Sinclair et al.[
Moreover, the fact that our patient developed an ARE at the site of Met 1 and Met 2 despite a hypofractionated approach, suggests that SF-GKRS would have led to greater perilesional edema and possibly substantial radionecrosis resulting in further neurologic damage. Several studies seem to support the latter proposal.[
As illustrated in this report, progressive extracranial disease remains a major problem for many patients with brain metastatic disease. Promising therapeutic breakthroughs in the field of medical uro-oncology are reshaping the management of mRCC; however, the long-term effects of most agents, such as checkpoint, multitargeted tyrosine kinase, and mammalian target of rapamycin inhibitors require much improvement, particularly in the context of concurrent metastatic disease in the central nervous system. The latter might require a better understanding of key concurrent antitumoral mechanisms aiming to optimize the use of radiation such as the modulation of T-cell expansion, the regulation of postradiation blood-brain barrier permeability and the use of “scavenging” agents targeting angiogenesis and endothelial cell proliferation to further “downturn” tumor radioresistance.[
In this case of mRCC brain disease, RRR proved effective in producing sustained ablation while limiting toxicity. We can cautiously assume that RRR had a positive impact over local tumor control and overall survival based on the following variables: (i) degree of local response of Met 1 and Met 2 to RRR, (ii) Time of survival (21 months) despite limited response / tolerance to systemic treatment (iii) known median overall survival in these cases (<11 months), and (iv) stable KPS- and neurological status throughout follow-up.
RRR should be considered in the acute/subacute management of mRCC brain metastases, particularly in those requiring a more tailored approach due to local anatomo-functional constraints. Yet, as illustrated here, overall metastatic activity remains a major challenge in many cases; thus, further studies on the synergetic role of radiation and specific antitumoral therapies are of interest and warranted.
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