Synchronous Brain Metastases as a Poor Prognosis Factor in Clear Cell Renal Carcinoma: A Strong Argument for Systematic Brain Screening

doi:10.21203/rs.3.rs-196626/v1

Download PDF

Research Article

Synchronous Brain Metastases as a Poor Prognosis Factor in Clear Cell Renal Carcinoma: A Strong Argument for Systematic Brain Screening

https://doi.org/10.21203/rs.3.rs-196626/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 10 Apr, 2021

Read the published version in Journal of Neuro-Oncology →

You are reading this latest preprint version

Purpose

Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group).

Methods

It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death.

Results

99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p=0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]).

Conclusions

Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.

Oncology

clear cell renal cell carcinoma

metastatic

synchronous brain metastases

stereotactic radiation

cabozantinib

immunotherapy

Brain metastases (BM) usually represent a poor prognostic factor in solid tumors and overall survival in these patients seems to be limited [1]. Moreover, quality of life may be affected by brain damage caused by tumoral lesions, as well as by the different focal treatments (radiotherapy, surgery) [2]. Indeed, the presence of the blood-brain barrier (BBB) limits the delivery and the efficacy of systemic anticancer therapies to the central nervous system (CNS). Multiple mechanisms are involved in this phenomenon: the limited passive diffusion of systemic agents, the presence of active efflux pumps, the different volume of distribution of the drug in the brain parenchyma... [3].

Local therapies have been subsequently developed in order to control tumor progression in the brain. The treatment of BM is based on surgery and radiotherapy: stereotactic radiotherapy (SRT, ie radiosurgery or hypofractionated stereotactic radiotherapy, which both have proven their efficacy on renal BM [4]), or whole brain radiotherapy (WBRT)[5]. A combined approach of surgery followed by post-operative SRT whenever possible seems to be the most efficient strategy [6][7]. When surgery is not possible and for patients with up to 3 small lesions, SRT alone compared to SRT followed by WBRT has shown less cognitive deterioration without impact on overall survival with however worse local control [8]. The total volume represented by BM, more than their number, should be a decision criteria for the use of SRT versus WBRT [9]. Unfortunately, despite these different treatment modalities some BM will present local progression or relapse.

About 10% of patients with metastatic renal cell carcinoma (RCC) have brain involvement [10] [11]. A high TN stage at diagnosis could be a predictive factor for the development of BM, as well as the presence of boneor thoracic metastases [10][11]. However, brain imaging is not routinely recommended for patients with localized or metastatic RCC in the absence of neurological symptoms. The proportion of patients with synchronous BM at diagnosis of metastatic RCC is low, probably less than 5%. Because patients with BM are usually excluded from clinical trials, the efficacy of tyrosine kinase inhibitors (TKI) in this population is not well known, and localized treatments remain mandatory to achieve local control of such lesions. Indeed, for patients with synchronous BM, focal treatment of the CNS is a priority, and has to be planned usually before the start of any systemic treatment.

We hypothesized that patients with synchronous BM present a worse prognosis than patients who developed BM during the course of their disease.

Study design

We retrospectively reviewed the files of patients with metastatic brain RCC treated with TKI in our institution. Our primary objective was to compare the median overall survival of patients with synchronous BM versus metachronous BM. Our secondary objectives were to describe the efficacy and the side effects of surgery and radiotherapy of the CNS in this population.

Population

Our population sample included all adult patients with clear cell renal cell carcinoma (ccRCC) metastatic to the brain and treated with at least one line of TKI. ccRCC was histologically or cytologically proven. We collected usual prognostic factors: the TN stage, the histological pattern, the Fuhrman nuclear grade and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score (composed of the Karnofsky performance status, the time from diagnosis to systemic treatment, neutrophil count, platelet count, haemoglobin levels and serum calcium levels). Patients treated with interleukine-2 or interferon monotherapy in first line were excluded because of the difference of prognosis of such disease before the era of TKI, as well as patients with non-clear cell subtypes (excepted for sarcomatoid feature). Patients with BM diagnosed within the first 3 months following diagnosis of metastatic disease composed the SynBM group, and patients who developed BM after 3 months composed the MetaBM group.

Treatments and endpoints

Systemic treatments were administered as standard practice according to national approval or within a clinical trial. SRT was defined as any type of hypofractionated focused radiation therapy of the brain (ie: hypofractionated radiation therapy and stereotactic radiosurgery). Brain progression was defined by a relapse on the site of the treated BM or by the occurrence of a new BM in a different site, proven by brain imaging (MRI or TDM). Overall survival (OS) was defined from the date of diagnosis of metastatic ccRCC to death or last follow-up. Specific brain overall survival (BM-OS) was defined from the diagnosis of BM to death or last follow-up. Brain progression-free survival (B-PFS) was defined as the time from focal brain therapy to brain progression, death, or last follow-up.

Statistical analysis

Statistical analyses were performed with SAS version 9.4 software (SAS Institute). Survival distributions were evaluated by the Kaplan-Meier method. Log-rank tests were used to compare sub-populations.

Ethics and consent to participate

The study was approved by the General Data Protection Regulation (GDPR) under Protocol MR04 (Non-Human Research, Health Studies and Evaluations) as R201-004-102 number.

Patients

99 patients with ccRCC metastatic to the brain and treated with TKI at the Centre Léon Bérard between January 2005 and December 2019 were analyzed. 44 of them (44%) presented with synchronous BM, and 55 of them (55%) developed metachronous BM. The sex ratio M/F was 3.7 with 78 men and 21 women. The median age was 58.9 years [32.2;83.2]. Characteristics of the population are shown in Table 1. Patients in the two groups were comparable in terms of age, sex, histological features, disease stages, and IMDC scores. Patients were treated with a median of 2 lines of systemic treatment [1–8]. 89 patients received a TKI in first line: 73 patients received sunitinib, 5 patients pazopanib, and 11 patients sorafenib. The most used TKI for all lines were sunitinib (89 patients), sorafenib (30 patients), axitinib (29 patients), and cabozantinib (17 patients). Only 12 patients received an immune checkpoint inhibitor (ICI), administered between the 2nd and the 6th line. The median follow-up from the diagnosis of metastatic disease to either death or last follow-up was 34.8 months (1.5; 144.8): 19.9 months (1.5; 112.8) in the SynBM group and 46.2 months (7.1; 146.8) in the MetaBM group.

Table 1: Characteristics of patients

	Synchronous brain metastasis		Metachronous brain metastasis		All patients
	Synchronous brain metastasis		Metachronous brain metastasis		All patients
	N=44		N=55		N=99
Clinical characteristics
Age (years)	57.9	[36.4;82.2]	60.6	[32.2;83,2]	58.9	[32.2;83.2]
Sexe
Man	36	(81.8%)	42	(76.4%)	78	(78.8%)
Woman	8	(18.1%)	13	(23.6%)	21	(21.2%)
T stage
1	5	(11.4%)	9	(16.4%)	14	(14.1%)
2	11	(25.0%)	11	(20.0%)	22	(22.2%)
3	25	(56.8%)	30	(54.5%)	55	(55.6%)
4	1	(2.3%)	2	(3.6%)	3	(3.0%)
Unknown	2		3		5
N stage
0	22	(50.0%)	25	(45.5%)	47	(47.5%)
1	5	(11.4%)	1	(1.8%)	6	(6.1%)
2	1	(2.3%)	4	(7.3%)	5	(5.1%)
Unknown	16		25		41
M stage
0	21	(47.7%)	27	(49.1%)	48	(48.5%)
1	23	(52.3%)	28	(50.9%)	51	(51.5%)
IMDC score
Favorable	2	(4.5%)	6	(10.9%)	8	(8.1%)
Intermediate	18	(40.9%)	15	(27.3%)	33	(33.3%)
Poor	9	(20.5%)	14	(25.5%)	23	(23.2%)
Unknown	15		20		35
Histological characteristics
Majoritary feature
Clear cell	43	(97.7%)	55	(100.0%)	98	(99.0%)
Sarcomatoid	1	(2.3%)	0	(0.0%)	1	(1.0%)
Minority feature 1
Clear cell	0	(0.0%)	1	(1.8%)	1	(1.0%)
Sarcomatoid	6	(13.6%)	9	(16.4%)	15	(15.2%)
Oncocytic	0	(0.0%)	1	(1.8%)	1	(1.0%)
Eosinophilic	3	(6.8%)	4	(7.3%)	7	(7.1%)
None	35		40		75
Minority feature 2
Sarcomatoid	1	(2.3%)	0	(0.0%)	1	(1.0%)
Rhabdoid	1	(2.3%)	0	(0.0%)	1	(1.0%)
None	42		55		97
Furhman grade
1	1	(2.3%)	0	(0.0%)	1	(1.0%)
2	10	(22.7%)	15	(27.3%)	25	(25.3%)
3	12	(27.3%)	22	(40.0%)	34	(34.3%)
4	11	(25.0%)	13	(23.6%)	24	(24.2%)
Unknown	10		5		15
Systemic treatments
Number of lines administered/patient	2.0	[1.0-7.0]	3.0	[1.0-8.0]	2.0	[1.0-8.0]
Molecules administered (any line)
Sunitinib	41	(93.2%)	48	(87.3%)	89	(89.9%)
Everolimus	9	(20.5%)	23	(41.8%)	32	(32.3%)
Sorafenib	13	(29.5%)	17	(30.9%)	30	(30.3%)
Axitinib	14	(31.8%)	15	(27.3%)	29	(29.3%)
Bevacizumab	8	(18.2%)	11	(20.0%)	19	(19.2%)
Cabozantinib	6	(13.6%)	11	(20.0%)	17	(17.2%)
Pazopanib	4	(9.1%)	8	(14.5%)	12	(12.1%)
Nivolumab	3	(6.8%)	9	(16.4%)	12	(12.1%)
Temsirolimus	4	(9.1%)	4	(7.3%)	8	(8.1%)
Gemcitabine + 5-Fluorouracile	2	(4.5%)	4	(7.3%)	6	(6.1%)
Interferon alpha	2	(4.5%)	0	(0.0%)	2	(2.0%)
Adriamycine	1	(2.3%)	0	(0.0%)	1	(1.0%)

Abbreviation : IMDC = International Metastatic Renal Cell Carcinoma Database Consortium

BM characteristics

73 patients had a progressive systemic disease at diagnosis of the first BM: 39 patients (88.6%) in the SynBM group and 34 patients (61.8%) in the MetaBM group. BM were discovered because of neurological symptoms in 72 patients, 28 patients (63.6%) in the SynBM group and 44 patients (80%) in the MetaBM group, and because of systematic imaging for 27 patients, 16 patients (36.3%) in the SynBM group and 11 patients (20%) in the MetaBM group. 54 patients first presented with a solitary BM: 22 in the SynBM group and 32 the MetaBM group. 10 patients (18%) in the MetaBM group never had a brain imaging before the diagnosis of BM.

Overall Survival

OS for the global population was 34.8 months (95%CI [26.7–45.5]). Patients with synchronous BM presented a clinically and statistically significant reduction in median overall survival: median OS in the MetaBM group was 49.4 months (95%CI [34.4–67.7]), versus 19.6 months (95%CI [12.1–30.6]) in the SynBM group, p = 0.0002 (Fig. 1). In the MetaBM group, 80% of patients were alive at 2 years and 38% at 5 years, vs respectively 41% and 14% in the SynBM group. BM-OS in the MetaBM group was 16.4 months (95%CI [6.6–20.0]) vs 19.1 months (95%CI [11.6–29.9]) in the SynBM group, p = 0.23 (Fig. 2). The median time between the apparition of BM and the diagnosis of metastatic disease in the MetaBM group was 22.9 months (4.3; 125.7).

87 patients had died at the time of our analysis. There was no significant difference between the 2 groups concerning the cause of death: 30/99 patients died of global progression of the disease (ie systemic plus brain progression), 29 patients of systemic progression, 8 patients (4 in the SynBM group and 4 in the MetaBM group) of brain progression, 18 patients of other or unknown causes.

Local BM treatment

In our 99 patients, 152 focal treatments were performed at diagnosis of BM: SRT for 101 lesions (66.4%), WBRT for 25 patients (16.4%), Surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). Brain progression free survival for each treatment was respectively 6.7 months, 3.9 months, 10.4 months and 15.5 months. 58 patients presented with brain progression after a first local treatment. B-PFS for all patients was 7 months (IC95% [5.0-10.5]). (Fig. 3). 10 patients didn’t receive any focal treatment for BM: 7 patients because of poor performance status and/or fast progression of the disease, and 3 patients because of stability of BM on systemic therapy, and the small lesion size and/or the absence of associated neurological symptoms.

Complications of BM treatments are described in the Table 2. Adverse events occurred in 36% of patients treated with WBRT (intracranial hypertension or symptomatic brain oedema in 28% of cases), versus 23.8% of surgeries, and 20.8% of SRT. Radionecrosis was the most frequent complication of SRT (7.9% of treatments).

Table 2
Complications of brain focal therapies
	Focal treatment of brain metastasis								All
	Surgery		WBRT		Surgery + SRT		SRT		All
	N = 21		N = 25		N = 5		N = 101		N = 152
None	16	(76.2%)	16	(64.0%)	5	(100.0%)	80	(79.2%)	117	(77.0%)
Intracranial hypertension or symptomatic oedema	0	(0.0%)	7	(28.0%)	0	(0.0%)	10	(9.9%)	17	(11.2%)
Radionecrosis	0	(0.0%)	0	(0.0%)	0	(0.0%)	8	(7.9%)	8	(5.3%)
Bleeding	2	(9.5%)	0	(0.0%)	0	(0.0%)	2	(2.0%)	4	(2.6%)
Seizure	3	(14.3%)	1	(4.0%)	0	(0.0%)	1	(1.0%)	5	(3.3%)
Cognitive impairment	0	(0.0%)	1	(4.0%)	0	(0.0%)	0	(0.0%)	1	(0.7%)
Abbreviations: WBRT = whole brain radiotherapy; SRT = stereotactic radiotherapy

The presence of BM is a poor prognostic factor in RCC with historical overall survival of less than one year [12, [13]. Since TKI have been developed, the prognosis of these patients seems to have improved, although it remains worse than for patients without brain involvement. Indeed, Dudek et al [14] showed in their retrospective study on metastatic RCC patients treated with TKI between 2008 and 2010, that OS in patients with BM was 33 months vs 80 months in patients without BM, p = 0.010. With an OS of 34.8 months for all patients in our study, we have concordant results with the current literature. Furthermore, our study is the first to our knowledge that demonstrates the poor prognosis of patients with synchronous BM in patients with ccRCC and brain metastases. However, it is still unclear whether brain imaging should be systematically performed at the diagnosis of metastatic disease. Choi et al [15], in their retrospective study of 93 patients with rCC and BM did not show any difference in survival between patients with synchronous or metachronous BM. However, they chose to consider OS from the time of BM diagnosis with similar results to ours (9.9 months for patients with metachronous BM vs 14.5 months for patients with synchronous BM, p = 0.4780). We chose in our study to consider OS from the diagnosis of metastatic RCC because the question of brain screening at this phase of the disease is controversial. OS was significantly different between our 2 groups (49.4 months in the MetaBM group vs 19.6 months in the SynBM group, p = 0.0002) whereas OSbm was not (p = 0.23). With a median time to develop BM of 26.7 months in the Choi study and 22.9 months in our study, we can extrapolate that the low BM-OS in the MetaBM group may be explained by the secondary drug resistance developed by RCC because of previous exposure to systemic therapies before the occurrence of BM. Furthermore, we can note that the apparition of metachronous BM seems to be an evolutionary turning point in the cancer disease, as patients at this point present a similar OS to patients with a diagnosis of synchronous BM.

Focal treatments were associated to systemic therapies in 89% of our patients in this study. Khan et al recently showed in their meta-analysis of seven studies that the combination of SRT with TKI in patients RCC with BM was associated with better OS and better local control compared to patients who didn’t received TKI [16]. In our study, SRT was used most of the time, followed by surgery. Better PFS was obtained with surgery followed by SRT orsurgery alone. Indeed, patients who are eligible to surgery must have good performance status and solitary or a small number of lesions [5], which are 2 favorable prognostic factors [17]. Surgery followed by focal radiation is the most efficient approach for brain control [7] but was used only 5 times, probably because the data that support this combined approach have only been recently published, and because not all lesions are accessible to surgical resection. WBRT was associated with the lowest PFS, probably because it was used for patients with advanced brain diseases. It may suggest that these patients with a poor prognosis could better benefit from exclusive supportive care without specific brain therapy, especially because of the cognitive impairment WBRT can cause [8]. SRT alone was the most used focal therapy in our study : indeed, it is an attractive option because of its efficiency on brain control even for multiple small lesions (4)[18][19], its feasibility and acceptability, with less cognitive impairment [8]. The most frequent adverse event of SRT was radionecrosis (7.9% of patients), which is concordant with the literature [4]. Furthermore, Wolf et al. showed that in patients treated with stereotactic radiosurgery, local control and overall survival are better for subcentimetimetric lesions [19], independently of the histology of the primitive tumor and the number of BM. This is another argument in favor of systematic brain screening in order to propose patients early and optimal focal therapy.

Most of our patients received sunitinib, which was the most used TKI in first line in France at the time of our study. The role of TKI on BM remains unclear. Sunitinib and sorafenib seem to reduce the occurrence of BM [20][21], and several case reports and small cohorts showed brain responses to sunitinib [22][23] and more recently cabozantinib [24][25]. However no prospective trial succeeded in demonstrating a benefit of TKI on BM so far [26]. Therefore, focal therapy with surgery and/or radiotherapy remains essential to achieve brain control. Cabozantinib is a reversible inhibitor targeting multiple tyrosine kinases such as VEGFR, AXL, RET and MET. BM tumor cells from renal primary overexpress MET in 35% of cases [27]. A retrospective trial of 12 patients with BM treated with cabozantinib reported intracerebral tumor control in 9 patients (75%), including 4 patients who didn’t received focal therapy to the brain [25]. A phase II trial (ET19-006 - CABRAMET, NCT03967522) is currently ongoing to assess the efficacy of cabozantinib in patients with RCC and brain metastases who have not previously received focal brain therapy.

We also note that only 12 patients received nivolumab in our study. Indeed, efficacy of ICI monotherapy on brain metastases has not been demonstrated in renal carcinoma. Flippot et al, in the BM subgroup of the prospective phase 2 NIVOREN trial, did not show any response with nivolumab on untreated BM, excepted for infracentimetric lesions [28]. However, the combination of ipilimumab plus nivolumab has already shown efficacy on untreated BM in melanoma [29], and encouraging signals in renal cancer with BM [30].

Our study presents several limitations: it is a retrospective analysis. We analyzed patients over a period of 14 years; the improvement of anti-cancer therapies during this period, especially for SRT, could have induced some heterogeneity in the population. In order to limit this bias, we chose not to include patients treated before the TKI era. It however gives interesting results to support early brain screening for patients with metastatic RCC.

Patients with ccRCC diagnosed with synchronous BM have a poorer prognosis than patients who develop BM later on. Nevertheless, the diagnosis of BM is of poor prognosis with a survival of 16-19 months regardless of synchronous or metachronous situation. Whenever possible, focal treatment (surgery or stereotactic radiotherapy) of BM should be used. The use of WBRT should be carefully discussed due to its limited efficacy and frequent side effects. Using a combination of systemic and focal treatments results in a median OS from diagnosis of metastatic disease of 1.6 years when BM are synchronous, compared to more than 4 years when BM are metachronous. Because synchronous BM is of poor prognosis, brain imaging should be performed at the time of diagnosis of metastasis in order to deliver optimal focal therapy, preserve quality of life and prolong survival. Specific clinical trials should also be encouraged.

The authors did not receive support from any organization for the submitted work.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Financial disclosures

Aude Fléchon:

- Honoraria and personal fees from BMS, IPSEN, ROCHE, PFIZER, MSD

Sylvie Négrier:

- research grant, personal fees and non-financial support from PFIZER,

- personal fees and non-financial support from BMS,

- research grant, personal fees and non-financial support from IPSEN,

- personal fees from NOVARTIS,

- personal fees and non-financial support from MSD.

Helen Boyle:

- Travel expenses from BMS, Pfizer, Janssen, Astellas, Sanofi, Ipsen

- Honoraria from Sanofi, Novartis, Janssen, Ipsen, Pfizer

Eve-Marie Neidhart:

- Honoraria and personal fees from NOVARTIS, BMS, MSD

Other authors have no financial disclosure.

Authors contribution

Conception and design: Valentine Ruste, Aude Flechon

Acquisition of data: Valentine Ruste, Melodie Carbonneaux, Guillaume Moriceau, Marie-Pierre Sunyach, Ronan Tanguy, Helen Boyle, Eve-Marie Neidhart, Emmanuel Jouanneau, Aude Flechon, Sylvie Négrier

Analysis and interpretation of data: Valentine Ruste, Aude Flechon

Drafting of the manuscript: Valentine Ruste, Aude Flechon, Sylvie Négrier, Sophie Robin

Stastistical analysis: Camille Schiffler, Valentine Ruste

Supervision: Aude Flechon, Sylvie Négrier

[1] D. N. Cagney et al., “Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study,” Neuro-Oncol., vol. 19, no. 11, pp. 1511–1521, Oct. 2017, doi: 10.1093/neuonc/nox077.

[2] R. Soffietti et al., “A European Organisation for Research and Treatment of Cancer Phase III Trial of Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With One to Three Brain Metastases From Solid Tumors After Surgical Resection or Radiosurgery: Quality-of-Life Results,” J. Clin. Oncol., vol. 31, no. 1, pp. 65–72, Jan. 2013, doi: 10.1200/JCO.2011.41.0639.

[3] L. L. Muldoon et al., “Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check,” J. Clin. Oncol., vol. 25, no. 16, pp. 2295–2305, Jun. 2007, doi: 10.1200/JCO.2006.09.9861.

[4] P. Lesueur et al., “Radiosurgery or hypofractionated stereotactic radiotherapy for brain metastases from radioresistant primaries (melanoma and renal cancer),” Radiat. Oncol., vol. 13, no. 1, p. 138, Dec. 2018, doi: 10.1186/s13014-018-1083-1.

[5] R. Soffietti et al., “Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO),” Neuro-Oncol., vol. 19, no. 2, pp. 162–174, Feb. 2017, doi: 10.1093/neuonc/now241.

[6] A. M. S. Kumar et al., “Postoperative hypofractionated stereotactic brain radiation (HSRT) for resected brain metastases: improved local control with higher BED10,” J. Neurooncol., vol. 139, no. 2, pp. 449–454, Sep. 2018, doi: 10.1007/s11060-018-2885-6.

[7] A. Mahajan et al., “Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial,” Lancet Oncol., vol. 18, no. 8, pp. 1040–1048, Aug. 2017, doi: 10.1016/S1470-2045(17)30414-X.

[8] P. D. Brown et al., “Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial,” JAMA, vol. 316, no. 4, p. 401, Jul. 2016, doi: 10.1001/jama.2016.9839.

[9] A. Niranjan, E. Monaco, J. Flickinger, and L. D. Lunsford, “Guidelines for Multiple Brain Metastases Radiosurgery,” in Progress in Neurological Surgery, vol. 34, A. Niranjan, L. D. Lunsford, and H. Kano, Eds. S. Karger AG, 2019, pp. 100–109.

[10] M. Bianchi et al., “Distribution of metastatic sites in renal cell carcinoma: a population-based analysis,” Ann. Oncol., vol. 23, no. 4, pp. 973–980, Apr. 2012, doi: 10.1093/annonc/mdr362.

[11] T. Chandrasekar, Z. Klaassen, H. Goldberg, G. S. Kulkarni, R. J. Hamilton, and N. E. Fleshner, “Metastatic renal cell carcinoma: Patterns and predictors of metastases—A contemporary population-based series,” Urol. Oncol. Semin. Orig. Investig., vol. 35, no. 11, p. 661.e7-661.e14, Nov. 2017, doi: 10.1016/j.urolonc.2017.06.060.

[12] D. A. Decker, V. L. Decker, A. Herskovic, and G. D. Cummings, “Brain metastases in patients with renal cell carcinoma: prognosis and treatment.,” J. Clin. Oncol., vol. 2, no. 3, pp. 169–173, Mar. 1984, doi: 10.1200/JCO.1984.2.3.169.

[13] O. Bennani et al., “Brain metastasis from renal cell carcinoma,” Neurochirurgie, vol. 60, no. 1–2, pp. 12–16, Feb. 2014, doi: 10.1016/j.neuchi.2013.12.001.

[14] A. Z. Dudek et al., “Brain Metastases from Renal Cell Carcinoma in the Era of Tyrosine Kinase Inhibitors,” Clin. Genitourin. Cancer, vol. 11, no. 2, pp. 155–160, Jun. 2013, doi: 10.1016/j.clgc.2012.11.001.

[15] S. Y. Choi et al., “Prognostic Factors for Survival of Patients With Synchronous or Metachronous Brain Metastasis of Renal Cell Carcinoma,” Clin. Genitourin. Cancer, vol. 15, no. 6, p. 717—723, Dec. 2017, doi: 10.1016/j.clgc.2017.05.010.

[16] M. Khan, Z. Zhao, S. Arooj, and G. Liao, “Impact of Tyrosine Kinase Inhibitors (TKIs) Combined With Radiation Therapy for the Management of Brain Metastases From Renal Cell Carcinoma,” Front. Oncol., vol. 10, p. 1246, Jul. 2020, doi: 10.3389/fonc.2020.01246.

[17] P. W. Sperduto et al., “Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient,” J. Clin. Oncol., p. JCO.20.01255, Sep. 2020, doi: 10.1200/JCO.20.01255.

[18] M. Yamamoto et al., “Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study,” Lancet Oncol., vol. 15, no. 4, pp. 387–395, Apr. 2014, doi: 10.1016/S1470-2045(14)70061-0.

[19] A. Wolf et al., “Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery,” J. Neurosurg., vol. 128, no. 1, pp. 23–31, Jan. 2018, doi: 10.3171/2016.10.JNS161036.

[20] C. Massard, J. Zonierek, M. Gross-Goupil, K. Fizazi, C. Szczylik, and B. Escudier, “Incidence of brain metastases in renal cell carcinoma treated with sorafenib,” Ann. Oncol., vol. 21, no. 5, pp. 1027–1031, May 2010, doi: 10.1093/annonc/mdp411.

[21] J. Verma, E. Jonasch, P. Allen, N. Tannir, and A. Mahajan, “Impact of tyrosine kinase inhibitors on the incidence of brain metastasis in metastatic renal cell carcinoma: TKIs and Brain Metastasis in mRCC,” Cancer, vol. 117, no. 21, pp. 4958–4965, Nov. 2011, doi: 10.1002/cncr.26138.

[22] M. E. Gore et al., “Sunitinib in metastatic renal cell carcinoma patients with brain metastases,” Cancer, vol. 117, no. 3, pp. 501–509, Feb. 2011, doi: 10.1002/cncr.25452.

[23] Z. D. Lim, A. Mahajan, J. Weinberg, and N. M. Tannir, “Outcome of Patients With Renal Cell Carcinoma Metastatic to the Brain Treated With Sunitinib Without Local Therapy:,” Am. J. Clin. Oncol., vol. 36, no. 3, pp. 258–260, Jun. 2013, doi: 10.1097/COC.0b013e3182467b9a.

[24] S. Négrier et al., “Activity of cabozantinib in radioresistant brain metastases from renal cell carcinoma: two case reports,” J. Med. Case Reports, vol. 12, no. 1, p. 351, Dec. 2018, doi: 10.1186/s13256-018-1875-9.

[25] G. Peverelli et al., “Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population,” Clin. Genitourin. Cancer, vol. 17, no. 4, pp. 291–298, Aug. 2019, doi: 10.1016/j.clgc.2019.05.002.

[26] C. Chevreau et al., “A Phase II Trial of Sunitinib in Patients With Renal Cell Cancer and Untreated Brain Metastases,” Clin. Genitourin. Cancer, vol. 12, no. 1, pp. 50–54, Feb. 2014, doi: 10.1016/j.clgc.2013.09.008.

[27] L. Derosa et al., “Inter and intra-tumor heterogeneity of PD-L1 and MET expression in metastatic renal cell carcinoma (mRCC).,” J. Clin. Oncol., vol. 35, no. 15_suppl, pp. 4569–4569, 2017, doi: 10.1200/JCO.2017.35.15_suppl.4569.

[28] R. Flippot et al., “Safety and Efficacy of Nivolumab in Brain Metastases From Renal Cell Carcinoma: Results of the GETUG-AFU 26 NIVOREN Multicenter Phase II Study,” J. Clin. Oncol., vol. 37, no. 23, pp. 2008–2016, Aug. 2019, doi: 10.1200/JCO.18.02218.

[29] H. A. Tawbi et al., “Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain,” N. Engl. J. Med., vol. 379, no. 8, pp. 722–730, Aug. 2018, doi: 10.1056/NEJMoa1805453.

[30] H. Emamekhoo et al., “Safety and efficacy of nivolumab plus ipilimumab (NIVO+IPI) in patients with advanced renal cell carcinoma (aRCC) with brain metastases: Interim analysis of CheckMate 920.,” J. Clin. Oncol., vol. 37, no. 15_suppl, pp. 4517–4517, May 2019, doi: 10.1200/JCO.2019.37.15_suppl.4517.

Download PDF

Journal Publication

published 10 Apr, 2021

Read the published version in Journal of Neuro-Oncology →

Reviews received at journal
07 Feb, 2021
Editor assigned by journal
04 Feb, 2021
Reviewers invited by journal
04 Feb, 2021
First submitted to journal
31 Jan, 2021

You are reading this latest preprint version

Synchronous Brain Metastases as a Poor Prognosis Factor in Clear Cell Renal Carcinoma: A Strong Argument for Systematic Brain Screening

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Study design

Population

Treatments and endpoints

Statistical analysis

Ethics and consent to participate

Results

Patients

BM characteristics

Overall Survival

Local BM treatment

Discussion

Conclusion

Declarations

References

Status:

Journal Publication

Version 1