Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening

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). 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. 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]). 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.


Introduction
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, i.e., radiosurgery or hypofractionated stereotactic radiotherapy, which both have proven their efficacy on renal BM [4]), or whole brain radiotherapy (WBRT) [5]. A combined approach with post-operative SRT following surgery leads to better local control [6,6]. 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 bone or thoracic metastases [10,10]. 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 (i.e.: 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.

Results
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.   [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).
Eighty-seven 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). Ten patients didn't receive any focal treatment for BM: seven 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).

Discussion
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 IMDC international metastatic renal cell carcinoma database consortium 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 two 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) [18,18], 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 Fig. 2 Overall survival from the diagnosis of BM (BM-OS OSbm ) in SynBM and MetaBM groups. SynBM synchronous brain metastases; MetaBM metachronous brain metastases 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, Fig. 3 Survival before brain progression for all patients 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.

Conclusion
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 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 to provide a better brain control and preserve patients quality of life. Specific clinical trials should also be encouraged. Funding 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.

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

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