The recent advances in the treatment of metastatic renal cell carcinoma (mRCC), from the introduction of the first antiangiogenic tyrosine kinase inhibitor (TKI) sorafenib in 2005 to the most recent approval of the first immune checkpoint inhibitor (CKI) nivolumab in 2015, allowed to improve the management of the disease and most importantly to prolong overall survival (OS) (1,2). In this era, especially after the publication of recent pivotal trials introducing three new therapeutic combinations in the first-line treatment setting (3-5), we can properly talk about the “embarrassment of riches” for the systemic therapy for clear-cell mRCC.
With such new treatment options, one could be enticed to rapidly switch treatment line in the case of oligoprogression, underestimating the importance of extending clinical benefit from each single treatment line. Nevertheless, saving resources is still a crucial point, also considering multidisciplinary approaches, potentially becoming relevant in the management of long-surviving patients.
Despite renal cancer was historically considered radioresistant, it is reported to have a lower α per β coefficient of the linear-quadratic model (6). Thus, irradiations with high dose per fraction are more likely to obtain good local control (LC). In the stereotactic body radiotherapy (SBRT) era, thanks to high-precision irradiation with image guided systems and lesion tracking, the dose per fraction can be increased, offering the possibility to maximize the effectiveness on the target lesion while minimizing the adverse effects on the surrounding healthy tissues (6). In the case of mRCC, SBRT may contribute to tackle the disease overtime, sometimes recovering the control of an oligoprogressive disease, or otherwise allowing the temporary discontinuation of systemic therapy, offering “treatment holidays” to responding oligometastatic patients, improving their quality of life without compromising the history of the disease.
Recently, an interesting report about the role of SBRT for the management of oligometastatic mRCC was published by Franzese et al. in The Journal of Urology (7), retrospectively describing the outcome of 73 irradiated extra-cranial metastases from 58 mRCC patients. The irradiated sites were mostly lung (53%), nodes (26%) and bone (10%).
The authors described the outcome of a mono-institutional population treated between 2004 and 2016, with contraindications to secondary surgery after previous nephrectomy, underwent SBRT for progression of isolated disease sites or to consolidate the response to systemic treatment. Endpoints of the study were the infield LC, progression free survival (PFS) of patients and OS. Acute and late SBRT-related toxicity was also explored (7).
The clinical target volume (CTV) was delineated by computed tomography (CT) scan. The radiotherapy technique was not specified (probably constituted by the intensity modulated arc therapy). Treatment was guided by daily Cone Beam CT. Median CTV diameter was 26 mm and planning target volume diameter 39 mm. Median total prescribed dose was 45 Gy in a median number of 5 fractions (7).
At the median follow-up of 16.1 months, the LC rate at 12 and 18 months was 90.2% in both time-points with PFS rate 46.2% and 35.0% respectively at 12 and 18 months. Such data are consistent with those of other similar reports from the literature (7-19).
Two further relevant data to be noticed among the results of this study are represented by the long median time to distant metastases, of 32.7 months, and by the median interval between diagnosis and the onset of systemic therapy, of 37.5 months, undoubtedly configuring a positively selected population, as then demonstrated by the 100% of surviving patients at 2-year (7). Anyhow, one could argue about those 5 months of metastatic disease without systemic therapy, strongly suggesting the possible utility of SBRT to delay the initiation of the systemic treatment. Indeed, since the authors clearly reported the timing of systemic therapies, we can conclude that only 65.5% of patients received systemic treatment before SBRT, whilst 20 patients (34.5%) didn’t receive any drug before the irradiation of the metastases. Notably, the median interval between SBRT and the subsequent systemic treatment onset was 9.7 (range, 3.1 to 18.9) months. In this setting, SBRT successfully controlled the disease at its onset, delaying the beginning of systemic drugs, thus preserving patient quality of life.
The safety of SBRT in the study population was also investigated. In the acute setting, no grade 3 or 4 (G3–4) adverse events were observed, whilst 1.7% of patients had G2 toxicity and 12% had G1 side effects (fatigue, pain, nausea/vomiting). Late toxicities were rare, but maybe less manageable, with G1–2 pneumonitis in 6.8% of cases (7). The authors did not report whether such toxicities occurred in patients undergoing systemic therapy during SBRT, not allowing to hypothesize a radiosensitizing effect possibly impacting also on tolerability. Nevertheless, the evidence about treatment with radiotherapy during systemic therapy with TKI is wide across several tumor types (20-22) and the safety of administrating TKI at the standard dose for renal cancer patients concurrently with radiotherapy was demonstrated in early phase trials (21).
Another interesting highlight from this study is represented by the reporting of a non-clear cell histology subgroup (10 patients) (7). Despite being only a case series, it addresses the literature lack about the issue of applying SBRT in such minor histotype of mRCC, which radiosensitivity is still largely unknown. At our knowledge, this is the first report published about the issue. Moreover, the authors performed a stratified analysis of patients with clear-cell histology, demonstrating that only for such subgroup the control of irradiated metastases positively correlated with the use of systemic therapies before SBRT [hazard ratio (HR) of 0.15; 95% CI, 0.026–0.85, P=0.032]. This element could suggest that the radiosensitising activity of TKI could be true for clear-cell mRCC, but unlikely when considering non-clear cell histologies (papillary and chromophobe cell carcinoma). Indeed, in the overall population, no benefit from receiving prior systemic therapy emerged in terms of PFS. On the other hand, other clinical elements with a positive impact of PFS were represented by the presence of metachronous vs. synchronous metastases (HR 0.20; 95% CI, 0.08–0.51, P=0.001) and of single vs. multiple metastases (HR 0.35; 95% CI, 0.18–0.69, P=0.002). Unexpectedly, OS was influenced only by the lesion diameter (HR 1.8; 95% CI, 1.06–3.06, P=0.028), but this was not confirmed at the multivariate analysis (7).
This work has nevertheless several limitations. The enrollment time is quite extended, from 2004 to 2016, including a likely heterogeneous population, up today already anachronistic, considering the rapidly evolving paradigm of treatment already cited for mRCC. Indeed, on a hand 46.5% received TKI, whilst 13.8% of patients only received unspecified intraosseous therapies and even 6.9% received only chemotherapy, creating a legitimate doubt of undertreatment for this study population (23). Therefore, the reliability of such results can be still feasible for TKI treated populations, but it suffers from lacking data about CKI treatment options, currently representing the mainstay of advanced renal cancer therapy.
Eventually, this study is retrospective, with consequent selection bias. It cannot be clarified whether the prolonged survival observed in this group is a result of a selected patient population with indolent tumors, or whether it is due to the treatment intervention with SBRT. These elements should be considered as both accountable for the possible survival improvement, because oligometastatic patients usually have more time to receive local therapies aside from systemic approaches, thus increasing their likeliness to improve survival. Once again, we have no real need to wonder if the chicken or the egg came first: the crucial point of the issue is the translation of these data into clinical practice, identifying the best candidates for integrated therapies among mRCC patients. A further step will necessarily be represented by the identification of the best sequence or combination of such local treatments with the novel immunotherapies. The combination of systemic immunotherapy and SBRT on metastatic sites could represent the best approach to oligometastatic mRCC in the next future, due to a possible abscopal effect (24). Moreover, combining CKI with SBRT could enhance the local and systemic efficacy of both treatments and overcome the radioresistance of certain tumors (25). Some trials are currently ongoing to address this hypothesis, investigating the feasibility and the activity of the combination of radiotherapy and immunotherapy for mRCC patients (26).
As already cited, further several reports from the literature, summarized by Table 1 (8-19), also demonstrated a high LC with SBRT, overall confirming the feasibility of such local approach for mRCC patients, especially in the case of oligometastatic disease. Probably, the more effective the systemic therapy, the more useful the loco-regional approach in the history of the disease (27), now opening the door on a golden era in which the treatment for oligometastatic or oligoprogressing mRCC will be really patient-tailored.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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