Local Control Rates of Metastatic Renal Cell Carcinoma (RCC) to Thoracic, Abdominal, and Soft Tissue Lesions Using Stereotactic Body Radiotherapy (SBRT)

The global annual incidence of renal cell carcinoma (RCC) is nearly 209,000 cases, killing over 100,000 people each year [5]. The majority of these patients present with isolated disease, however, about 30 % of these patients recur after treatment either locally or, more frequently, distantly and about the same percentage present with metastatic spread at the time of diagnosis [18]. In the setting of metastatic disease, RCC most commonly spreads to the lung, accounting for approximately 60 % of metastatic cases. Hepatic involvement occurs in about 20 % of cases. Prognosis is generally favorable for patients with non-metastatic disease however the two-year survival in patients with widespread disease is much worse (10–20 %) [18].

As patients with RCC continue to live longer given the rapid advances seen in systemic treatment for RCC with targeted agents (eg, tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) inhibitors, and mTOR inhibitors), localized treatment of enlarging or anatomically problematic masses is becoming increasingly utilized to further lengthen and improve quality of life [4, 6, 11]. In patients with oligo-metastatic disease, surgical resection has been employed with promising results. For instance, Loizzi et al. demonstrated improved overall survival, four-year survival of 50 %, after surgically resecting easily accessible RCC lung lesions [9].

In addition to surgical therapy, traditionally fractionated radiotherapy has been used to treat metastatic disease despite the traditional thinking of RCC being “radioresistant”. However, over the past decade, increased use of hypofractionation with stereotactic body radiotherapy (SBRT) has allowed clinicians to accurately target lesions and deliver more ablative doses. Efficacy of SBRT has been demonstrated in multiple metastatic sites, with local control rates above 90 % [13, 17, 18]. Bextracranial stereotactic radiotherapyextracranial stereotactic radiotherapysingle-institution studies demonstrating high local control rates using SBRT, we sought to directly compare the radiographic outcomes of RCC lesions between traditional or conventional fractionation (CF-EBRT) and SBRT in our institution to enhance the dataset analyzing the radiosensitivity of RCC. Additionally, the goal of this study was to further define the most effective radiation delivery by estimating a minimum dose, either fraction size or biologic effective dose (BED) cutoff, needed to achieve long term local control.

As assessment of radiation therapy’s effectiveness in RCC is dependent on the BED administered and this work provides an important comparison between SBRT and EBRT in this regard. Presently, the majority of SBRT data for RCC tumors focuses on osseous metastatic sites, with less data on non-bony locations. In the era of SBRT, our findings in addition to other single institutional studies, have demonstrated long-term radiographic local control rates for RCC lesions with the use of SBRT instead of CF-EBRT. The data presented here is an update of prior data published at our institution, which had included 25 lesions (in 13 RCC patients) treated with SBRT; the results here, which includes more lesions with longer follow up, confirms our prior findings that aggressive SBRT can result in good local control rates. Additional institutions have also demonstrated similar results [12, 18]. Wersall and colleagues published their results and demonstrated local control rates above 90 % in their series of RCC treated sites including lung, renal bed, lymph nodes, and adrenal gland; 30 % of patients had complete regression of lesions within 3–36 months, 60 % with partial volume reduction or no change after a median follow-up of 37 months, 2 % had progression, and 8 % were non-evaluable due to early death or atelectasis 18]. Svedman et al. demonstrated very similar findings with a 98 % local control rate. Complete response in their cohort was observed in 21 % of the patients and 58 % of the patients had a partial volume reduction or local stable disease after a median follow-up of 52 months [16]. These findings are similar to our results, with local control rates of 90 % or higher. Taken together, these single institutional studies suggest that SBRT may be more effective at controlling RCC lesions, which were once thought to be radioresistant with the use of lower dose, conventional therapy.

The results presented here also illustrate predictors for local response included BED ≥ 100 and fraction size ≥ 9 Gy. These findings are again supported by earlier results published at our institution evaluating the use of SBRT and doses needed to establish effective control rates for metastatic melanoma and RCC [1, 15]. Stinauer and colleagues included 25 RCC lesions treated with 40–50 Gy in 5 fractions or 42–60 Gy in 3 fractions and had a local control rate of 88 % at 18 months [15]. Predictors of in-field local control included BED > 100 Gy and fraction size > 11 Gy, comparable to our findings. BED has been confirmed to be a strong predictive factor in many other studies, including several Radiation Therapy Oncology Group (RTOG) clinical trials evaluating local control rates with SBRT [10, 13, 17]. Radiobiologically, the higher dose per fraction with SBRT-based treatments has been shown to provide improved local control over standard fractionation. As the survival and proliferation of tumor cells are directly dependent on the blood supply, SBRT has been shown to have a direct effect on tumor vasculature. Hypoxia can increase the expression of vascular endothelial growth factors, which is associated with higher grade tumors and metastatic disease [3]. High-dose single fractionation at 10 Gy or higher has been shown to cause severe vascular damage in human tumor xenografts or animal tumors [2, 8]. SBRT, coupled with targeted agents including vascular endothelial growth factor (VEGF) inhibitors and TKIs, may have both a synergistic local effect in addition to systemic effect and is currently being studied. Additionally, the vascular injury and ensuing chaotic intratumor environment such as hypoxic, acidic and nutritionally-deprived environment caused by high-dose fraction SBRT, may significantly hinder the repair of radiation damage [14]. RCC has several hypothesized mechanisms for radiation resistance with EBRT. One may be a mutation or silencing of the von Hippel-Lindau (VHL) gene which is present in over 50 % of cases and is thought to lead in the accumulation of hypoxic-inducible factor 1-alpha (HIF1A), which then creates angiogenesis leading to further tumor growth and potential disease spread [7]. As described, the mechanism in which SBRT can cause endothelial apoptosis with single high dose treatments may help overcome this pathway.

Currently, the role of systemic therapy in RCC continues to improve with more targeted therapies, providing patients with improved survival and quality of life. Because of this, SBRT is positioned to play a valuable role in providing not only high local control rates but prolonged duration of symptomatic control from months to years. This in turn could translate into both symptomatic relief for the patients and improved survival, especially in those with oligo-progressive disease. In addition, new agents are constantly being developed that may have a synergistic effect with SBRT and will need to be evaluated in clinical trials.

Our study is limited by its retrospective nature, short-term follow up which may have underestimated disease recurrence rates and long term toxicity, and variability in treatment (specifically, fractionation size and total dosage). A common weakness in these studies is the inherent selection bias that may exist as patients who are treated with SBRT may have had less systemic burden, lower comorbidities, and better overall performance status. However, as our endpoints focuses on local radiographic control, it is unlikely these factors contribute significantly to our findings. Further, this study includes data over a long period of time, where technical and systemic treatment approaches have vastly changed. Additionally, due to the relative small numbers of lesions included in this study, subset analysis of each group was difficult. The majority of our patients who underwent SBRT were asked to hold their systemic therapies such as TKIs the day prior to starting SBRT and resumed the day after completion; future studies would need to evaluate toxicity of combining TKIs and other targeted agents with SBRT. Lastly, long term follow up of how these treatments influence the overall survival of patients with RCC is unknown and worthy of prospective follow up.

To conclude, based on our results and emerging data from other investigators, a difference in efficacy between SBRT and CF-EBRT is emerging in the treatment of RCC. Future prospective studies are needed to evaluate efficacy and toxicity of SBRT in the setting of oligometastatic disease for RCC, especially in the setting of newer immune-modulating therapies. With the current published single institutional studies available, SBRT appears to significantly improve local control rates and symptom relief for metastatic RCC to the bone and should be considered for these patients.