Approximately 30% of the patients with renal cell carcinoma (RCC) initially present with synchronous distant metastasis, while another 30% develop metachronous metastasis [1,2]. However, because of its radioresistant nature, the role of radiation therapy (RT) in treating primary RCC has been relatively limited [3,4]. For spinal metastasis from RCC, on the other hand, RT is the principle local therapy for both pain palliation and local control. Historically, spinal metastasis has been treated with external beam RT and recently, several studies have demonstrated that stereotactic body radiation therapy (SBRT) could offer durable local control and pain palliation [5-7].

Though the prognosis of metastatic RCC was dismal for many years [8], it has improved dramatically since the introduction of targeted molecular agents such as sunitinib, a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI), and temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor [9]. Antiangiogenic agents induce normalization of vasculature in the tumor, resulting in a synergistic antitumor effect when used concurrently with RT [10]. Two prospective studies have reported the feasibility of concurrent use of targeted molecular therapy and radiation in various types of cancers [11,12]. However, level 1 evidence supporting the benefit of concurrent use of targeted molecular therapy during the course of RT for RCC is lacking. In addition, the optimal timing of administration (before, during, or after RT) has not yet been determined.

In our institution, patients with metastatic RCC receive targeted molecular therapy as the first-line systemic therapy and the metastatic lesions, spine in particular, are commonly treated with RT. The purpose of this study was to evaluate the difference in clinical outcome according to the use of concurrent targeted molecular therapy with RT in spinal metastasis from RCC.

We evaluated the outcomes of spinal RT and investigated the effect of concurrent use of targeted molecular therapy for spinal metastasis from RCC. Although several studies have reported outcomes of RT for spinal metastasis from RCC, none have focused on the effect of concurrent use of targeted molecular therapy. Since distinguishing post-RT change and tumor progression is challenging, we adopted the latest recommendation by the SPINO group [14].

The 1-year LPFR was significantly improved in patients who administered concurrent targeted molecular therapy compared to patients who underwent RT only. Whereas, the 1-year OS did not differ between two groups. After adjusting for other clinical factors, concurrent use of targeted molecular therapy tended to show improved local control. The biologic background of the possibility of a synergistic effect from combination of targeted molecular therapy and RT has been previously suggested [10]. Sunitinib, the most-studied TKI in the treatment of RCC, has already been observed to potentiate the radiation-induced response. It affects T-cell priming and increases radiation sensitivity by normalizing the tumor microenvironment such as tumor vasculature. In addition, it also reduces the level of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) and co-inhibitory molecules. Although sorafenib has some immune-suppressive effects, it reduces Treg and decreases natural killer (NK) cell inhibition, resulting in immune-stimulatory effects. Pazopanib is a newer TKI, and not much is known about its mechanism. However, it is suspected that pazopanib in combination with RT might have similar effects to those of sunitinib. The mTOR inhibitors, such as temsirolimus and everolimus, are known to enhance CD8+ T cell activation. When used in combination with radiation, mTOR inhibitors might further boost the immuno-stimulatory effect.

Although the dose response relationship of radiation is well established in RCC [16], we did not observe any dose response relationship in our study. In a previous study where 24 painful bone metastatic lesions from RCC were treated with SBRT, applying BED (α/β of 7) >85 Gy achieved faster and more durable pain relief compared to those treated with BED <85 Gy [17]. A more recent study comparing local control after SBRT or non-SBRT for bone metastasis from RCC reported that BED (α/β of 7) ≥80 Gy was a meaningful predictive factor [18]. The discrepancy between previous results and ours may be from the suboptimal RT dose applied in our study, for which the median BED (α/β of 7) was 51.4 Gy (range, 31.4 to 130.3 Gy). This lower median BED was mainly due to the large portion of patients who received non-SBRT. Despite the lower dose, those who received concurrent targeted molecular therapy with RT showed a LPFR of 90%, which is in the same order of magnitude as LPFR of previous studies using SBRT [5] and is better than LPFR from studies using non-SBRT [19]. More investigations are needed to evaluate the RT dose response relationship in the setting of concurrent use of targeted molecular therapy.

Pain response after RT was the only significant predictor of LPFR after multivariate analysis. The relationship between pain relief and local tumor control was suggested in a previous study [20]. Though not clearly disclosed, several origins of the pain from bone metastasis have been suspected [21]. The two main mechanisms, mechanical factor and chemical mediator resulting from metastatic tumor cells, are closely related to tumor burden in the metastatic site. Therefore, patients with early pain response may exhibit a more prominent decrease in tumor burden, which may be related to better local control than those without remarkable pain relief. Although this should be confirmed in a larger cohort, pain relief after RT may serve as an early predictor for local tumor control in spine metastasis from RCC.

One of the concerns regarding the use of targeted molecular therapy concurrently with radiation is the possibility of increased toxicity. In a phase II trial that tested the efficacy and toxicity of combination of sunitinib and hypofractionated RT, 28% of patients experienced grade ≥3 acute toxicities [12]. In contrast, we only observed 4 patients with grade 1 toxicities. Several factors might account for the lower toxicity rates observed in our study. Although our study only treated bone metastasis, the previous prospective trial treated lesions other than bone metastasis, such as lung and lymph nodes. Therefore, more severe toxicities may have been shown due to the critical organs near the treated lesion. In addition, the retrospective nature could have underestimated the actual incidence of toxicities. We surmise that concurrent targeted molecular therapy with radiation may be delivered safely in patients with spinal metastasis from RCC.

Several limitations should be taken into account due to the retrospective nature of our study. The radiation dose, target volume, and targeted agents were heterogeneous. In addition, the study population was small, which might make it difficult to achieve statistically significant results. Also, we divided patients into two groups according to the use of concurrent targeted molecular therapy without considering different radiation response mechanisms proven in other studies due to the small study cohort. Furthermore, the follow-up period was short and follow-up visits were irregular in some patients.

In conclusion, our results suggest the possibility of benefit from the concurrent use of targeted molecular therapy during radiation in treating spinal metastasis from RCC. However, we used this study to generate hypotheses that can be addressed by future prospective studies with larger populations.