Renal cell carcinoma (RCC) is the most common form of kidney cancer and its incidence has risen in recent years [
]. Due to increased incidental detection rates of kidney tumors, more RCC are still confined to the kidney at the time of diagnosis. The standard treatment for Stage I RCC is a partial renal resection. Radical nephrectomy is only performed for centrally located tumors or when partial resection is not feasible. Patients with bilateral tumors, contralateral recurrent tumor after unilateral nephrectomy, metastases from RCC in the contralateral kidney or preexisting chronic kidney disease are special candidates for partial nephrectomy. In these patients preserving renal parenchyma is essential to avoid chronic kidney disease.
As a possible therapeutic approach robotic stereotactic ablative radiotherapy (SABR) is currently under investigation as a non-invasive treatment option for patients with RCC. Renal cell carcinoma is frequently reported as a radio-resistant tumor. However, pathologic complete responses have been described after ablative radiotherapy previously [
]. Tumor motion and the need for high ablative radiation doses while preserving the remaining renal parenchyma, poses a major challenge. Robotic radiosurgery allows continuous tumor tracking under free breathing and therefore minimal gross tumor volume (GTV) to planning target volume (PTV) margins are needed. Robotic SABR for moving tumors is already established as a standard treatment option for patients with early stage non-small cell lung cancer [
Although current data seem to demonstrate that SABR provides good tumor control while preserving the renal function [
], most studies are limited to patients with normal renal function. In this study, we analyzed the safety and efficacy of image-guided CyberKnife (Accuray Inc., Sunnivale, USA) radiosurgery in RCC in a specific subgroup of patients with preexisting impaired renal function. Feasibility and technical aspects of robotic SABR will be provided as well.
Retrospective analysis of patient data was approved by the Ethics Committee Campus Charité Mitte (EA1/233/18). We identified all histology proven RCC patients, who were treated with robotic SABR in our center between June 2012 and April 2017. We collected data on patient characteristics regarding disease stage, preexisting kidney disease, estimated glomerular filtration rate (eGFR), clinical outcome, complications, local tumor control and overall survival. Dose-volume parameters were analyzed including prescription dose, fractionation, treatment dose (D
max,), GTV, PTV, new conformity index (nCI), PTV coverage, tumor motion and tracking accuracy.
Robotic SABR planning and delivery
The patients were referred to CyberKnife irradiation from the nephrology department, all at increased risk for progression to end-stage renal disease caused by further invasive treatment. The decision to perform a robotic SABR was recommended by a multidisciplinary urology board review for patients who are at increased risk for progression to end-stage renal disease due to partial nephrectomy or other ablative techniques.
One gold fiducial marker (1.0 mm × 5.0 mm) was implanted within or close to each tumor using an 18-G needle under computed tomography (CT)-guidance in local anesthesia. A tissue sample was taken in the same procedure if there was no prior pathology report available. High-resolution native thin-slice (1.0 mm) planning CT was performed within a median of 8 days (range: 1–21) after fiducial insertion to allow for fiducial settlement [
]. For accurate tumor delineation, magnetic resonance images (MRI) were co-registered with the planning CT and contouring was performed on all axial slices. The GTV was defined as the tumor volume based on CT and MR images. The clinical target volume (CTV) was equivalent to the GTV. The PTV was obtained by adding in median a 3 mm (range: 0–5 mm) isotropic margin to the GTV. Depending on tumor size or organs at risk (OAR) two different dose concepts were used, either single fraction SABR of 24 or 25 Gy, or 36 Gy in 3 fractions (12 Gy/fraction) prescribed each to the 70% isodose covering the PTV. Treatment planning and dose calculations were obtained by MultiPlan 4.6 (Accuray Inc., Sunnyvale, USA) using the Ray-tracing algorithm.
The linear-quadratic model, assuming an a/ß ratio of 2.6–6.9 Gy for RCC [
], was used to calculate the biologically equivalent dose (BED) and the equivalent dose in 2 Gy fractions (EQD2). The calculated BED
encompassing the PTV for single fraction were 107.5 Gy and 83.3 Gy, and 98.6 Gy and 76.4 Gy for the 3-fraction treatment.
Dose constraints for OAR for single fraction treatments were as follows: < 5 cm
of small bowel loops could receive up to 10.0 Gy with a maximum point dose of 19.0 Gy; for the extratumoral kidney parenchyma < 200 cm
could receive up to 8.0 Gy. The normal tissue constraints for three fractions were: < 5 cm
could receive up to 16.0 Gy with a maximum point dose of 27.0 Gy for small bowel, and less than 33% of the remaining kidney parenchyma could receive a total of 15.0 Gy. The dose constraints for spinal cord, liver, stomach and large intestine were set according to published standard limits [
]. The nCI [(
], which describes the conformity between the prescription isodose and the volume and shape of the PTV, was also used for treatment plan evaluation.
The CyberKnife System installed in July 2011 in Berlin combines two systems, a lightweight linear accelerator mounted on a robotic arm with 6-MV photon energy and an image guidance system consisting of two orthogonally positioned x-ray cameras. For patient positioning, an automatic tracking algorithm compares live x-rays with digital reconstructed images from planning CT. For respiratory motion compensation, the CyberKnife Synchrony® Respiratory Motion Tracking System (MTS) was used. Thereby, the external motion of LED markers located on the chest of the patient was correlated with the internal tumor motion represented by the fiducial position and determined by the x-ray images. The individually measured correlation model is continuously updated and synchronizes the radiation beam in real time such that the beam always remains aligned with the target. An accuracy of less than 1.0 mm is technically achieved and allows clinicians to reduce safety margins significantly, while eliminating the need for gating or breath-hold techniques. During treatment, the motion patterns for each patient were recorded in logfiles.
Follow-up and statistics
Clinical and radiological follow-up with CT or MRI was frequently performed after robotic SABR and the latest available follow-up was used in this analysis. For local control the MRI scans were evaluated by the senior physician in charge to verify treatment response. Tumor response was analyzed using response evaluation criteria in solid tumors (RECIST version 1.1). The treatment response of each RCC was categorized using OsiriX MD 10.0 (Pixmeo SARL, Bernex, Switzerland) to compare baseline MRI and planning CT with the latest available follow up images in 1) complete remission (CR): no measurable lesion; 2) partial remission (PR) defined as a volume reduction ≥ 30%; 3) stable disease (SD); 4) progressive disease (PD) defined as a
≥ 20% increase in volume or
≥ 5 mm increase in size. Local control (LC) was calculated from the end of SABR until last available follow-up or PD.
Overall survival (OS) was calculated from the end of SABR until last follow-up or death. LC and OS were estimated using Kaplan-Meier curves. Common Terminology Criteria for Adverse Event V4.03 (CTCAE) for acute and late radiosurgery related side effects were recorded separately. Renal function at baseline and latest available follow up was calculated according to the chronic kidney disease epidemiology collaboration (CKD-EPI) formula at baseline and last available follow up.
Due to respiratory induced kidney motion, the motion patterns and total targeting errors between the predicted and the actual position of the tumor were evaluated. Overall, the motion pattern and targeting accuracy of 19 out of 21 treatment sessions could be extracted. Motion pattern evaluation and statistical analysis were done with MATLAB 9.3 (The MathWorks, Inc., Natick, USA).
In this retrospective study the efficacy of robotic SABR was assessed retrospectively in 10 patients with RCC and moderate to severe chronic kidney disease. Our study demonstrates that this minimal invasive and highly sophisticated treatment method provides good response rates and local control with negligible toxicity. SABR with motion compensation is a nephron-sparing treatment that perfectly adapts to patients with RCC and significant preexisting chronic renal failure.
Our results concerning local tumor control in 92.3% of all lesions and mild toxicity appear to be consistent with those available in the literature. A previous systematic review of 126 patients described a weighted local control rate of 94% and a grade 3 toxicity rate of 3.8% [
]. Since that study, 3 single-institution, prospective studies of 19 patients [
], 40 patients [
], and 33 patients [
] have reported similar findings, with local control rates ranging from 98 to 100% and grade
3 toxicity rates from 0 to 15.8%. Recently, 9 centers across Germany, Australia, the United States, Canada, and Japan formed an International Radiosurgery Oncology Consortium for Kidney and reported data of 223 patients [
]. The rates of LC, cancer-specific survival, and progression-free survival at 2 and 4 years were 97.8, 95.7, 77.4% and 97.8, 91.9, 65.4%, respectively. Multi-fraction SABR was associated with poorer progression-free survival and worse cancer-specific survival. Grade 1 and 2 toxicities were reported for 35.6% of patients whereas grade 3 and 4 toxicities were recorded in only 1.3% [
In patients with bilateral tumors or contralateral tumor recurrences after unilateral nephrectomy or partial resection treatment is especially challenging. The resection of the remaining kidney consecutively leads to the progression of chronic kidney disease including the need for hemodialysis treatment. In such cases, minimally invasive ablative techniques such as cryosurgery, radiofrequency ablation and SABR are possible alternatives to nephrectomy. A 2016 systematic review and meta-analysis reporting on survival across management strategies demonstrated a 95 to 100% cancer specific survival after nephrectomy and thermal ablation with a median follow-up period of 22 to 120 months. Whereas, for tumors more than 40 mm (T1b) survival rates decrease to around 90% and for tumors more than 70 mm (T2) between 82.5 and 86.7% [
]. A mostly retrospective data analysis by Kunkle and Uzzo [
] showed local tumor progression rates of 12.9% after RFA and 5.2% after renal cryoablation. In our series, tumor progression was recorded in 7.7% of all lesions, accordingly in one out of 10 patients (10%). In this case the tumor size was above the median, located close to renal pelvis and the PTV coverage was less than 90%.
Notably, renal function remained stable following treatment in all patients despite the high doses of radiation delivered to the kidney. This result raises two considerations. Firstly, preservation of renal function was assumed to be due to compensatory mechanisms of the contralateral kidney and the spared ipsilateral kidney volume described as renal functional reserve [
]. These results also suggest that it might be possible to rely on a compensatory capacity of the ipsilateral kidney in patients who already had contralateral nephrectomy and that, whenever oncologically suitable, a selective approach aimed to avoid post-treatment severe chronic kidney disease should be pursued. A second point concerns the radiation tolerance of the peritumoral kidney and the reliability of tumor tracking in robotic SABR. Cassady [
] proposed a threshold dose of 15 Gy for renal injury based on data of bilateral whole kidney irradiation in 3 fractions. Nevertheless, ours and other previous studies demonstrate a good tolerance to higher doses and stable kidney function. The prescribed dose (1 × 24–25 Gy or 3 × 12 Gy prescribed to the 70% isodose) was relatively high in order to overcome the radio-resistance of RCC. The fraction number and prescribed dose of the two large studies from Staehler et al. [
] and Sun et al. [
] were similar to our dose concepts. Overall, they treated 80 patients with either 25 Gy in one fraction or 38 Gy in 3 fractions prescribed to the 70 or 80% isodose line. Both studies reported only grade 1 side effects with > 90% local control in a relatively short follow-up.
Svedman et al. [
] evaluated kidney injury following 3 fractions SABR in 7 patients with primary or metastatic renal disease with only one functioning kidney. In 5 patients, kidney function remained unaffected after SABR, with a kidney volume of 37.3% receiving 15 Gy (V15), whereas 2 patients exhibited modest changes in renal function without the requirement for medical intervention or hemodialysis. In SABR patients, a V15 limited to less than one third of the normal single remaining kidney could be an appropriate dose-volume constraint in patients with preexisting kidney disease. We therefore considered this dose constraint in our series for the three-fraction regiment.
Furthermore, the high doses used and the treatment result in terms of remission, local control and sparing of renal function, demonstrate that the robotic SABR is highly reliable in terms of targeting precision and dose delivery. According to our data, the median targeting accuracy was within 2.2 mm. This provided us an important information regarding the margins to be used. In fact, we believe that, unlike margins of up to 10 mm, as used in other studies, a moderate expansion of the tumor (i.e. 3.0 mm) is sufficient for the CyberKnife MTS. Since only one marker was implanted, rotations could neither be directly detected nor corrected. However, geometric calculations have shown that a 3.0 mm margin appears to be sufficient also if small rotations (< 5 °) occur.
This study has several limitations. This is a retrospective series with a limited number of cases collected and a relatively short follow-up for renal function. Nevertheless, it should be considered as a proof-of-concept study for SABR on patients with impaired renal function gaining satisfactory results and providing a low risk for treatment-related side effects.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.