Renal atrophy after stereotactic body radiotherapy for renal cell carcinoma

Before treatment, all patients with RCC whose maximum tumor diameter was 50 mm or less were assessed by a urologist. For patients who were judged to be inoperable, patients who were judged to be operable but for whom SBRT was preferred and patients who refused surgery, a radiation oncologist assessed the indication for SBRT. SBRT for RCC was performed for 17 consecutive patients at our institute between April 2010 and February 2014. Of those patients, eligibility criteria for current study were availability of follow-up CT images taken 12–24 months after SBRT, no requirement for hemodialysis before SBRT and no additional invasive therapy (such as nephrectomy or radiofrequency ablation) having been performed. Two patients underwent hemodialysis before SBRT and one operable patient declined to continue SBRT and underwent nephrectomy. A total of 14 patients with 14 tumors were retrospectively analyzed. The pretreatment characteristics of the patients are summarized in Table 1. Two patients had previously undergone nephrectomy and therefore had only one kidney. Nine patients were implanted with one to two gold fiducial markers in the kidney parenchyma near the tumor before SBRT. None of the patients had a histologically proven tumor, and assessment by radiologists and a urologist was therefore needed. First, the dynamic CT and MRI were interpreted by two or more radiologists, and agreement with radiographic diagnosis of RCC was needed. Second, the patients underwent examination by a urologist. Operability was judged by the urologist. Assessment that the patient was inoperable, the patient was operable but SBRT was better option than surgical resection, or the patient was operable but refused surgery was needed. Finally, patients received an explanation from a radiation oncologist, and written informed consent was obtained by the radiation oncologist. This study was approved by the Ethical Committee of Tohoku University Hospital (2011-100), and informed consent was obtained from all patients.

Each patient was immobilized in the supine position with a body frame (Vac-loc, Med-tek, Orange City, IA), and movement of the implanted fiducial marker or diaphragm was measured to estimate respiratory tumor motion using continuous X-ray images in a simulator (Ximatron or Acuity system, Varian Medical Systems, Palo Alto, CA). To control respiratory movement, abdominal compression was used in 6 patients and the breath hold technique was used in 1 patient. All patients underwent a planning CT scan at a slice thickness of 2 mm with a multi-detector CT scanner (GE Light Speed Qxi, GE Healthcare, Waukesha, WI); 7 patients underwent a fast CT scan, 5 patients underwent a 4-dimensional CT scan and 2 patients underwent a slow-rotation CT scan (4 s/slice). The internal margin was determined from a planning CT image and from movement of the implanted fiducial marker or diaphragm.

Gross tumor volume (GTV) was defined as visible extent of the tumor on planning CT images, sometimes using CT and MRI fusion images. Clinical target volume (CTV) was equal to GTV. Internal target volume (ITV) was expansion of CTV for the internal margin. A planning target volume (PTV) margin of 5 mm around the ITV was added for patient positioning and set-up uncertainty.

The SBRT plan was created with a 3-dimensional radiotherapy planning system (Eclipse, Varian Medical Systems, Palo Alto, CA), and an analytical anisotropic algorithm (AAA version 8.6.15) was used for dose calculation. Fifty Gy in 10 fractions, 60 Gy in 10 fractions or 70 Gy in 10 fractions covering 95 % of the PTV (D95) was delivered. The prescribed dose was selected on the basis of the highest dose within dose constraints of the organ at risk (Table 2). Seven tumors were prescribed 70 Gy in 10 fractions, 2 tumors were prescribed 60 Gy in 10 fractions and 5 tumors were prescribed 50 Gy in 10 fractions. In only one case, 50 Gy in 10 fractions was delivered to the isocenter to meet dose constraints. The median isocenter dose was 68.8 Gy (range: 50.0–76.4 Gy). SBRT was delivered with a linear accelerator (Clinac 23EX, Varian Medical Systems, Palo Alto, CA) using 6 MV and/or 15 MV X-ray beams with 5 to 8 coplanar and non-coplanar multi-static ports. SBRT was performed on consecutive treatment days. Concomitant tyrosine kinase inhibitor or interferon was not administered.

Patients underwent follow-up examinations every 3 months for 3 years by a radiation oncologist and urologist. CT and MRI were also performed every 6 months for 3 years. When CT examination was performed, enhanced CT images were recommended but were not essential because it was expected that serum creatinine had worsened. Patients often underwent ultrasound examinations of the abdomen, but there were no protocol requirements about ultrasound.

Each functional kidney parenchyma was defined as the contoured kidney avoiding renal cysts and renal pelvis (Fig. 1). Kidney volume was defined as functional kidney parenchyma minus GTV. Pretreatment functional kidney parenchyma was delineated using planning CT images. When the slow-rotation scanning technique was used for radiotherapy planning, the use of pretreatment diagnostic CT and planning CT rigid fusion images were permitted to avoid overestimation of kidney volume. When the non-contrast enhanced CT images were used for radiotherapy planning, the use of diagnostic MRI and planning CT rigid fusion images were permitted because there was no difference between CT and MRI for volumetry [18]. Post-SBRT kidney volume was assessed using follow-up diagnostic CT images with a slice thickness ≤ 2 mm, and the use of follow-up CT and follow-up MRI fusion images was permitted as appropriate. Volumetric analysis was performed using Eclipse. The DVH parameter regarding kidney volume was analyzed using V_n (%), which was defined as percentage volume of the kidney receiving at least n dose in Gy. Percent changes in parameters was defined as post-SBRT parameters divided by pre-SBRT parameters in percent.

Time to an event was calculated from the first day of SBRT to the day an event was confirmed. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Correlations between continuous variables were examined by Spearman’s rank correlation, and r was the correlation coefficient. Simple linear regression was applied to create a linear regression equation. Differences in continuous variables between two groups were evaluated by the Mann-Whitney test. Changes from pre-SBRT parameters to post-SBRT parameters were assessed using the Wilcoxon signed-rank test. A p-value < .05 was defined as significant in all tests. JMP Pro v.11.2 (SAS Institute, Cary, NA) was used for statistical analyses.

The median interval between SBRT and renal atrophy assessment CT was 16.9 months (range: 12.0–21.8 months), and no patient was administered tyrosine kinase inhibitor or interferon during that interval. The median tumor volume shrunk from 14.8 cc (range: 3.0–55.6 cc) to 10.6 cc (range: 1.3–38.9 cc, p = 0.12). The median post-treatment tumor volume in percent was 73.4 % (range: 41.5–144.6 %). Change in median irradiated kidney volume was from 160.4 cc (range: 99.4–295.5 cc) to 137.1 cc (range: 70.6–258.7 cc, p < .01). The median post-treatment irradiated kidney volume in percent was 82.6 % (range: 61.3–96.4 %, Fig. 2). Change in median contralateral kidney volume was from 147.0 cc (range: 118.1–183.6 cc) to 143.9 cc (range: 114.5–191.8 cc, p = 0.73). The median post-treatment contralateral kidney volume in percent was 99.3 % (range: 89.4–109.0 %, Fig. 2). The median follow-up period for all patients was 31.2 months (range: 16.2–54.2 months). During follow-up, no grade 2 or higher renal and gastrointestinal toxicity occurred and there was no intervention. None of the patients had progression of hypertension and none of the patients required hemodialysis. The pre-SBRT median serum creatinine level was 1.1 mg/dl (range: 0.4–2.0 mg/dl). The post-SBRT peak value seen in intervals of 0.3–48.1 months was 1.6 mg/dl (p < .01), and the post-SBRT value at the time of reporting was 1.3 mg/dl (p = 0.05). Serum creatinine of each patient over time was showed in Fig. 3.