To evaluate the clinical outcomes of patients who underwent radiation therapy with or without targeted molecular therapy for the treatment of spinal metastasis from renal cell carcinoma (RCC).
A total of 28 spinal metastatic lesions from RCC patients treated with radiotherapy between June 2009 and June 2015 were retrospectively reviewed. Thirteen lesions were treated concurrently with targeted molecular therapy (concurrent group) and 15 lesions were not (nonconcurrent group). Local control was defined as lack of radiographically evident local progression and neurological deterioration.
At a median follow-up of 11 months (range, 2 to 58 months), the 1-year local progression-free rate (LPFR) was 67.0%. The patients with concurrent targeted molecular therapy showed significantly higher LPFR than those without (p = 0.019). After multivariate analysis, use of concurrent targeted molecular therapy showed a tendency towards improved LPFR (hazard ratio, 0.13; 95% confidence interval, 0.01 to 1.16). There was no difference in the incidence of systemic progression between concurrent and nonconcurrent groups. No grade ≥2 toxicities were observed during or after radiotherapy.
Our study suggests the possibility that concurrent use of targeted molecular therapy during radiotherapy may improve LPFR. Further study with a large population is required to confirm these results.
Approximately 30% of the patients with renal cell carcinoma (RCC) initially present with synchronous distant metastasis, while another 30% develop metachronous metastasis [
Though the prognosis of metastatic RCC was dismal for many years [
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.
From June 2009 to June 2015, 28 spinal metastatic lesions from 24 patients with pathologically confirmed RCC were treated with either SBRT or non-SBRT. A spinal metastatic lesion involving more than one contiguous spine level was counted as one treated lesion. Among patients treated, the maximum number of spine metastasis was 6 lesions. Eleven patients were excluded from this study due to incomplete RT (n = 4) and insufficient follow-up (n = 7).
Imaging studies were performed to precisely define the extent of disease before treatment. Pre-treatment computed tomography (CT) was available for all lesions. Magnetic resonance imaging (MRI) and positron emission tomography (PET) were not performed routinely and were available for 19 and 8 lesions, respectively.
Among the 28 treated lesions, 8 lesions were treated with SBRT and 20 lesions with non-SBRT. Immobilization devices were applied in patients treated with SBRT. Thermoplastic head-shoulder masks were used when treating cervical lesions and customized total body vacuum bags were used for thoracic and lumbar lesions.
For SBRT, the clinical target volume was defined as the involved area of the skeletal structures. Treatment planning for SBRT was performed by helical tomotherapy using the Hi-Art (TomoTherapy Inc., Madison, WI, USA) planning station or by Cyberknife (Accuray Inc., Sunnyvale, CA, USA). The dose schedules were 24 Gy in 3 fractions (n = 3), 40 Gy in 5 fractions (n = 1), 48 Gy in 4 fractions (n = 1), and 18 Gy in single fraction (n = 3). The dose was prescribed at an 80% isodose level.
Non-SBRT was planned using three-dimensional RT. The involved vertebral bodies with sufficient margins and one adjacent level of spines were defined as the target volume. Various dose schedules were used, while the most frequently used schedule was 30 Gy in 10 fractions, ranging from 20 to 40 Gy in 5–12 fractions.
Biologic effective dose (BED) was calculated according to the linear quadratic model to compare the effects of various fraction sizes and total doses. We adopted an α/β value of 7, given the radioresistant nature of RCC [
Targeted molecular therapies were used in 22 patients, either before (n = 6), after (n = 5), or simultaneously (n = 11) with RT. Two patients had not received any kind of targeted molecular therapy during the course of their disease. Either a VEGF tyrosine kinase inhibitor (sunitinib [n = 5], sorafenib [n = 6], pazopanib [n = 8]) or mTOR inhibitor (temsirolimus [n = 1], everolimus [n = 2]) was administered.
Follow-up CT or MRI was performed every 1–3 months after treatment for the first year and every 6 months thereafter. The response of spinal metastasis after RT was classified as controlled or progressed, according to the response assessment criteria suggested by the SPine response assessment in Neuro-Oncology (SPINO) group [
A physician interviewed the patients before the start of treatment, at 1 month after RT, and every 3 months thereafter. Pain was assessed using a numerical rating scale, where 0 represented ‘no pain’ and 10 was ‘pain as bad as you can imagine.’ A decrease in pain score after treatment was considered relief of pain.
Local progression-free rate (LPFR) and overall survival (OS) were defined as the time from start of RT to local progression and to death from any cause, respectively. LPFR and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. To determine factors associated with LPFR after RT, Cox proportional hazards method was used at both univariate and multivariate levels. Factors proven to be significant in univariate analysis were entered in a multivariate analysis. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated. A p-value <0.05 was considered to be significant in all statistical analysis. The data were analyzed using IBM SPSS ver. 20 (IBM, Armonk, NY, USA).
The patient and spine characteristics for 28 lesions from 24 patients are summarized in
The median follow-up duration was 11 months (range, 2 to 58 months). Local progression of the treated spine occurred in 10 lesions (35.7%) and the median time to recurrence was 5.8 months (range, 1.1 to 25.2 months). The 1-year LPFR and OS were 67.0% and 60.7%, respectively (
The factors associated with LPFR are described in
On multivariate analysis, favorable pain response after treatment remained a significant factor associated with LPFR (HR, 0.19; 95% CI, 0.04 to 0.92), while concurrent use of targeted molecular therapy showed a tendency for improved LPFR (HR, 0.13; 95% CI, 0.01 to 1.16). However, presence of spinal cord compression was not an independently significant predictor.
The patterns of first failure are shown in
None of the patients developed grade ≥2 toxicity during RT. Only grade 1 toxicities were observed in 4 patients (16.6%). Two patients (8.3%) reported grade 1 nausea at the time of treatment, and another 2 patients (8.3%) complained of fatigue after treatment.
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 [
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 [
Although the dose response relationship of radiation is well established in RCC [
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 [
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 [
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.
(A) Local progression-free rate (LPFR) and (B) overall survival of the entire cohort.
Local progression-free rate (LPFR) of the patients who received concurrent targeted therapy and those who did not.
Patient and spine characteristics
Characteristic | Total (n = 24) | Target therapy |
|
---|---|---|---|
Nonconcurrent/none (n = 13) | Concurrent (n = 11) | ||
Age (yr) | 65 (34−82) | - | - |
Sex | |||
Male | 16 (66.7) | 8 (61.5) | 8 (72.7) |
Female | 8 (33.3) | 5 (38.5) | 3 (27.3) |
ECOG PS | |||
0–1 | 14 (58.3) | 7 (53.8) | 7 (63.6) |
2–4 | 10 (41.7) | 6 (46.2) | 4 (36.4) |
Spine | 28 | 15 | 13 |
Location of spine tumor | |||
Cervical | 1 (2.8) | - | - |
Thoracic | 9 (25.0) | - | - |
Lumbar | 16 (44.4) | - | - |
Sacral | 10 (27.8) | - | - |
Cord compression | |||
No | 20 (71.4) | 10 (66.7) | 10 (76.9) |
Yes | 8 (28.6) | 5 (33.3) | 3 (23.1) |
SINS | |||
0–6 | 9 (32.1) | 5 (33.3) | 4 (30.8) |
7–12 | 18 (64.3) | 9 (60.0) | 9 (69.2) |
13–18 | 1 (3.6) | 1 (6.7) | 0 (0) |
Prior irradiation | |||
No | 24 (85.7) | 13 (86.7) | 11 (84.6) |
Yes | 4 (14.3) | 2 (13.3) | 2 (15.4) |
Dose scheme | |||
Non-SBRT | 20 (71.4) | 11 (73.3) | 9 (69.2) |
SBRT | 8 (28.6) | 4 (26.7) | 4 (30.8) |
Dose (BED) | 51.4 (31.4−130.3) | ||
<51.4 | 12 (42.9) | 6 (40.0) | 6 (46.2) |
≥51.4 | 16 (57.1) | 9 (60.0) | 7 (53.8) |
Pain response | |||
No | 10 (35.7) | 5 (33.3) | 5 (38.5) |
Yes | 18 (64.3) | 10 (66.7) | 8 (61.5) |
Values are presented as median (range) or number (%).
ECOG PS, Eastern Cooperative Oncology Group performance status; SINS, Spinal Instability Neoplastic score; SBRT, stereotactic body radiation therapy; BED, biological effective dose.
Results of univariate and multivariate analyses of local progression-free rate
Variable | UVA |
MVA |
||||
---|---|---|---|---|---|---|
HR | 95% CI | p-value | HR | 95% CI | p-value | |
ECOG PS | 0.79 | 0.21−2.98 | 0.726 | - | - | - |
Target therapy | 0.12 | 0.02−0.98 | 0.048 | 0.13 | 0.01−1.16 | 0.068 |
SINS group | 0.86 | 0.21−3.62 | 0.837 | - | - | - |
Cord compression | 7.38 | 1.54−35.28 | 0.012 | 4.28 | 0.78−23.39 | 0.093 |
Prior irradiation | 1.10 | 0.22−5.45 | 0.905 | - | - | - |
Dose scheme | 0.75 | 0.15−3.74 | 0.729 | - | - | - |
Radiation dose (BED) | 0.52 | 0.13−2.11 | 0.357 | - | - | - |
Pain response | 0.23 | 0.05−0.96 | 0.044 | 0.19 | 0.04−0.92 | 0.039 |
UVA, univariate analysis; MVA, multivariate analysis; HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; SINS, Spinal Instability Neoplastic score; BED, biological effective dose.
Patterns of first failure
Pattern of failure | Nonconcurrent/none | Concurrent |
---|---|---|
Local progression | 2 (13.3) | 0 (0) |
Systemic progression | 11 (73.3) | 9 (69.3) |
Both local and systemic progression | 2 (13.3) | 0 (0) |
No progression | 0 (0) | 4 (30.7) |
Values are presented as number (%).