Survival After Surgery for Renal Cell Carcinoma Metastatic to the Spine: Impact of Modern Systemic Therapies on Outcomes

Abstract

BACKGROUND

Modern medical management of metastatic renal cell carcinoma (RCC) includes therapies targeting tyrosine kinases, growth pathways (mammalian target of rapamycin (mTOR)), and immune checkpoints.

OBJECTIVE

To test our hypothesis that patients with spinal metastases would benefit from postoperative systemic therapy despite presenting with disease that, in many cases, was resistant to prior systemic therapy.

METHODS

This is an Institutional Review Board-approved clinical retrospective cohort analysis. A sample of adult patients with RCC metastatic to the spine who underwent operative intervention between January 2010 and December 2017 at 2 large academic medical centers was used in this study.

RESULTS

We identified 78 patients with metastatic RCC in whom instrumented stabilization was performed in 79% and postoperative stereotactic radiosurgery was performed in 41% of patients. Of patients presenting with weakness or myelopathy, 93% noted postoperative improvement and 78% reported improvement in radicular and axial paraspinal pain severity. Increased overall survival (OS) (913 d (95% CI: 633-1975 d, n = 49) vs 222 d (95% CI: 143-1005 d, n = 29), P = .003) following surgery was noted in patients who received postoperative systemic therapy a median of 80 d (interquartile range 48-227 d) following the surgical intervention.

CONCLUSION

Postoperative outcomes and palliation of symptoms for metastatic RCC without targeted therapies in this cohort are similar to those reported in earlier series prior to the adoption of these systemic therapies. We observed a significantly longer OS among patients who received modern systemic therapies postoperatively. These findings have implications for the preoperative evaluation of patients with systemic disease who may have been deemed poor surgical candidates prior to the availability of these systemic therapies.

Graphical Abstract

Graphical Abstract.

ABBREVIATIONS

CI

confidence interval

EBRT

external beam radiation therapy

ESCC

epidural spinal cord compression

KPS

Karnofsky performance scores

mTOR

mammalian target of rapamycin

OS

overall survival

PFS

progression-free survival

RCC

renal cell carcinoma

SINS

Spinal Instability Neoplastic Score

SRS

stereotactic radiosurgery

TKI

tyrosine kinase inhibitors

VEGF

vascular endothelial growth factor

Synchronous metastatic disease at the time of presentation is present in one-third of patients with renal cell carcinoma (RCC),¹ with skeletal system representing a common site of metastases. Given the lack of sensitivity of renal cell cancer to radiation therapy, patients with symptomatic spine metastases are often treated with a multi-modality approach including surgical decompression, radiosurgery, and systemic cancer therapies to palliate neurologic symptoms.² Given the vascularity of these lesions, preoperative planning may include embolization to reduce blood loss. However, even with such optimization, these surgical interventions carry an inherent risk of systemic disease progression during postoperative recovery and beyond.³

Recent genome level analyses of somatic mutations occurring in RCC have revealed that distant metastases demonstrate evolution such that there is considerable genetic diversity across metastatic sites within a given patient.^4,5 The management of metastatic RCC has dramatically evolved in recent years with incorporation of multiple mechanistic classes of targeted systemic agents including tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF) receptors and platelet derived growth factor receptors,^6-8 mammalian target of rapamycin (mTOR) inhibitors,⁹ and immune checkpoint inhibitors.^10,11

The study period described here represents a unique epoch in the management of RCC given the transition to these therapies as standard of care. Especially because therapeutic response may be noted with even a fifth line of therapy,¹² we hypothesized that patients with metastatic RCC to the spine will demonstrate improved outcomes with the use of modern systemic therapies.

METHODS

Study Population and Design

We retrospectively studied 78 consecutive patients who underwent spine surgery for metastatic RCC to the spine at 2 large academic medical centers between 2010 and 2017. This study was approved by the Institutional Review Board, which granted access to an institutional spine tumor patient registry and waived the need of consent from the subjects.

Data Collection

Baseline characteristics were recorded, including Karnofsky performance scores (KPS), primary tumor histology and Fuhrman grade, and extent of systemic disease. The Heng score is a previously described 6-point scale developed from a retrospective analysis of baseline lab values to predict prognosis for patients with metastatic RCC following treatment with anti-VEGF agents (0 points – favorable (43.2 mo), 1-2 points – intermediate (22.5 mo), and ≥3 points – poor (7.8 mo)).¹³ Therefore, when these preoperative labs for calculating the Heng score were available (white blood cell, platelets, creatinine, hemoglobin, calcium, and albumin), they were collected from the patient record prior to surgical intervention on the spine as a proxy for predicting suitability for postoperative systemic therapy. Pre-procedural imaging was reviewed to assign Spinal Instability Neoplastic Score (SINS)¹⁴ and the epidural spinal cord compression (ESCC)¹⁵ classification. Postoperative therapies including use of radiation and systemic therapies were noted, along with progression-free survival (PFS) and overall survival (OS) following spine surgical intervention was noted by chart review. Progression was further characterized as a local or distant relative to the treated site. Complications following surgery or radiation therapy were obtained through chart review. The use of systemic therapies was noted preoperatively and postoperatively.

Procedures

Surgical interventions consisted of standard conventional procedures to decompress neural elements and spinal stabilization (Table). Postoperative stereotactic radiosurgery (SRS) consisted of 16 to 18 Gy in a single fraction to the 100% isodose line with an integrated boost to gross disease of 22 to 24 Gy. Postoperative external beam radiation therapy (EBRT) consisted of 30 to 36 Gy in 3-Gy fractions.

TABLE.

Perioperative Cohort Characteristics

Gender	Number (%)
Male	55 (71%)
Female	23 (29%)
Age at time of spine intervention	Median	Range
	63.5 yr	56.8-70.8
Fuhrman Grade	Number (%)
1	3 (5%)
2	15 (23%)
3	30 (45%)
4	18 (27%)
Histology	Number (%)
Clear cell	66 (92%)
Granular	2 (3%)
Sarcomatoid	2 (3%)
Eosinophilic	1 (1%)
Chromophobe	1 (1%)
Location of spine disease	Number (%)
Cervical	8 (10%)
Cervicothoracic	2 (3%)
Thoracic	35 (46%)
Thoracolumbar	7 (9%)
Lumbar	23 (29%)
Sacrum	2 (3%)
KPS	Median	Range
	70	30-100
SINS	Median	Range
Composite	10	8-11
Mechanical	3	2-3
Location	2	1-3
Lytic	2	2
Alignment	0	0
Collapse	2	0-3
Posterolateral elements	1	0-3
ESCC	Number (%)
0	5 (10%)
1a	6 (12%)
1b	8 (16%)
1c	4 (8%)
2	11 (22%)
3	21 (42%)
Preoperative Heng Score	Number (%)
0	3 (7%)
1	4 (9%)
2	9 (20%)
3	12 (27%)
4	13 (29%)
5	2 (4%)
6	2 (4%)
Exposure to preoperative systemic therapy	Number (%)
TKI	28 (36%)
mTOR	5 (6%)
PD-L1	2 (3%)
IL-2	3 (4%)
Presence of synchronous visceral metastasis	Number (%)
Any non-skeletal organ	65 (83%)
Lung	55 (71%)
Liver	18 (23%)
Adrenal glands	16 (21%)
Brain	12 (15%)
Pancreas	8 (10%)
Spine intervention and postoperative systemic therapy
Postoperative systemic therapy	No	Yes
Decompression alone	0	3
Decompression with radiation therapy	7	6
Decompression with instrumented stabilization	6	4
Decompression, stabilization, EBRT	9	17
Decompression, stabilization, SRS	7	19

Statistical Analysis

Kaplan-Meier survival analysis was performed to quantify survival following the interventions and to assess for proportionality given our planned use of Cox proportional hazard regression. Bivariate analyses were undertaken with univariable Cox proportional hazards. The threshold for statistical significance was set a priori at P < .05. Data were analyzed using R statistical software (R Foundation for Statistical Computing, Vienna, Austria; version 3.3.3).

RESULTS

A total of 78 patients who underwent surgery for metastatic RCC lesions to the spine between 2010 and 2017 were included (Figure 1 and Table). The median KPS for this cohort was 70 (40-90). Patients developed a spine metastasis requiring surgical intervention at a median of 292 d (interquartile range 0-1708 d) following the initial diagnosis. Metastatic disease to the spine requiring operative intervention was the first manifestation of RCC in 22 patients (28%). Aside from skeletal metastases, 65 patients (83%) were noted to also have metastatic disease of viscera, with the lung as the most common site (55 patients, 71%; Table). At the time of intervention for spine metastasis, a total of 38 (49%) patients had received or were receiving systemic therapy with 28 (36%) patients receiving tyrosine kinase inhibitors (TKI), 3 (1%) receiving IL-2, 5 (6%) patients receiving an mTOR inhibitor, and 2 (3%) receiving an immune checkpoint inhibitor. Eight of these patients had been administered at least 2 different systemic therapies preoperatively.

FIGURE 1.

Patient flow diagram for this retrospective cohort of patients undergoing surgery for metastatic RCC to the spine between 2010 and 2017.

Preoperative tumor embolization was performed in 63% of patients with similar intraoperative blood loss (800 cc (50-12 000 cc) with embolization vs 800 cc (50-5000 cc) without embolization). A total of 13 patients underwent surgery alone, and 65 patients underwent surgery followed by radiation therapy (Table).¹⁶ Preoperative imaging revealed median ESCC was 2 (mode 3) and median SINS was 10 (interquartile range 8-11). The majority of patients were noted to have a preoperative Heng score¹³ correlating with the poorest prognosis (64%; Table).

The median PFS was 179 d (95% CI: 153-409 d), and median OS was 717 d (95% CI: 526-1109) (Figure 2). Of the 58 patients with preoperative axial paraspinal or radicular pain, 45 reported improvement in symptoms (78%). Of the 28 patients presenting with myelopathy or weakness secondary to compressive epidural disease, 26 demonstrated improvement in strength testing and ambulation postoperatively (93%). One patient experienced postoperative mortality within 30 d. Postoperative complications included 5 related to wound healing and 1 pulmonary embolus requiring anticoagulation. Two patients presented with fractured rods at 27 and 45 mo postoperatively, respectively, and required revision of hardware.

FIGURE 2.

Postoperative OS for the contemporary cohort is longer than previously reported series. The A, median PFS was 179 d (95% CI: 153-409 d), and B, median OS was 717 d (95% CI: 526-1109) for the overall cohort.

Postoperative systemic therapies were administered to 63% of patients (49/78), including TKI (n = 21), mTOR inhibitors (n = 18), and PD-L1 inhibitors (n = 10) initiated within a median of 80 d postoperatively (interquartile range 48-227 d). A trend toward longer PFS was noted when patients were treated with postoperative systemic therapies (173 (95% CI: 117-717 d) vs 300 (95% CI: 160-531 d), P = .75; Figure 3A), although given the size of our sample, this failed to meet significance. A statistically significant increase in OS was noted in patients who received postoperative systemic therapies (913 d (95% CI: 633-1975 d, n = 49) vs 222 d (95% CI: 143-1005 d, n = 29), P = .003; Figure 3B). Overall, when assessing postoperative survival, the proportionality assumption appeared to be met. Bivariate analyses showed that OS was not significantly correlated with Fuhrman grade (P = .20) or Heng score (P = .71) but was significantly associated with KPS score (P = .005). The significance of the association between postoperative systemic therapies and postoperative survival was maintained in a bivariate analysis with KPS < 80 (P = .01 for postoperative systemic therapy; Figure 3C). Median survival for patients with a poor prognosis as calculated by the Heng score was 264 d (95% CI: 148-1761 d, 29 patients). A trend toward longer survival was noted even in this subset of “poor prognosis” patients who received postoperative systemic therapies compared to those who did not (633 d (95% CI: 211 d – not reached, n = 12 patients) vs 179 d (95% CI: 120 d – not reached, n = 17 patients), P = .107).

FIGURE 3.

Postoperative OS is prolonged in patients who receive adjuvant therapies. A, PFS is not significantly affected by the use of postoperative adjuvant therapies. B, Increased OS following surgery was noted in patients who received postoperative targeted therapies (1376 ± 719 d, n = 36, red) compared to those who did not (490 ± 214 d vs n = 24, blue, P = .009). C, Patients who received adjuvant therapies were noted to have prolonged survival even when segregating by KPS (P = .01).

DISCUSSION

Key Results

In this retrospective cohort study, OS was significantly higher in patients who received modern targeted therapies after spinal surgery for RCC metastatic to bone. Across all patients in this study, we noted a longer postoperative median OS compared to a recently published study of a similar series of patients with metastatic RCC treated from 1993 to 2007.³ In comparison, our study examined patients managed operatively between 2010 and 2017. We believe that this difference in outcomes is at least partially related to improvements in systemic therapies available for patients with metastatic RCC. These observations may inform the clinical care of patients with spine metastases. First, postoperative multimodal management should be considered which represents a subject of future prospective work. Second, preoperative evaluation of patients with systemic disease should consider candidacy for surgery in light of available systemic therapy options.

Outcomes in the management of metastatic RCC have improved with the introduction of targeted therapies against growth pathways, angiogenesis, and immune checkpoints. Despite these advances, there continues to be variability in outcomes and therapeutic response. Much of this bears out in the patient population affected by vertebral body metastases, rendering challenges for preoperative prognostication and choice of postoperative systemic therapies to maximize survival and quality of life metrics. Given the potential concerns for the effect of TKI on wound healing, alternative systemic therapies of mTOR inhibitors and immunotherapy provide reasonable options in the perioperative setting.

Limitations

We recognize the cohort size as a limitation of this study. However, this is directly related to the relatively low prevalence of RCC, which is 3% of all cancers.¹⁷ Of these cases, approximately 20% to 35% will develop skeletal metastases during the disease course, and a fraction of these will specifically develop spinal metastases that result in neurologic compromise necessitating surgical intervention. The depth of data that was extracted on each of the described patients identified at the 2 institutions allowed for the granular analysis performed in this study. The ongoing development of multicenter, international outcomes registries in metastatic spinal oncology (Metastatic Tumor Research and Outcomes Network, NCT02830451) will allow for improved statistical power when performing such analyses in the future.

Interpretation and Generalizability

It should be acknowledged that surgical intervention for metastatic RCC of the vertebral column has a notable complication profile. Nonetheless, the survival benefit associated with the postoperative systemic therapies is an important consideration in the multimodal perioperative management for this population. Future analyses of the molecular alterations in metastatic RCC of the spine may further resolve the natural history and predicted treatment response, as evidenced by recent studies detailing differences in outcomes with respect to key genomic events.⁵ Furthermore, in the present study, we establish that the sensitivity of the metastatic disease in the spine to certain classes of systemic therapies may be different from the primary tumor given the underlying genomic evolution.¹⁸ Therefore, in addition to the palliative effects of the surgical interventions described in this study, accessing the tumor for diagnostic purposes to guide postoperative medical adjuvants vis-à-vis molecular analysis could confer significant value in optimizing postoperative survival.

CONCLUSION

We asked whether postoperative systemic cancer therapy is beneficial for patients with RCC metastatic to the spine. In this retrospective cohort study of 78 patients treated between 2010 and 2017, postoperative OS was significantly longer (913 d vs 222 d) when a postoperative systemic therapy was initiated at a median of 80 d following the surgical intervention. Surgical intervention for metastatic RCC of the vertebral column has a notable risk profile; however, the survival benefit associated with the inclusion of postoperative systemic therapies is an important consideration in the multimodal perioperative management of this patient population.

Disclosures

This work is supported by the AOSpine North America Young Investigator Research Grant and NIH (K08NS107634-01A1) (to Dr Shankar). The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.