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Ilya Laufer, J. Bryan Iorgulescu, Talia Chapman, Eric Lis, Weiji Shi, Zhigang Zhang, Brett W. Cox, Yoshiya Yamada and Mark H. Bilsky

Object

Decompression surgery followed by adjuvant radiotherapy is an effective therapy for preservation or recovery of neurological function and achieving durable local disease control in patients suffering from metastatic epidural spinal cord compression (ESCC). The authors examine the outcomes of postoperative image-guided intensity-modulated radiation therapy delivered as single-fraction or hypofractionated stereotactic radiosurgery (SRS) for achieving long-term local tumor control.

Methods

A retrospective chart review identified 186 patients with ESCC from spinal metastases who were treated with surgical decompression, instrumentation, and postoperative radiation delivered as either single-fraction SRS (24 Gy) in 40 patients (21.5%), high-dose hypofractionated SRS (24–30 Gy in 3 fractions) in 37 patients (19.9%), or low-dose hypofractionated SRS (18–36 Gy in 5 or 6 fractions) in 109 patients (58.6%). The relationships between postoperative adjuvant SRS dosing and fractionation, patient characteristics, tumor histology–specific radiosensitivity, grade of ESCC, extent of surgical decompression, response to preoperative radiotherapy, and local tumor control were evaluated by competing risks analysis.

Results

The total cumulative incidence of local progression was 16.4% 1 year after SRS. Multivariate Gray competing risks analysis revealed a significant improvement in local control with high-dose hypofractionated SRS (4.1% cumulative incidence of local progression at 1 year, HR 0.12, p = 0.04) as compared with low-dose hypofractionated SRS (22.6% local progression at 1 year, HR 1). Although univariate analysis demonstrated a trend toward greater risk of local progression for patients in whom preoperative conventional external beam radiation therapy failed (22.2% local progression at 1 year, HR 1.96, p = 0.07) compared with patients who did not receive any preoperative radiotherapy (11.2% local progression at 1 year, HR 1), this association was not confirmed with multivariate analysis. No other variable significantly correlated with progression-free survival, including radiation sensitivity of tumor histology, grade of ESCC, extent of surgical decompression, or patient sex.

Conclusions

Postoperative adjuvant SRS following epidural spinal cord decompression and instrumentation is a safe and effective strategy for establishing durable local tumor control regardless of tumor histology–specific radiosensitivity. Patients who received high-dose hypofractionated SRS demonstrated 1-year local progression rates of less than 5% (95% CI 0%–12.2%), which were superior to the results of low-dose hypofractionated SRS. The local progression rate after single-fraction SRS was less than 10% (95% CI 0%–19.0%).

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Jian-Hua Zhong, Hua-Jun Zhou, Tao Tang, Han-Jin Cui, A-Li Yang, Qi-Mei Zhang, Jing-Hua Zhou, Qiang Zhang, Xun Gong, Zhao-Hui Zhang and Zhi-Gang Mei

OBJECTIVE

Reactive astrogliosis, a key feature that is characterized by glial proliferation, has been observed in rat brains after intracerebral hemorrhage (ICH). However, the mechanisms that control reactive astrogliosis formation remain unknown. Notch-1 signaling plays a critical role in modulating reactive astrogliosis. The purpose of this paper was to establish whether Notch-1 signaling is involved in reactive astrogliosis after ICH.

METHODS

ICH was induced in adult male Sprague-Dawley rats via stereotactic injection of autologous blood into the right globus pallidus. N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) was injected into the lateral ventricle to block Notch-1 signaling. The rats’ brains were perfused to identify proliferating cell nuclear antigen (PCNA)-positive/GFAP-positive nuclei. The expression of GFAP, Notch-1, and the activated form of Notch-1 (Notch intracellular domain [NICD]) and its ligand Jagged-1 was assessed using immunohistochemical and Western blot analyses, respectively.

RESULTS

Notch-1 signaling was upregulated and activated after ICH as confirmed by an increase in the expression of Notch-1 and NICD and its ligand Jagged-1. Remarkably, blockade of Notch-1 signaling with the specific inhibitor DAPT suppressed astrocytic proliferation and GFAP levels caused by ICH. In addition, DAPT improved neurological outcome after ICH.

CONCLUSIONS

Notch-1 signaling is a critical regulator of ICH-induced reactive astrogliosis, and its blockage may be a potential therapeutic strategy for hemorrhagic injury.

Free access

Yoshiya Yamada, Evangelia Katsoulakis, Ilya Laufer, Michael Lovelock, Ori Barzilai, Lily A. McLaughlin, Zhigang Zhang, Adam M. Schmitt, Daniel S. Higginson, Eric Lis, Michael J. Zelefsky, James Mechalakos and Mark H. Bilsky

OBJECTIVE

An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment.

METHODS

All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3–6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor's histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression.

RESULTS

A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2–141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7–57 months). The median prescribed dose was 2400 cGy (range 1600–2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose).

CONCLUSIONS

High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p < 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes.

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Hugh D. Moulding, James B. Elder, Eric Lis, Dale M. Lovelock, Zhigang Zhang, Yoshiya Yamada and Mark H. Bilsky

Object

Adjuvant radiation following epidural spinal cord decompression for tumor is a powerful tool used to achieve local disease control and preserve neurological function. To the authors' knowledge, only 1 published report addresses adjuvant stereotactic radiosurgery after this procedure, but that study used significantly lower doses than are currently prescribed. The authors review their experience using high-dose single-fraction radiosurgery as a postoperative adjuvant following surgical decompression and instrumentation to assess long-term local tumor control, morbidity, and survival.

Methods

A retrospective chart review identified 21 patients treated with surgical decompression and instrumentation for high-grade, epidural, spinal cord compression from tumor, followed by single-fraction high-dose spinal radiosurgery (dose range 18–24 Gy, median 24 Gy). Spinal cord dose was limited to a cord maximal dose of 14 Gy. Tumor histologies, time between surgery and radiosurgery, time to local recurrence after radiosurgery as assessed by serial MR imaging, and time to death were determined. Competing risk analysis was used to evaluate these end points.

Results

In this series, 20 tumors treated (95%) were considered highly radioresistant to conventional external beam radiation. The planning target volume received a high dose (24 Gy) in 16 patients (76.2%), and a low dose (18 or 21 Gy) in 5 patients (23.8%). During the study, 15 (72%) of 21 patients died, and in all cases death was due to systemic progression as opposed to local failure. The median overall survival after radiosurgery was 310 days (range 37 days to not reached). One patient (4.8%) underwent repeat surgery for local failure and 2 patients (9.5%) underwent spine surgery for other reasons. Local control was maintained after radiosurgery in 17 (81%) of 21 patients until death or most recent follow-up, with an estimated 1-year local failure risk of 9.5%. Of the failures, 3 of 4 were noted in patients receiving low-dose radiosurgery, equaling an overall failure rate of 60% (3 of 5 patients) and a 1-year local failure estimated risk of 20%. Those patients receiving adjuvant stereotactic radiosurgery with a high dose had a 93.8% overall local control rate (15 of 16 patients), with a 1-year estimated failure risk of 6.3%. Competing risk analysis showed this to be a significant difference between radiosurgical doses. One patient experienced a significant radiation-related complication; there were no wound-related issues after radiosurgery.

Conclusions

Spine radiosurgery after surgical decompression and instrumentation for tumor is a safe and effective technique that can achieve local tumor control until death in the vast majority of patients. In this series, those patients who received a higher radiosurgical dose had a significantly better local control rate.

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Robert J. Rothrock, Yi Li, Eric Lis, Stephanie Lobaugh, Zhigang Zhang, Patrick McCann, Patricia Mae G. Santos, T. Jonathan Yang, Ilya Laufer, Mark H. Bilsky, Adam Schmitt, Yoshiya Yamada and Daniel S. Higginson

OBJECTIVE

To characterize the clinical outcomes when stereotactic body radiation therapy (SBRT) alone is used to treat high-grade epidural disease without prior surgical decompression, the authors conducted a retrospective cohort study of patients treated at the Memorial Sloan Kettering Cancer Center between 2014 and 2018. The authors report locoregional failure (LRF) for a cohort of 31 cases treated with hypofractionated SBRT alone for grade 2 epidural spinal cord compression (ESCC) with radioresistant primary cancer histology.

METHODS

High-grade epidural disease was defined as grade 2 ESCC, which is notable for radiographic deformation of the spinal cord by metastatic disease. Kaplan-Meier survival curves and cumulative incidence functions were generated to examine the survival and incidence experiences of the sample level with respect to overall survival, LRF, and subsequent requirement of vertebral same-level surgery (SLS) due to tumor progression or fracture. Associations with dosimetric analysis were also examined.

RESULTS

Twenty-nine patients undergoing 31 episodes of hypofractionated SBRT alone for grade 2 ESCC between 2014 and 2018 were identified. The 1-year and 2-year cumulative incidences of LRF were 10.4% (95% CI 0–21.9) and 22.0% (95% CI 5.5–38.4), respectively. The median survival was 9.81 months (95% CI 8.12–18.54). The 1-year cumulative incidence of SLS was 6.8% (95% CI 0–16.0) and the 2-year incidence of SLS was 14.5% (95% CI 0.6–28.4). All patients who progressed to requiring surgery had index lesions at the thoracic apex (T5–7).

CONCLUSIONS

In carefully selected patients, treatment of grade 2 ESCC disease with hypofractionated SBRT alone offers a 1-year cumulative incidence of LRF similar to that in low-grade ESCC and postseparation surgery adjuvant hypofractionated SBRT. Use of SBRT alone has a favorable safety profile and a low cumulative incidence of progressive disease requiring open surgical intervention (14.5%).

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Jennifer Keam, Mark H. Bilsky, Ilya Laufer, Weiji Shi, Zhigang Zhang, Moses Tam, Joan Zatcky, Dale M. Lovelock and Yoshiya Yamada

Object

Radiation therapy is known to impair wound healing. Higher dose per fraction is believed to increase this risk. This study sought to quantify rates of wound complication in patients receiving preoperative conventionally fractionated radiotherapy (XRT) or high-dose hypofractionated image-guided radiation therapy (IGRT) for spinal metastasis, and to identify predictors of wound complication.

Methods

The records of 165 consecutive patients who underwent spine surgery for metastasis at Memorial Sloan–Kettering Cancer Center between 1999 and 2010, with a history of prior radiation therapy, were reviewed. Patients with primary spine tumors, 2 courses of prior radiation therapy to the surgical site, total dose < 9 Gy, or radiation therapy adjacent to or partially overlapping the surgical site, were excluded. One hundred thirty patients received XRT (≤ 3 Gy/fraction) and 35 received IGRT (> 3 Gy/fraction). The total dose prescribed to the 100% isodose line to treat the planning target volume was 18–30 Gy in 1–5 fractions. Clinical factors evaluated included age, Karnofsky Performance Scale score, body mass index, presence of diabetes, smoking, ambulatory status, prior surgery at same spinal site, preoperative laboratory results (hemoglobin, lymphocyte count, and albumin), perioperative chemotherapy or steroids, estimated blood loss, extent of stabilization hardware, time between radiation therapy and surgery, number of vertebral bodies irradiated, total radiation dose, and dose per fraction of radiation therapy. Wound complication was defined as poor healing, dehiscence, or infection. Potential predictors of wound complication were assessed by univariate analyses using competing-risk methods to adjust for risk of death.

Results

For XRT patients, median dose was 30 Gy (range 11.5–70 Gy) with 72% of them receiving 3 Gy × 10 fractions. For IGRT patients, 66% received 18–24 Gy × 1 fraction and 23% received 6 Gy × 5 fractions. Groups differed only by the mean number of vertebral bodies treated (4.6 XRT and 1.8 IGRT, p < 0.0001). Wound complications occurred at a median of 0.95 months (range 0.4–3.9 months). A total of 22 wound events occurred in the XRT group and 2 in the IGRT group. The 6-month cumulative incidence of wound complications for XRT was 17% and for IGRT was 6%. There was no significant difference in wound complications between groups (IGRT vs XRT: hazard ratio 0.31, 95% CI 0.08–1.3; p = 0.11). Higher dose per fraction appeared to be associated with a lower risk of wound complication (hazard ratio 0.27, 95% CI 0.06–1.15; p = 0.08), which trended toward significance. Univariate analyses did not reveal any significant predictors of wound complications.

Conclusions

Patients who underwent XRT or IGRT did not have significantly different rates of postoperative wound complications. This finding may be explained by the treatment of fewer vertebral bodies in IGRT patients, or by the low overall number of total events. With a wound complication rate of 6%, preoperative IGRT, a highly conformal treatment, resulted in a very low rate of surgical wound complication.