Intraoperative and percutaneous iridium-192 high-dose-rate brachytherapy for previously irradiated lesions of the spine

Brachytherapy 12 (2013) 449e456

Intraoperative and percutaneous iridium-192 high-dose-rate brachytherapy for previously irradiated lesions of the spine Michael R. Folkert1, Mark H. Bilsky2, Gil’ad N. Cohen3, Marco Zaider3, Eric Lis4, George Krol4, Ilya Laufer2, Yoshiya Yamada1,* 1

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 2 Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY 3 Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 4 Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY

ABSTRACT

PURPOSE: Advances in stereotactic radiosurgery have improved local control of spine metastases, but local failure is still a problem and repeat irradiation is limited by normal tissue tolerance. A novel high-dose-rate (HDR) brachytherapy technique has been developed to treat these previously irradiated lesions. METHODS AND MATERIALS: Five patients with progressive disease at previously irradiated sites in the spine who were not amenable to further external beam radiation were treated. Catheters were placed intraoperatively in 2 patients and percutaneously implanted in 3 patients with imageguided techniques. Conformal plans were generated to deliver dose to target tissues and spare critical structures. Patients received single-fraction treatment using HDR iridium-192 brachytherapy. RESULTS: Median dose was 14 Gy (range, 12e18 Gy) with a median gross total volume D90 of 75% (range, 31e94%); spinal cord/cauda equina dose constraints were met. At a median followup of 9 months, no local progression of disease has been observed. Four patients had reduction in pain 1e4 weeks after treatment. No brachytherapy-related complications have been observed. CONCLUSIONS: Intraoperative and percutaneous iridium-192 HDR spine brachytherapy techniques were not associated with complications or acute toxicity. There has been no local progression at treated sites, and most patients experienced reduction in cancer-related pain. Ó 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords:

Metastases; Recurrent; Reirradiation; Spine; Brachytherapy; High-dose-rate

Introduction

Received 27 November 2012; received in revised form 8 January 2013; accepted 8 January 2013. This was presented as a poster presentation in part at the Annual European Society for Therapeutic Radiology and Oncology (ESTRO)/ American Brachytherapy Society (ABS) World Congress of Brachytherapy meeting in Barcelona, Spain on May 10e12, 2012 and is not being considered for publication elsewhere. Disclosures: Dr. Yamada is a consultant for Varian Medical Systems, Inc. and a member of the Speakers Bureau for the Institute for Medical Education; Dr. Bilsky is a consultant for DePuy Synthes Companies of Johnson & Johnson, Spine Wave, Inc., and Medtronic, Inc.; Dr. Laufer is a consultant for Spine Wave, Inc.; the other authors have no financial disclosures or conflicts of interest to report. * Corresponding author. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 22, New York, NY 10065. Tel.: þ1-212-639-2950; fax: þ1-212-639-8876. E-mail address: [email protected] (Y. Yamada).

Spine metastases will develop in 10e40% of patients with cancer, resulting in bony pain and potentially mechanical instability and spinal cord or cauda equina compromise (1e3). Current treatment regimens for metastatic lesions in the spine include a range of external beam fractionation schedules, ranging from conventional low-dose-perfraction (high total dose) treatments extending over many weeks to high-dose single-fraction treatments delivered in a single day (3). Local control rates range from less than 50% with conventional radiation regimens (4) to more than 90% with high-dose image-guided single-fraction treatments (5, 6). Although advances in stereotactic external beam radiation therapy (EBRT) have improved local control of spinal metastases, local failure is still a problem and repeat irradiation is complicated by normal tissue tolerance, particularly that of the spinal cord; additionally, prior treatment may have

1538-4721/$ - see front matter Ó 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2013.01.162

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already delivered doses near tolerance to nearby structures, such as bowel, kidney, or esophagus. Intraoperative and percutaneous high-dose-rate (HDR) interstitial brachytherapy techniques have been developed to address technical difficulties and complications related to multiple courses of prior radiation and to improve local tumor and pain control and prevent progressive neurologic deficits. Using these techniques, tumoricidal doses of radiation are delivered directly to lesions in the vertebral bodies and paraspinal tissues using an iridium-192 (192Ir) HDR brachytherapy source delivered via catheters placed using image-guided techniques. Multichannel HDR allows prescription of conformal dose to the target tissues and sparing critical structures within and near the spine, including the spinal cord, cauda equina, bowel, kidney, and esophagus. In this study, we present initial data on these techniques developed at our institution for treatment of previously irradiated spine lesions.

Methods and materials Patients Between May 2010 and April 2012, 5 patients were identified with symptomatic progressive disease at previously irradiated sites in the spine; in all cases, their prior treatments to the site of progression were reviewed by our institutional multidisciplinary Spine Tumor Board, comprising radiation oncologists, neurosurgeons, orthopedic surgeons, neuroradiologists, physical medicine and rehabilitation physicians, and palliative care medicine physicians. Doses for spinal cord/cauda equina and other organs at risk (OARs) for all prior radiation treatments were converted to biologically effective doses (BEDs) using the formula BED 5 D  [1 þ d/(a/b)], where D is the total dose, d is the dose per fraction, and the a/b ratio is the dose at which linear and quadratic components of cell killing are equal (7). Assuming an a/b ratio of two for late cord toxicity as per Sahgal et al. (8), the BED was then converted to 2 Gy equivalent BEDs (BED2/2) by dividing the BED by [1 þ d/(a/b)] 5 2, where d and a/b are both 2 Gy. Relevant bowel and kidney BED and 2 Gy equivalent BEDs were calculated as well, using a/b ratios of 3 and 2, respectively (BED2/3 or BED2/2). A decision was made to proceed with HDR spine brachytherapy based on a review of their prior treatment and a determination that additional EBRT using either conventional or image-guided stereotactic radiosurgical techniques would exceed departmental dose constraint guidelines to the spinal cord, cauda equina, or other critical structures including bowel and kidney. Although a complete review of all our institutional constraints would be too extensive for the scope of this work, a brief summary of the relevant constraints at our institution is as follows. For hypofractionated radiosurgery, in the setting of prior radiation, the spinal cord may receive a maximum point dose

of 17.5 Gy in five fractions, 15.2 Gy in four fractions, or 13.5 Gy in three fractions with one course of prior radiation more than 6 months previously at an equivalent prescription dose of #30 Gy in 3-Gy fractions (BED2/2 5 37.5 Gy). The cauda equina may receive 20 Gy in five fractions or 14 Gy in three fractions, again with one course of prior radiation more than 6 months previously at an equivalent prescription dose of #30 Gy in 3-Gy fractions. The stomach or bowel may receive a maximum of an equivalent of 85 Gy in 2Gy fractions to previously treated regions over all courses of radiation with at least 3 months between prior radiation and retreatment, assuming an a/b ratio of 3 (BED2/3 5 85 Gy). There are no allowances for reirradiation of the kidney; less than 33% of the spared kidney volume and 35% of the total kidney volume may receive 10 Gy for single-fraction treatment, 15 Gy for treatment in three fractions, or 18 Gy for treatment in five fractions (BED2/2 5 25e30 Gy). The esophagus may be reirradiated to a maximum point dose of 25 Gy in five fractions (BED2/3 5 40 Gy) with up to 45 Gy of prior treatment. Patients who had already received retreatment with hypofractionated radiosurgery to spinal cord or cauda equina constraint doses received external beam radiation treatment less than 6 months before proposed retreatment or would exceed constraints to other OARs, particularly the bowel, kidney, or esophagus, were considered ineligible to receive therapeutic doses from conventional or image-guided stereotactic radiosurgical techniques. These patients were then recommended to receive treatment using HDR spine brachytherapy. Two patients with simultaneous intraosseous and epidural disease subsequently received HDR brachytherapy in the inpatient setting using catheters placed intraoperatively in the vertebral bodies during surgery with fluoroscopic verification; in this setting, the surgery consisted of a posterolateral decompressive surgery with maximal safe debulking. In both cases, the patients had previously had hardware stabilization. Three patients without epidural involvement were treated with HDR brachytherapy as outpatients using percutaneously implanted catheters with the assistance of biplanar fluoroscopy. The goals of treatment were alleviation of pain and prevention of further local disease progression. Procedure In all cases, catheter placement was performed under general anesthesia using either direct visualization or fluoroscopic guidance. Jamshidi needles were placed into the vertebral body via either direct cannulation through the pedicle or a paraspinal approach. Flexible afterloading catheters were placed through the needles, which were then removed. The position of the catheters was confirmed by fluoroscopic imaging using radio-opaque inserts (Figs. 1 and 2). A fine-slice (~1-mm thick slices with 1-mm spacing) planning CT scan was taken in the prone treatment

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Fig. 1. Placement and verification of trocars for high-dose-rate brachytherapy catheter placement; needle depth is checked using radio-opaque markers to show adequate clearance to the front of vertebral body.

position; using this intraoperative CT scan and preoperative imaging, the patient’s spinal cord/cauda equina, gross tumor volume (GTV, based on prior positron emission tomography/CT and MRI), and a clinical target volume (including the entire involved vertebral body) were contoured in the treatment planning system (Brachyvision; Varian Medical Systems, Inc., Palo Alto, CA) (Fig. 3). Delineation of the spinal cord/cauda equina was performed after fusion of preoperative MRI to the planning CT scan. Relevant nearby critical structures, such as the kidney, bowel, or esophagus, were contoured and served as additional dose-limiting structures (Dmax ! 8 Gy, with further constraints based on prior treatment). Anesthesia was reversed once the planning CT was obtained. Treatment plans were generated and checked by brachytherapy physics as well as reviewed and approved by the radiation oncologist (Fig. 4). The patients were then transferred for treatment to a shielded room. Fluoroscopic images were acquired and compared with intraoperative images to

Fig. 3. High-dose-rate brachytherapy planning image; catheter trajectories shown with critical structures including GTV, CTV, and cord indicated. GTV 5 gross tumor volume; CTV 5 clinical target volume.

confirm the integrity of the treatment geometry. Patients were treated with a single fraction using HDR 192Ir brachytherapy, after which the catheters were removed. All treatments were performed using a two-stage interstitial catheter system (Mick Radio-Nuclear Instruments, Inc., Mount Vernon, NY) and GammaMed Plus HDR afterloaders (Varian Medical Systems, Inc., Palo Alto, CA). Assessment/followup Patients were followed with comprehensive physical examination including neurologic examination and MRIbased imaging of the spine (or CT-based imaging if MRI was contraindicated) 2e4 weeks after treatment and every 3 months thereafter. Local recurrence was defined as radiographic increase in the size of the treated lesion. Patients were assessed before treatment and at each followup visit using the standardized 11-point (0e10) Numeric Rating Scale 11 (9, 10). Grading of toxicity was based on the Common Terminology Criteria for Adverse Events version 4.0. Statistics

Fig. 2. Verification images showing depth of insertion of the radio-opaque fiducials.

All outcome measurements were measured from the date of completion of brachytherapy to time of event. Overall survival was defined as the time of death from any cause. Local failure is recurrence of disease at the site specifically treated with brachytherapy. Local progression-free survival was defined as the time to first clinical or pathologic evidence of local failure. Patients were censored at the date of last followup or death. Outcomes were estimated using the KaplaneMeier statistics. Statistical analysis was performed using SPSS v.20.0.0 (SPSS, Inc., Chicago, IL).

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Fig. 4. Doseevolume histogram for a representative plan; GTV, CTV, and cord doses are indicated. GTV 5 gross tumor volume; CTV 5 clinical target volume.

Results Patient cohort The mean age of the cohort was 64 (range, 46e76). Histologies included 2 patients with prostate cancer and 1 each with uterine leiomyosarcoma, renal cell carcinoma, and thyroid carcinoma. All patients were previously treated with external beam radiation to the site receiving HDR brachytherapy in this study; all patients received at least two courses of prior radiation. The median spinal cord or cauda equina BED2/2 was 65.3 Gy2/2 (range, 51e72 BED2/2), and Patient 3 received radiation to the spinal cord within 3 months of proposed retreatment. Although Patient 4 had a relatively low spinal cord BED2/2 of 51 Gy, his esophagus had been treated to a BED2/3 of 116 Gy. Patients 1 and 5 had prior bowel BED2/3 doses approaching our institutional limits (range, 62e81 BED2/3). Patient 5 previously received radiation to at least 35% of the kidney volume to a total BED2/2 of 28.9 Gy. Of the locations treated, three were in the lumbar spine (L2eL3) and two were in the lower thoracic spine (T9eT11) (Table 1).

Treatment characteristics Median dose delivered was 14 Gy (range, 12e18 Gy) with a median as-treated GTV V100%of 67% (range, 35e83%) and median as-treated GTV D90%. of 75% (range, 31e94%). When normalizing to a prescription dose of 14 Gy, the GTV V100% and D90% were 54% and 75%, respectively; normalizing to 12 Gy, the GTV V100% and D90% were 81% and 88%, respectively. The median number of catheters used to treat was four (range, 2e10 catheters). In all cases, the spinal cord/cauda equina maximum dose constraints were met; median cord/cauda equina Dmax was 7 Gy (range, 5.8e10 Gy) with median mean cord/

cauda equina dose of 4 Gy (3e5.6 Gy). No significant difference was noted between the intraoperative or percutaneous approach (Table 2). Outcomes At a median follow-up of 9 months (range, 4e17 months), there has been no local progression of disease. Four patients had reduction in pain within 1e4 weeks after treatment; 2 patients described complete resolution of pain, and 2 patients described mild reduction in pain. Two patients have died, both in the group treated with intraoperatively placed catheters; cause of death was cancer progression outside the treated field in both patients. Actuarial overall survival rates at 6 and 12 months were 100% and 66.7% (95% confidence interval, 12.3e100%), respectively. Toxicity Treatment was successfully delivered in all cases with no brachytherapy-related complications. There were no instances of radiation myelitis or hospitalization secondary to radiation treatment.

Discussion Although EBRT techniques are one of the most common approaches to the management of osseous metastases, reirradiation of recurrent lesions becomes progressively more complicated with each treatment. The generally accepted dose limit for the spinal cord is 45 Gy at 1.8e2.0 Gy/ fraction (11); doses up to 50 Gy are often observed in otherwise healthy patients treated with definitive intent when the tumor proximity to the cord limits the technical ability to

Table 1 Patient characteristics

Spine HDR Patient Age Gender technique

Histology

Prior chemotherapy

HDR treated site

Time between HDR and last course RT (months) Relevant prior RT courses

ADT, docetaxel, mitoxantrone

71

M

Intraoperative Prostate

L2

12

2

46

F

L5 Intraoperative Uterine Gemcitabine, leiomyosarcoma docetaxel, temozolomide

11

3

76

M

Percutaneous

Prostate

ADT, docetaxel

T11

3

4

64

M

Percutaneous

Renal

Sunitinib

T9, T10

9

5

62

F

Percutaneous

Thyroid

None

L3/right 26 paravertebral

1. 37.6 Gy/16 Fx L3eS1 1. Cauda equina, bowel 2004 Dmax 5 37.6 Gy 2. Cauda equina Dmax 5 16 2. 30 Gy/5 Fx L4 2006 Gy; bowel Dmax 5 4.4 3. 30 Gy/5 Fx L1eL3 2009 Gy 4. 10 Gy/1 fx L2 2011 (P-32 3. Cauda equina Dmax 5 10 IORT) Gy; bowel Dmax 5 16 Gy 4. Cauda equina Dmax 5 0.5 Gy 1. 24 Gy/3 Fx L3eL4 2009 1. Cauda equina Dmax 5 14 2. 18 Gy/1 Fx L5 2009 Gy, bowel Dmax 5 4.2 Gy 2. Cauda equina Dmax 5 12 3. 25 Gy/5 Fx T12eL3 Gy; bowel Dmax 5 14.3 2009 Gy 3. Cauda equina Dmax 5 minimal; bowel Dmax 5 2.5 Gy 1. Spinal cord Dmax 5 14 1. 24 Gy/1 Fx T11 2009 2. 153Sm 2011 Gy; esophagus Dmax 5 15 Gy; stomach/bowel Dmax 5 10.8 Gy 2. Spinal cord Dmax 5 8 Gy, esophagus Dmax 5 3.8 Gy 1. 30 Gy/10 Fx T7eT11 1. Spinal cord, stomach/ 2010 bowel, esophagus 2. 10 Gy/1 Fx T9 2011 (PDmax 5 30 Gy 2. Spinal cord Dmax 5 0.5 32 IORT) Gy 3. 30 Gy/3 Fx T9 2011 3. Spinal cord Dmax 5 10 Gy; esophagus Dmax 5 30.4 Gy 1. 39 Gy/13 Fx L1eL3 1. Cauda equina, bowel 1997 Dmax 5 39 Gy; kidney 13 Gy (35% of volume) 2. 25 Gy/5 Fx L1eL4 2010 2. Cauda equina Dmax 5 16 Gy; bowel Dmax 5 22.6 Gy; kidney 5 15.2 Gy (35% of volume)

Total BED2/2 (Gy), kidney (35% of volume)

Total BED2/3 (Gy), esophagus

Total BED2/3 (Gy), bowel

72.0

NR

NR

61.6

65.3

NR

NR

34.5

63.2

NR

56.3

26.0

51.1

NR

115.9

30.0

69.6

28.9

NR

80.8

453

Normal tissue BED2/2 values in bold denote values near or exceeding dose constraints. HDR 5 high-dose-rate brachytherapy; RT 5 radiation therapy; OAR 5 organs at risk; BED 5 biologically effective dose; BED2/2 5 2 Gy equivalent BED (where a/b 5 2); BED2/3 5 2 Gy equivalent BED (where a/b 5 3); M 5 male; F 5female; ADT 5 androgen deprivation therapy; Fx 5 number of treatment fractions; P32 5 phosphorus-32; IORT 5 intraoperative radiation therapy; NR 5 not relevant; 153Sm 5 samarium-153.

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1

Total BED2/2 (Gy) spinal Relevant OAR dose at HDR site, cord/cauda per treatment course equina

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Table 2 GTV dosimetry comparison (median values) Intraoperative

Percutaneous

Overall

Prescription dose normalization

GTV D90 (%)

GTV V100 (%)

GTV D90 (%)

GTV V100 (%)

GTV D90 (%)

GTV V100 (%)

As treated Expressed as % of 14 Gy Expressed as % of 12 Gy

63 61 71

59 48 69

75 75 88

67 67 81

75 75 88

67 54 81

GTV 5 gross tumor volume; D90 5 minimum dose delivered to 90% of the volume; V100 5 volume receiving at least 100% of the prescribed dose.

deliver therapeutic dose, carrying a 5% risk of myelopathy at 5 years (11, 12). For patients receiving high-dose radiosurgical procedures in the spine, cord tolerance is defined as a cord maximal dose (Dmax) of 14 Gy or less than 10 Gy to 10% volume of the spinal cord per level (5, 13). Although local control has improved dramatically with higher stereotactic radiosurgery dose regimens and improved tumor coverage, local failure is always a possibility and dose limitations after prior radiation may preclude or impair the ability of radiation oncologists to offer effective salvage therapy with external beam techniques. Toxicity resulting from repeat irradiation is a subject of open investigation, with BED thresholds for late cord complication of 135 Gy (BED2/2 67.5 Gy) proposed by Nieder et al. (14) and BED 100 Gy (BED2/2 50 Gy) by Rades et al. (15). A recent comprehensive analysis of patients treated with reirradiation by stereotactic body radiation therapy (RT) by Sahgal et al. (8) proposed that constraining the total thecal sac BED2/2 to doses less than 70 Gy appears to reduce the risk of late radiation myelopathy. Although this guideline is not explicitly used at our institution, review of the prior treatments of the patients in this study (Table 1) demonstrates that these constraints and those of other OARs had already been met or would have been exceeded with additional EBRT. For patients who have local progression after maximal external beam radiation for lesions in the spine, options include aggressive surgical intervention, systemic chemotherapy, or protracted courses of steroid therapy. These alternatives come at the price of high morbidity and low efficacy, and often these patients are poor surgical candidates or have already failed multiple lines of chemotherapy and as such have no further meaningful systemic options available (3). A percutaneous or intraoperative brachytherapy approach creates the possibility of retreatment in the setting of previously irradiated lesions of the spine. Low-dose-rate (LDR) brachytherapeutic approaches have previously been used in the spine (Table 3); both Nori et al. (16) and Sundaresan et al. (17) reported on patients with metastatic lung cancer; in the latter study, 25 patients with invasion of the spine, 19 (76%) of whom had prior radiation, were treated with 192Ir brachytherapy to doses of 30e40 Gy delivered in the immediate postoperative setting (4e7 days after surgery) via LDR brachytherapy catheters implanted in the surgical bed intraoperatively; of note, this technique was not devised to treat gross disease but to sterilize the resection margin. They observed a 20%

improvement in ambulation, and 90% of patients experienced initial pain relief, with two-thirds of patients experiencing durable pain relief at 6 months. Gutin et al. (18) also reported their experience with LDR iodine-125 seed implantation of recurrent skull base and spine tumors; the single patient treated with spine disease received 50 Gy and developed a nonmalignant postoperative fistula between the cervical spine tumor bed and the posterior pharynx; this was repaired, and there was no observed recurrence. More recently, other institutions have investigated similar modes of treatment to that presented in this study, although none have investigated HDR brachytherapy for retreatment after RT and none have used conformal techniques with limitation of dose to nearby critical structures. Currently used techniques include electron cone applicators requiring an invasive open procedure with poor conformality (19); use of the Intrabeam electron applicator (XRS 4; Carl Zeiss Surgical, Carl Zeiss AG, Oberkochen, Germany) that delivers a nonconformal dose via a percutaneous technique (20, 21), and injection of samarium-153 (153Sm) during kyphoplasty, again with limited conformality (22, 23) (Table 3). Intraoperative treatment of metastatic spinal tumors using an electron accelerator was described by Seichi et al. (19); they reported on 37 patients who received nonconformal intraoperative electron beam RT to the spine; 11e20 MeV electron energies were used to treat the operative bed to doses of approximately 20 Gy, with lead blocking to shield the cord. Twenty-two patients (59.5%) also had additional EBRT perioperatively. All patients had improvement in pain, and there was no clinical or radiographic evidence of local recurrence at the treated site. Only 1 patient (2.7%) developed radiation myelopathy of the spine, and no other toxicities were reported. Cardoso et al. (23) reported on a procedure in which they performed kyphoplasty coupled with the delivery of 153 Sm for vertebral metastases. They performed 24 procedures in 19 patients; bone-related pain improved significantly in all patients, and no toxicities were observed. Ashamalla et al. (22) also reported on their experience using 153Sm with kyphoplasty; they performed 33 procedures in 26 patients. One procedure (3%) was complicated by leakage of the cement/153Sm mixture; otherwise, no toxicities were reported, and there was a significant improvement in patient pain scores. In both studies, it was uncertain as to whether the pain improvement was

None reported Sm leakage in 1 patient (3%) 153

153

I 5 iodine-125; Ir 5 iridium-192; LDR 5 low-dose-rate brachytherapy;

192

125

No No 50-kV photons LDR, 153Sm Wenz et al. (20), Schneider et al. (21) Ashamalla et al. (22), Cardoso et al. (23)

Percutaneous Percutaneous

Sm 5 samarium-153.

None None

None reported Postoperative fistula in 1 patient (100%) Radiation myelopathy in 1 patient (2.7%) 68 100 27

30e40 Gy 50 Gy 20e30 Gy, with O40% delivered to ventral portion of tumor 10 Gye1 cm 1e4 mCi 153Sm Yes Yes No LDR, 192Ir LDR, 125I Electron beam Nori et al. (16), Sundaresan et al. (17) Gutin et al. (18) Seichi et al. (19)

Open Open Open

Dose delivered Open or percutaneous Conformal Treatment technique Study

Table 3 Selected prior studies using intraoperative and percutaneous brachytherapy techniques for treatment of lesions of the spine

Prior radiation to treated site (%)

Complications

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because of the kyphoplasty element of the procedure, the administration of 153Sm, or the combination of the two; the rapid response noted in Ashamalla et al. (response within 1 day) suggests that the mechanical stabilization of the kyphoplasty cement was the major contributor (22). Additionally, although localization of the radionuclide was demonstrated using whole-body scans, dose delivery was not conformal and target coverage was unknown. Wenz et al. (20) had reported on a novel technique of intraoperative RT during kyphoplasty using the Intrabeam x-ray generator (XRS 4, Carl Zeiss), in which they successfully treated a patient with metastatic breast cancer using a 50-kV X-ray source, followed by kyphoplasty. No acute toxicities were noted. Schneider et al. (21) also reported on a theoretical study of intraoperative RT during kyphoplasty using the Intrabeam x-ray generator to deliver an experimental dose of 10 Gy to 1 cm. No actual patients were treated, but they were able to demonstrate in a cadaver model that the cord dose was limited to 3.8 Gy. Our technique represents a novel application of HDR brachytherapy to the management of previously irradiated lesions of the spine, allowing high-dose delivery of therapeutic radiation in a conformal manner. Although radiosurgical techniques are able to deliver a higher and more uniform dose, catheter-based HDR brachytherapy may represent an alternative treatment when additional EBRT using conventional or radiosurgical techniques would exceed dose constraints of OARs, including the spinal cord, cauda equina, esophagus, bowel, and kidney. To achieve optimal dose distribution, proper catheter placement is essential; this requires careful planning and an understanding of what paths through the bony structures of the spine are appropriate for instrumentation. Use of image-guided surgical navigation may allow preplanned catheter trajectories to be optimized and reproducibly executed, providing improved delivery of radiation dose. As such, we have proposed a clinical trial that will use image-guided surgical navigation tools to incorporate preplanned entry points and catheter trajectories to improve localization and coverage.

Conclusions Intraoperative and percutaneous 192Ir HDR spine brachytherapy techniques are not associated with complications or acute toxicity; although this novel methodology is in the early investigational stages, it may provide a safe and effective means of treating previously irradiated sites of progression in the spine. Validation of this technique will be investigated in a prospective clinical trial at our institution.

Acknowledgments The authors thank Lawrence A. Herman, who provided editorial assistance in the preparation of the final version of this manuscript.

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Conflict of interest statement: Dr. Yamada is a Consultant for Varian Medical Systems, Inc. and a member of the Speakers Bureau for the Institute for Medical Education; Dr. Bilsky is a consultant for DePuy Synthes Companies of Johnson & Johnson, Spine Wave, Inc., and Medtronic, Inc.; Dr. Laufer is a consultant for Spine Wave, Inc.; the other authors have no financial disclosures or conflicts of interest to report. References [1] Perrin RG, Laxton AW. Metastatic spine disease: Epidemiology, pathophysiology, and evaluation of patients. Neurosurg Clin N Am 2004;15:365e373. [2] Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004; 350:1655e1664. [3] Bartels RH, van der Linden YM, van der Graaf WT. Spinal extradural metastasis: Review of current treatment options. CA Cancer J Clin 2008;58:245e259. [4] Klekamp J, Samii H. Surgical results for spinal metastases. Acta Neurochir (Wien) 1998;140:957e967. [5] Yamada Y, Bilsky MH, Lovelock DM, et al. High-dose, singlefraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 2008;71: 484e490. [6] Moulding HD, Elder JB, Lis E, et al. Local disease control after decompressive surgery and adjuvant high-dose single-fraction radiosurgery for spine metastases. J Neurosurg Spine 2010;13: 87e93. [7] Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys 1982; 8:1981e1997. [8] Sahgal A, Ma L, Weinberg V, et al. Reirradiation human spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 2012;82:107e116. [9] Downie WW, Leatham PA, Rhind VM, et al. Studies with pain rating scales. Ann Rheum Dis 1978;37:378e381. [10] Paice JA, Cohen FL. Validity of a verbally administered numeric rating scale to measure cancer pain intensity. Cancer Nurs 1997; 20:88e93.

[11] Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 1995;31: 1093e1112. [12] Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21: 109e122. [13] Ryu S, Jin JY, Jin R, et al. Partial volume tolerance of the spinal cord and complications of single-dose radiosurgery. Cancer 2007;109: 628e636. [14] Nieder C, Grosu AL, Andratschke NH, et al. Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients. Int J Radiat Oncol Biol Phys 2005;61:851e855. [15] Rades D, Stalpers LJ, Veninga T, et al. Spinal reirradiation after short-course RT for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 2005;63:872e875. [16] Nori D, Sundaresan N, Bains M, et al. Bronchogenic carcinoma with invasion of the spine. Treatment with combined surgery and perioperative brachytherapy. JAMA 1982;248:2491e2493. [17] Sundaresan N, Bains M, McCormack P. Surgical treatment of spinal cord compression in patients with lung cancer. Neurosurgery 1985; 16:350e356. [18] Gutin PH, Leibel SA, Hosobuchi Y, et al. Brachytherapy of recurrent tumors of the skull base and spine with iodine-125 sources. Neurosurgery 1987;20:938e945. [19] Seichi A, Kondoh T, Hozumi T, et al. Intraoperative radiation therapy for metastatic spinal tumors. Spine 1999;24:470e473. discussion 474e475. [20] Wenz F, Schneider F, Neumaier C, et al. Kypho-IORTdA novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases. Radiat Oncol 2010;5:11. [21] Schneider F, Greineck F, Clausen S, et al. Development of a novel method for intraoperative radiotherapy during kyphoplasty for spinal metastases (Kypho-IORT). Int J Radiat Oncol Biol Phys 2011;81: 1114e1119. [22] Ashamalla H, Cardoso E, Macedon M, et al. Phase I trial of vertebral intracavitary cement and samarium (VICS): Novel technique for treatment of painful vertebral metastasis. Int J Radiat Oncol Biol Phys 2009;75:836e842. [23] Cardoso ER, Ashamalla H, Weng L, et al. Percutaneous tumor curettage and interstitial delivery of samarium-153 coupled with kyphoplasty for treatment of vertebral metastases. J Neurosurg Spine 2009;10:336e342.