Spinal brachytherapy

Abstract

Brachytherapy remains an underrecognized and underutilized radiation therapy modality for the treatment of spinal tumors. This article summarizes the existing body of medical literature on the usage, indications, techniques, and outcomes of brachytherapy for the treatment of spine tumors. The disease pathology most commonly treated with brachytherapy is metastatic spine cancer, rather than primary bone tumors of the spine. Brachytherapy can be used alone, as percutaneous needle injections; however, it is more often used in conjunction with open surgery or cement vertebral body augmentation. Although the data are still relatively sparse, studies show consistent benefit from brachytherapy in terms of improvements in pain, function, local recurrence rate, and overall survival. Brachytherapy is also associated with a favorable complication profile.

The close proximity of the spinal column to key neurovascular structures poses a challenge to both traditional open surgical and radiation treatment of metastatic and primary spinal tumors. The goal of treatment is to maximize local tumor control while minimizing neurologic morbidity. To meet that need, medical and surgical treatment paradigms for metastatic and primary spinal tumors have continued to evolve over the years, with the advent of novel therapeutic agents and targeted therapies. Surgery, radiation, and systemic therapy remain the pillars of cancer treatment.¹ On the medical front, individualized pharmacotherapy based on tumor genetics provides longer survival times and improved local control of metastatic lesions. Although advances in the biomedical device industry provide an increasingly powerful armamentarium for surgeons to restore spinal stability and alignment in advanced destructive spine lesions, optimal long-term survival outcomes remain dependent on appropriate systemic and radiation therapy.

Technological advancements have facilitated a shift from conventional external beam radiation therapy (cEBRT) to stereotactic body radiotherapy (SBRT), allowing for the focal administration of high-dose radiation to contoured target volumes.² Traditionally, postoperative stereotactic radiosurgery has been routine after surgical decompression to enable less invasive surgical approaches that offer decreased morbidity while still providing effective local tumor control. Despite these advances in radiosurgery, there are still limitations in delivering effective conformational doses with low toxicity to critical structures.

Spinal brachytherapy offers an alternative route of radiation delivery through direct placement of the radiation source to the target area.³ This can be accomplished through both open and percutaneous techniques, which are often combined with cement augmentation. Although brachytherapy was introduced 4 decades ago, its use remains rare.⁴ However, advancements in surgical technology and the increasing emphasis on smaller, less aggressive tissue exposures work well in conjunction with brachytherapy.

Brachytherapy uses radioactive seeds, which are constructed as a radioactive core within a sealed capsule that can be implanted directly into or adjacent to a tumor with subsequent release of continuous low-dose x- or γ-rays that directly induce sustained tumoricidal effects.^5–10 For sources such as Iodine 125 (¹²⁵I), the radiation emitted from each seed rapidly attenuates over a short distance, minimizing the reach of the radiation to surrounding healthy tissue. In this review, we will describe the clinical indications, reported outcome measures, advantages, and disadvantages of brachytherapy compared with traditional radiation therapy in the field of spinal oncology. We will also assess current SBRT, its role as an adjuvant or alternative to open surgery, and its complication profile.

Indications for Brachytherapy in Spinal Tumor Disease

A 2018 systematic review of brachytherapy by Zuckerman et al.⁴ identified 15 key articles with descriptive results that could be used for quantitative analysis. This analysis described 370 patients who underwent brachytherapy. The mean age of the patients assessed was 57.1 ± 5.7 years.^3,11,12 The vast majority (78%) of the lesions resulted from metastatic disease, which can be expected given the low incidence of primary spine tumors and high prevalence of metastatic spine lesions.¹³ In this study, lung cancer was the most common histology (30%) for metastatic tumors, while chordoma was the most common primary spine tumor.⁴ This is consistent with previous studies that show that breast, prostate, lung, thyroid, and kidney cancers account for up to 80% of all skeletal metastases.^14–16

In this systematic review by Zuckerman et al.,⁴ 161 of 193 patients had undergone previous radiotherapy before receiving brachytherapy. Of these 161 patients, 9% received cEBRT and 91% did not specify the form of radiation therapy received. Only 5 articles reporting a total of 65 patients documented post-brachytherapy radiation, with over 80% having received SBRT and 20% without specifying the radiation type.^17–20

Indications for brachytherapy remain broad, with the most common reason cited as disease progression despite prior surgery, chemotherapy, and radiation (Table 1).^{3,4,11,12,18,19,21–26} General indications for oncologic treatment were focal lesion identified on spinal imaging and as intractable pain localized to the region. Specific indications for brachytherapy showed disease progression refractory to previous treatments as the number one reason, followed by inability to tolerate systemic treatments or open surgery. Limited number of vertebral segments involvement was also mentioned as another factor in 13% of cases.⁴ With improvements in survival with systemic therapy, brachytherapy remains primarily a salvage therapy option in most cases.

Table 1.

Indications for Brachytherapy in 218 Patients Evaluated Across 10 Studies^*

Treatment Indications	Patients, n (%)
Indications for oncologic treatment
Lesion identified on neuroimaging	188 (86)
Intractable pain	139 (64)
Indications for brachytherapy
Refractory to all prior treatments	90 (41)
Inability to tolerate chemotherapy and   radiation therapy	46 (21)
Inability to tolerate open surgery	46 (21)
Vertebral involvement at more than 3 levels	29 (13)

Table adapted from Zuckerman et al.⁴

*Data aggregated from 10 studies analyzed by Zuckerman et al.⁴

Modes of Delivery

The systematic review by Zuckerman et al.⁴ identified ¹²⁵I as the most common radioactive source, used in 55% of patients (Table 2). After ¹²⁵I, the next most common isotopes were Phosphorus 32 (³²P) and Iridium 125/192, which were used to treat another 25% and 13% of the patients, respectively. The remaining 6% of patients treated by brachytherapy were exposed to Samarium 153 and Yttrium 90. The preferred form of radiation delivery was seed placement in 10 of the 15 studies analyzed.

Table 2.

Brachytherapy Modalities^*

Modalities for Brachytherapy	Patients, n (%)
Radioactive source
Iodine 125	205 (55)
Phosphorus 32	93 (25)
Iridium 125/192	48 (13)
Samarium 153	19 (5)
Yttrium 90	5 (1)
Form of radiation
Seed	215 (58)
Implant/plaque	155 (42)
Mode of brachytherapy delivery
Percutaneous	178 (48)
Open	198 (52)
Surgical technique
Decompression	186 (50)
Cement augmentation	174 (47)
Pedicle screw fixation	167 (45)
Needle delivery of brachytherapy	175 (47)

Table adapted from Zuckerman et al.⁴

*Percentages calculated from aggregate of 370 patients across all 15 studies. Percentages for radioactive sources do not add to 100 due to combined use of several radioactive sources in 2 studies.

¹²⁵I is preferred due to its uncharacteristically low half-life of 60 days and long energy (27–35 keV), which allow for continuous, sustained delivery of low-dose radiation to the surrounding tumor bed while minimizing deeper collateral tissue damage.^7,2732S decays into ³²P via beta decay with a half-life of 14 days and has historically been investigated for the identification of malignant tumors because of the increased accumulation of phosphate in cancerous cells compared with normal cells. Iridium 125/192 decays via a combination of beta particles and gamma radiation, with a relatively long half-life of 73.8 days. Yttrium 90 is another isotope capable of delivering high-dose radiation via beta decay with limited tissue penetration, similar to ¹²⁵I, making it ideal for intraoperative treatment after epidural tumor resection.²⁸ Its half-life is more limited, at 64 hours.

The overall medical health of the patient for open surgery and the degree of spinal instability as well as epidural spinal cord compression will dictate the method of brachytherapy delivery. Patients who can tolerate more invasive surgery and who have significant epidural spinal cord compression or evidence of instability from enlarging lytic lesions will likely benefit more from an open approach. The percutaneous approach is associated with significantly less blood loss, as well as decreased wound-related and other surgical approach-related morbidity, while minimizing anesthesia time. The percutaneous approach can also be used with cement augmentation (ie, percutaneous vertebral augmentation [PVA]) to provide structural support and can be performed in the outpatient setting.

Whether delivered via a percutaneous or open surgical approach, brachytherapy monotherapy is often combined with stabilization procedures such as pedicle screw instrumentation or cement augmentation. Clinical data show that metastatic infiltration of weight-bearing bones creates a significant risk of pathologic fracture, with up to 25% of patients with bone metastases presenting with pathological fractures.^29–31 Transpedicular seeding of radioactive material with or without cement can be easily accomplished. Otherwise, Folkert et al.^19,23 have described ³²P plaques sealed in Ioban films placed in the epidural place for 15 minutes after circumferential separation surgery to allow high-dose intraoperative radiation without excessive toxicity to neural elements. Overall, about half (51.9%) of patients assessed by Zuckerman et al.⁴ underwent open surgery while the other half (48.1%) underwent percutaneous (needle) delivery. The surgical cohort comprised groups that underwent spinal decompression for epidural disease (50%), cement augmentation to stabilize the vertebral body (47%), and pedicle screw insertion for posterior fusion (45%).

In the percutaneous cohort, the vast majority of patients undergo the procedure guided by computed tomography to allow for precise calculation of number, activity of seeds, and depth of placement. ¹²⁵I seeds are typically distributed approximately 1 cm apart in a 3-dimensional fashion to accommodate a preset target volume of 1 cubic centimeter.²

Radiation doses also vary widely across studies. Doses vary between 10 and 142 Gy, depending on the study and patient tolerance. The number of seeds used also changes based on the disease pattern, surgical exposure, and levels affected, with an average of 20 seeds placed per procedure. The span and length of circumferential epidural tumor involvement as measured on computed tomography and magnetic resonance imaging is commonly used to estimate the required dose.^2,4

Clinical Outcomes

Functional performance status, pain, survival, and local control rates are all key outcome measures after brachytherapy.

Overall Survival and Local Control Rates

Due to the limited number of studies, the reported mortality rates vary drastically. In fact, in 8 studies, the mortality rates ranged from 8% to 91%, depending on the final time points measured in each study.⁴ Four studies provide survival data at 6 months after brachytherapy, showing a more consistent 66%–100%, depending on the pathology and clinical status of the patients.^17,19,23,25 Recurrence rate is more similar across studies, averaging around 25% (18%–27%) at different time points across 4 studies (Table 3).^18–21 Differences in recurrence rates between primary and metastatic lesions also seem inconclusive based on 2 studies by Folkert et al. Although Folkert noted a significantly lower recurrence rate in metastatic tumors versus primary tumor in his 2012 study utilizing ³²P (17.6% vs. 37.5%, respectively), he found no significant difference between the 2 pathologies in his 2013 study utilizing Iridium 192.

Table 3.

Tumor Recurrence and Patient Survival After Brachytherapy^*

Study (Year)	Median Follow-up Time, Months (Range)	Mortality	Recurrence Rate	Median Time to Failure, Months (Range)	Overall Survival
Sundaresen et al. (1985)11	N/A (6–36 mo)	8% at 1 mo	N/A	N/A	Median survival 6 mo
Armstrong et al. (1991)17	N/A	53% at 12 mo 88% at 24 h 91% at 34 mo	49%	15 (1–43)	66% at 6 mo 46% at 12 mo 20% at 18 mo
Rogers et al. (2002)21	N/A	N/A	13% (SN) 27% (MN)	24 (SN) 36 (MN)	36% at 16 mo 24% at 24 mo
DeLaney et al. (2003)18	24 (10–34)	63% at 3 mo	25%	N/A (6–14)	88% at 3 mo 38% at 34 mo
Folkert et al. (2012)19	4.4 (2.6–23.3)	N/A	24%	N/A	87% at 4.4 mo 83% at 6 mo 68% at 23.3 mo
Folkert et al. (2013)23	9 (4–17)	N/A	N/A	N/A	100% at 6 mo 67% at 12 mo
Cao et al. (2014)3	19 (2–69)	35% at 34 mo	18%	N/A (8–34)	N/A
Li et al. (2014)25	3 (N/A)	Na	N/A	N/A	76% at 6 mo
Folkert et al. (2015)20	N/A	N/A	25.5%	12	60% at 12 mo

Abbreviations: MN, multineedle; N/A, not available; SN, single needle.

*Table adapted from Zuckerman et al.⁴

Sharma et al.² specifically looked at the use of ¹²⁵I in a systematic review and summarized the findings of 8 studies reporting post-brachytherapy local control rates. Seven of the 8 studies reported excellent control rates at 1 year, with 4 of those 8 studies showing 100% control rate at 1 year, and 1 of the 8 reporting a control rate of 14% at 3-year follow-up.

Pain Relief

Tumor-related spinal pain measured by visual analog scale (VAS) scores showed significant improvement (P < .05) across multiple studies after brachytherapy (Table 4).⁴ The mechanism of brachytherapy pain reduction may be due to the underlying inhibition of kinins and prostaglandins as a result of the decrease in tumor size, as well as blocking of nerve impulse transmissions.⁷ A weighted average of 8 study outcomes showed a mean VAS change of 5.35 (P < .001).⁴ Yang et al.³² combined ¹²⁵I with transarterial chemo-embolization and noted VAS reduction from 6.7 to 3.4 at 12-week follow-up.

Table 4.

Pain Outcomes After Brachytherapy^*

Reference	BT Intervention	Pretreatment VAS	Posttreatment VAS
Cardoso et al. (2009)22	PVA and percutaneous 153Sm seed implantation	8.5 ± 2	2.6 ± 3.1
Yang et al. (2013)24	PVA and percutaneous 125I seed implantation	8.3 ± 0.3	1.3 ± 0.4
Cao et al. (2014)3	percutaneous 125I seed implantation	4.5 ± 2.0	1.2 ± 1.4
Huang et al. (2014)34	PVA and percutaneous 125I seed implantation	7.1 ± 1.5	2.3 ± 1.1
Li et al. (2014)25	PVA and percutaneous 125I seed implantation	7.7 ± 1.3 (SN) 8.0 ± 1.2 (MN)	2.6 ± 1.0 (SN) 2.4 ± 1.1 (MN)
Wang et al. (2015)26	PVA and percutaneous 125I seed implantation	6.4 ± 1.7	1.3 ± 1.8
Qian et al. (2016)12	Pedicle fixation and percutaneous 125I seed implantation	7.4 ± 1.0	4.3 ± 1.0

Abbreviations: BT, brachytherapy; MN, multineedle; PVA, percutaneous vertebral augmentation; SN, single needle; VAS, visual analog score.

*Table adapted from Zuckerman et al.⁴

Unfortunately, the wide variation of surgical techniques used in these studies confounds any accurate interpretation of the effect size of brachytherapy intervention, especially with a high percentage of patients also receiving cement augmentation at time of brachytherapy. Cement augmentation,^{24–26,33,34} surgical tumor resection,²² and pedicle screw fixation¹² are often used in various combinations during an open procedure to treat the pathology. Cement augmentation can independently reduce pain relief by stabilizing bone microfractures, thereby eliminating the stimulation of nociceptive nerve endings by mechanical friction or movement.⁷ Vertebroplasty was more commonly used for cement delivery than balloon-assisted kyphoplasty, likely due to the higher usage of segmental instrumentation to provide biomechanical support or correction of the associated instability.

A 2014 study by Cao et al.³ was one of the few to report monotherapy brachytherapy without another surgical intervention, and noted a VAS improvement from 4.5 to 1.2 after brachytherapy. Sharma et al.² compared VAS outcomes of ¹²⁵I brachytherapy with and without cement augmentation and noted statistically significant pain reduction in both cohorts, albeit slightly more favorable results for the combined cement and brachytherapy cohort. It is important to note that findings from these smaller studies are not always conclusive, as some show no difference in pain outcomes between brachytherapy with or without cement augmentation.^26,32,35,36 In a meta-analysis of all published ¹²⁵I brachytherapy data, monotherapy ¹²⁵I brachytherapy produced a mean pain reduction of ≥2 points, whereas brachytherapy with cement produced a greater mean pain reduction of ≥4 points.²

Functional Outcomes

Functional performance as measured by the Karnofsky Performance Scale (KPS) was also assessed in 2 recent studies.^12,25 Qian et al.¹² studied a group of 7 patients with metastatic thoracolumbar spinal tumors, who were treated using pedicle screw fixation and needle implantation of ¹²⁵I. In these patients, Qian et al. observed an increase in KPS from 53 to 73. Li et al.²⁵ studied a cohort of 29 patients who underwent percutaneous single- and multineedle ¹²⁵I seed implantation for osteolytic metastatic vertebral tumors. Both groups showed significant improvement in KPS, from 54 to 80 in the single-needle group and from 42 to 86 in the multineedle group.

Cardoso et al.²² used the Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status instead of KPS, but also found significant improvement and change from pretreatment to posttreatment. Another study by Wang et al.²⁶ also measured changes in daily living performance (eg, showering, eating, clothing, and bowel/bladder function) and reported significant improvements in the Barthel Index. Sharma et al.² looked at KPS specifically for ¹²⁵I, and found 3 studies that reported improvement after treatment, with improvements in 2 of the studies reaching statistical significance.^18,23,37

Complication Risks After Brachytherapy

In their 2021 meta-analysis of 14 ¹²⁵I studies using percutaneous seed placement techniques, Sharma et al.² noted an overall clinical complication rate of 19%. Common adverse events after percutaneous seed placement included postoperative fever, myelosuppression, seed displacement, and small subcutaneous hemorrhages that were easily controlled with external compression. Seed displacement is also well documented in prostate and lung cancer treatments,^38–40 but is relatively rarer for spinal applications, where it was observed in less than 1% of cases.² Seed displacement can be a detrimental factor in radiation delivery, especially when prior studies of brachytherapy suggest a noticeable difference in post-implant dosimetry compared to pre-implant planned dose coverage.^41–44 Rare adverse events included isolated reports of hydropneumothorax and de novo compression fractures at the treatment sites at 3 and 6 months after brachytherapy without evidence of tumor progression. Finally, wound healing complications can be a naturally expected sequalae of having prolonged local radiation of the wound from the seeds. Numerous case series of ¹²⁵I percutaneous seed placement have shown minimal risk of infection but frequently documented local wound reactions, such as transient erythema, with no reports of deep wound infections through the stab incisions.² Open surgical cases, on the other hand, have had reports of deep wound infections (2 of 35,¹⁷ and 2 of 24²¹) when used in conjunction with brachytherapy, sometimes leading to sepsis and mortality (1 of 35¹¹), although the numbers reported are too small to assess the true impact of brachytherapy on the already-increased infections rates within the medically susceptible cancer patient population.

Brachytherapy versus Convention External Beam Radiation Therapy

Brachytherapy differs from cEBRT in several distinct ways. Traditional radiation therapy carries well-known risks of both subacute and acute toxicities that require additional medical treatment and increased healthcare utilization costs, and that negatively affect a patient’s quality of life.⁴⁵ Postoperative external radiation therapy impairs wound healing regardless of the fractionation of the dose.⁴⁶ Some 54%–63% of patients with spine metastasis who are treated with radiation therapy suffer toxicities,^47–49 running the gamut from gastrointestinal injury to radiation myelopathy. Although SBRT offers more targeted therapy with fewer systemic side effects and lower toxicity rates, it has not been widely used historically due to higher cost burdens.^24,48,49 The increased adoption of SBRT at academic centers in recent years is a possible contributing factor to the delayed recognition of brachytherapy as an adjunctive therapy, as well as the clear paucity of clinical data or controlled trials in support of any clear advantages of SBRT over cEBRT.⁵⁰

Shi et al.⁴⁵ directly compared surgical cohorts of patients with metastatic epidural spinal cancer who received brachytherapy versus cEBRT in a retrospective study. Sixty postoperative brachytherapy patients were compared with 62 postoperative cEBRT patients. No significant baseline differences were found between the groups in terms of age, gender, ECOG Performance Status, overall extra-spinal cancer burden, and ambulatory status. VAS was significantly improved in both groups after treatment (P < .001); however, postoperative VAS in the brachytherapy group was lower than the cEBRT group at 1, 3, and 6 months after treatment (P < .05). Both posttreatment survival (7.4 vs 7.3 months, P = .37) and return to ambulation rates (90% vs 84%) were similar in both groups. Overall, more patients experienced complications in the cEBRT group (47%) versus the brachytherapy group (25%), which is even more pronounced when considering only radiation-related complications (8.3% vs 38.7%, P < .001). However, surgical complication rates (8% vs 13%, P = .35) were comparable between groups.

The theoretical advantages of brachytherapy include earlier radiotherapy of the residual tumor bed, which begins immediately upon implantation of the seeds, rather than the 2–4 weeks postoperatively associated with cEBRT (during which time the tumor may continue to grow and expand). Selective placement of the seed allows for controlled conformal delivery of the dose, while the placement of the seeds in the tumor bed ensures that the highest radiation dosage is naturally concentrated on the surrounding tumor rather than overlying wound or soft tissue, thereby decreasing the risk of secondary injury to the spinal cord or wound.⁴⁵ In addition, the lasting presence of the seeds allows for continuous delivery of radiation, which may be more effective in controlling tumor recurrence.

There are also several relative disadvantages of brachytherapy. The natural decay of radioactivity over the source’s half-life means that additional conventional radiotherapy may be required for sufficient tumor control after the initial few weeks. Additionally, even with a carefully executed surgical plan for seed placement, underdosing can occur by over 20% in post-implant dosimetry—likely due to a combination of surrounding tissue inflammation and seed displacement after surgery.⁴¹ Furthermore, the lack of clinical response data for the various tumor pathologies and brachytherapy dosing plan mean that exact dosing requirements for common tumors are unknown, which leads to the risk of both an excessive dose causing unnecessary neural morbidity and an insufficient dose that cannot prevent early recurrence. Finally, the ongoing radioactivity of the seeds does theoretically place the surrounding family members at risk of radiation exposure.

Conclusion

Although brachytherapy remains an inadequately described radiation therapy modality for spinal axis tumors in the literature, its application as an adjuvant therapy after conventional surgery, radiation, and systemic therapy across a wide range of spinal neoplasms has shown consistent evidence for increased survival, local control rate, and functional capacity with reductions in pain. Precise quantification of the various benefits of brachytherapy remains difficult due to major heterogeneity in clinical patient populations, which also makes direct comparisons and summarization of the data difficult. With the larger incidence of metastatic spinal lesions, brachytherapy has been used predominantly for metastatic disease, such as lung cancer, rather than for primary pathologies, such as chordoma. The primary indication for brachytherapy remains as a salvage therapy for disease progression despite conventional treatments, while the proportion of medically frail cancer patients who cannot tolerate systemic therapy or open surgery are also reasonable candidates for brachytherapy. Currently, ¹²⁵I and ³²P remain the most common element used for brachytherapy. Seed placement has been the preferred technique over implant or plaque placement. Open surgery is the more common route of seed introduction in patients who can tolerate it, whereas percutaneous placement is often coupled with cement augmentation to provide extra biomechanical stability to the affected levels.

Future Directions

The survival and outcome benefits of brachytherapy are well established in numerous studies from the past 2 decades. The overall use of brachytherapy still appears low based on the number of publications, and most studies are still relegated to major cancer treatment centers. Greater widespread use in local and regional cancer hospitals may generate more granular data that will allow for more precise quantification of the specific indications, and outcome effect sizes that can be used to create more specific indication guidelines based on different tumor pathologies and staging characteristics. Disease-specific data will also allow exact planning of radiation dose and more accurate prognostication. These limitations emphasize the need for standardization of brachytherapy indications, delivery, and outcome measurements to gather reliable outcome data and promote its use as a reliable, mainstream spine tumor treatment.

Funding

No funding was used in support of this project.

Supplement sponsorship. This supplement is sponsored by GT Medical Technologies, Inc., the makers of GammaTile^® Therapy for brain tumors. GammaTile is FDA-cleared to deliver radiation therapy in patients with newly diagnosed malignant intracranial neoplasms and recurrent intracranial neoplasms. For full product and safety information, refer to the instructions for use.

Conflict of interest statement. None declared.