Special Section on Intraoperative Radiation Therapy and Electronic BrachytherapyIntraoperative brachytherapy for resected brain metastases
Introduction
Brain metastases, the most common intracranial neoplasms in adults (1), develop in approximately 30% of all cancer patients, and is the cause of death in up to 50% of these individuals (2). They are commonly located at the gray–white matter interface where the blood vessel caliber decreases, and their dissemination corresponds with blood flow: 80% of patients develop multiple intracranial metastases, with 80% occurring in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem (3). Incidence rates are expected to rise with the emergence of increasingly effective systemic agents that, while conferring improved systemic control translating to increased survival, possess limited ability to bypass the blood–brain barrier (4). As only 10% of patients become symptomatic from brain metastases, incidence rates are also increasing with improved surveillance (2). Primary lung cancers account for over 50% of intracranial metastases, with breast cancers, melanoma, and colon cancers, respectively, accounting for approximately 20%, 10%, and 5% of all brain metastasis primaries (2). Epidemiologically, these primaries are also among the most common malignancies in the United States. Conversely, small cell lung cancers, melanoma, germ cell tumors, and choriocarcinomas demonstrate proportionally high neurotropism rates.
Symptomatic management options include corticosteroids and supportive care (5). Chemotherapeutic agents historically demonstrated little efficacy in treating brain metastases owing to the inability to enter the central nervous system. However, the utility of targeted agents and immunotherapy in the context of multidisciplinary treatment strategies is currently an area of active investigation. Commonly utilized treatment options include whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and surgical resection.
WBRT was the initial standard therapy and continues to play a pivotal role in treating brain metastases, particularly in the setting of multiple lesions, and in the presence of recurrent metastases or leptomeningeal disease. The first Radiation Therapy Oncology Group (RTOG) randomized trials established WBRT as an effective modality for patients with favorable performance status and/or well-controlled primary disease. However, these initial studies reported overall survival (OS) rates of only a few months (6). Patchell et al. improved on these outcomes in a randomized trial comparing WBRT to surgical resection followed by WBRT among patients with a single brain metastasis. They demonstrated that surgery followed by WBRT improved OS to 40 weeks, compared to 15 weeks with WBRT alone (7). Patchell and colleagues subsequently randomized 95 patients who underwent surgical resection of a single metastasis to observation or postoperative WBRT and reported no significant difference in OS among the cohorts. However, tumor recurrence was reduced from 46% in the observation group to 10% in the WBRT group, as well as a reduction in new brain metastases and death due to neurological causes in the WBRT group, thus establishing postoperative WBRT as the standard of care for brain metastases (8).
SRS is a minimally invasive option for patients in lieu of, or in combination with surgery; however, there is a dearth of appropriately powered randomized control trials comparing surgical resection and SRS alone for brain metastases. RTOG 9508 demonstrated that an SRS boost improves local control (LC) after WBRT with no difference in survival among patients with one to three brain metastases (9). Conversely, several randomized trials evaluating SRS alone vs. SRS with WBRT demonstrated that the latter may improve local and distant tumor control, but OS rates remained the same as using SRS alone [10], [11], [12]. Patients undergoing WBRT were also more likely to exhibit neurological decline [13], [14]. These findings, alongside studies showing SRS, may be an appropriate option for patients with multiple brain metastases (15), which promotes its increasing utilization over WBRT.
Surgical resection is offered to patients who require pathological confirmation, have a large (greater than 2 cm) metastasis, or are acutely experiencing mass effect or neurological symptoms refractory to steroids (16). Conversely, patients with a poor performance status, a large number of brain metastases, or a high risk of surgery-related morbidity (e.g., if the metastasis is adjacent to eloquent brain structures) may be deemed unresectable (16). Patients may also elect for SRS in lieu of surgical resection. Surgical resection without any adjuvant intracranial treatment has 1- to 2-year LC rates of 47–59%, and thus, adjuvant radiotherapy is typically given in an effort to maximize LC [8], [12], [17]. Given concerns of neurocognitive decline after WBRT, the paradigm is shifting to postoperative SRS [17], [18], [19]. The relative benefits and disadvantages of giving SRS preoperatively are also under investigation, with a retrospective multi-institutional study comparing preoperative SRS to postoperative WBRT showing no differences in OS and local recurrence at 2 years (20). The only prospective trial evaluating preoperative SRS demonstrated an 85.6% 1-year LC rate without radionecrosis (21), and one trial (NCT02514915) is currently accruing.
Another appealing option to improve postoperative LC rates and obviate the need for adjuvant radiation and commute for postoperative radiation treatments entails intracavitary brachytherapy. This review discusses the rationale, technique, outcomes, evidence, and future directions regarding the use of intracavitary brachytherapy as an adjunct treatment to surgical treatment. We discuss various types of brachytherapy and radioactive isotopes available for this procedure, as well as the benefits of the most novel radioisotope, Cesium-131 (Cs-131), which offers a great promise as the radioisotope of choice in the future.
Section snippets
Changes in resection cavity volume
An early retrospective study of 72 patients treated with postoperative SRS to one to four metastases, in which the resection cavity was targeted without a margin, demonstrated that LC was significantly higher among those with less conformal plans (22). A subsequent study targeting the resection cavity with a 2 mm margin in patients with one to over five metastases improved 1-year local failure rates from 16% to 3% without a significant increase in toxicity (3% with a 2 mm margin vs. 8% without
Rationale for perioperative brachytherapy
Brachytherapy, entailing the implantation of a radioactive source within the tumor resection cavity at the time of surgery, has several appealing advantages over WBRT and SRS with regards to the plethora of concerns described previously and in Table 1, Table 2.
Perioperative brachytherapy offers an immediately available radiotherapy option that avoids tumor cell repopulation as radiotherapy treatment begins immediately intraoperatively. This treatment option does not require extensive
I-125 brachytherapy
Although several radioisotopes options exist for brachytherapy (Table 3), including palladium-103 and gold-198, historically, iodine-125 (I-125) was the most common radioactive source used in CNS tumors and is administered using either temporarily placed interstitial catheters or implants or as permanent implants. Temporary implants are reusable sources with an activity of 10–20 mCi per source, photon energies of 27–35 keV, and a dose rate of 40–60 cGy per hour (32). They possess a half-value
High-activity I-125 brachytherapy
Bernstein and colleagues used high-activity I-125 seeds to treat 10 patients with single brain metastases that recurred after initial treatment with craniotomy, and WBRT. I-125 seeds (20–40 mCi) with a mean dose rate of 67.3 cGy per hour were implanted with 70 Gy prescribed to the tumor. Three catheters were used when seven implants were required, two catheters were used when two implants were placed, and one catheter was used when only a single implant was needed. Implant volumes ranged from
Limitations and complications with I-125 brachytherapy
Acute side effects of interstitial brachytherapy include seizures, infection, impaired perioperative healing, hemorrhage, and other neurological sequelae, which are more common with high-activity temporary implants. Radionecrosis is also a major concern, with reported rates as high as 29% (37). The largest criticism of permanent I-125 brachytherapy is its' relatively long half-life, which subjects the patient to radiation for a prolonged period and may potentially expose surgical staff to
Cesium-131 (Cs-131) brachytherapy
Since obtaining FDA approval in 2003, Cs-131 has been used as radioactive permanent seed implants for treatment of prostate, head and neck, and lung malignancies. Cs-131 has a half-life of 9.69 days, a dose rate of 0.342 Gy per hour, and an average energy of 30.4 KeV. Comparative studies of radioactive seeds used in prostate brachytherapy suggested that Cs-131 has preferable dose homogeneity, required fewer seeds to provide comparable prostate coverage, and enabled superior sparing of the
Cs131 brachytherapy outcomes in brain metastases
Wernicke et al. evaluated the safety, feasibility, and efficacy of permanent intraoperative Cs-131 brachytherapy after resection in a prospective Phase I/II study of 24 patients with one to four newly diagnosed brain metastases. Cs-131 stranded seeds were placed with a dose of 80 Gy to a 5 mm depth from the resection cavity surface. Each Cs-131 suture-stranded string contained 10 seeds (0.5 cm interseed spacing), were cut into shorter segments as dictated by cavity size, and were permanently
I-125 vs. Cs-131 brachytherapy
Cs-131 possessed several physical and radiobiological advantages over I-125. The intrinsically lower Cs-131 seed activity, juxtaposed with lower dose prescriptions in the aforementioned studies, enables excellent LC rates while minimizing the incidence of radiation necrosis. Cs-131 has a higher dose rate than I-125 (0.342 Gy per hour vs. 0.069 Gy per hour), translating to 90% Cs-131 dose absorption within 33 days of implantation, whereas only 32% of I-125 would be absorbed at this juncture.
Future directions
Trials are needed to directly compare the efficacy of I-125 to Cs-131, as well as to directly compare the efficacy of intraoperative brachytherapy to preoperative and postoperative SRS while stratifying brain metastases by size. These trials may be paradigm-changing in the setting of large metastases, recurrent disease or for patients with a need to expediently start systemic therapy or who may not reliably follow up for adjuvant treatment.
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Conflicts of interest: The authors do not have any conflicts of interest to declare.