Phase I/II study of resection and intraoperative cesium-131 radioisotope brachytherapy in patients with newly diagnosed brain metastases

Clinical article

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Object

Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole-brain radiotherapy (WBRT) remains the standard of care with a local control rate > 90%. However, WBRT is delivered over 10–15 days, which can delay other therapy and is associated with acute and long-term toxicities. Permanent cesium-131 (131Cs) implants can be used at the time of metastatic resection, thereby avoiding the need for any additional therapy. The authors evaluated the safety, feasibility, and efficacy of a novel therapeutic approach with permanent 131Cs brachytherapy at the resection for brain metastases.

Methods

After institutional review board approval was obtained, 24 patients with a newly diagnosed metastasis to the brain were accrued to a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung cancer (16), breast cancer (2), kidney cancer (2), melanoma (2), colon cancer (1), and cervical cancer (1). Stranded 131Cs seeds were placed as permanent volume implants. The prescription dose was 80 Gy at a 5-mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. The primary end point was local (resection cavity) freedom from progression (FFP). Secondary end points included regional FFP, distant FFP, median survival, overall survival (OS), and toxicity.

Results

The median follow-up was 19.3 months (range 12.89–29.57 months). The median age was 65 years (range 45–84 years). The median size of resected tumor was 2.7 cm (range 1.5–5.5 cm), and the median volume of resected tumor was 10.31 cm3 (range 1.77–87.11 cm3). The median number of seeds used was 12 (range 4–35), with a median activity of 3.82 mCi per seed (range 3.31–4.83 mCi) and total activity of 46.91 mCi (range 15.31–130.70 mCi). Local FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI 63.2%–99.1%). One-year distant FFP was 48.4% (95% CI 26.3%–67.4%). Median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated) and 1-year OS was 50.0% (95% CI 29.1%–67.8%). Complications included CSF leak (1), seizure (1), and infection (1). There was no radiation necrosis.

Conclusions

The use of postresection permanent 131Cs brachytherapy implants resulted in no local recurrences and no radiation necrosis. This treatment was safe, well tolerated, and convenient for patients, resulting in a short radiation treatment course, high response rate, and minimal toxicity. These findings merit further study with a multicenter trial.

Abbreviations used in this paper:125I = iodine-125; 131Cs = cesium-131; FFP = freedom from progression; OS = overall survival; QOL = quality of life; RTOG = Radiation Therapy Oncology Group; SRS = stereotactic radiosurgery; WBRT = whole-brain radiotherapy.

Abstract

Object

Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole-brain radiotherapy (WBRT) remains the standard of care with a local control rate > 90%. However, WBRT is delivered over 10–15 days, which can delay other therapy and is associated with acute and long-term toxicities. Permanent cesium-131 (131Cs) implants can be used at the time of metastatic resection, thereby avoiding the need for any additional therapy. The authors evaluated the safety, feasibility, and efficacy of a novel therapeutic approach with permanent 131Cs brachytherapy at the resection for brain metastases.

Methods

After institutional review board approval was obtained, 24 patients with a newly diagnosed metastasis to the brain were accrued to a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung cancer (16), breast cancer (2), kidney cancer (2), melanoma (2), colon cancer (1), and cervical cancer (1). Stranded 131Cs seeds were placed as permanent volume implants. The prescription dose was 80 Gy at a 5-mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. The primary end point was local (resection cavity) freedom from progression (FFP). Secondary end points included regional FFP, distant FFP, median survival, overall survival (OS), and toxicity.

Results

The median follow-up was 19.3 months (range 12.89–29.57 months). The median age was 65 years (range 45–84 years). The median size of resected tumor was 2.7 cm (range 1.5–5.5 cm), and the median volume of resected tumor was 10.31 cm3 (range 1.77–87.11 cm3). The median number of seeds used was 12 (range 4–35), with a median activity of 3.82 mCi per seed (range 3.31–4.83 mCi) and total activity of 46.91 mCi (range 15.31–130.70 mCi). Local FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI 63.2%–99.1%). One-year distant FFP was 48.4% (95% CI 26.3%–67.4%). Median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated) and 1-year OS was 50.0% (95% CI 29.1%–67.8%). Complications included CSF leak (1), seizure (1), and infection (1). There was no radiation necrosis.

Conclusions

The use of postresection permanent 131Cs brachytherapy implants resulted in no local recurrences and no radiation necrosis. This treatment was safe, well tolerated, and convenient for patients, resulting in a short radiation treatment course, high response rate, and minimal toxicity. These findings merit further study with a multicenter trial.

Brain metastases are the most common intracranial tumors, occurring in up to 40% of cancer patients.8,43 Authors recently reported that brain metastases account for approximately 60% of solid metastases arising primarily from lung, breast, kidney, and colon cancer and skin melanoma, causing major morbidity and mortality.34,54 In the last decade the incidence of brain metastases has been rising, attributed to the increased survival of cancer patients.59

Without treatment, prognosis is dismal with survival of only 1–2 months. However, survival can be extended to 3–6 months with whole-brain radiotherapy (WBRT) and to 11 months with either surgery followed by adjuvant WBRT or surgery plus adjuvant stereotactic radiosurgery (SRS).19,20,29,45 Although WBRT is effective in preventing local recurrence and controlling distant disease, it has been associated with acute detriments to quality of life (QOL)10,32 and deterioration in neurocognitive abilities.9,12,15,41 In addition, WBRT, as compared with local therapy, offers no overall survival (OS) benefit.2,44,55 For these reasons, attention has turned to the option of aggressive local therapy for oligometastatic disease, deferring salvage WBRT for disease recurrence.

A variety of local postresection treatment strategies are available in this setting. Among such options are postoperative SRS4,16,18,23–25,27,28,30,31,35,38,46,48,56 and intraoperative brachytherapy application of either permanent lowdose7,13,22,51 or temporary high-dose5,39,42,50,63 radioisotopes (generally iodine-125 [125I]) into the surgical cavity. Postoperative SRS is the more commonly used of these treatment modalities because of its wider availability. Although125I has been shown to confer local control comparable to that of postoperative SRS and WBRT,5,7,13,22,39,42,50,51,63 the rates of radiation necrosis have been criticized. A novel radioisotope, 131Cs confers both physical and radiobiological advantages over postoperative SRS and 125I brachytherapy. In this prospective study, we evaluated the safety, feasibility, and efficacy of a novel treatment of permanent intraoperative 131Cs brachytherapy for brain metastases.

Methods

Patient Selection

Between 2010 and 2012, patients with newly diagnosed brain metastases, in whom surgery was deemed appropriate per the inclusion criteria, were accrued to an institutional review board–approved prospective trial and signed informed consent. In general, selection criteria included a metastatic tumor for which surgery was indicated to relieve mass effect, to reduce symptoms, to obtain pathology for diagnostic purposes, or based on a size > 2.5 cm. Patients had to have Eastern Cooperative Oncology Group (ECOG)/Zubrod Performance Status 0, 1, or 2 and expected survival ≥ 6 months. Exclusion criteria included tumor proximity to the chiasm or brainstem (increasing the risk of radiation treatment), small cell carcinoma metastatic to the brain, and pregnancy or unwillingness to practice a form of birth control (abstinence, oral contraceptives, and so forth).

Treatment Approach

Patients underwent maximally safe resection of lesions. The extent of resection and whether surgery was performed en bloc or piecemeal was noted intraoperatively and from postoperative MR images obtained within 48 hours of surgery. At the time of resection, the size of the removed tumor (maximum diameter and volume), its location (supratentorial vs infratentorial), and its relationship to the pia mater (pial vs nonpial) were noted. Also at the time of resection, 131Cs stranded seeds (IsoRay) with an activity of 3–5 mCi were inserted with a planned dose of 80 Gy to a depth 5 mm from the surface of the resection cavity. The volume implant was precalculated based on preoperative data on tumor size and our institutional physics nomogram and was adjusted real time for the resulting intracavitary volume of the resected metastasis (Fig. 1A). The 10-cm, suture-stranded 131Cs seeds (0.5-cm interseed spacing) were delivered in strings of 10 seeds per string, subsequently cut into smaller lengths per the nomogram, and placed as a permanent volume implant along the cavity in a tangential pattern to maintain a 7- to 10-mm spacing between seeds. As a result, the cavity was lined with the seeds in a pattern like barrel staves or parallel tracks (Fig. 1B). The seeds were then covered with Surgicel (Ethicon) to prevent seed migration and alteration of dosimetry (Fig. 1C), and Tisseel (Baxter) was used to line the cavity to limit cavity shrinkage and further prevent seed dislodgement (Fig. 1D). Within 24–48 hours postimplant, the patient underwent CT scanning to determine dose distribution (Fig. 2).

Fig. 1.
Fig. 1.

Resection cavity throughout the implant procedure. A: Empty resection cavity. B: Resection cavity lined with 131Cs seeds in a pattern like barrel staves or parallel tracks. C: Cesium-131 seeds covered with Surgicel. D: Cesium-131 seeds covered with Tisseel.

Fig. 2.
Fig. 2.

Computed tomography scans of 131Cs brachytherapy seeds in the postoperative resection cavity. A: Axial plane. B: Sagittal plane. C: Coronal plane. D: Three-dimensional radiation cloud from the 80-Gy isodose line. E: Enlarged axial view of isodose lines.

Follow-Up

Follow-up examination consisted of MRI studies and physical evaluation every 2 months. Magnetic resonance imaging was performed utilizing the following sequences: T1-weighted, FLAIR, T2-weighted, gradient recalled echo, and diffusion-weighted imaging. Moreover, postcontrast Gd-enhanced T1-weighted MR images were obtained in the axial, sagittal, and coronal planes with 3-mm slice thicknesses. Lesion stability on MRI was defined as the absence of new lesions or increased contrast enhancement < 25% in the product of the three perpendicular diameters. Patients were also clinically assessed via physical examination every 2 months with specific attention to any new neurological deficits and symptoms of radiation necrosis, seizures, headaches, personality changes, and motor or sensory deficits, to name a few. The Radiation Therapy Oncology Group (RTOG) scale was used as the radiation toxicity scale.11 At the time of disease progression, new metastases (distant and regional) were treated with SRS (range 18–20 Gy in one fraction)1,2,53 or WBRT (30 Gy in 10 fractions),43–45 depending on the number of lesions.

End Points and Statistical Methods

Descriptive statistics, including the mean, standard deviation, median, range, frequency, and percent, were calculated to characterize the study cohort. Primary end points of the trial were local (resection cavity) freedom from progression (FFP). Secondary end points included regional and distant FFP, median survival, overall survival (OS), and toxicity. Treatment response was rated based on follow-up brain MRI compared with prior MRI. Local FFP was defined as the absence of new nodular contrast enhancement 5 mm or less from the resection cavity. Regional failure was defined as new or increased contrast enhancement more than 5 mm from the resection cavity. Distant failure was defined as new or increased contrast enhancement elsewhere in the brain. All survival end points were defined as the time from the date of resection and implantation of the 131Cs brachytherapy seeds until 1) the date of local recurrence for local FFP, 2) the date of regional recurrence for regional FFP, 3) the date of new metastasis for distant FFP, or 4) the date of death for OS. Patients without these events were censored at the date of their last follow-up. Kaplan-Meier survival analysis was performed to generate survival curves for the defined survival outcomes. Median and 1-year local FFP, regional FFP, distant FFP, and OS were estimated as appropriate, and 95% confidence intervals were calculated to assess the precision of obtained survival estimates. The Spearman rank correlation coefficient was used to evaluate the correlation between 131Cs brachytherapy seed characteristics of interest. All p values are 2-sided with statistical significance evaluated at the 0.05 alpha level. All analyses were performed using SPSS version 21.0 (SPSS Inc.) and Stata version 12.0 (StataCorp).

Results

Patient Characteristics

Patient characteristics are summarized in Table 1. There were 14 females and 10 males with a median age of 65 years (range 45–84 years). Brain metastases were located in the frontal (10), parietal (7), cerebellar (4), occipital (2), and temporal (1) regions. The histology from the metastases was lung (16), breast (2), kidney (2), colon (1), and cervical (1) cancer and melanoma (2).

TABLE 1:

Summary of characteristics in 24 patients with brain metastases

VariableNo. (%)
sex
 male10 (41.67)
 female14 (58.33)
age in yrs
 range45–84
 median65
no. of tumors
 115 (62.5)
 24 (16.67)
 33 (12.5)
 >32 (8.33)
prior RT
 none21 (87.5)
 SRS3* (12.5)
tumor location
 frontal10 (41.67)
 parietal7 (21.97)
 cerebellar4 (16.67)
 occipital2 (8.33)
 temporal1 (4.17)
tumor histology
 lung cancer16 (66.67)
 breast cancer2 (8.33)
 kidney cancer2 (8.33)
 melanoma2 (8.33)
 colon cancer1 (4.17)
 cervix cancer1 (4.17)

One patient had both SRS and WBRT.

Treatment Parameters

Treatment details are shown in Table 2. Among the 24 patients who underwent resection and 131Cs brachytherapy implantation, gross-total resection (defined as resection of contrast enhancing disease) was achieved in every case. According to preoperative MRI, the median size of resected tumor was 2.7 cm (range 1.5–5.5 cm), and the median volume of resected tumor was 10.31 cm3 (range 1.77–87.11 cm3). Based on intraoperative measurements, the median volume of the cavity after tumor resection was 3.13 cm3 (range 1–17 cm3), indicating a 69.6% decrease in cavity volume before the seeds were placed. The median number of seeds used was 12 (range 4–35) with a median activity of 3.82 mCi per seed (range 3.31–4.83 mCi) and total activity of 46.91 mCi (range 15.31–130.70 mCi).

TABLE 2:

Summary of treatment details in 24 patients treated with resection and 131Cs brachytherapy*

VariableValue (%)
extent of resection
 GTR24 (100)
 STR0 (0)
preop tumor vol based on MRI (cm3)
 median10.31
 range1.77–87.11
intraop cavity vol (cm3)
 median3.13
 range1–17
no. of seeds placed
 median12
 range4–35
seed activity (IU)
 median2.44
 range2.11–3.08
total activity (IU)
 median29.9
 range9.76–83.3
activity per seed (mCi)
 median3.82
 range3.31–4.83
total seed activity (mCi)
 median46.91
 range15.31–130.7

GTR = gross-total resection; STR = subtotal resection.

Patient Survival

At a median follow-up of 19.3 months (range 12.89–29.57 months), 11 patients were still alive and 13 were dead. Table 3 lists the treatment details for each patient. Among the 11 patients who were still alive, 8 had a primary tumor originating in the lung, 2 in the breast, and 1 in the colon. One of these patients had previously undergone SRS for a brain metastasis in a different area and then 131Cs brachytherapy for a second lesion. Of the 13 patients who died, 8 had a primary tumor originating in the lung, 2 in the kidney, 1 in the cervix, and 2 from melanoma. One of these patients had undergone SRS to a different area of the brain and one had undergone both SRS and WBRT. The median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated; Fig. 3). One-year OS was 50.0% (95% CI 29.1%–67.8%).

TABLE 3:

Treatment details for 24 patients treated with resection and 131Cs brachytherapy for brain metastases*

Primary Tumor HistologyPrior SRS to Lesion Elsewhere in BrainPrior WBRTSubsequent SRS to Different LesionSite of Recurrence (local, regional, distant)No. of Regional or Distant LesionsSalvage SRSSalvage WBRTDeceased
cervixdistant>3yes
lungdistant>3yesyes
lungyesyes
melanomayesdistant2yes
lungyes
lungyesdistant1
colon
lungyesyesyes
breastdistant3yes
lungregional, distant2yes
lungyes
lungyes
breastyesdistant3
melanomadistant>3yes
lungdistant1yes
lung
kidneydistant>3yes
lung
lungyes
lungyesyes
kidneyyes
lung
lungdistant1yes
lungdistant>3yes

— = no.

Fig. 3.
Fig. 3.

Overall survival.

Freedom From Progression

There were no cases of local recurrence within 5 mm of the resection cavity (Fig. 4). This yielded a local recurrence FFP of 100%. One patient had a regional recurrence (> 5 mm from the resection cavity), which yielded a 1-year regional FFP of 93.8% (95% CI 63.2%–99.1%; Fig. 5). This case was evident 7 months postimplantation and was leptomeningeal in origin (Fig. 6). This patient was subsequently treated with SRS to a dose of 18 Gy based on RTOG 90–0553 and was still alive at the time of analysis. Twelve patients had distant metastases, which yielded a median distant FFP of 7.6 months (95% CI 4.1 months, upper limit not estimated) and a 1-year distant FFP of 48.4% (95% CI 26.3%–67.4%; Fig. 7). Five patients were treated with subsequent SRS to a different lesion, and three patients were treated with salvage SRS for distant recurrences; all doses ranged from 18 to 20 Gy based on tumor size.53 Multiple distant brain metastases developed in one patient. She was originally treated with 131Cs brachytherapy for a resected 2-cm lesion from adenocarcinoma of the lung. The patient underwent salvage WBRT at a dose of 30 Gy in 10 fractions. No dose adjustment was made to account for the intraoperative 131Cs brachytherapy.

Fig. 4.
Fig. 4.

Magnetic resonance imaging series of local FFP. A: Preoperative. B: Postoperative. C: One month postoperative. D: Two months postoperative. E: Four months postoperative. F: Six months postoperative. G: Eleven months postoperative. H: Thirteen months postoperative.

Fig. 5.
Fig. 5.

Regional FFP.

Fig. 6.
Fig. 6.

Magnetic resonance imaging series of regional recurrence. A: Preoperative. B: Postoperative. C: One month postoperative. D: Four months postoperative. E: Seven months postoperative.

Fig. 7.
Fig. 7.

Distant FFP.

Complications

Postoperatively, the patients were treated with 4 mg of dexamethasone twice a day for 2 weeks. There were no instances of radiation necrosis. There was one instance of a dural tear, which required reoperation at 1.2 months postimplantation. Additional complications included one case each of infection and seizure.

Discussion

Resection of brain metastases has been used to establish a histological diagnosis, provide rapid relief of symptoms resulting from the mass effect of a large tumor, and improve local control. Unfortunately, tumor recurrence following surgery alone has been as high as 46%.44 Recurrence rates correlate with factors such as tumor size, location, and histology as well as en bloc resection. With the addition of postoperative radiation therapy, classically in the form of WBRT, the rates of recurrence can be reduced to 10%–20% but at the expense of a good QOL and neurocognitive function.9,10,12,15,32,41,45 For this reason, attention has turned to the addition of focal radiation, such as postoperative SRS and intraoperative brachytherapy, to the resection bed in an effort to reduce the incidence of local failure.

The use of postoperative SRS to the resected surgical cavity has been increasing, with a number of recent publications. Although a Phase III trial from the North Central Cancer Treatment Group (N107C) comparing postoperative SRS with WBRT in the postoperative setting for brain metastases is in progress, the results of Phase I and II trials demonstrated that local control of the resection cavity with SRS is similar to that with WBRT, ranging from 73% to 94%, with an incidence of radiation necrosis ranging from 0% to 10%.4,16,18,23–25,27,28,30,31,35,38,46,48,56 Intracranial distant failure was reported in 44%–65% of cases at 1 year, and death due to neurological causes was noted in approximately 25%.4,16,18,23–25,27,28,30,31,35,38,46,48,56 The typical time frame for the delivery of postoperative SRS can be as long as 6 weeks after resection to allow adequate wound healing and the cavity to shrink to a smaller, stable size. The delay in treatment can be disadvantageous, as radiographically evident repopulation of tumor cells has been shown to occur in this time period.58 Furthermore, the ideal target for SRS is a small round cavity. Tumor cavities of an irregular shape or larger size (> 3 cm) present not only a challenge in developing a treatment plan with a high degree of conformality, but also a potential decrease in local control. Indeed, it has been shown that larger tumor cavities treated with SRS have poor local control as a result of less conformal treatment plans.1,17,37 The actuarial local control rate at 1 year for lesions ≤ 3 cm3 was 96% (95% CI 90%–100%), and for those > 3 cm3 was 59% (95% CI 39%–79%).1 Furthermore, the volume of irradiated tissue is clearly correlated with symptomatic radiation necrosis in patients treated with SRS.6,40 Blonigen et al. reported that symptomatic radiation necrosis was observed in 10% and asymptomatic radiation necrosis in 4% of patients who had undergone SRS at a mean dose of 18 Gy.6 Multivariate regression analysis showed that tumor volume (volume receiving 8 Gy [V8]–V16 Gy) was most predictive of symptomatic radiation necrosis (p < 0.0001). Minniti et al. also reported that following SRS, radiation necrosis occurred in 24% of treated lesions and that as the size of the lesion increases (V12 Gy > 8.5 cm3), there is a greater risk for radiation necrosis.40

Intraoperative interstitial brachytherapy has several physical and radiobiological advantages for improving local control of resected brain metastases. First of all, intraoperative brachytherapy allows treatment to be delivered at the time of resection, avoiding the time lag apparent in SRS, which allows the tumor cells to repopulate.58

Unlike SRS, brachytherapy is not limited by the shape or size of the resection cavity, thus allowing homogeneous dose delivery to even irregularly shaped and large surgical cavities.1,17,37 Intraoperative brachytherapy means delivery of the entire treatment (resection plus radiation) in one procedure, which may be more convenient for the patient and may increase patient satisfaction. The ability to deliver all treatment in one setting is particularly appealing for patients who live far from a medical center, for whom travel may be prohibitively expensive and/or time consuming, especially in a weakened state. Hence, compliance may be increased. Brachytherapy is also more cost effective than WBRT and SRS.60 Lastly, in contrast to postoperative SRS, which generally requires the application of a metal stereotactic frame affixed with screws to a patient skull, brachytherapy requires no frame or special fixation, as it is performed at the time of surgery.

There are also radiobiological advantages to using brachytherapy. The continuous radiation dose rate of brachytherapy at 0.3–3.5 Gy/hour inhibits mitosis and causes proliferating tumor cells to accumulate in G2, a radiosensitive phase of the cell cycle.21 There is less radioresistance of hypoxic cells treated with brachytherapy because of impaired repair of sublethal damage under hypoxic conditions36 and the opportunity for hypoxic cells to become reoxygenated during the treatment.21 Additionally, brachytherapy allows delivery of a high dose of radiation to a localized area while also providing very steep dose fall-off, thus sparing normal brain tissue outside the vicinity of the tumor bed.49

Prior studies utilizing intraoperative brachytherapy (most commonly 125I) have shown local control of the resection cavity between 80% and 95%.5,7,12,22,40,45,51,52,61 Brachytherapy has been used for the treatment of primary brain tumors as well; however, studies have yet to confirm a benefit, and thus standard therapy consists of radiotherapy and chemotherapy or a combination of those depending on the specific histology.52 Note that criticisms of brachytherapy have focused on the high rates of radiation necrosis, from 0% up to 26% reported in some series.22 Moreover, the use of permanent brachytherapy seeds leads to the possibility of seed migration, which may impact dose distribution.57 The use of brachytherapy for local control of newly resected metastases without WBRT has been reported more recently. In these series, radiation necrosis has been more common when using high-dose temporary brachytherapy, such as the GliaSite balloon, with a 23% rate of radiation necrosis.50 In the permanent continuous low-dose brachytherapy setting, 0% radiation necrosis rates were shown by Bogart et al., who used seeds with an activity of 0.32–0.45 mCi and a cumulative dose of 80–160 Gy using a median of 13 seeds,7,47 but achieved a local control rate of only 80%. On the other hand, Huang et al. reported a 26% rate of radiation necrosis using a median of 43 125I seeds with a median activity of 0.79 mCi and median dose of 800 Gy to the surface (200 Gy to a depth of 1 cm), with a local control rate of 92%.22 Using these data, Huang et al. concluded that a lower seed activity coupled with a lower prescription dose will probably decrease the rate of radiation necrosis with only a minimal impact on local control.

We carefully took into account the aforementioned information and pitfalls of increased median activity as a direct correlate of an increased risk of radiation necrosis when designing our prospective trial using intraoperative131Cs to minimize the incidence of radiation necrosis. The lowered seed activity of 131Cs and a lowered dose prescription in our study not only achieved a high rate of local control (100%), but also produced no incidence of radiation necrosis. The rationale behind using 131Cs instead of125I lies in several physical and radiobiological advantages of the former. Whereas 125I has a dose rate of 0.069 Gy/hr, 131Cs has a higher dose rate at 0.342 Gy/hr. In essence, this means that after the 131Cs implant, 90% of the dose is absorbed by 33 days, as opposed to 32% of the dose absorption that occurs with 125I. This short half-life of 9.69 days (compared with 59.4 days for 125I) ensures a shorter average life of the radioactive seed, which not only means increased safety for the family and treating physicians, but also provides an early possibility of initiating adjuvant systemic therapy after only 1 month of implantation. In the current study, one patient required reoperation for a dural tear at 1.2 months postimplantation. Given the short half-life of 131Cs, there was no risk of exposure to the surgical team at that time point. The high mean energy of 131Cs of 29 keV allows fewer radioactive seeds to be implanted per given volume. Dosimetric studies comparing various isotopes in prostate cancer have shown the superiority of 131Cs across the board versus 125I and palladium-103.61

Another reason for our success may be a more careful, conformal placement of the seeds to prevent areas of inadequate dosing. Complicating the use of interstitial brachytherapy is the gradual shrinkage of the resection cavity, a poorly understood process that progressively moves the seeds closer together over time.3,14,26,61 However, cavity shrinkage would probably result in pockets of higher dose delivery and higher rates of radiation necrosis, which we did not observe.33,62 We undertook several measures to decrease the degree of cavity shrinkage once the seeds were placed. The seeds were not placed as individual seeds but were attached by strings with tensile strength. These strings lined the cavity like barrel staves, maintaining a certain amount of outward pressure on the cavity to keep it from collapsing. Additionally, fibrin glue was placed over the seeds not only to keep them from moving but to create outward pressure on the cavity to prevent cavity shrinkage. Since most of the mass effect of the tumor bulk was relieved after the initial surgery, indicated by the 69.6% shrinkage in cavity volume prior to seed placement, the maintenance of a smaller residual volume during the treatment period did not compromise the surgical goal of relieving mass effect.

Results from the RTOG 90–05 trial have formed the standard of care for recurrent brain metastases treated with single-fraction SRS in the setting of brain metastases previously irradiated with WBRT.53 Because of the increased risk of radiation necrosis, we concluded that dose depends on tumor volume. In fact, the SRS dose was stratified based on the size of the tumor as follows: 24, 18, and 15 Gy for tumors ≤ 20, 21–30, and 31–40 mm in maximum diameter, respectively. It is interesting to note that these results have formed the basis for prescribed doses in patients without previous radiation as well. The authors reported radiation necrosis rates of 5%, 8%, 9%, and 11% at 6, 12, 18, and 24 months, respectively. However, this included both patients with brain metastases previously treated at a median dose of 30 Gy and patients with primary brain tumors with prior radiation therapy at a median dose of 60 Gy. Therefore, in our study, no dose adjustment was made to account for intraoperative 131Cs brachytherapy. Another reason for the absence of radiation necrosis in our study is that only one patient proceeded to salvage WBRT. Additionally, our study did not have a considerable amount of large tumors (5 tumors ≤ 20 mm, 12 tumors 21–30 mm, and 7 tumors > 31 mm). Historically, radiotherapy to large tumors has been associated with high rates of radiation necrosis, as seen in RTOG 90–05.

The goal of this novel treatment is to provide a simpler, safer, and more effective method of achieving local control in this patient population. With this treatment modality, there is minimal radiation exposure to family and staff. Additionally, because of the dose fall-off that occurs at 3 feet, patients are not required to have a private room or wear a special lead hat, and family members do not need to be kept at a distance unless they are children or pregnant. At the same time, the method provides the added benefit of delivering two treatments in one procedure and avoids the necessity of numerous visits to the hospital for SRS or WBRT.

Study Limitations

In this analysis, we report results for the initial 24 patients. More substantial numbers of patients from other institutions treated in such a manner will be required to make more definitive conclusions. A multiinstitutional study is underway. Further randomized comparisons between intraoperative brachytherapy and postoperative SRS are indicated. The details of the kinetics and dynamics of the size and shape of the resection cavity and its changes over time will be required for more precise treatment planning, and these studies are ongoing. Finally, formal objective measures of QOL and cognitive processing as well as cost will help in comparing 131Cs brachytherapy with other treatment options.

Conclusions

This is the first prospective analysis of patients with newly diagnosed metastases treated with maximally safe resection and intraoperative application of 131Cs. To date, this method of brachytherapy, based on our institutional nomogram and surgical technique, has rendered excellent local control and has proved to be safe and efficacious. A multicenter trial will soon be underway to evaluate this novel radioisotope as a promising modality in the treatment of patients with brain metastases requiring neurosurgical intervention.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Dr. Wernicke was supported by the NIH KL2 Grant No. 3KL2RR024997, and Dr. Christos was partially supported by the Clinical Translational Science Center Grant No. UL1-TR000457-06.

Author contributions to the study and manuscript preparation include the following. Conception and design: Wernicke, Kovanlikaya. Acquisition of data: Wernicke, Yondorf, Peng, Trichter, Nedialkova, Sabbas, Kulidzhanov, Christos, Pannullo, Boockvar, Stieg, Schwartz. Analysis and interpretation of data: Wernicke, Yondorf, Peng, Christos, Kovanlikaya. Drafting the article: Wernicke, Yondorf, Schwartz. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Wernicke. Statistical analysis: Yondorf, Christos. Administrative/technical/material support: Wernicke, Trichter, Nedialkova, Sabbas, Kulidzhanov, Parashar, Pannullo, Stieg, Schwartz. Study supervision: Wernicke, Schwartz.

This article contains some figures that are displayed in color online but in black-and-white in the print edition.

Portions of this work were presented as an oral presentation at ASTRO's 54th Annual Meeting held in Boston, Massachusetts, on October 28–31, 2012.

References

  • 1

    Aoyama HShirato HOnimaru RKagei KIkeda JIshii N: Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull. Int J Radiat Oncol Biol Phys 56:7938002003

  • 2

    Aoyama HShirato HTago MNakagawa KToyoda THatano K: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:248324912006

  • 3

    Atalar BChoi CYHarsh GR IVChang SDGibbs ICAdler JR: Cavity volume dynamics after resection of brain metastases and timing of postresection cavity stereotactic radiosurgery. Neurosurgery 72:1801852013

  • 4

    Beal KChan KChan TYamada YNarayana ALymberis S: A phase II prospective trial of stereotactic radiosurgery boost following surgical resection for brain metastases. Int J Radiat Oncol Biol Phys 75:SupplS126S1272009. (Abstract)

  • 5

    Bernstein MCabantog ALaperriere NLeung PThomason C: Brachytherapy for recurrent single brain metastasis. Can J Neurol Sci 22:13161995

  • 6

    Blonigen BJSteinmetz RDLevin LLamba MAWarnick REBreneman JC: Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 77:99610012010

  • 7

    Bogart JAUngureanu CShihadeh EChung TCKing GARyu S: Resection and permanent I-125 brachytherapy without whole brain irradiation for solitary brain metastasis from non-small cell lung carcinoma. J Neurooncol 44:53571999

  • 8

    Bradley KAMehta MP: Management of brain metastases. Semin Oncol 31:6937012004

  • 9

    Chang ELWefel JSHess KRAllen PKLang FFKornguth DG: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:103710442009

  • 10

    Chow EDavis LHolden LTsao MDanjoux C: Prospective assessment of patient-rated symptoms following whole brain radiotherapy for brain metastases. J Pain Symptom Manage 30:18232005

  • 11

    Cox JDStetz JPajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:134113461995

  • 12

    Crossen JRGarwood DGlatstein ENeuwelt EA: Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 12:6276421994

  • 13

    Dagnew EKanski JMcDermott MWSneed PKMcPherson CBreneman JC: Management of newly diagnosed single brain metastasis using resection and permanent iodine-125 seeds without initial whole-brain radiotherapy: a two institution experience. Neurosurg Focus 22:3E32007

  • 14

    Dale RGJones BColes IP: Effect of tumour shrinkage on the biological effectiveness of permanent brachytherapy implants. Br J Radiol 67:6396451994

  • 15

    DeAngelis LMDelattre JYPosner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:7897961989

  • 16

    Do LPezner RRadany ELiu AStaud CBadie B: Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases. Int J Radiat Oncol Biol Phys 73:4864912009

  • 17

    Elaimy ALMackay ARLamoreaux WTFairbanks RKDemakas JJCooke BS: Clinical outcomes of stereotactic radiosurgery in the treatment of patients with metastatic brain tumors. World Neurosurg 75:6736832011

  • 18

    Gans JHRaper DMShah AHBregy AHeros DLally BE: The role of radiosurgery to the tumor bed after resection of brain metastases. Neurosurgery 72:3173262013

  • 19

    Gaspar LScott CRotman MAsbell SPhillips TWasserman T: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:7457511997

  • 20

    Gaspar LEScott CMurray KCurran W: Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47:100110062000

  • 21

    Hall EJGiaccia AJ: Radiobiology for the Radiologist ed 7PhiladelphiaLippincott Williams & Wilkins2011. 86101

  • 22

    Huang KSneed PKKunwar SKragten ALarson DABerger MS: Surgical resection and permanent iodine-125 brachytherapy for brain metastases. J Neurooncol 91:83932009

  • 23

    Hwang SWAbozed MMHale AEisenberg RLDvorak TYao K: Adjuvant Gamma Knife radiosurgery following surgical resection of brain metastases: a 9-year retrospective cohort study. J Neurooncol 98:77822010

  • 24

    Iwai YYamanaka KYasui T: Boost radiosurgery for treatment of brain metastases after surgical resections. Surg Neurol 69:1811862008

  • 25

    Jagannathan JYen CPRay DKSchlesinger DOskouian RJPouratian N: Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases. Clinical article. J Neurosurg 111:4314382009

  • 26

    Jarvis LASimmons NEBellerive MErkmen KEskey CJGladstone DJ: Tumor bed dynamics after surgical resection of brain metastases: implications for postoperative radiosurgery. Int J Radiat Oncol Biol Phys 84:9439482012

  • 27

    Jensen CAChan MDMcCoy TPBourland JDdeGuzman AFEllis TL: Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. Clinical article. J Neurosurg 114:158515912011

  • 28

    Kalani MYFilippidis ASKalani MASanai NBrachman DMcBride HL: Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary results. Clinical article. J Neurosurg 113:Suppl90962010

  • 29

    Kalkanis SNKondziolka DGaspar LEBurri SHAsher ALCobbs CS: The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96:33432010

  • 30

    Karlovits BJQuigley MRKarlovits SMMiller LJohnson MGayou O: Stereotactic radiosurgery boost to the resection bed for oligometastatic brain disease: challenging the tradition of adjuvant whole-brain radiotherapy. Neurosurg Focus 27:6E72009

  • 31

    Kelly PJLin YBYu AYAlexander BMHacker FMarcus KJ: Stereotactic irradiation of the postoperative resection cavity for brain metastasis: a frameless linear accelerator-based case series and review of the technique. Int J Radiat Oncol Biol Phys 82:951012012

  • 32

    Kondziolka DNiranjan AFlickinger JCLunsford LD: Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients' perspective regarding complications. Am J Clin Oncol 28:1731792005

  • 33

    Lazow SPYondorf MKovanlikaya INori DChao KCBoockvar JA: Temporal changes in MRI edema and resection cavity dynamics subsequent to implantation of cesium-131 (Cs-131) brachytherapy in patients with brain metastases: a volumetric analysis from a prospective study. Int J Radiat Oncol Biol Phys 87:SupplS256S2572013. (Abstract)

  • 34

    Le Chevalier TSmith FPCaille PConstans JPRouesse JG: Sites of primary malignancies in patients presenting with cerebral metastases. A review of 120 cases. Cancer 56:8808821985

  • 35

    Limbrick DD JrLusis EAChicoine MRRich KMDacey RGDowling JL: Combined surgical resection and stereotactic radiosurgery for treatment of cerebral metastases. Surg Neurol 71:2802892009

  • 36

    Ling CCSpiro IJMitchell JStickler R: The variation of OER with dose rate. Int J Radiat Oncol Biol Phys 11:136713731985

  • 37

    Linskey MEAndrews DWAsher ALBurri SHKondziolka DRobinson PD: The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96:45682010

  • 38

    Mathieu DKondziolka DFlickinger JCFortin DKenny BMichaud K: Tumor bed radiosurgery after resection of cerebral metastases. Neurosurgery 62:8178242008

  • 39

    McDermott MWCosgrove GRLarson DASneed PKGutin PH: Interstitial brachytherapy for intracranial metastases. Neurosurg Clin N Am 7:4854951996

  • 40

    Minniti GClarke ELanzetta GOsti MFTrasimeni GBozzao A: Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol 6:482011

  • 41

    Nieder CSchwerdtfeger KSteudel WISchnabel K: Patterns of relapse and late toxicity after resection and whole-brain radiotherapy for solitary brain metastases. Strahlenther Onkol 174:2752781998

  • 42

    Ostertag CBKreth FW: Interstitial iodine-125 radiosurgery for cerebral metastases. Br J Neurosurg 9:5936031995

  • 43

    Patchell RA: The management of brain metastases. Cancer Treat Rev 29:5335402003

  • 44

    Patchell RATibbs PARegine WFDempsey RJMohiuddin MKryscio RJ: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280:148514891998

  • 45

    Patchell RATibbs PAWalsh JWDempsey RJMaruyama YKryscio RJ: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:4945001990

  • 46

    Pieper DSuen AWGrills ISNandalur SMohammed NMitchell C: Gamma Knife stereotactic radiosurgery for resected brain metastases. Int J Radiat Oncol Biol Phys 72:SupplS227S2282008. (Abstract)

  • 47

    Prasad SCBassano DAFear PIKing GA: Dosimetry of I-125 seeds implanted on the surface of a cavity. Med Dosim 15:2172191990

  • 48

    Quigley MRFuhrer RKarlovits SMKarlovits BJJohnson M: Single session stereotactic radiosurgery boost to the postoperative site in lieu of whole brain radiation in metastatic brain disease. J Neurooncol 87:3273322008

  • 49

    Ravi AKeller BMPignol JP: A comparison of postimplant dosimetry for (103)Pd versus (131)Cs seeds on a retrospective series of PBSI patients. Med Phys 38:604660522011

  • 50

    Rogers LRRock JPSills AKVogelbaum MASuh JHEllis TL: Results of a phase II trial of the GliaSite Radiation Therapy System for the treatment of newly diagnosed, resected single brain metastases. J Neurosurg 105:3753842006

  • 51

    Schulder MBlack PMShrieve DCAlexander E IIILoeffler JS: Permanent low-activity iodine-125 implants for cerebral metastases. J Neurooncol 33:2132211997

  • 52

    Schwarz SBThon NNikolajek KNiyazi MTonn JCBelka C: Iodine-125 brachytherapy for brain tumours—a review. Radiat Oncol 7:302012

  • 53

    Shaw EScott CSouhami LDinapoli RKline RLoeffler J: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 47:2912982000

  • 54

    Sheline GEBrady LW: Radiation therapy for brain metastases. J Neurooncol 4:2192251987

  • 55

    Sneed PKSuh JHGoetsch SJSanghavi SNChappell RBuatti JM: A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:5195262002

  • 56

    Soltys SGAdler JRLipani JDJackson PSChoi CYPuataweepong P: Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys 70:1871932008

  • 57

    Suh JHBarnett GH: Brachytherapy for brain tumor. Hematol Oncol Clin North Am 13:635650viiiix1999

  • 58

    Suwinski RSowa ARutkowski TWydmanski JTarnawski RMaciejewski B: Time factor in postoperative radiotherapy: a multivariate locoregional control analysis in 868 patients. Int J Radiat Oncol Biol Phys 56:3994122003

  • 59

    Weil RJ: Does trastuzumab increase the risk of isolated central nervous system metastases in patients with breast cancer?. Nat Clin Pract Oncol 3:2362372006

  • 60

    Wernicke AGChao KSNori DParashar BYondorf MBoockvar JA: The cost-effectiveness of surgical resection plus cesium-131 (Cs-131) brachytherapy versus stereotactic radiosurgery versus surgery + whole brain radiotherapy (WBRT) versus WBRT in the treatment of metastatic brain tumors. Neuro Oncol 14:Suppl 6vi139vi1412012. (Abstract)

  • 61

    Yang RWang JZhang H: Dosimetric study of Cs-131, I-125, and Pd-103 seeds for permanent prostate brachytherapy. Cancer Biother Radiopharm 24:7017052009

  • 62

    Yondorf MNedialkova LParashar BNori DChao KCBoockvar JA: Resection cavity dynamics following implantation of cesium-131 (Cs-131) brachytherapy for resection brain metastases based on CT-planning. Int J Radiat Oncol Biol Phys 87:SupplS161S1622013. (Abstract)

  • 63

    Zamorano LYakar DDujovny MSheehan MKim J: Permanent iodine-125 implant and external beam radiation therapy for the treatment of malignant brain tumors. Stereotact Funct Neurosurg 59:1831921992

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: A. Gabriella Wernicke, M.D., M.Sc., Weill Medical College of Cornell University, Stich Radiation Oncology, 525 E. 68th St., New York, NY 10065. email: gaw9008@med.cornell.edu.

Please include this information when citing this paper: published online May 2, 2014; DOI: 10.3171/2014.3.JNS131140.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Resection cavity throughout the implant procedure. A: Empty resection cavity. B: Resection cavity lined with 131Cs seeds in a pattern like barrel staves or parallel tracks. C: Cesium-131 seeds covered with Surgicel. D: Cesium-131 seeds covered with Tisseel.

  • View in gallery

    Computed tomography scans of 131Cs brachytherapy seeds in the postoperative resection cavity. A: Axial plane. B: Sagittal plane. C: Coronal plane. D: Three-dimensional radiation cloud from the 80-Gy isodose line. E: Enlarged axial view of isodose lines.

  • View in gallery

    Overall survival.

  • View in gallery

    Magnetic resonance imaging series of local FFP. A: Preoperative. B: Postoperative. C: One month postoperative. D: Two months postoperative. E: Four months postoperative. F: Six months postoperative. G: Eleven months postoperative. H: Thirteen months postoperative.

  • View in gallery

    Regional FFP.

  • View in gallery

    Magnetic resonance imaging series of regional recurrence. A: Preoperative. B: Postoperative. C: One month postoperative. D: Four months postoperative. E: Seven months postoperative.

  • View in gallery

    Distant FFP.

References

1

Aoyama HShirato HOnimaru RKagei KIkeda JIshii N: Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull. Int J Radiat Oncol Biol Phys 56:7938002003

2

Aoyama HShirato HTago MNakagawa KToyoda THatano K: Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:248324912006

3

Atalar BChoi CYHarsh GR IVChang SDGibbs ICAdler JR: Cavity volume dynamics after resection of brain metastases and timing of postresection cavity stereotactic radiosurgery. Neurosurgery 72:1801852013

4

Beal KChan KChan TYamada YNarayana ALymberis S: A phase II prospective trial of stereotactic radiosurgery boost following surgical resection for brain metastases. Int J Radiat Oncol Biol Phys 75:SupplS126S1272009. (Abstract)

5

Bernstein MCabantog ALaperriere NLeung PThomason C: Brachytherapy for recurrent single brain metastasis. Can J Neurol Sci 22:13161995

6

Blonigen BJSteinmetz RDLevin LLamba MAWarnick REBreneman JC: Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 77:99610012010

7

Bogart JAUngureanu CShihadeh EChung TCKing GARyu S: Resection and permanent I-125 brachytherapy without whole brain irradiation for solitary brain metastasis from non-small cell lung carcinoma. J Neurooncol 44:53571999

8

Bradley KAMehta MP: Management of brain metastases. Semin Oncol 31:6937012004

9

Chang ELWefel JSHess KRAllen PKLang FFKornguth DG: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:103710442009

10

Chow EDavis LHolden LTsao MDanjoux C: Prospective assessment of patient-rated symptoms following whole brain radiotherapy for brain metastases. J Pain Symptom Manage 30:18232005

11

Cox JDStetz JPajak TF: Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 31:134113461995

12

Crossen JRGarwood DGlatstein ENeuwelt EA: Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy. J Clin Oncol 12:6276421994

13

Dagnew EKanski JMcDermott MWSneed PKMcPherson CBreneman JC: Management of newly diagnosed single brain metastasis using resection and permanent iodine-125 seeds without initial whole-brain radiotherapy: a two institution experience. Neurosurg Focus 22:3E32007

14

Dale RGJones BColes IP: Effect of tumour shrinkage on the biological effectiveness of permanent brachytherapy implants. Br J Radiol 67:6396451994

15

DeAngelis LMDelattre JYPosner JB: Radiation-induced dementia in patients cured of brain metastases. Neurology 39:7897961989

16

Do LPezner RRadany ELiu AStaud CBadie B: Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases. Int J Radiat Oncol Biol Phys 73:4864912009

17

Elaimy ALMackay ARLamoreaux WTFairbanks RKDemakas JJCooke BS: Clinical outcomes of stereotactic radiosurgery in the treatment of patients with metastatic brain tumors. World Neurosurg 75:6736832011

18

Gans JHRaper DMShah AHBregy AHeros DLally BE: The role of radiosurgery to the tumor bed after resection of brain metastases. Neurosurgery 72:3173262013

19

Gaspar LScott CRotman MAsbell SPhillips TWasserman T: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 37:7457511997

20

Gaspar LEScott CMurray KCurran W: Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 47:100110062000

21

Hall EJGiaccia AJ: Radiobiology for the Radiologist ed 7PhiladelphiaLippincott Williams & Wilkins2011. 86101

22

Huang KSneed PKKunwar SKragten ALarson DABerger MS: Surgical resection and permanent iodine-125 brachytherapy for brain metastases. J Neurooncol 91:83932009

23

Hwang SWAbozed MMHale AEisenberg RLDvorak TYao K: Adjuvant Gamma Knife radiosurgery following surgical resection of brain metastases: a 9-year retrospective cohort study. J Neurooncol 98:77822010

24

Iwai YYamanaka KYasui T: Boost radiosurgery for treatment of brain metastases after surgical resections. Surg Neurol 69:1811862008

25

Jagannathan JYen CPRay DKSchlesinger DOskouian RJPouratian N: Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases. Clinical article. J Neurosurg 111:4314382009

26

Jarvis LASimmons NEBellerive MErkmen KEskey CJGladstone DJ: Tumor bed dynamics after surgical resection of brain metastases: implications for postoperative radiosurgery. Int J Radiat Oncol Biol Phys 84:9439482012

27

Jensen CAChan MDMcCoy TPBourland JDdeGuzman AFEllis TL: Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis. Clinical article. J Neurosurg 114:158515912011

28

Kalani MYFilippidis ASKalani MASanai NBrachman DMcBride HL: Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary results. Clinical article. J Neurosurg 113:Suppl90962010

29

Kalkanis SNKondziolka DGaspar LEBurri SHAsher ALCobbs CS: The role of surgical resection in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96:33432010

30

Karlovits BJQuigley MRKarlovits SMMiller LJohnson MGayou O: Stereotactic radiosurgery boost to the resection bed for oligometastatic brain disease: challenging the tradition of adjuvant whole-brain radiotherapy. Neurosurg Focus 27:6E72009

31

Kelly PJLin YBYu AYAlexander BMHacker FMarcus KJ: Stereotactic irradiation of the postoperative resection cavity for brain metastasis: a frameless linear accelerator-based case series and review of the technique. Int J Radiat Oncol Biol Phys 82:951012012

32

Kondziolka DNiranjan AFlickinger JCLunsford LD: Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients' perspective regarding complications. Am J Clin Oncol 28:1731792005

33

Lazow SPYondorf MKovanlikaya INori DChao KCBoockvar JA: Temporal changes in MRI edema and resection cavity dynamics subsequent to implantation of cesium-131 (Cs-131) brachytherapy in patients with brain metastases: a volumetric analysis from a prospective study. Int J Radiat Oncol Biol Phys 87:SupplS256S2572013. (Abstract)

34

Le Chevalier TSmith FPCaille PConstans JPRouesse JG: Sites of primary malignancies in patients presenting with cerebral metastases. A review of 120 cases. Cancer 56:8808821985

35

Limbrick DD JrLusis EAChicoine MRRich KMDacey RGDowling JL: Combined surgical resection and stereotactic radiosurgery for treatment of cerebral metastases. Surg Neurol 71:2802892009

36

Ling CCSpiro IJMitchell JStickler R: The variation of OER with dose rate. Int J Radiat Oncol Biol Phys 11:136713731985

37

Linskey MEAndrews DWAsher ALBurri SHKondziolka DRobinson PD: The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline. J Neurooncol 96:45682010

38

Mathieu DKondziolka DFlickinger JCFortin DKenny BMichaud K: Tumor bed radiosurgery after resection of cerebral metastases. Neurosurgery 62:8178242008

39

McDermott MWCosgrove GRLarson DASneed PKGutin PH: Interstitial brachytherapy for intracranial metastases. Neurosurg Clin N Am 7:4854951996

40

Minniti GClarke ELanzetta GOsti MFTrasimeni GBozzao A: Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol 6:482011

41

Nieder CSchwerdtfeger KSteudel WISchnabel K: Patterns of relapse and late toxicity after resection and whole-brain radiotherapy for solitary brain metastases. Strahlenther Onkol 174:2752781998

42

Ostertag CBKreth FW: Interstitial iodine-125 radiosurgery for cerebral metastases. Br J Neurosurg 9:5936031995

43

Patchell RA: The management of brain metastases. Cancer Treat Rev 29:5335402003

44

Patchell RATibbs PARegine WFDempsey RJMohiuddin MKryscio RJ: Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 280:148514891998

45

Patchell RATibbs PAWalsh JWDempsey RJMaruyama YKryscio RJ: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:4945001990

46

Pieper DSuen AWGrills ISNandalur SMohammed NMitchell C: Gamma Knife stereotactic radiosurgery for resected brain metastases. Int J Radiat Oncol Biol Phys 72:SupplS227S2282008. (Abstract)

47

Prasad SCBassano DAFear PIKing GA: Dosimetry of I-125 seeds implanted on the surface of a cavity. Med Dosim 15:2172191990

48

Quigley MRFuhrer RKarlovits SMKarlovits BJJohnson M: Single session stereotactic radiosurgery boost to the postoperative site in lieu of whole brain radiation in metastatic brain disease. J Neurooncol 87:3273322008

49

Ravi AKeller BMPignol JP: A comparison of postimplant dosimetry for (103)Pd versus (131)Cs seeds on a retrospective series of PBSI patients. Med Phys 38:604660522011

50

Rogers LRRock JPSills AKVogelbaum MASuh JHEllis TL: Results of a phase II trial of the GliaSite Radiation Therapy System for the treatment of newly diagnosed, resected single brain metastases. J Neurosurg 105:3753842006

51

Schulder MBlack PMShrieve DCAlexander E IIILoeffler JS: Permanent low-activity iodine-125 implants for cerebral metastases. J Neurooncol 33:2132211997

52

Schwarz SBThon NNikolajek KNiyazi MTonn JCBelka C: Iodine-125 brachytherapy for brain tumours—a review. Radiat Oncol 7:302012

53

Shaw EScott CSouhami LDinapoli RKline RLoeffler J: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90–05. Int J Radiat Oncol Biol Phys 47:2912982000

54

Sheline GEBrady LW: Radiation therapy for brain metastases. J Neurooncol 4:2192251987

55

Sneed PKSuh JHGoetsch SJSanghavi SNChappell RBuatti JM: A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases. Int J Radiat Oncol Biol Phys 53:5195262002

56

Soltys SGAdler JRLipani JDJackson PSChoi CYPuataweepong P: Stereotactic radiosurgery of the postoperative resection cavity for brain metastases. Int J Radiat Oncol Biol Phys 70:1871932008

57

Suh JHBarnett GH: Brachytherapy for brain tumor. Hematol Oncol Clin North Am 13:635650viiiix1999

58

Suwinski RSowa ARutkowski TWydmanski JTarnawski RMaciejewski B: Time factor in postoperative radiotherapy: a multivariate locoregional control analysis in 868 patients. Int J Radiat Oncol Biol Phys 56:3994122003

59

Weil RJ: Does trastuzumab increase the risk of isolated central nervous system metastases in patients with breast cancer?. Nat Clin Pract Oncol 3:2362372006

60

Wernicke AGChao KSNori DParashar BYondorf MBoockvar JA: The cost-effectiveness of surgical resection plus cesium-131 (Cs-131) brachytherapy versus stereotactic radiosurgery versus surgery + whole brain radiotherapy (WBRT) versus WBRT in the treatment of metastatic brain tumors. Neuro Oncol 14:Suppl 6vi139vi1412012. (Abstract)

61

Yang RWang JZhang H: Dosimetric study of Cs-131, I-125, and Pd-103 seeds for permanent prostate brachytherapy. Cancer Biother Radiopharm 24:7017052009

62

Yondorf MNedialkova LParashar BNori DChao KCBoockvar JA: Resection cavity dynamics following implantation of cesium-131 (Cs-131) brachytherapy for resection brain metastases based on CT-planning. Int J Radiat Oncol Biol Phys 87:SupplS161S1622013. (Abstract)

63

Zamorano LYakar DDujovny MSheehan MKim J: Permanent iodine-125 implant and external beam radiation therapy for the treatment of malignant brain tumors. Stereotact Funct Neurosurg 59:1831921992

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