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Keywords:

  • brain metastasis;
  • stereotactic radiosurgery;
  • stereotactic radiotherapy;
  • hypofractionation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

BACKGROUND:

This retrospective review evaluated the efficacy and toxicity profiles of various dose fractionations using hypofractionated stereotactic radiotherapy (HSRT) in the treatment of brain metastases.

METHODS:

Between 2004 and 2007, 36 patients with 66 brain metastases were treated with HSRT. Nine of these subjects were excluded because of the absence of post-treatment magnetic resonance imaging scans, resulting in 27 patients with a total of 52 lesions. Of these 52 lesions, 45 lesions were treated with whole-brain radiotherapy plus a HSRT boost and 7 lesions were treated with HSRT as the primary treatment. The median prescribed dose was 25 grays (Gy) (range, 20 Gy-36 Gy) with a median of 5 fractions (range, 4 fractions-6 fractions) to a median 85% isodose line (range, 50%-100%). The median follow-up interval was 6.6 months (range, 0.9 months-26.8 months).

RESULTS:

The median overall survival time was 10.8 months, and 66.7% of patients died of disease progression. After HSRT treatment of 52 brain lesions, 13 lesions demonstrated complete responses, 12 lesions demonstrated partial responses, 22 lesions demonstrated stable disease, and 5 lesions demonstrated progressive disease. Actuarial local tumor control rates at 6 months and 1 year were 93.9% and 68.2%, respectively. Maximum tumor dimension, concurrent chemotherapy, and a tumor volume <1 cc were found to be statistically significant factors for local tumor control. One patient had a grade 3 toxicity (according to National Cancer Institute Common Terminology Criteria for Adverse Events).

CONCLUSIONS:

HSRT provides a high level of tumor control with minimal toxicity comparable to single-fraction stereotactic radiosurgery (SRS). The results of the current study warrant a prospective randomized study comparing single-fraction SRS with HSRT in this patient population. Cancer 2009. © 2009 American Cancer Society.

Patients with brain metastases are traditionally treated with surgery, whole-brain radiotherapy (WBRT), or stereotactic radiosurgery (SRS).1, 2 In the past decade, the use of SRS in the treatment of brain metastases has grown considerably. Recent studies have revealed an overall survival advantage with the incorporation of SRS after WBRT.3

Although SRS is commonly used in the treatment of patients with brain metastases, the application of a stereotactic head frame is associated with patient discomfort and a reluctance to undergo the procedure.4 Along with the development of single-fraction SRS treatment, radiosurgery systems were developed to allow fractionated stereotactic radiotherapy (SRT) approaches for the treatment of intracranial tumors. Because of the radiobiologic advantage of fractionated treatment on sensitive structures in the brain,5 relocatable head frames were developed to allow for stereotactic delivery over many days and weeks without the need for repeated invasive head frame applications. Such systems were found to provide accuracy equivalent to that of single-fraction systems, while providing fractionated protection of eloquent structures.1

With the growth of the use of fractionated SRT in the brain, some investigators began to explore the use of SRT for the treatment of brain metastases.6-8 Although these reported experiences have been encouraging, to our knowledge, no clear treatment guidelines have been provided to date due to the paucity of data. Beginning in 2004, our group began to treat brain metastases with hypofractionated stereotactic radiotherapy (HSRT). The current study describes our experience.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Patients Studied

Between August 2004 and June 2007, 36 patients with ≤4 brain metastases were treated with HSRT at the Department of Radiation Oncology at Cooper University Hospital. Of these 36 patients, 15 patients had a solitary brain lesion and 21 patients had oligometastases, defined as 2 to 4 lesions. From these 36 patients, we retrospectively evaluated 27 patients who had at least 1 post-treatment follow-up magnetic resonance imaging (MRI) scan for inclusion in this analysis. Detailed patient and tumor characteristics are summarized in Table 1. This retrospective study was approved and governed by the Cooper Health System's Institutional Review Board.

Table 1. Patient and Tumor Characteristics
CharacteristicNo.Percentage
  1. KPS indicates Karnofsky performance score; NSCLC, nonsmall cell lung cancer; RPA, recursive partitioning analysis.

Total no. of patients27 
Gender  
 Male829.6
 Female1970.4
Age, y  
 Median57.7 
 Range38.1 
KPS  
 ≥702385.2
 <70414.8
Status of primary tumor  
 Active2281.5
 Inactive518.5
No. of lesions treated  
 11244.4
 2725.9
 3622.3
 427.4
Primary tumor  
 Lung2074.1
 Breast27.4
 Melanoma27.4
 Others311.1
Pathology  
 NSCLC1451.9
 Small cell414.8
 Adenocarcinoma311.1
 Melanoma27.4
 Others311.1
 Unknown13.7
Previous chemotherapy  
 Yes1555.6
 No1244.4
Extracranial metastasis  
 Yes1970.4
 No829.6
Concurrent chemotherapy  
 Yes622.2
 No2177.8
RPA class9  
 I27.4
 II2281.5
 III311.1
Prior resection of brain lesion  
 Yes622.2
 No2177.8

Treatment

HSRT was performed in all patients on an outpatient basis. Stereotactic treatment was performed using a multiple noncoplanar converging arcs technique. The patient was supine on the treatment table while the gantry moved through a given arc. Irradiation was performed with 6-megavolt photons from a linear accelerator (Varian Clinac 600C; Varian, Palo Alto, Calif) using a linear particle accelerator (linac)-based stereotactic system. The Gill-Thomas-Cosman (GTC) relocatable head ring, LCMA-2 Couch Mount (Radionics, Burlington, Mass), and bite block were used to reproduce the same exact position between fractions. Axial spacing of 2.0 mm between slices was used for the computed tomography (CT) scan. A contrast agent was given to allow for proper contrast enhancement of the metastatic lesions before the CT scan. MRI scans of the brain with gadolinium contrast were used for all patients and fused with the CT images for treatment planning. The macroscopic (gross) tumor volume (GTV) was drawn on the MRI images. The dosimetric planning was performed with the XKnife RT3 (Radionics) 3-dimensional dose planning system. The prescription isodose line was generally 1 to 2 mm larger than the GTV to account for fixation inaccuracy.

At each treatment, alignment of the lateral lasers and ceiling mounted laser systems was calibrated in the LINAC room. Radionics mechanical isocenter standard and LCMA-2 Couch mount systems were used to check laser light and system alignment. The initial machine isocenter and patient isocenter were filmed at 3 gantry angles: left lateral, right lateral, and anteroposterior. The films were taken with a 17.5-mm cone and the plastic stick-and-ball phantom supplied by the manufacturer. Tolerance of the discrepancy between the radiation isocenter and the patient isocenter was 0.75 mm. The GTC depth helmet was used to evaluate the accuracy of the repositioning of the patient relative to the CT position. Measurements at 26 directions were recorded during the initial CT scan. For each fraction, these measurements were repeated and compared with the initial measurements. The tolerance for the setup error was 2 mm between the pretreatment and the initial measurements.

The treatment volume ratio (TVR) was defined as the total volume receiving the prescription dose divided by the tumor lesion volume. The TVR was calculated for relative comparison between plans as a measure of the conformality of the dose distribution to the tumor lesion volume.

Various schemes of total doses (20 Gy-36 Gy) and fractionations (4 fractions-6 fractions) were prescribed in this patient cohort. Patients received treatment daily on consecutive days, Monday through Friday, for as many days as the fractionation required. The most common fractionation regimen was 5 Gy in 5 fractions. Of 27 patients, 22 patients received upfront WBRT followed by a HSRT boost and 5 patients received HSRT as their primary treatment without the incorporation of WBRT. The WBRT dose in the majority of patients was 37.5 Gy administered in 15 fractions.

At the time of presentation, all patients with brain metastases were offered WBRT. If they were eligible for an SRT boost after WBRT or if they refused upfront WBRT and opted for SRT alone, SRT was offered. Although our institutional policy was to offer all patients HSRT, patients all consented to the use of single-fraction SRS as an alternative. Because the hypofractioned approach avoided the need for an invasive head frame, there were no patients who opted for that approach within our patient cohort.

With regard to dosing guidelines, a majority of the patients were prescribed 25 Gy in 5 fractions for lesions measuring ≤30 mm in dimension. In patients with lesions measuring <20 mm and having a favorable performance status, a common dose regimen of 30 Gy in 5 fractions was also used. Furthermore, a smaller group of patients received 36 Gy in 6 fractions. The maximum dose to the optic apparatus was limited to 20 Gy in 5 fractions and that to the brainstem was limited to 25 Gy in 5 fractions.

Follow-up

Patients were seen at least 4 weeks after HSRT and were evaluated with MRI and a physical examination. Each lesion was measured for local tumor response and graded using the criteria of MacDonald et al with the following 4 categories: 1) complete remission (CR) indicated the disappearance of all enhancing lesions on MRI, 2) partial remission (PR) indicated evidence of a >50% reduction in the cross-sectional dimension of the tumor on MRI, 3) progressive disease (PD) indicated a >25% increase in size, and 4) stable disease (SD) indicated all other responses.10 Local tumor control was defined as CR, PR, and SD. Any significant increase in tumor size (>25%) in the interval was defined as local tumor control failure and the appearance of any new lesion was considered to be an overall brain tumor control failure. Any toxicity (defined as an adverse event) was recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (version 3.0). We followed all patients who underwent SRT and returned for follow-up. We did not exclude patients who had more serious conditions and we attempted to include all patients irrespective of outcome. We obtained survival data for all patients by contacting the family, social security index, primary care provider, et cetera.

Statistical Analysis

We evaluated local tumor control, overall brain tumor control, overall survival, and toxicity as endpoints. The data was analyzed using SPSS statistical software (version 15.0.1; SPSS Inc., Chicago, Ill). The survival rate was calculated from the date of the end of treatment to either the date of death or last follow-up using the Kaplan-Meier method. Univariate log-rank tests were used to assess the significance of prognostic factors affecting survival and local tumor control. It was noted that 1 of the limitations of the current study was the small sample size, but it was considered to be unavoidable to generate a hypothesis.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

Tumor Lesions

Of the 52 brain metastases from the 27 patients in the current study, 45 lesions were treated with WBRT followed by a planned HSRT boost and 7 lesions were treated with HSRT as the primary treatment. The median prescribed total dose was 25 Gy (range, 20 Gy-36 Gy) administered in a median of 5 fractions (range, 4 fractions-6 fractions) to a median 85% isodose line (range, 50%-100%). The median maximum tumor dimension, treatment volume, and TVR were 11.6 mm (range, 1.7 mm-31.2 mm), 0.52 cc (range, 0.05 cc-15.41 cc), and 3.4 (range, 1.7-24.0), respectively. Detailed tumor characteristics are summarized in Table 2. The median follow-up interval was 6.6 months (range, 0.9 months-26.8 months).

Table 2. Lesion and Treatment Characteristics
CharacteristicNo.Percentage
  1. NSCLC indicates nonsmall cell lung cancer; Gy, grays; WBRT, whole-brain radiotherapy; SRT, stereotactic radiotherapy.

No. of lesions52 
Histology  
 NSCLC2955.8
 Adenocarcinoma611.5
 Small cell611.5
 Melanoma59.6
 Others59.6
 Unknown11.9
Location  
 Supratentorial3261.5
 Infratentorial2038.5
Treatment volume, cc  
 Median0.52 
 Range0.05-15.41 
 ≤13159.60
 >1 to ≤2815.4
 >21325.0
Largest dimension, mm  
 Median11.6 
 Range1.7-31.2 
 ≤204382.7
 >20 to ≤30815.4
 >3011.9
Maximum dose, Gy  
 Median30.9 
 Range22.1-60 
Isodose, %  
 Median85 
 Range50-100 
Treatment volume ratio  
 Median3.4 
 Range1.7-24.0 
Previous WBRT  
 Yes4586.5
 No713.5
SRT dose, Gy  
 2035.8
 253159.6
 ≥301834.6

Local Tumor Control

Of the 52 lesions treated, 47 (90.4%) had been assessed as having local tumor control (CR, PR, or SD), with a mean follow-up of 21.2 months (range, 3.4 months-26.8 months; 95% confidence interval, 16.7 months-25.7 months); radiographic shrinkage (CR and PR) was reported to occur in 25 of the 52 treated lesions (48.1%) (Fig. 1). The actuarial local tumor control rates for all lesions at 6 months and 1 year were 93.9% and 68.2%, respectively. Table 3 presents the HSRT stratification and response according to the maximum tumor dimension and HSRT dose. After HSRT treatment of 52 brain lesions, 13 lesions achieved CR, 12 lesions achieved PR, 22 lesions achieved SD, and 5 lesions had PD. Among the 5 lesions that progressed after treatment, 2 lesions resulting from nonsmall cell lung cancer (NSCLC) and transitional carcinoma of the bladder, respectively, both measured <20 mm and received 25 Gy; 1 lesion resulting from NSCLC measured <20 mm and received 30 Gy; 1 lesion resulting from endometrial adenocarcinoma measured between 20 mm and 30 mm and received 25 Gy; and 1 lesion resulting from a melanoma measured >30 mm and received 36 Gy.

thumbnail image

Figure 1. Kaplan-Meier local tumor control curve of the 52 treated lesions at a mean follow-up of 21.2 months (range, 3.4 months-26.8 months [95% confidence interval, 16.7 months-25.7 months]).

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Table 3. HSRT Stratification and Local Tumor Control According to Maximum Tumor Dimension and HSRT Dose
Maximum Tumor DimensionHSRT DoseFractionsCRPRSDPDNo. of Lesions
  1. HSRT indicates hypofractionated stereotactic radiotherapy; CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.

≤20 mm20004 12 3
 250057611226
 30005632112
 36006  2 2
>20 mm to ≤30 mm25005 1315
 30005  2 2
 36006 1  1
>30 mm36006   11
Total  131222552

Overall Survival

After the HSRT treatment, 18 (66.7%) of the 27 patients eventually died of their disease with a median survival of 10.8 months. Actuarial survival rates at 6 months and 1 year were 66.7% and 43.9%, respectively (Fig. 2).

thumbnail image

Figure 2. Kaplan-Meier survival curve of 27 patients at a mean follow-up of 15.7 months (range, 1.2 months-36.8 months [95% confidence interval, 10.5 months-20.9 months]).

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Progression in Distant Brain Site

In addition to local tumor control failure, the appearance of any new brain lesions was defined as overall brain tumor control failure. After treatment, 7 patients (25.9%) were found to have new distant brain lesions at a median follow-up of 6.47 months. Five of these 7 patients received WBRT followed by a HSRT boost and 2 patients received HSRT alone as upfront treatment. Among the 7 patients who failed in a distant brain site, 5 had extracranial metastases before HSRT treatment.

Prognostic Factors

As shown in Table 4, concurrent chemotherapy (P < .001) and the number of treated lesions (P = .036) were found to be statistically significant factors that affected overall survival. Both concurrent chemotherapy and having a large number of treated lesions were found to have an adverse effect on overall survival.

Table 4. Log-rank Tests for Prognostic Factors Affecting Overall Survival
FactorsP
  • KPS indicates Karnofsky performance score; RPA, recursive partitioning analysis.

  • *

    Factor was found to be statistically significant (P < .05).

Gender.124
Age (≤65 y vs >65 y).846
KPS (<70 vs ≥70).267
Primary lung cancer.862
Primary tumor status.649
Extracranial metastases.364
Resection of prior brain lesion.645
Concurrent chemotherapy<.001*
Previous chemotherapy.475
Previous radiotherapy.150
RPA class.173
No. of treated lesions.036*

As shown in Table 5, there was a significant difference in local tumor control rates among the treatment groups segregated by maximum tumor dimension (≤20 mm vs >20 mm and ≤30 mm vs >30 mm; P = .033). Crude local control rates for a maximum tumor dimension ≤20 mm versus >20 mm were 93.0% and 77.8%, respectively. Actuarial local control rates for a maximum tumor dimension ≤20 mm versus >20 mm at 6 months were 93.1% and 100%, respectively. However, actuarial local tumor control rates at 1 year for a maximum tumor dimension ≤20 mm versus >20 mm were 81.5% and 37.5%, respectively. Tumor volume <1 cc was found to be a statistically significant prognostic factor for local tumor control (P = .028). Actuarial local tumor control rates for a tumor volume ≤1.0 cc versus >1.0 cc at 6 months were 100% and 87.5%, respectively. Furthermore, the actuarial local tumor control rates for a tumor volume ≤1.0 cc versus >1.0 cc at 1 year were 100% and 46.7%, respectively. Radiation dose (P = .684) and use of WBRT (P = .191) were not found to be statistically significant factors for local tumor control.

Table 5. Log-rank Tests for Prognostic Factors Affecting Local Tumor Control
FactorsP
  • KPS indicates Karnofsky performance score; RPA, recursive partitioning analysis; HSRT, hypofractionated stereotactic radiotherapy; SRT, stereotactic radiotherapy; Gy, grays.

  • *

    Factor was found to be statistically significant (P < .05).

Gender (female vs male).591
Age (≤65 y vs >65 y).748
KPS (<70 vs ≥70).914
Primary lung cancer.299
Primary tumor status (progressive vs stable/regressing).122
Extracranial metastases.917
Resection of prior brain lesion.501
Concurrent chemotherapy.024*
Previous chemotherapy.701
Previous radiotherapy.820
RPA class.985
Tumor location (supratentorial/infratentorial).503
HSRT boost treatment.191
SRT dose.684
SRT dose (20 Gy vs 25 Gy vs ≥30 Gy).780
SRT dose (20 Gy vs ≥25 Gy).562
SRT dose (≤25 Gy vs ≥30 Gy).596
SRT dose (≤30 Gy vs >30 Gy).253
Maximum tumor dimension, mm.033*
 ≤20 vs >20 and ≤30 vs >30
 ≤20 vs >20.236
 ≤30 vs >30.009*
Tumor volume (≤1 cc vs >1 cc).028*
Tumor volume (≤2 cc vs >2 cc).068
Tumor volume (≤3 cc vs >3 cc).085

In addition, using Cox regression analysis, patients without concurrent chemotherapy were found to be significantly more likely to have local tumor control compared with patients treated with concurrent chemotherapy (P < .001). This significantly decreased risk was sustained when adjusted for age (odds ratio of 0.11). The age coefficient indicated that lesions occurring in patients aged ≤65 years had a significantly higher probability of achieving local tumor control than lesions diagnosed in patients aged >65 years, after adjusting for concurrent chemotherapy status (P < .001).

Toxicity

Nineteen patients did not have any adverse events >grade 1. The majority of common adverse events were grade 2 headaches (reported in 4 patients; 14.8%), grade 2 motor neuropathy (reported in 2 patients; 7.4%), and grade 2 lethargy (reported in 2 patients; 7.4%). One patient (3.7%) developed a grade 3 headache 5 months after receiving HSRT to a total dose of 30 Gy. The patient's brain lesion was controlled locally. Of 52 lesions, 3 lesions (5.8%) from 3 different patients demonstrated radiation necrosis after treatment. All 3 lesions were the result of NSCLC and had maximum tumor dimensions of 19.2 mm, 12.7 mm, and 19.8 mm, respectively. The lesions received maximum doses of 34.2 Gy, 35.3 Gy, and 31.6 Gy, respectively.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References

For the treatment of brain metastases, WBRT followed by a planned SRS boost has gained much support from several randomized trials. Kondziolka et al first reported that WBRT with SRS had a 92% local control rate at 1 year compared with 0% with WBRT alone in 27 patients with 2 to 4 brain metastases each.11 In the Radiation Therapy Oncology Group (RTOG) 9508 study, 333 patients with 1 to 3 brain metastases each were randomized to WBRT plus SRS versus WBRT alone. The results demonstrated better local control rates at 1 year in the group treated with WBRT and SRS compared with the patients treated with WBRT alone (82% vs 71%; P = .01).3

SRS is typically delivered in a single fraction using an invasive head frame. Although the frame provides accurate localization and minimizes motion, patients are often reluctant to undergo standard head frame placement because of pain and general discomfort. Because of the radiobiologic advantage of fractionated treatment on sensitive structures in the brain,5 radiosurgery systems were developed with relocatable head frames to allow for stereotactic delivery over multiple fractions without the need for repeated invasive head frame applications. Such fractionated approaches have been found to provide accuracy equivalent to that of single-fraction SRS, while providing protection for eloquent structures through fractionation.

The results of this retrospective study demonstrate that HSRT is a very effective and safe treatment approach that is comparable to SRS at controlling brain metastases. Although radiographic shrinkage occurred in 25 (48.1%) of the 52 treated lesions, durable, long-term local tumor control was still maintained in a large percentage of the remaining patients who did not demonstrate a radiographic response. In this respect, the median overall survival time was 10.8 months and the actuarial local tumor control rates at 6 months and 1 year were 93.9% and 68.2%, respectively. These results are similar to those of previous single-fraction SRS studies.7, 12 Compared with WBRT plus SRS as used in the RTOG 9508 trial (which reported local control rates of 82% and 71%, respectively, at 3 months and 1 year),3 the local tumor control rates produced by HSRT in the current series were comparable.

With regard to overall survival, concurrent chemotherapy (P < .001) and the number of treated lesions (P = .036) were found to be statistically significant factors that affected overall survival. Concurrent chemotherapy and having a large number of treated lesions were found to be negatively correlated with overall survival. This was considered to be because patients treated with concurrent chemotherapy have more extensive or bulkier extracranial disease and patients with more metastatic lesions have a more advanced stage of disease. Both cases were found to be worse outcomes.

Previous investigators have demonstrated that maximum tumor dimension (in mm) and volume (in cc) are prognostic factors for local tumor control and toxicity.13 We found similar results in the current study and there was a significant difference in the local tumor control rates among the treatment groups when segregated by maximum tumor dimension (≤20 mm vs >20 mm and ≤30 mm vs >30 mm; P = .033). Tumors measuring ≤20 mm were found to have better actuarial local control rates at 1 year than tumors measuring >20 mm (81.5% vs 37.5%). With regard to tumor volume, patients with a tumor volume ≤1.0 cc were found to have a better tumor control rate (P = .028). Actuarial local tumor control rates for tumors with volumes ≤1.0 cc and >1.0 cc at 6 months were 100% and 87.5%, respectively. Furthermore, local control rates for tumors with volumes of ≤1.0 cc and >1.0 cc at 1 year were 100% and 46.7%, respectively. This finding also may be closely supported by the discovery that even the treatment group with tumor volumes ≤2.0 cc had a better chance of achieving local tumor control than those with tumor volumes >2.0 cc (P = .068). Similarly, Varlotto et al reported that a larger tumor size significantly decreased the rate of local tumor control in patients treated with SRS (P = .0029).14 In their study, tumors with volumes ≤2 cc and tumors with volumes >2 cc had actuarial local control rates of 95.2% and 83.3%, respectively, at 1 year. For larger tumor volumes, the results of the current study demonstrated a trend toward even poorer tumor control. With a larger patient cohort, this likely would have been statistically significant. The current study demonstrated a difference in the local tumor control rate between tumors with volumes ≤3.0 cc (95%) and tumors with volumes >3.0 cc (75%) (P = .085). Aoyama et al reported that the actuarial local tumor control rates of tumors with volumes ≤3.0 cc and >3.0 cc at 1 year were 96% and 59%, respectively.15 We also found that a maximum tumor dimension of <30 mm was statistically significant for local tumor control rates (P = .009) but, considering the sample size of tumors with a maximum dimension of >30 mm in the current study, it was a less reliable finding.

Early in our experience, we started with a HSRT prescription of 25 Gy delivered in 5 fractions. This dose selection was chosen based on the inferior outcomes of administering 20 Gy in 4 to 5 fractions as shown by Ernst-Stecken et al and Shepherd et al.12, 16 Furthermore, previous investigators had shown the safety and efficacy of higher doses within the range of 30 Gy to 40 Gy.17 Vordermark et al demonstrated that a HSRT dose of 30 Gy resulted in longer overall survival than doses of <30 Gy while being able to be delivered safely and effectively.18 For the upper limit, Shepherd et al previously reported that a HSRT dose of 30 Gy to 35 Gy was tolerable but a dose of >40 Gy was a significant predictor of radiation damage.16 In the current study, the total HSRT dose was not found to be a statistically significant factor for local tumor control (P = .684), and there was no major difference in tumor control noted between the treatment groups who received HSRT doses of 20 Gy, 25 Gy, and ≥30 Gy. Crude local control rates were 100%, 90.3%, and 88.9%, respectively, in these 3 groups. However, we were unable to demonstrate that other dose classifications (20 Gy, 25 Gy, and ≥30 Gy) were statistically significant for local tumor control because of our limited sample size. Therefore, there is a great need for a comparison of the multiple levels of doses between 25 Gy and 35 Gy in a prospective study.

Investigators have previously examined the influence of WBRT in conjunction with SRS on tumor control.19 Lindvall et al compared WBRT with a HSRT boost with HSRT alone and reported that WBRT combined with HSRT demonstrated better local control than HSRT alone for brain metastases (100% vs 84%).8 However, we found that HSRT alone or WBRT with a HSRT boost had actuarial local tumor control rates of 100% and 92.9%, respectively, at 6 months. Thus, we were unable to demonstrate an effect on local tumor control from WBRT. In our experience, the influence of WBRT was difficult to ascertain potentially because of the disproportionate number of patients in our sample (86.5% [45 of 52 patients]) who had received prior WBRT with an HSRT boost.

Previous investigators have examined the possibly favorable radiobiologic effect of HSRT because it allows for the delivery of a higher dose with fewer adverse events than SRS.6-8 In the current study, 1 patient of 27 had a grade 3 adverse event (3.7%), a finding that was similar to previous studies.11 In the Eastern Cooperative Oncology Group 6397 SRS study, there was 1 grade 3 seizure and 2 other grade 3 adverse events (fatigue and neutropenia, respectively) reported among 31 patients.19 When we examined the influence of higher total doses on toxicity, no relation was found. None of the 4 tumor lesions that received 36 Gy in 6 fractions developed grade 3 toxicity or radiation necroses. Future studies including a larger number of patients and close follow-up will be needed to understand this issue better.

Conclusions

In the current study, we found HSRT to be comparable to single-fraction SRS in terms of local tumor control and toxicity, and thus we believe it provides an alternative treatment choice for patients with brain metastases. We also confirmed that tumor size is a strong prognostic factor for local tumor control. We found fraction dose and prior WBRT were not statistically significant factors with regard to local tumor control with our limited sample size. Therefore, we believe there is a need for a larger prospective study to establish dosing guidelines for HSRT and to pave the way for a randomized trial to compare single-fraction SRS with a hypofractionated approach.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. References
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    MacDonald DR,Cascino TL,Schold SC, et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990; 8: 1277-1280.
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    Kondziolka D,Patel A,Lunsford LD, et al. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys. 1999; 45: 427-434.
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    Ernst-Stecken A,Ganslandt O,Lambrecht U, et al. Phase II trial of hypofractionated stereotactic radiotherapy for brain metastases: results and toxicity. Radiother Oncol. 2006; 81: 18-24.
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    Schomas DA,Roeske JC,MacDonald RL, et al. Predictors of tumor control in patients treated with linac-based stereotactic radiosurgery for metastatic disease to the brain. Am J Clin Oncol. 2005; 28: 180-187.
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    Varlotto JM,Flickinger JC,Niranjan A, et al. Analysis of tumor control and toxicity in patients who have survived at least 1 year after radiosurgery for brain metastases. Int J Radiat Oncol Biol Phys. 2003; 57: 452-464.
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