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  Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 3  |  Page : 202-206
 

Evaluatıon of hypofractıonated stereotactıc radıotherapy (HFSRT) to the resectıon cavıty after surgıcal resectıon of braın metastases: A sıngle center experıence


Department of Radiation Oncology, University of Health Sciences, Gulhane Medical Faculty, Ankara, Turkey

Date of Web Publication19-Jul-2019

Correspondence Address:
Ferrat Dincoglan
Department of Radiation Oncology, University of Health Sciences, Gulhane Medical Faculty, Ankara
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_345_18

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 » Abstract 


INTRODUCTON: Adjuvant radiotherapy after surgical resection is used for the treatment of patients with brain metastasis. In this study, we assessed the use of adjuvant hypofractionated stereotactic radiotherapy (HFSRT) to the resection cavity for the management of patients with brain metastasis.
MATERIALS AND METHODS: A total of 28 patients undergoing surgical resection for their brain metastasis were treated using HFSRT to the resection cavity. A total HFSRT dose of 25–30 Gray (Gy) was delivered in 5 consecutive daily fractions. Patients were retrospectively assessed for toxicity, local control, and survival outcomes. Kaplan-Meier method and log-rank test were used for statistical analysis.
RESULTS: Median planning target volume (PTV) was 27.2 cc (range: 6–76.1 cc). At a median follow-up time of 11 months (range: 2–21 months.), 1-year local control rate was 85.7%, and 1-year distant failure rate was 57.1% (16 patients). Median overall survival was 15 months from HFSRT. Higher recursive partitioning analysis class (P = 0.01) and the presence of extracranial metastases (P = 0.02) were associated with decreased overall survival on statistical analysis. There was no radiation necrosis observed during follow-up.
CONCLUSION: HFSRT to the resection cavity offers a safe and effective adjuvant treatment for patients undergoing surgical resection of brain metastasis. With comparable local control rates, HFSRT may serve as a viable alternative to whole brain irradiation.


Keywords: Brain metastasis, hypofractionated stereotactic radiotherapy (HFSRT), whole brain irradiation (WBI)


How to cite this article:
Dincoglan F, Sager O, Uysal B, Demiral S, Gamsiz H, Gündem E, Elcim Y, Dirican B, Beyzadeoglu M. Evaluatıon of hypofractıonated stereotactıc radıotherapy (HFSRT) to the resectıon cavıty after surgıcal resectıon of braın metastases: A sıngle center experıence. Indian J Cancer 2019;56:202-6

How to cite this URL:
Dincoglan F, Sager O, Uysal B, Demiral S, Gamsiz H, Gündem E, Elcim Y, Dirican B, Beyzadeoglu M. Evaluatıon of hypofractıonated stereotactıc radıotherapy (HFSRT) to the resectıon cavıty after surgıcal resectıon of braın metastases: A sıngle center experıence. Indian J Cancer [serial online] 2019 [cited 2019 Aug 20];56:202-6. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/202/263031





 » Introduction Top


Resection of brain metastases followed by postoperative whole brain irradiation (WBI) has been a standard treatment in the management of brain metastases for years.[1],[2],[3] While WBI after surgical resection of brain metastasis decreases the recurrence risk and neurological death rates, there is increasing concern about the adverse effects of WBI including considerable cognitive decline.[4],[5],[6],[7] The deleterious effect of WBI itself on neurocognitive functionality is usually hard to assess because of wide diversity and heterogeneity of patient populations and study designs; nevertheless, it is considered that WBI may lead to profound impairment of neurocognitive functions such as verbal memory, executive functioning, and processing speed particularly in patients with a longer life span.[4] These important concerns about neurocognitive functional impairment have caused a shift in decision-making for radiotherapeutic management of patients with brain metastasis after surgical resection, and currently, there is an increasing trend toward favoring stereotactic radiosurgery (SRS) focused on the resection cavity after surgery while deferring WBI to be reserved for the salvage setting.[8]

Given that studies focusing on the role of WBI for patients receiving surgery or SRS for brain metastases have reported no significant benefit of WBI on survival, there has been a shift toward reserving WBI for the salvage setting because of concerns about WBI-induced neurocognitive function impairment.[1],[3],[5],[6] In this regard, several studies have assessed the utilization of single-fraction SRS to the resection cavity after surgical removal of brain metastasis.[8],[9],[10] However, delivery of single-fraction high-dose SRS directed at large resection cavities have raised concerns about radiation-induced toxicity.[11] In addition, it has been shown that single-fraction SRS to the resection cavity of brain metastasis with larger than 3 cm size in the preoperative period resulted in a shorter time to recurrence with the consequent need for salvage WBI at a shorter time interval.[12] Given these unfavorable aspects of single-fraction SRS, studies have recently focused on hypofractionated stereotactic radiotherapy (HFSRT) with an attempt to improve the toxicity profile of radiation delivery particularly in the setting of larger metastatic lesions and larger resection cavities.[12],[13],[14],[15] The use of HFSRT for the management of resected large brain metastases was found to be associated with a lower risk of radiation necrosis.[16]

In this study, we assessed the use of adjuvant HFSRT to the resection cavity for the management of patients with brain metastasis and report our single center experience.


 » Methods and Materials Top


Between June 2013 and January 2017, 28 patients undergoing surgical resection for their brain metastasis were delivered HFSRT in the postoperative period to 28 resection cavities. These patients were retrospectively assessed for toxicity and local control outcomes. All patients were ≥18-year-old. They had Karnofsky performance status (KPS) of ≥60, and metastatic brain lesions, which were removed surgically with gross total resection. Written informed consent was provided for every patient before radiation treatment at our institution. HFSRT was delivered to the resection cavity using a total dose of 25–30 Gray (Gy) in 5 consecutive daily fractions.

Thermoplastic mask (Novastereo; Novater, Milano, Italy) and a mouthpiece (Civco, USA) fixed to a stereotactic head frame were used in treatment simulation for all patients to assure robust immobilization. Computed tomography (CT) simulation was performed at the dedicated CT-simulator (GE Lightspeed RT; GE Health-care, Chalfont St. Giles, UK) using a slice thickness of 1.25 mm. Delineation process at the contouring workstation (SimMD; GE, UK) included localization of organs-at-risk (OAR) along with the clinical target volume (CTV) and planning target volume (PTV) using fused CT and gadolinium-enhanced postcontrast T1-weighted magnetic resonance (MR) images with 1 mm slice thickness. The CTV was generated by the delineation of the resection cavity and expanded uniformly by 2 mm margin to generate the PTV. After contouring was accomplished, structure sets including the OARs, CTV, and PTV were sent to the radiosurgery treatment planning workstation (ERGO++ planning system, Elekta) using the network. Treatment planning was performed using the volumetric modulated arc treatment technique using arc modulation optimization algorithm for computation of arc weighting. 6-MV photons and 3 or 5-mm dynamic multileaf collimators were used with dose prescription to 85%–95% isodose line encompassing the PTV. Reference planning CT images were matched with the kilovoltage cone-beam computed tomography (kV-CBCT) images using bony anatomy registration by use of the X-ray volumetric imaging system (version 4.0) for verification of set-up. Statistical Package for the Social Sciences (SPSS) version 21.0 software version (SPSS, Inc.) was used for statistical analysis of data with the P value set at <0.05 for statistical significance. The Kaplan-Meier method was used in calculation of overall survival, local recurrence, and distant failure. The log-rank test was used in assessment of differences between survival curves. Overall survival was calculated from the date of HFSRT until last follow-up visit or death. Local recurrence was defined as the occurrence of a new lesion in the resection cavity or in close vicinity detected on T1-weighted postcontrast images. Distant failure was defined as leptomeningeal involvement or the occurrence of a new lesion outside the irradiation field. HFSRT was delivered after 3 to 4 weeks from surgical resection of brain metastasis using a total dose of 25–30 Gray (Gy) delivered in 5 consecutive daily fractions.

Follow-up visits including thorough neurological examination and imaging with detailed brain MRI were scheduled for every patient firstly 1 month after HFSRT and then periodically at 2-month intervals afterward. Additional assessments were performed when considered by the treating physician. The patients were instructed to inform their physician in case of any unexpected neurological worsening irrespective of the follow-up schedule.


 » Results Top


Patient and treatment characteristics are shown in [Table 1]. All patients underwent gross total resection of their brain metastasis 3 to 4 weeks before HFSRT. Out of the total 28 patients with 28 resection cavities, 17 patients (61%) were male and 11 patients (39%) were female. The median age was 55.5 years (range: 27–77). Primary cancer diagnosis was non-small cell lung cancer in 12 patients (43%), breast cancer in 10 patients (36%), soft tissue sarcoma in 2 patients (7%), malignant melanoma in 2 patients (7%), renal cell cancer in 1 patient (3.5%), and colorectal cancer in 1 patient (3.5%). Brain metastases were located supratentorially in 16 patients (57%) and infratentorially in 12 patients (43%). Ten patients (36%) had no brain metastasis at the time of HFSRT. Eleven patients (39%) had 1 synchronous metastasis, 5 patients (18%) had 2 synchronous metastases, and 2 patients (7%) had 3 synchronous metastases at the time of HFSRT. All of these synchronous metastatic lesions were treated with single-dose SRS. As per the recursive partitioning analysis (RPA) stratification, 13 patients (46.5%) were RPA class 1, 13 patients (46.5%) were RPA class 2, and 2 patients (7%) were RPA class 3. Median KPS was 80 (range: 60–100). All patients received a total HFSRT dose of 25–30 Gy delivered in 5 consecutive daily fractions of 5–6 Gy. Cavity delineation was according to fused CT and MR images. The median PTV was 27.2 cc (range: 6–76.1 cc). Out of the total 28 patients, 5 patients (18%) had a resection cavity of ≤3 cm, whereas remaining 23 patients (82%) all had resection cavities of >3 cm. The median follow-up time was 11 months (range: 2–21 months.) The median overall survival was 15 months (range: 2–21 months) from HFSRT [Figure 1]. Parameters of age, gender, primary cancer, site of resection cavity, RPA class, KPS, PTV volume, status of extracranial metastases, number of synchronous intracranial metastases, and total HFSRT dose were assessed for association with overall survival, local control, and distant failure. While no parameters were associated with local control, statistical analysis revealed that higher RPA class (P = 0.01) and the presence of extracranial metastases (P = 0.02) were associated with decreased overall survival [Figure 2]. Overall, 7 patients (25%) had cavity recurrence after HFSRT. Median time interval between HFSRT and cavity recurrence was 4.2 months. Out of the 7 patients with cavity recurrence after HFSRT, 2 patients underwent reoperation, whereas 2 patients received HFSRT and 3 patients received WBI. One-year local control rate was 85.7% according to detailed imaging assessment of resection cavities. One-year distant failure rate was 57.1% (16 patients). The presence of extracranial metastasis (P = 0.03) and synchronous metastases at the time of resection (P = 0.04) was associated with distant failure on statistical analysis. Out of the 16 patients with distant failure, salvage treatment was SRS for 6 patients, WBI for 8 patients, and surgery followed by WBI in 2 patients. At the time of analysis, 13 patients (46%) out of the total 28 patients received salvage WBI. There were no patients suffering from radiation necrosis during the follow-up period. Symptomatic edema developed in 4 patients (14%), which resolved after steroid treatment. [Figure 3] shows axial (A), sagittal (B), coronal (C) MR images, and HFSRT planning images (D) of a patient with resected brain metastasis.
Table 1: Patient Characteristics

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Figure 1: Kaplan–Meier curve of survival by RPA Class. RPA = recursive partitioning analysis

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Figure 2: Kaplan–Meier curve of overall survival

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Figure 3: Axial (a), sagittal (b), coronal (c) MR images, and HFSRT planning images (d) of a patient with resected brain metastasis

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 » Discussion Top


Since its introduction by the Swedish neurosurgeon Lars Leksell in 1951, the utility of SRS has grown rapidly to address a variety of benign and malign conditions including brain metastases, arteriovenous and cavernous malformations, vestibular schwannomas, meningiomas, recurrent glioblastomas, craniopharyngiomas, aglomus jugulare tumors, obsessive-compulsive disorders, epilepsy, and Parkinson's disease.[17]

Resection of brain metastasis for patients with good performance status and a single metastatic lesion has been found to be associated with improvement in overall survival.[18],[19] In addition to ameliorating symptoms resulting from the mass effect, surgical resection also aids in establishing the diagnosis with histopathological confirmation in cases of unknown primary tumors metastasizing to the brain. WBI has traditionally been the standard treatment after surgical resection of brain metastasis by providing reduced neurological death rates along with decreased intracranial local and distant recurrences.[1] However, studies have shown no significant survival benefit of WBI, and concerns have risen regarding the detrimental effects of WBI on neurocognitive functions.[4],[5],[6],[7] Within this context, there has been an increasing trend toward the utilization of postoperative SRS and HFSRT directed at the resection cavity particularly for patients with good performance status (≥70) and limited number of brain metastases.

Recent studies reported 1-year local control rates in the range of 72% to 91% with single-fraction SRS to the resection cavity.[9],[10],[20],[21],[22],[23] Although these local control rates may be acceptable, HFSRT has been considered as a viable and favorable alternative to SRS because it may offer the radiobiological advantages of fractionation and improve the toxicity profile of radiation delivery particularly in the setting of large resection cavities. A study by Eaton et al.[16] focusing on the comparison of single-fraction SRS and HFSRT for the treatment of resection cavities larger than 3 cm demonstrated that 6-month and 12-month cumulative rate of local failure was 18.9% (0.07–0.34) versus 15.9% (0.06–0.29) and 25.6% (0.12–0.42) versus 27.2% (0.14–0.42), P = 0.80 with HFSRT and single-fraction SRS, respectively. As for radiation necrosis, cumulative radiation necrosis incidence (95% CI) was 3.3% (0.00–0.15) versus 10.7% (0.03–0.23) and 10.3% (0.02–0.25) versus 19.2% (0.08–0.34), P = 0.28 at 6 and 12 months for HFSRT and single-fraction SRS, respectively.[16] Multivariate analysis of this study revealed that single-fraction SRS was associated with a higher risk of radiation necrosis (HR: 3.81, 95% CI 1.04–13.93, P = 0.043). The authors concluded that HFSRT could be more favorable for radiosurgical management of cavities ≥3–4 cm.[16]

Fokas et al.[24] reported similar local progression-free survival duration for HFSRT and SRS, but an unfavorable toxicity profile for SRS in spite treated resection cavities were larger for HFSRT. Minniti et al.[15] reported local control rates of 93% and 84% at 1 and 2 years, respectively for 101 patients with brain metastases receiving HFSRT (9 Gy × 3 fractions) to large resection cavities. However, 9% of the patients experienced radiation necrosis in the study. We have not observed radiation necrosis in our study, which may be partly explained by the delivery of a lower total dose and dose per fraction. Nevertheless, 4 patients (14%) in our study suffered from symptomatic edema, which was manageable with steroid treatment.

In a recent study by Ahmed et al.[13] HFSRT at a total dose of 20–30 Gy delivered in 5 fractions was used for the treatment of 65 resection cavities. Local control at 1 year was 88% for radiosensitive brain metastases and 85.6% for radioresistant brain metastases. Multivariate analysis of this study revealed that resection cavity volume of ≥17 cm 3 was a predictor of local failure.

Lima et al.[25] evaluated 41 patients with brain metastasis receiving HFSRT after surgical resection. The patients received HFSRT in 5 fractions with a dose per fraction of 5–6 Gy or in 10 fractions with a dose per fraction of 3 Gy. Local control was 89.4% at 1 year and 77.1% at 2 years, with no significant difference between the two dose-fractionation schemes in terms of local control and distant progression.

In the study by Specht et al.[26] 46 patients with large (>3 cm) resection cavities after surgical resection of their brain metastases received HFSRT at a total dose of 35 Gy delivered in 5 fractions, and 1-year local control rate was 88%.

One-year local control rate was 85.7% and 1-year distant failure was 57.1% in our study, which is consistent with the literature. There was no radiation necrosis observed during the follow-up period in our study in spite majority of the patients (82%) had resection cavities of >3 cm, which has potential implications for the safety of HFSRT with lower complication rates along with comparable local control rates.

Limitations of our study include its retrospective design and limited sample size. Clearly, randomized prospective studies are warranted to assess the role of HFSRT to the resection cavity after surgery of brain metastases and its comparison with single-fraction SRS.

In conclusion, HFSRT to the resection cavity offers a safe and effective adjuvant treatment for patients undergoing surgical resection of brain metastasis. With comparable local control rates, HFSRT may serve as a viable alternative to WBI despite the need for further studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study. J Clin Oncol 2010;29:134-41.  Back to cited text no. 3
    
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Iorio-Morin C, Masson-Cote L, Ezahr Y, Blanchard J, Ebacher A, Mathieu D. Early gamma knife stereotactic radiosurgery to the tumor bed of resected brain metastasis for improved local control. J Neurosurg 2014;121(Suppl):69-74.  Back to cited text no. 9
    
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Hartford AC, Paravati AJ, Spire WJ, Li Z, Jarvis LA, Fadul CE, et al. Postoperative stereotactic radiosurgery without whole-brain radiation therapy for brain metastases: Potential role of preoperative tumor size. Int J Radiat Oncol Biol Phys 2013;85:650-5.  Back to cited text no. 12
    
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Ahmed KA, Freilich JM, Abuodeh Y, Figura N, Patel N, Sarangkasiri S, et al. Fractionated stereotactic radiotherapy to the postoperative cavity for radioresistant and radiosensitive brain metastases. J Neurooncol 2014;118:179-86.  Back to cited text no. 13
    
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Steinmann D, Maertens B, Janssen S, Werner M, Frühauf J, Nakamura M, et al. Hypofractionated stereotactic radiotherapy (hfSRT) after tumour resection of a single brain metastasis: Report of a single-centre individualized treatment approach. J Cancer Res Clin Oncol 2012;138:1523-9.  Back to cited text no. 14
    
15.
Minniti G, Esposito V, Clarke E, Scaringi C, Lanzetta G, Salvati M, et al. Multidose stereotactic radiosurgery (9 Gy x 3) of the postoperative resection cavity for treatment of large brain metastases. Int J Radiat Oncol Biol Phys 2013;86:623-9.  Back to cited text no. 15
    
16.
Eaton BR, LaRiviere MJ, Kim S, Prabhu RS, Patel K, Kandula S, et al. Hypofractionated radi-osurgery has a better safety profile than single fraction radiosurgery for large resected brain metastases. J Neurooncol 2015;123:103-11.  Back to cited text no. 16
    
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Ling DC, Vargo JA, Wegner RE, Flickinger JC, Burton SA, Engh J, et al. Postoperative stereotactic radiosurgery to the resection cavity for large brain metastases: Clinical outcomes, predictors of intracranial failure, and implications for optimal patient selection. Neurosurgery 2015;76:150-6.  Back to cited text no. 20
    
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Kelly PJ, Lin YB, Yu AY, Alexander BM, Hacker F, Marcus KJ, et al. Stereotactic irradiation of the post-operative resection cavity for brain metastasis: A frameless linear accelerator based case series and review of the technique. Int J Radiat Oncol Biol Phys 2012;82:95-101.  Back to cited text no. 21
    
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Choi CY, Chang SD, Gibbs IC, Adler JR, Harsh GR 4th, Lieberson RE, et al. Stereotactic radiosurgery of the postoperative resection cavity for brain metastases: Prospective evaluation of target margin on tumor control. Int J Radiat Oncol Biol Phys 2012;84:336-42.  Back to cited text no. 22
    
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Brennan C, Yang TJ, Hilden P, Zhang Z, Chan K, Yamada Y, et al. A phase 2 trial of stereotactic radiosurgery boost after surgical resection for brain metastases. Int J Radiat Oncol Biol Phys 2014;88:130-6.  Back to cited text no. 23
    
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Fokas E, Henzel M, Surber G, Kleinert G, Hamm K, Engenhart-Cabillic R. Stereotactic radiosurgery and fractionated stereotactic radiotherapy: Comparison of efficacy and toxicity in 260 patients with brain metastases. J Neurooncol 2012;109:91-8.  Back to cited text no. 24
    
25.
Lima LC, Sharim J, Levin-Epstein R, Tenn S, Teles AR, Kaprealian T, et al. Hypofractionated stereotactic radiosurgery and radiotherapy to large resection cavity of metastatic brain tumors. World Neurosurg 2017;97:571-9.  Back to cited text no. 25
    
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Specht HM, Kessel KA, Oechsner M, Meyer B, Zimmer C, Combs SE. HFSRT of the resection cavity in patients with brain metastases. Strahlenther Onkol 2016;192:368-76.  Back to cited text no. 26
    


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