|Year : 2014 | Volume
| Issue : 1 | Page : 97-102
Fractionated stereotactic radiosurgery with volumetric modulated arc therapy (Rapid Arc) for reradiation in recurrent high grade gliomas
Anil K Anand1, Pankaj Kumar1, Rana Patir2, Sandeep Vaishya2, Anil K Bansal3, Amal R Chaudhoory1, Anirudh U Punnakal1, Heigrujam Malhotra3, Ram K Munjal3
1 Department of Radiation Oncology, Max Cancer Centre, Max Hospital, Saket, India
2 Department of Neurosurgery, Max Hospital, Saket, New Delhi, India
3 Department of Medical Physics, Max Cancer Centre, Max Hospital, Saket, India
|Date of Web Publication||23-Apr-2014|
Anil K Anand
Department of Radiation Oncology, Max Cancer Centre, Max Hospital, 2, Press Enclave Road, Saket, New Delhi - 110 017
Source of Support: None, Conflict of Interest: None
Background: To evaluate 'Rapid Arc (RA)' technique for delivering fractionated stereotactic radiosurgery (FSRS) in patients with recurrent high grade gliomas (HGGs) for minimizing the dose to previously radiated high dose brain volume.
Materials and Methods: Between April 2010 and February 2011, 16 consecutive patients with recurrent HGGs and previously treated with intensity modulated radiation therapy (IMRT) and Temozolamide received FSRS. The median time between IMRT and FSRS was 10.72 months. FSRS to a dose of 30 Gy in a median of 5 fractions was delivered to the recurrent tumor (gross tumor volume [GTV]). Brain volume around the GTV and previously treated to a mean dose >50 Gy was delineated as "Avoidance Volume (AV)." Patients were planned with both RA and Dynamic Conformal Arc (DCA) to achieve minimum dose to AV. Dose received by GTV, AV, rest of the normal brain (brain minus PTV) and conformity index (CI) and heterogenecity index (HI) were compared by the two techniques.
Results: At a median follow up of 7.33 months, median progression free and overall survival was 6.4 and 9.3 months, respectively. Mean dose to AV was significantly lower with RA as compared with DCA (10.8 Gy vs. 15.5 Gy, P - 0.0001) with no significant difference in the dose delivered to GTV. No patient developed radiation necrosis.
Conclusion: As compared with DCA, RA delivered significantly less dose to previously radiated high dose brain volume. It may contribute to minimizing the risk of radionecrosis with stereotactic radiosurgery (SRS) in patients with recurrent HGG.
结果：随访7.33个月（中位数），无进展时间和总生存时间分别为6.4个月和9.3个月（中位数）。AV平均剂量：RA明显低于DCA（10.8Gy vs. 15.5Gy, P=0.001），GTV剂量无明显差异。没有病人发生放射性脑坏死。
Keywords: Fractionated stereotactic radiosurgery, recurrent high grade glioma, reradiation
|How to cite this article:|
Anand AK, Kumar P, Patir R, Vaishya S, Bansal AK, Chaudhoory AR, Punnakal AU, Malhotra H, Munjal RK. Fractionated stereotactic radiosurgery with volumetric modulated arc therapy (Rapid Arc) for reradiation in recurrent high grade gliomas. J Can Res Ther 2014;10:97-102
|How to cite this URL:|
Anand AK, Kumar P, Patir R, Vaishya S, Bansal AK, Chaudhoory AR, Punnakal AU, Malhotra H, Munjal RK. Fractionated stereotactic radiosurgery with volumetric modulated arc therapy (Rapid Arc) for reradiation in recurrent high grade gliomas. J Can Res Ther [serial online] 2014 [cited 2021 Jul 26];10:97-102. Available from: https://www.cancerjournal.net/text.asp?2014/10/1/97/131403
| > Introduction|| |
The prognosis of malignant high grade gliomas (HGGs) remains poor despite recent advancements in radiotherapy (RT) and the use of concurrent and adjuvant temozolomide after surgical resection. Nearly all patients develop tumor recurrence or progression at the site or vicinity of high-dose volume of postoperative RT. , Further treatment of recurrence is a challenge. Resurgery and second line chemotherapy have shown only limited success. , Recently, bevacizumab with or without irinotecan combination has demonstrated efficacy in delaying tumor progression.  Reirradiation with stereotactic radiosurgery (SRS) and stereotactic radiation therapy (SRT) have shown benefit with median progression-free survival (PFS) of 5-8 months in patients with recurrent HGG. ,
However, there is some concern regarding radionecrosis associated with SRS since the volume of the brain around the recurrent tumor has been previously exposed to high dose of radiation during the primary treatment and is therefore, at maximum risk of developing radiation complications including radionecrosis. Radiation necrosis rate of 8% and 11% have been reported with single dose SRS at 12 and 24 months, respectively, in patients with recurrent previously irradiated primary brain tumors and brain metastasis. , Another complication associated with SRS was the reoperation rate, reported in 10-22% patients. ,
Rapid Arc (RA) is a novel technique (Varian Medical Systems), which is based on volumetric modulated arc therapy (VMAT) as described by Otto.  It is an arc-based solution that improves sparing of organs at risk and other nontarget tissues as compared with static field intensity modulated radiation therapy (IMRT). Additionally RA maintains or improves target coverage, utilizes much less Monitor units and is associated with significant reduction in treatment time. It has shown benefit in few other clinical sites such as head and neck and prostate especially with regard to sparing of organs at risk. , Dynamic conformal arc (DCA) is another commonly used technique to deliver SRS and involves shaping of multileaf collimator (MLC) to target lesion during gantry rotation. Both the techniques were compared in this study with the aim to minimize the dose to the region of normal brain around the recurrent tumor, which has been previously exposed to high dose (>50 Gy), in order to reduce the risk of radiation necrosis.
Here, we report our experience with "RA" fractionated stereotactic radiosurgery (FSRS) in patients with recurrent HGGs and its comparison with DCA.
| > Materials and Methods|| |
From April 2010 to February 2011, 16 patients of HGG with Karnofsky Performance Scale (KPS) of more than 80 and radiographic evidence of recurrence or progression primary treatment were treated with FSRS in our department [Table 1]. Study was conducted after approval from hospital institutional review board.
At the time of initial diagnosis, all patients underwent maximal safe neurosurgical excision followed by IMRT to a median dose of 60 Gy (range 56-66 Gy) in a median of 30 fractions (range 28-31) [Table 1]. All patients had received concurrent temozolomide and 14 patients (87.5%) had also received adjuvant temozolomide for a median of 6 cycles (range 6-10).
Twelve patients were symptomatic at the time of recurrence while four patients were asymptomatic. Recurrence was detected by magnetic resonance imaging (MRI) scan (T 1 and T 2 weighted, short tau inversion recovery [STIR] images) and perfusion scan if required. Four patients underwent positron emission tomography-computed tomography PET-CT scan and three patients had gluco haptonate acid (GHA) scan for confirmation of recurrence. Three patients underwent resurgery and histopathology revealed recurrent tumor in all three patients [Table 1]. The median time to reirradiation after primary RT was 10.72 months (range 7.2-31.1 months) and maximum tumor diameter was <5 cm.
High precision SRS was performed using a linear accelerator (Novalis-Tx, Varian, Palo Alto, USA) with 6-MV photons and leaf width of 2.5 mm in 8 × 8 cm central part of the collimator. Patients were immobilized with a 'frameless' SRS fixation system (Brainlab, AG, Munich, Germany) and contrast enhanced planning CT scans were taken with 1.5 mm slice thickness, which were fused with MRI/PET scans. Gross tumor volume (GTV) was defined as contrast-enhancing lesion in T1-weighted MRI or PET lesion. Planning target volume (PTV) was defined by growing GTV isotropically by 2 mm radially and 3 mm craniocaudally. A volume called "Avoidance volume" (AV) was created around the previous tumor bed and in CT slices 2 cm cranially and caudally [Figure 1]. It was delineated as the volume conforming to a mean dose of >50 Gy from previous radiation. For this purpose, 50 Gy isodose volume was extracted from treatment planning system (TPS) plan generated at the time of previous radiation therapy. It was overlaid on the planning CT scan of the current treatment after fusing both the scans on Eclipse TPS [Figure 1]. All effort was made during radiation planning and optimization to minimize the dose to this volume to reduce the chances of radiation necrosis. Dose constraints were given to critical structures like eye, optic nerve/chiasma, and brain stem depending upon the dose received previously. Dose constraint for AV was mean dose <15 Gy.
|Figure 1: Avoidance volume (AV) and comparative dose distribution of FSRS (30 Gy/5 fractions) with Dynamic Conformal Arc (DCA) and Rapid Arc (RA). (a): T2-weighted MRI of a patient of GBM showing resection cavity (black). White line represents Avoidance Volume (AV) for reradiation with FSRS and is encompassed by 50 Gy isodose line from previous radiation with IMRT. (b): Planning CT scan of the same patient at the time of recurrence with 50 Gy Isodose line (gray) from previous radiation superimposed on planning CT Scan (AV). FSRS dose distribution with "DCA" (black-30 Gy, gray-20 Gy, white-15 Gy) with mean dose of 6.9 Gy to AV. (c): FSRS dose distribution of the same patient with "Rapid Arc". Note - considerable constriction of all the isodose curves resulting in significant dose reduction to 'AV' (mean dose 5.7 Gy, 19.2% less than DCA)|
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FSRS was prescribed at a dose of 30 Gy in 5-6 fractions with 80-95% isodose line enclosing the PTV. All the patients were planned by two modalities - namely RA and DCA and dose volume histograms were compared. RA optimization technique involved optimization of gantry rotation speed, Dose-rate and MLC leaf position.  Both MLC position and monitor units were included as optimization parameters, with a cost function based on dose volume constraints of the target and normal tissues. Two arcs with 360° gantry rotation in opposite direction and collimator angles of 45° and 315° for respective arcs were employed. Treatment planning was done on "Eclipse" planning system (Varian, version 10.0, Palo Alto, USA). DCA technique involved shaping of MLC to target lesion during gantry rotation. DCA plans were generated on "iPlan Brainlab system" (Version 4.1, Brainlab, AG, Munich, Germany) using five Non co-planner arcs and MLC margin of 3 mm.
For GTV, D95% and D2% (dose received by 95% and 2% of the GTV) and V95% and V110% (volume receiving at least 95% or 110% of prescription dose, respectively) were defined for target coverage, maximum and minimum dose. For AV, parameters included D2% (maximum dose), Dmean (mean dose) and D95% (minimum dose). For normal brain (brain minus PTV) V10%, V30%, and V40% (volumes receiving 10%, 20%, or 40% of the prescription dose) were calculated. The conformity index (CI) was calculated as the ratio of the volume receiving at least 95% of the prescribed dose and the GTV volume. Homogeneity index (HI) of GTV was calculated as the difference of dose received by 5% and 95% of the GTV volume (D5%-D95%).
All patients were treated with RA technique and setup verification was done with 'Exactrac System' (Brainlab, AG, Munich, Germany) before each fraction of FSRS. Setup on first day was verified by cone beam CT also. Eleven (68.7%) patients received temozolomide starting 4 weeks after the completion of FSRS. First follow-up visit was after 2 weeks and thereafter every 2 months with contrast enhanced MRI scan. Additional scans including MR spectroscopy, PET-CT, and GHA scans were done as required to distinguish between tumor progression and radiation necrosis. Toxicity was graded as per Radiation therapy oncology group central nervous system (RTOGCNS) toxicity criteria [Table 2]. 
Overall survival (OS) duration was calculated from the date of primary diagnosis to date of death or last contact. PFS was calculated from time of FSRS until further tumor progression or death, whichever occurred earlier. Statistical analysis was done using the Statistical Package for Social Sciences (SPSS), version 12.0. Survival was calculated using the Kaplan-Meier method and prognostic factors were determined by log rank test. Statistical significance of difference in mean values was computed using paired 't' test. A P value of <0.05 was considered to indicate statistical significance.
| > Results|| |
At the time of analysis, overall median follow-up was 20.98 months (range 11.67-47.6 months) and median follow up after FSRS was 7.33 months (range 3.8-12.77 months). Eight patients were alive and coming for follow-up.
At 2 months after FSRS, radiological response or stable disease on MRI was observed in 12 (75%) patients and 4 (25%) patients showed tumor progression. The median time to progression after FSRS was 4.37 months (range 1.3-8.13 months). The median, 6-months and 1-year PFS after FSRS was 6.4 months, 53.47% and 26.74%, respectively. The median, 6-months, and 1-year OS after FSRS, was 9.3 months, 73.43%, and 41.3%, respectively [Figure 2].
The median GTV volume was 28.4 cc (range 4.5-67.2 cc) and median GTV equivalent diameter was 3.8 cm (range 2.0-5.0 cm). Typical dose distribution with RA and DCA for one of the patient is shown in [Figure 1]. Median delivered dose (D95) to GTV was 30 Gy with both RA and DCA with a range of 29.9-30.6 and 29.5-30.1 Gy, respectively in a median of 5 fractions (range 5-6). There was no significant difference in most of the parameters of the dose delivered to GTV by either RA and DCA. However, there was significantly higher dose (D2%, D5%, and V110) to a small volume within the GTV with DCA [Table 3]. The median CI of GTV was 1.25 (range 1-2.05) for RA and 2.1 (range 1.4-3.5) for DCA. Median HI of GTV was 1.8 (range 0.9-3.2) and 3.65 (range 2.0-5.8) for RA and DCA, respectively.
|Figure 2: Kaplan-Meier estimates of progression free survival (a) and overall survival (b) with FSRS in recurrent high grade gliomas.|
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|Table 3: Dosimetric parameters of rapid arc Vs. Dynamic conformal arc for FSRS in recurrent HGG|
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Median "AV" was 94.65 cc (range 35.3-209.1 cc). The mean dose received by "AV" was significantly lower with RA as compared with DCA (10.8 Gy vs. 15.5 Gy, 'P' - 0.0001) [Table 3]. Similarly, high dose volume (D2%) within AV received significantly lower dose with RA as compared with DCA. There was considerable constriction of isodose curves around the GTV with RA as compared with DCA, accounting for significant reduction in mean dose to AV [Figure 1]. Dose delivered to GTV and high risk "AV" with RA and DCA in each patient is shown in [Figure 3]. Dose to GTV, AV, and normal brain (Brain-PTV) is depicted in [Table 3]. Dose to normal brain was not significantly different in the two techniques except V40%, which was lower with RA as compared with DCA.
|Figure 3: Dose delivered to GTV and high risk "Avoidance Volume" (AV) with FSRS (30 Gy/5 fractions) in each patient. (a): Dose delivered to 95% volume of GTV (D95%) with DCA and RA in different patients. (b): Mean dose delivered to high risk "AV" with DCA and RA in the same patients. Mean dose to 'AV' was significantly less ( P−0.0001) with RA as compared with DCA in all the patients.|
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FSRS regimen was well tolerated and the treatment was completed in all the patients. RTOG CNS toxicity of grade 1, 2, 3, 4, and 5 was seen in 1 (6.2%), 2 (12.5%), 1 (6.2%), 0%, and 0% patients, respectively. Two patients were admitted within 2-5 weeks after FSRS with somnolence and neurological deterioration. One patient had altered sensorium with deteriorating biochemical liver functions due to worsening hepatitis 'B'. He succumbed to hepatic encephalopathy 3 weeks later. Second patient had signs of radiological evidence of tumor progression.
The impact of various patient and treatment-related factors were analyzed. On both univariate and multivariate analysis, patients who did not show response to FSRS had significantly poor survival as compared with patients who responded to FSRS and had stable disease (P = 0.01). Volume of GTV (<30 cc vs. >30 cc) did not have any impact on PFS (P = 0.95) and OS (P = 0.72). There was no impact of histology (AA vs. GBM), age (≤50 vs. >50), gender, and resurgery.
| > Discussion|| |
Despite considerable advancements in the treatment of HGGs, most of the patients relapse after a median time of 9-12 months and the site of recurrence is predominantly in or around the tumor bed. , Options of treatment for recurrence include resurgery, chemotherapy, bevacizumab, reirradiation with conventional fractionation, and SRS.
The most valid end point comparing various modalities of treatment for recurrent HGG has been reported to be 6 months PFS (PFS - 6) and has been used in various phase II studies.  Resurgery alone has not shown any significant improvement in PFS and OS and is only indicated if there is significant pressure effect or for confirmation of recurrent tumor.  Recently, bevacizumab has been approved for recurrent HGG and has yielded PFS - 6 of 40-50% and median OS of 7-9 months either alone or in combination with irinotecan. , Altered regimen of temozolomide and other chemotherapeutic agents have shown PFS - 6 of 21-35%. ,
Various radiation techniques like SRS, FSRS, and fractionated stereotactic radiotherapy (FSRT) have been employed for patients with recurrent HGG. SRS provides considerable benefit due to increased conformality of radiation dose, which can spare previously irradiated brain tissue thus limiting the toxicity. SRS with a dose of 10-20 Gy has been reported to yield PFS - 6 of 33% and median PFS of 5-8 months. , PFS - 6 of FSRS in our study was 53.47%, which compares favorably with the options of bevacizumab and other chemotherapeutic agents in patients with recurrent HGG.
There are, however, some concerns about neurologic deterioration and radiation necrosis following reirradiation with SRS. Radiation necrosis rates of up to 8-11% have been reported with SRS and FSRT in patients of HGG treated at recurrence. , Another neurological complication reported with SRS is hypersomnolence syndrome. Clinical surrogate end point of presumed radiation damage was defined as neurologic deterioration without evidence of progressive tumor, which improved and was maintained for at least 2 months on corticosteroids and was reported in 36% of their patients.  In few studies, reoperation rates of 10-22% have been reported after SRS due to worsening neurological status. ,
Various factors contributing to higher incidence of complications have been studied. FSRS dose of more than 40 Gy and larger tumor volume (more than 2 cm in diameter in RTOG 90-05 study) or more than 35 cc were associated with a trend toward higher risk of complications. , Combs et al. modified the technique and patients with tumor volume of 50 cc. or less were treated with SRS and FSRS and those with tumor volume of more than 50 cc received FSRT. 
In our study, only patients with tumor size of <5 cm were included. Few other precautions were taken to minimize the risk of radiation necrosis. Instead of single fraction SRS, we used a regime of fractionated SRS, over 5-6 fractions, which can contribute to lower incidence of radiation-induced complications due to radiobiological advantage of fractionation.  Region of the normal brain around the recurrent tumor, which had received high dose from previous radiation therapy ("AV"), was delineated in all the patients in this study as already described. VMAT has shown to further improve normal tissue sparing over IMRT in HGG and other clinical sites like head and neck and prostate. ,, 'RA' technique, which utilizes the concept of VMAT, was employed in these patients to minimize the dose to "AV" since this area was thought to have the highest risk of developing radiation necrosis. RA technique delivered significantly lower dose to AV as compared with DCA technique (P - 0.0001), which can contribute to minimizing the risk of radiation necrosis.
In our study, 3 out of 16 patients showed clinical and neurological deterioration 2-5 weeks after FSRS. They seemed to have developed presumed radiation damage and they improved with either initiation or escalated dose of dexamethasone (RTOG CNS toxicity of Grade 2 and 3). However, no patient developed radiation necrosis or required reoperation for worsening neurological status in our study.
| > Conclusion|| |
As compared with DCA, RA achieved significantly less dose to the high risk brain volume, which had received high dose from previous radiation therapy. It can help in reducing the CNS radiation toxicity including radiation necrosis and can make SRS a safer treatment option in recurrent HGG. However, further study with more number of patients is warranted to confirm these observations.
| > Acknowledgments|| |
The authors wish to acknowledge Ms. Meenakshi for secretarial assistance in compiling the manuscript.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]