Journal of Cancer Research and Therapeutics

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 12  |  Issue : 4  |  Page : 1243--1248

Salvage stereotactic radiosurgery for recurrent glioblastoma multiforme with prior radiation therapy


Douglas E Holt1, Mark E Bernard1, Kimmen Quan1, David A Clump1, Johnathan A Engh2, Steven A Burton1, Dwight E Heron1,  
1 Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
2 Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Correspondence Address:
Dwight E Heron
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 5230 Centre Avenue, Pittsburgh, PA 15232
USA

Abstract

Background: Glioblastoma multiforme (GBM) carries a poor prognosis with high recurrence rates. Salvage stereotactic radiosurgery (SRS) may be an effective treatment option. Methods: We retrospectively reviewed 34 patients (41 lesions) treated with salvage SRS for recurrent GBM between 2004 and 2012. Initial surgical treatments were gross total resection (58%), subtotal resection (STR) (24%), and biopsy (18%). All patients were treated with prior radiation therapy. Recurrent disease was treated with salvage SRS with a median dose and fractions of 23.4 Gy (range, 12–30) and 3 (range, 1–3), respectively. Cox proportional hazards regression was conducted to establish predictive factors (P ≤ 0.05) Results: Median follow-up from salvage SRS was 10.8 months (interquartile range [IQR], 7.0–15.6). The median time from initial radiation therapy to salvage SRS was 13.7 months (IQR, 2.9–25.0). The 6- and 12-month overall survival from salvage SRS were 84.9% and 42.5%, respectively. On univariate analysis, STR was associated with inferior survival from salvage SRS (P ≤ 0.05). The 6- and 12-month local control (LC) estimates were 63.1% and 16.4%, respectively. On univariate analysis, higher biological effective dose and prior temozolomide were associated with superior LC. Concerning toxicity, there were 4 (12%) grade 2 and 1 (3%) grade 3 adverse events within this patient series. No grade 4 or grade 5 toxicities were observed. Conclusion: Our outcomes suggest that SRS is a feasible treatment option with acceptable salvage survival rates, given the poor prognosis of this disease.



How to cite this article:
Holt DE, Bernard ME, Quan K, Clump DA, Engh JA, Burton SA, Heron DE. Salvage stereotactic radiosurgery for recurrent glioblastoma multiforme with prior radiation therapy.J Can Res Ther 2016;12:1243-1248


How to cite this URL:
Holt DE, Bernard ME, Quan K, Clump DA, Engh JA, Burton SA, Heron DE. Salvage stereotactic radiosurgery for recurrent glioblastoma multiforme with prior radiation therapy. J Can Res Ther [serial online] 2016 [cited 2017 Nov 23 ];12:1243-1248
Available from: http://www.cancerjournal.net/text.asp?2016/12/4/1243/199537


Full Text

 Introduction



Glioblastoma multiforme (GBM) is an aggressive malignancy with high rates of recurrence at a median interval of 8 months despite aggressive treatment.[1],[2],[3]

Management of GBM relapse is challenging. Salvage surgical resection is limited due to the increased risk of neurological morbidity.[4] Stereotactic radiosurgery (SRS) is a feasible option with the ability to deliver a relatively high dose of radiation to a defined target with a rapid dose falloff.[5],[6],[7],[8],[9]

We therefore updated our institution's experience with salvage SRS for recurrent GBM patients previously treated with surgical resection followed by adjuvant external beam radiotherapy (EBRT) with or without temozolomide.

 Methods



Following Institutional Review Board approval (PRO 13020306), a retrospective review was performed on patients treated with SRS for recurrent GBM with prior EBRT between February 2004 to November 2012 at the University of Pittsburgh Cancer Institute with a total of 34 patients (41 lesions) being updated from our previous report.[10] Patients received salvage therapy on CyberKnife ® Robotic Radiosurgery System, Trilogy™ Intensity-Modulated Radiosurgery, or TrueBeam STS™ platforms. Demographic data collected included diagnosis, histology, genetic profiling of resection tissue, surgery type, lesion location, prior and salvage prescription dose, and planning treatment volume (PTV). Further, baseline and subsequent neurological symptoms along with radiographic evidence of change in tumor size were also obtained. Biological effective dose (BED) was calculated with α/β ratio of 7.

Local failure was determined based on serial magnetic resonance imaging (MRI) with increased contrast enhancement and radiographic progression utilizing the Response Evaluation Criteria in Solid Tumors Versions 1.1 (RECIST v1.1).[11] However, to confirm tumor recurrence against treatment effect, the use of serial MRIs was utilized and compared. For example, if an increase in lesion size was followed by a decrease afterward without intervention, the lesion was coded as not having local failure. Magnetic resonance spectroscopy was not readily available and was therefore not used in delineating tumor progression. Treatment-related toxicities were scored using Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). For concerns of under-reporting low-grade toxicities, only grade 2 or greater toxicities were recorded. Any associated increase in neurological symptoms or new symptoms after re-irradiation without radiographic disease progression on MRI was also considered radiation-related.

Overall survival (OS) from diagnosis and time of salvage SRS and local control (LC) from salvage SRS were estimated using the Kaplan–Meier estimation to either the date of failure or the last follow-up/death. OS from diagnosis and salvage SRS was estimated for all 34 patients, whereas LC from salvage SRS was estimated for all 41 lesions. For univariate analysis, predictive factors for OS from initial diagnosis and salvage SRS were analyzed with Cox proportional hazards (PH) regression whereas LC from salvage SRS was analyzed with Cox PH regression with frailty model due to correlated data. Significant variables (P ≤ 0.05) from univariate analysis were selected for multivariate analysis using a forward stepwise selection with a P ≤ 0.05. Statistical significance was set with a two-sided P ≤ 0.05. All analyses were performed in Stata version 13.1 (StataCorp., 2013. Stata Statistical Software: Release 13.1 College Station, TX, USA: StataCorp LP).

 Results



Patient characteristics and initial treatment

A detailed list of patient characteristics can be found in [Table 1] and [Table 2]. All patients had histologically confirmed GBM. The median age at salvage SRS was 60 years (range, 30–79), with 59% of the patients being male. Among those with known genomic data, 18% displayed methylguanine methyltransferase, 59% amplified epidermal growth factor receptor, and 18% mutated p53. For patients with known surgical status, 58% underwent gross total resection, 24% subtotal resection (STR), and 18% biopsy only. Chemotherapy data were limited to 18 patients with 88% treated with prior temozolomide before disease recurrence. The median adjuvant radiation therapy dose delivered was 60.0 Gy (range, 54.0–60.0), with a median fraction number of 30 (range, 29–33). The median time to recurrence from initial radiation therapy was 13.7 months (interquartile range [IQR], 2.9–25.0). The pattern of recurrence was solitary in 85% of the patients with the remaining displaying multifocal disease (15%). The most common locations of recurrence were frontal (39%), temporal (38%), and parietal (21%). The median follow-up from salvage SRS was 10.8 months (IQR, 7.0–15.6).{Table 1}{Table 2}

Salvage stereotactic radiosurgery treatment characteristics

The salvage SRS treatment characteristics can be found in [Table 3]. Briefly, the median PTV was 9.2 cm 3 (range, 1.0–100.0). The median dose was 23.4 Gy (range, 12–30), with the median prescription fraction of 3 (range, 1–3). The most common fractionation schedules utilized were 27 Gy in three fractions, 21 Gy in one fraction, and 24 Gy in three fractions. The median prescription isodose line was 80.0% (range, 80.0–97.0%). Of the 41 treated lesions, the platforms utilized were CyberKnife (95%), Trilogy (2%), and Truebeam (2%).{Table 3}

Overall survival

At the time of analysis, only 2 of the 34 patients (6%) were still alive. The median time to death from initial diagnosis was 23.9 months (95% confidence interval [CI], 21.1–31.4) [Figure 1]. The 12- and 24-month OS from diagnosis were 91.2% (95% CI, 75.1–97.1%) and 50.0% (95% CI, 32.4–65.3%), respectively. Statistical analysis is detailed in [Table 4]. On univariate analysis, only STR was associated with inferior survival (P = 0.050, hazard ratio [HR] 2.35 [95% CI, 1.00–5.54]). The use of temozolomide therapy was not statistically significant (P = 0.054) although it trended toward superior survival. In regards to OS from salvage SRS, the median survival was 10.9 months (95% CI, 8.3–13.2) [Figure 2]. The 6- and 12-month OS from salvage SRS were 84.9% (95% CI, 67.5–93.4%) and 42.5% (95% CI, 25.6–58.4%), respectively. On univariate analysis, STR was associated with inferior survival (P = 0.021) whereas prior treatment of temozolomide was associated with superior survival (P = 0.032). On multivariate analysis, prior temozolomide therapy was the only significant factor (P = 0.032, HR 0.31 [95% CI, 0.10–0.95]). Neither time to recurrence nor lesion size was associated with OS from salvage SRS.{Figure 1}{Table 4}{Figure 2}

Local control

At the time of analysis, 31 out of 41 (75.6%) treated lesions had locally failed. The median time to local failure was 7.1 months (95% CI, 5.3–9.0 months) [Figure 3]. The 6- and 12-month LC estimates were 63.1% (95% CI, 45.1–76.7%) and 16.4% (95% CI, 6.0–31.1%), respectively. Univariate analysis showed that both prior temozolomide therapy (P = 0.001) and higher BED (P = 0.015) were associated with superior LC [Table 5]. However, only prior temozolomide was significant in multivariate analysis (P = 0.001, HR 0.10 [95% CI, 0.03–0.35]). Genetic mutational status, time to recurrence, and PTV were not significantly associated with local failure.{Figure 3}{Table 5}

Radiation-related toxicity

There were five patients with reported symptomatic radiation-related toxicities from salvage SRS. The median time to development of symptoms for these patients for the toxicity was 3.2 months (range, 1.6–6.3). Four patients displayed grade 2 toxicities with one patient developing a grade 3 radiation-related toxicity. For the grade 2 toxicities, three patients with headache were treated with NSAIDS, steroids, or neurontin with another patient displaying persistent symptomatic radiation injury which was managed with steroids and increased anticonvulsant dose. The patient who displayed grade 3 toxicity (seizure) became symptomatic approximately 3 months after the salvage SRS was managed with steroids which resulted in a resolution of symptoms.

 Discussion



GBM remains a fatal disease despite aggressive multimodality therapy.[10] Median survival rates are poor even with favorable pathologic features.[3] Unfortunately, the vast majority of the patients will succumb to recurrence leading to neurocognitive deficits and eventual mortality. Treatment options for recurrence include surgical management, systemic therapy, and re-irradiation.

Surgical management should be considered, especially for patients who are young have a good performance, and have a long interval from treatment.[2],[4],[12],[13] Median survival rates after re-operation range from 3 to 9 months.[2],[4],[12],[13] The survival benefit of greater tumor resection seen in the initial management implies surgery may be considered an option in the recurrent setting.[14] However, operating in a previous surgical field with prior radiation therapy may increase morbidity and decrease the efficacy of re-operation.

Bevacizumab has shown promising results in the recurrent setting. In a phase II trial conducted at Duke University Medical Hospital, bevacizumab with irinotecan had objective response rates of 38% and a median salvage survival of approximately 9 months.[15] However, grade 3 or higher toxicity was high at 46% for the bevacizumab alone group and 66% for bevacizumab plus irinotecan. Although intracranial hemorrhage rates were below 5%, we reported a limited grade 3 toxicity of only 3%.

Re-irradiation is also a treatment option, albeit, not without its caveats. Conventional EBRT is limited given the concern to respect normal organ tolerance. The optic chiasm/nerves, brainstem, and normal brain may have reached near maximum tolerated doses during their previous treatment. Brachytherapy is also an option for these patients given its ability to deliver a high dose of localized radiation with rapid dose fall off. However, it requires a second surgical procedure for patients who may already have significant neurological morbidity as sequelae from their disease recurrence. Salvage SRS has the benefit of being a nonoperative procedure able to deliver a high dose of radiation therapy with greater sparing of normal tissue due its rapid dose fall off. Salvage SRS is a noninvasive procedure and able to deliver an ablative conformal dose to the target while minimizing the dose to nearby critical organs.

Our results compare well with other techniques used in the literature. We report a median salvage survival from SRS of 10.9 months. Scharfen et al. conducted a study on 307 patients with recurrent gliomas treated with salvage brachytherapy using iodine.[16] The 106 patients with recurrent GBM had a median salvage survival of 49 weeks (approximately 12.3 months). They reported a 6% severe toxicity rate, 1% life-threatening toxicity, and 1% fatal toxicity rate. However, 40% of their patient population required an additional operation for radiation necrosis. We reported a 3% grade 3 toxicity rate with no grade 4 or 5 toxicity with only one episode of grade 2 radiation necrosis. SRS may be a safer option in terms of toxicity when compared to brachytherapy.

Combs et al. reported outcomes for salvage fractionated stereotactic radiation therapy (FSRT) for 172 patients with recurrent gliomas of which 59 had GBM.[17] Median salvage survival from FSRT for GBM patients was 8 months with only one patient having histologically and radiographically confirmed radionecrosis. Our salvage survival results from SRS were comparable (10.8 vs. 8 months) with a lower median dose (23.4 vs. 36 Gy). Their rates of toxicity were also lower when compared to those of salvage brachytherapy.

Kong et al. also reported results from a prospective cohort study analyzing the efficacy of salvage SRS for recurrent malignant gliomas.[18] Out of their 114 patient cohorts, 65 patients had recurrent GBM. The median marginal dose was 16 Gy to the 50% isodose line for Gamma Knife (96% of patients) and to the 80% isodose line for the linear accelerator (14% of patients). Their median salvage survival from SRS for GBM was 13 months. Their median survival was comparable to ours; however, they reported a 24.4% radiographic radiation necrosis rate while only one of our patients had grade 2 radiation necrosis. This is a noticeable difference despite similar median treatment volumes (9.2 vs. 10.6 cm 3). This could be explained by the higher dose delivered used by Gamma Knife while we only used linear accelerators resulting a lower median dose.

While SRS is a feasible treatment option, following this with further systemic therapy is also an option. The University of Pittsburgh reported on 353 GBM patients who received adjuvant or salvage Gamma Knife SRS.[19] Eleven patients with recurrent GBM treated with Gamma Knife SRS followed by bevacizumab were identified. The median survival after SRS was 18 months and 1-year salvage survival after SRS was 73%. Grade 3 toxicity was low (9%). They also noticed a survival benefit when compared to those who had salvage SRS without bevacizumab (12 vs. 18 months). Therefore, the addition to systemic therapy to SRS may provide a further benefit.

This study is limited due to its respectospective nature and limited population size. The reported radiation-related toxicities may be underreported due to difficulty of capturing these data in the retrospective setting. Despite these limitations, our study suggests that salvage SRS in the setting of prior EBRT provides acceptable LC with low toxicity rates. Future investigation is warranted in improving outcomes of salvage SRS concurrent with newer targeted therapies.

 Conclusion



Salvage radiosurgery provides a viable treatment option for recurrent GBM with minimal toxicity. Our low toxicity rate suggests this is a feasible treatment option with acceptable salvage survival rates despite the poor prognosis GBM diagnosis carries.

Acknowledgments

Data was presented at Society Of Neuro-Oncology 20th Annual Scientific Meeting, San Antonio, TX, November of 2015.

Financial support and sponsorship

This project was supported by award number T32AG021885 (PI: Greenspan) from the National Institutes of Health and by the University of Pittsburgh Clinical Scientist Training Program and Clinical Translational Science Institute (UL1TR000005).

Conflicts of interest

There are no conflicts of interest.

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