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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 175-180

Adaptive hypofractionated radiotherapy combined with chemotherapy and anti-angiogenic therapy for residual and recurrent glioblastoma after surgery: A case report

Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Date of Submission17-Nov-2020
Date of Decision16-Dec-2020
Date of Acceptance26-Dec-2020
Date of Web Publication1-Feb-2021

Correspondence Address:
Dr. Jianping Xiao
17th of Panjiayuan Rd., Chaoyang District, Beijing
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_26_20

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Glioblastoma is the most common primary brain tumor in adults. There is no standard treatment for residual or recurrent glioblastoma and the prognosis is poor. Here, we report the case of a 72-year-old woman with a glioblastoma who underwent subtotal resection, after which her tumor recurred rapidly. Adaptive hypofractionated radiotherapy combined with temozolomide and bevacizumab was administered, resulting in a long progression-free survival. The study was approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences, China.

Keywords: Anti-angiogenic therapy, case report, chemotherapy, glioblastoma, hypofractionated radiotherapy, recurrent

How to cite this article:
Ma Y, Xiao J. Adaptive hypofractionated radiotherapy combined with chemotherapy and anti-angiogenic therapy for residual and recurrent glioblastoma after surgery: A case report. Glioma 2020;3:175-80

How to cite this URL:
Ma Y, Xiao J. Adaptive hypofractionated radiotherapy combined with chemotherapy and anti-angiogenic therapy for residual and recurrent glioblastoma after surgery: A case report. Glioma [serial online] 2020 [cited 2022 Dec 8];3:175-80. Available from: http://www.jglioma.com/text.asp?2020/3/4/175/308485

  Introduction Top

Glioblastoma (GBM) is the most common primary brain tumor in adults.[1] Standard management of newly diagnosed GBM comprises surgery followed by a 6-week course of radiotherapy (RT) to 60 Gy in 30 fractions with concurrent and adjuvant temozolomide (TMZ).[2] For older patients or those with poor performance status, 40 Gy in 15 fractions or an even shorter course of hypofractionated radiotherapy (HFRT) is considered not inferior to conventional fractionated RT.[3],[4],[5] However, GBM remains a therapeutic challenge because of the poor local control rate and survival time, and the frequency of recurrent disease. There is currently no standard treatment for residual and recurrent GBM. We, therefore, present a case of recurrent GBM after surgery treated with HFRT administered with a novel technique and regimen, combined with TMZ and bevacizumab (BEV), to provide another option for managing this refractory tumor type.

  Case Report Top

A 72-year-old woman was admitted to Cancer Hospital, Chinese Academy of Medical Sciences, because of development of speech disorder and anomic aphasia 1 month after resection of a GBM. The patient had first developed anomic aphasia 2 months previously and had undergone subtotal resection (STR) of a brain tumor in the left temporal lobe. The pathological diagnosis was GBM with necrosis (WHO Grade IV[6]). Immunohistochemistry tests showed H3k27Me3 (-), S-100 (3+), Vim (3+), EMA (-), CD8 (-), ATRX (3+), INI-1 (3+), GFAP (3+), Olig2 (3+), p53 (2+), and Ki-67 (40%+). Gene testing showed MGMT promoter methylation (+), 1p19q (no deletion), IDH1 (wild type), IDH2 (wild type), BRAF V600E (wild type), and TERT C250T (mutant type). Her symptoms resolved temporarily after surgery but recurred within a month. At that time, magnetic resonance imaging (MRI) showed a diffuse, approximately 5.9 cm × 4.5 cm × 3.2-cm mass in the left frontal and temporal lobes [Figure 1]. Residual and recurrent GBM was diagnosed.
Figure 1: Brain magnetic resonance images obtained before radiation. (A– E) Enhanced T1-weighted image sequence; (F– J) T2-weighted fluidattenuated inversion recovery sequence. There is a diffuse, approximately 5.9 cm × 4.5 cm × 3.2-cm mass in the left frontal and temporal lobes (arrows) that shows equal signal in the T1-weighted image sequence, nonuniform high signal in T2-weighted fluid-attenuated inversion recovery, and obviously enhanced signal in the enhanced T1-weighted image sequences. There is obvious edema around the tumor and the midline of the brain has shifted to the right

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Because there was severe edema around the lesion and the patient had central nervous system (CNS) symptoms, she was given BEV (5 mg/kg) once before commencing RT. She then underwent HFRT with helical tomotherapy (HT) and concurrent chemotherapy with TMZ at 75 mg/m2/day. The gross tumor volume (GTV) was 51.9 cm3, being defined as the extent of contrast-enhanced tumor, not including the area of edema, on the MRI. The GTV was expanded and contracted by 5 mm to create the planning target volume (PTV) and boost target. The prescription was 60 Gy with 3 Gy/fraction (f), 66 Gy with 3.3 Gy/f, and 76 Gy with 3.8 Gy/f in 20 fractions for PTV, GTV, and boost, respectively [Figure 2]. The patient's symptoms resolved after she had received nine fractions. Another MRI was performed and the GTV recontoured accordingly, then being 27.6 cm3. The phase-2 prescription was 33 Gy and 39.6 Gy in 11 fractions for PTV and GTV, respectively. After a total of 15 fractions, the patient underwent another MRI scan, the findings of which resulted in reducing the GTV to 18.5 cm3 [Figure 3]. In summary, the total doses for PTV, GTV, and boost were 60 Gy, 69.3 Gy, and 73.8 Gy in 20 fractions, respectively, administered within 30 days. After chemo-RT, the patient's anomic aphasia resolved and her speech was only slightly slurred. An MRI showed a residual lesion of maximum area about 2.1 cm × 1.3 cm [Figure 4].
Figure 2: Radiation target contouring of phase 1 plan (A– E) and dose distribution (F– J). The blue, red, and green lines denote GTV, boost, and PTV, respectively. The GTV in the phase 1 plan is 51.9 cm3. GTV: Gross tumor volume, PTV: Planning target volume

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Figure 3: Radiation target contouring of phase 2 and 3 plans. (A– E) Phase 2; (F– J) phase 3. The red and green lines denote GTV and PTV, respectively. GTVs in phase 2 and 3 are 27.6 and 18.5 cm3, respectively. GTV: Gross tumor volume, PTV: Planning target volume

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Figure 4: Brain magnetic resonance imaging right after radiation. (AE) Enhanced T1-weighted sequence; (FJ) T2-weighted fluid-attenuated inversion recovery sequence. The maximum area of the lesion is about 2.1 cm 1.3 cm (arrows), and signal enhancement has significantly weakened

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The patient then received maintenance chemotherapy with TMZ at 150 mg/m2 on days 1–5 for every 28 days. Brain MRIs performed every 2–3 months showed that the lesion volume remained stable with weakened enhancement of signal compared with that of pretreatment images [Figure 5]. The associated edema worsened 8 months after RT and decreased after one 5 mg/kg dose of BEV. The patient remains alive with no evidence of progression 15 months from RT.
Figure 5: Follow-up brain magnetic resonance images (enhanced T1-weighted sequences). The lesion volume remained stable with weakened enhancement of signal (arrows) compared with that of pretreatment images. RT: Radiotherapy

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The patient signed the informed consent before treatment and the study was approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences, China.

  Discussion Top

The optimal treatment strategy for residual and recurrent GBM is currently controversial. Administration of HFRT for newly diagnosed GBM has been investigated for decades. Giving higher doses per fraction over a shorter time has the advantages of increasing the killing of cells and reducing the rate of tumor cell regrowth.[7] Such protocols were initially used to treat older or frail patients with the aim of reducing treatment time and improving tolerance to it. Recent investigation of treatment of young patients with curative intent has shown that HFRT is comparable to conventional fractionated RT in terms of survival time and toxicities.[7],[8],[9],[10],[11]

Lim et al.[12] retrospectively reviewed 33 patients with GBM who had one or more of the following risk factors: Eastern Cooperative Oncology Group (ECOG) score ≥3, biopsy only, or rapid disease progression immediately after surgery, and were treated with HFRT with concomitant TMZ. The median RT dose was 45 Gy (30–45 Gy) with 3 Gy/fraction. The median overall and progression-free survivals (PFS) were 10.6 and 7.5 months, respectively, and CNS toxicities were acceptable. In the present case, our elderly patient evidenced rapid disease progression after surgery; however, her ECOG score was 1. She was administered high-dose HFRT with concomitant and adjuvant TMZ, and her PFS at the time of writing was 15 months with no late CNS adverse events. The novel aspects of this case are as follows: first, the RT dose was radical. However, we did not expand the GTV by 2 cm to create a traditional clinical target volume, believing that the dose provided by the scatter around the GTV would prove adequate. Second, we used a simultaneous integrated boost with HT to increase the dose to the lesion without further damaging the normal brain tissue, with the aim being to achieve satisfactory local control with acceptable toxicity. This approach was informed by several reports of favorable results of administering simultaneous integrated boosts for adjuvant RT of GBM.[13],[14] Last but not the least, the patient underwent two MRI re-examinations during HFRT to enable reductions in target volumes in parallel with changes in the size of the lesion. This tactic enshrines the principle of adaptive RT and reduces the dose to normal brain tissue. Some retrospective studies have shown that adaptive RT can improve target coverage while reducing the irradiated volume to various types of tumor, such as nasopharyngeal and bladder cancers.[15],[16]

In our case, chemotherapy with TMZ and anti-angiogenic therapy with BEV would likely have also contributed to achieving local control and longer PFS. BEV has been approved for recurrent GBM by the Food and Drug Administration on the basis of demonstrated improvement in PFS.[17],[18] It may reduce the volume of blood vessels in the tumor, inhibit the formation of new vessels, and decrease blood–brain barrier permeability, resulting in less contrast enhancement and vasogenic edema.[19],[20] Some recent prospective trials investigating BEV plus RT for newly diagnosed GBM have failed to demonstrate improvement in overall survival. However, some patients with specific types of gene mutation may achieve a prolonged PFS.[21],[22] Further studies based on molecular biomarkers and risk factors are warranted.

  Conclusion Top

Residual and recurrent GBM remains a therapeutic challenge. Adaptive HFRT combined with chemotherapy and anti-angiogenic therapy may provide an effective option for these patients. Studies investigating treatment based on risk stratification and molecular biomarkers are needed.

Financial support and sponsorship


Institutional review board statement

The study was approved by the ethics committee of Cancer Hospital, Chinese Academy of Medical Sciences, China, and was conducted in full compliance with all principles of the Declaration of Helsinki.

Declaration of participant consent

The authors certify that they have obtained the patient consent form. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that her name and initial will not be published and due efforts will be made to conceal her identity.

Conflicts of interest

There are no conflicts of interest.

  References Top

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Lim YJ, Kim IH, Han TJ, Choi SH, Park SH, Park CK, et al. Hypofractionated chemoradiotherapy with temozolomide as a treatment option for glioblastoma patients with poor prognostic features. Int J Clin Oncol 2015;20:21-8.  Back to cited text no. 12
Scoccianti S, Krengli M, Marrazzo L, Magrini SM, Detti B, Fusco V, et al. Hypofractionated radiotherapy with simultaneous integrated boost (SIB) plus temozolomide in good prognosis patients with glioblastoma: A multicenter phase II study by the brain study group of the Italian association of radiation oncology (AIRO). Radiol Med 2018;123:48-62.  Back to cited text no. 13
Zhong L, Chen L, Lv S, Li Q, Chen G, Luo W, et al. Efficacy of moderately hypofractionated simultaneous integrated boost intensity-modulated radiotherapy combined with temozolomide for the postoperative treatment of glioblastoma multiforme: A single-institution experience. Radiat Oncol 2019;14:104.  Back to cited text no. 14
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Chitapanarux I, Chomprasert K, Nobnaop W, Wanwilairat S, Tharavichitkul E, Jakrabhandu S, et al. A dosimetric comparison of two-phase adaptive intensity-modulated radiotherapy for locally advanced nasopharyngeal cancer. J Radiat Res 2015;56:529-38.  Back to cited text no. 16
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Carlson JA, Reddy K, Gaspar LE, Ney D, Kavanagh BD, Damek D, et al. Hypofractionated-intensity modulated radiotherapy (hypo-IMRT) and temozolomide (TMZ) with or without bevacizumab (BEV) for newly diagnosed glioblastoma multiforme (GBM): A comparison of two prospective phase II trials. J Neurooncol 2015;123:251-7.  Back to cited text no. 21
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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