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Table of Contents
MDT CASE DISCUSSION
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 24-29

East meets West for the treatment of glioma: A discussion of real-world cases


1 Department of Neurosurgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, China
2 Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China
3 Department of Radiation Oncology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, China
4 Department of Pathology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning Province, China
5 Department of Neurology, Division of Clinical Neuro-Oncology, University of Bonn, Bonn, Germany
6 Department of Neuropathology, University Hospital Heidelberg; German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany

Date of Submission25-Dec-2019
Date of Acceptance03-Mar-2020
Date of Web Publication13-Apr-2020

Correspondence Address:
Prof. Zhong-ping Chen
Department of Neurosurgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_29_19

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  Abstract 

Background and Aim: The standard of care for patients with gliomas should follow established guidelines. In real-world management, however, the management sometimes deviates from these guidelines. We organized a discussion of real-world clinical cases and summarized different considerations from Chinese and European specialists.Case Presentation: A multidisciplinary team comprising experts from Europe and China discussed two patients with glioma treated at Sun Yat-sen University Cancer Center and Liaoning Cancer Hospital and Institute, China. Patient 1 was a 43-year-old man with a recurrent oligodendroglioma in the left frontal lobe diagnosed based on histology alone. He had undergone a biopsy and was diagnosed with an oligodendroglioma 3 years previously. He underwent chemoradiotherapy followed by 12 cycles of chemotherapy with temozolomide (TMZ), and complete remission was achieved. However, the tumor recurred within a short period of time and was resected by a second surgery. The pathologic diagnosis of the recurrent tumor was a glioblastoma because 1p/19q was intact when detected by sequencing. Pathologic consultation from another hospital still considered an anaplastic oligodendroglioma based on the positive result of 1p19q loss of heterozygosity (LOH) determined by fluorescence in situ hybridization. Patient 2 was a 50-year-old man with a left temporal glioblastoma. He underwent tumor resection but no radiotherapy. After seven cycles of TMZ (5/28-day regimen), his symptoms deteriorated, and his treatment was changed to a TMZ dose-dense regimen (7 days on/7 days off) and bevacizumab (7.5 mg/kg every 2 weeks), plus tumor-treating field therapy. Consultation Results: The pathological diagnosis based on biopsy for Patient 1 was an oligodendroglioma (World Health Organization Grade II), whereas the result of the second surgical sample was glioblastoma or anaplastic oligodendroglioma (questionable). Although the accuracy of fluorescence in situ hybridization for the detection of 1p/19q LOH requires improvement, 1p/19q LOH is typically not reconstituted in oligodendroglioma. More likely, it was due to sampling; a positive observation field may be missed with consequent negative results, and both oligodendroglioma (with 1p/19q co-deletion and isocitrate dehydrogenase mutation) and astrocytoma (without 1p/19q co-deletion) may exist. With respect to further treatment for cases such as Patient 1, both Chinese and European experts agree that procarbazine + lomustine chemotherapy is appropriate, while re-irradiation is suggested only if the tumor recurs outside the original radiotherapy field or within the radiotherapy field in the future. Considering the medical history, the rapid tumor regrowth without postoperative radiotherapy in Patient 2 was not surprising. After application of a rescue treatment regimen, the general condition of the patient improved, which may have resulted from the bevacizumab. A consensus was reached between the Chinese and European experts regarding subsequent treatment of Patient 2. Continuation of TMZ and bevacizumab was suggested until further deterioration. Whether tumor-treating field therapy should play a role in this patient could not be evaluated. However, some other molecular targeted agents (e.g. vascular endothelial growth factor receptor tyrosine kinase inhibitors such as regorafenib or apatinib) after bevacizumab failure, the effectiveness of these drugs remains unclear. Conclusion: In clinical practice, although we should follow established guidelines, the final treatment regimen requires informed consent from the patient. Thus, some real-world cases may deviate from the established guidelines. When patients reach end-stage disease with a marked decrease in their performance status and no standard treatment options, active antitumor treatment might be more likely to be attempted in China, while symptomatic treatment is more frequently performed in Europe. Although treatment philosophies for patients with glioma are slightly different between Eastern and Western medical experts, any treatment strategies should satisfy these patients.

Keywords: Anaplastic oligodendroglioma, bevacizumab, chemotherapy, diagnosis, glioblastoma, high-grade glioma, individualized treatment, radiotherapy, temozolomide, tumor recurrence


How to cite this article:
Piao H, Zhang Y, Guo C, Zhu L, Liu L, Herrlinger U, Sahm F, Chen Zp. East meets West for the treatment of glioma: A discussion of real-world cases. Glioma 2020;3:24-9

How to cite this URL:
Piao H, Zhang Y, Guo C, Zhu L, Liu L, Herrlinger U, Sahm F, Chen Zp. East meets West for the treatment of glioma: A discussion of real-world cases. Glioma [serial online] 2020 [cited 2022 Nov 27];3:24-9. Available from: http://www.jglioma.com/text.asp?2020/3/1/24/282427


  Introduction Top


The standard of care for patients with gliomas should follow the established guidelines of different countries and geographical areas. Management of individual cases sometimes differs substantially from the established guidelines.[1] In the present report, we consulted with Chinese and German specialists regarding two patients with gliomas treated at Chinese hospitals and summarized the different considerations of the Chinese and European specialists.


  Case Presentations Top


Patient 1

Patient 1 was a 43-year-old man. In October 2016, the patient was first admitted to the hospital because of a 9-month history of space-occupying lesions in the left fronto-insular and corpus callosum regions. The patient had no clinical symptoms when the lesions were found during a routine medical checkup. The patient's Karnofsky performance score (KPS) at that time was 100. Magnetic resonance imaging (MRI) revealed a large space-occupying mass in the left frontal lobe, insula, and corpus callosum, with mixed signal intensity on T1- and T2-weighted images. The margins were unclear, and no obvious enhancement was observed in the majority of the tumor [Figure 1] and [Figure 2]. Fractions of patchy enhancement and mild peripheral edema were found. The patient underwent open biopsy on October 20, 2016. The pathological examination revealed an oligodendroglioma (World Health Organization [WHO] Grade II). Molecular profiling showed that the tumor was O6-methylguanine DNA methyltransferase (MGMT) promoter methylated, isocitrate dehydrogenase-1 (IDH1) mutant, telomerase reverse transcriptase (TERT) mutant, 1p19q loss of heterozygosity (LOH) (fluorescence in situ hybridization [FISH]) positive, IDH2 wild type, and BRAF wild type. On November 7, 2016, the patient began treatment with chemoradiotherapy (radiation dose of 5994 cGy, 27 F concurrent with temozolomide [TMZ] at 75 mg/m[2] daily), followed by 12 cycles of chemotherapy with TMZ (340 mg/m[2], 5/28-day regimen). During treatment, the patient had four seizure episodes and was treated with oral valproic acid (0.5 g, twice daily) and oral levetiracetam (0.5 g, twice daily). Routine follow-up MRI scans showed a complete response after treatment until February 2019 [Figure 3].
Figure 1: Magnetic resonance imaging scans of Patient 1 before biopsy. Magnetic resonance imaging scans revealed large space-occupying masses (red arrows) in the left frontal lobe. The margins were unclear, and no obvious enhancement was observed in the majority of the tumor. Fractions of patchy enhancement and mild peripheral edema were noticed

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Figure 2: Magnetic resonance imaging scans of Patient 1 at 1 month after biopsy (before chemoradiotherapy). Ring and solid enhancements (red arrows) were noticed at the biopsy and behind site

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Figure 3: Magnetic resonance imaging scans of Patient 1 confirmed complete response after last cycle of temozolomide treatment

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On April 4, 2019, considering tumor recurrence within the previous radiation area, the patient underwent tumor removal via an extended left frontoparietal approach [Figure 4] and [Figure 5]. The postoperative pathology revealed anaplastic oligodendroglioma morphology (WHO Grade III). Molecular profiling showed that the tumor was MGMT promoter methylated, IDH1 mutated, TERT C228T mutated, 1p/19q intact (sequencing), and BRAF V600E wild type. The pathological slides were sent to two different hospitals for pathology consultation, which produced different opinions. One hospital reported high-grade glioma, consistent with glioblastoma (WHO Grade IV, IDH mutated), and further molecular testing showed IDH1 R123H mutation, IDH2 wild type, MGMT promoter methylated, 1p deletion, and 19q intact. The other hospital reported anaplastic oligodendroglioma with massive necrosis (consistent with postradiotherapy changes), IDH mutation type, 1p/19q co-deletion, and WHO Grade III (consistent with the first hospital). On May 3, 2019, the patient started a new chemotherapy regimen with procarbazine and lomustine (PC; lomustine 180 [110 mg/m[2]] day 1+ procarbazine 100 mg [60 mg/m[2]], days 8–21, 8 weeks per cycle). During chemotherapy, the patient's general condition was good, but he developed severe myelosuppression that was relieved after symptomatic supportive treatment. As of the discussion date (October 12, 2019), the patient had completed three cycles of chemotherapy. His clinical condition was good with the exception of fatigue. His KPS was 90, and no neurological impairment was noted. Follow-up MRI scans showed a good response to the treatment [Figure 6].
Figure 4: Magnetic resonance imaging scans of Patient 1 at 1 year after completion of temozolomide treatment. New enhancement (red arrows) in the previous radiation area was noticed

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Figure 5: Magnetic resonance imaging scans of Patient 1 at 4 days after surgery. No enhancement was noted after surgical resection

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Figure 6: Magnetic resonance imaging scans of Patient 1 after three cycles of procarbazine and lomustine chemotherapy. No enhancement was noticed

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Patient 2

Patient 2 was a 50-year-old man. He was admitted to the hospital because of a 1-week history of sudden-onset slurred speech in January 2019. Physical examination showed decreased muscle strength of the right limbs (Grade IV) and mild olfactory hallucination. No signs of cognitive impairment were observed. His KPS was 60. MRI revealed a space-occupying lesion with significant enhancement in the left temporal and thalamus regions. The patient underwent surgery, and the lesions in the thalamus and deep temporal regions were partially removed under the guidance of a neuronavigation system on January 9, 2019 [Figure 7]. Postoperative histopathologic examination of the tumor revealed a glioblastoma (WHO Grade IV). Molecular profiling revealed MGMT promoter methylation, 1p intact, and 19q loss; no mutation was detected for IDH1 R132, IDH2 R172, TERT C228T and C250T, and BRAF V600E. The patient's recovery process was uneventful. His symptoms were not relieved after surgery. Because the patient refused radiotherapy after surgery, chemotherapy with TMZ on a 5/28-day regimen (150–200 mg/m[2], 5 days on and 23 days off) was given beginning on January 22, 2019. After seven cycles of chemotherapy with TMZ, the patient's symptoms deteriorated. He developed mild neurocognitive impairment, further decreased muscle strength, and sensory disorder of the right limbs. In July 2019, follow-up MRI showed enlargement of the enhanced tumor area [Figure 8]. On August 6, 2019, the patient began another treatment protocol including TMZ on a 7/7-day regimen (150 mg/m[2], 7 days on and 7 days off), intravenous bevacizumab (7.5 mg/kg, every 2 weeks), and tumor-treating field (TTF) therapy.
Figure 7: Magnetic resonance imaging scan of Patient 2 before surgery (January 2019). Areas of enhancement (red arrows) were noticed in the thalamus region and deep temporal lobe

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Figure 8: Magnetic resonance imaging scans of Patient 2 after surgery (July 2019). The lesion was enlarged 6 months after surgery (red arrows)

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As of the discussion date (October 12, 2019), the new regimen had been well tolerated, five cycles of TMZ and bevacizumab had been completed, and TTF therapy had been given for 2 months with mild adverse effects. The patient's cognitive function had slightly improved, although his decreased muscle strength and sensory disorder of the right limbs persisted. His KPS had improved from 60 (before the new treatment) to 70. MRI at 2 months after treatment with the rescue regimen (October 2019) showed a partial response of the enhancement [Figure 9].
Figure 9: Magnetic resonance imaging scan of Patient 2 in October 2019 (2 months after rescue regimen). The enhancement (red arrow) was slightly resolved when compared with that of July 2019

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  Discussion Top


Diagnosis

Since the launch of the updated WHO classification for central nervous system tumors in 2016, the pathologic diagnosis of gliomas has combined histology with molecular characteristics. According to the pathological results for Patient 1 after the first biopsy, the diagnosis of oligodendroglioma, WHO Grade II was unquestionable because the molecular profiling results indicated 1p/19q co-deletion and IDH mutation, further supported by TERT promoter mutation. However, the results of the second postoperative pathological examination are inconsistent among different hospitals, and the results of 1p/19q detection are also different. These differences might be related to several factors: (1) the accuracy of FISH (previously considered the gold standard for the detection of 1p/19q LOH) has been increasingly replaced by high-throughput molecular arrays and next-generation sequencing and still needs to be improved, or more reliable sequencing has become questionable;[2] (2) in the present case, 1p/19q co-deletion was more likely to be present because 1p/19q co-deletion rarely disappears in oligodendroglioma, and one of the analyses at the time of recurrence was in line with the initial evaluation; and (3) sampling and the content of nonneoplastic cells may also have impeded the evaluation. Considering the tumor progression and recurrence within 2.5 years in this patient with WHO Grade II oligodendroglioma, we cannot exclude the possibility that the original tumor itself had high-grade astrocytoma components and that no 1p/19q co-deletion existed in this part of the tumor. After the second operation, one pathologist diagnosed the patient with WHO Grade IV glioblastoma based on histological findings of a high-grade tumor component with necrosis and comparative rapid tumor progression; however, no 1p/19 co-deletion was detected in this workup. Although the necrosis might have been caused by previous radiation treatment, the possibility of a WHO Grade IV glioblastoma cannot be excluded. Histological diagnosis of glioblastoma (WHO Grade IV) in the second patient was clear. A clinical consideration for this patient could be IDH wild type without TERT mutation. However, his molecular profiling has only been detected with IDH1 R132, IDH2 R172, and TERT C228T and C250T showing no mutations; thus, other mutation sites might be missed.

In China, we routinely recommend six to eight molecular tests for patients with glioma. These tests mainly include IDH mutation, 1p19q LOH, TERT mutation, MGMT promoter methylation, ATRX, BRAF, vascular endothelial growth factor receptor (VEGFR), and H3K27M. If financial situations permit, patients can undergo additional molecular tests such as whole-exome sequencing. However, although molecular detection of gliomas is very important, it is of high cost such as whole-exome sequencing which is performed only in selected cases. Such clinical application is similar in European countries.

Treatment

In the present report, Patient 1 was diagnosed with oligodendroglioma through biopsy 3 years before the current presentation. He received radiotherapy concurrent with TMZ followed by 12 cycles of TMZ chemotherapy. However, the tumor recurred and progressed rapidly in a comparatively short period of time. This is indeed not common in clinical practice. The possibility of high-grade astrocytoma components in the tumor could not be excluded, but low-grade oligodendroglioma may also progress within a short period of time after treatment. When the patient underwent the second surgery with a diagnosis of a high-grade glioma, he was considered to undergo re-irradiation. However, most radiotherapy experts are still cautious. The consensus was that if the tumor recurred outside the original radiotherapy field or a small tumor recurs within the radiotherapy field in future, appropriate radiotherapy will be considered to achieve disease control. This consensus was agreed upon by Chinese and European experts participating in this consultation. The regimen procarbazine, lomustine, and vincristine (PCV) reportedly has good results for oligodendroglioma, especially with 1p/19q co-deletion.[3] However, PC is routinely not available in China and thus only TMZ but not PCV regimen can be usually used.[4] Fortunately, this patient was able to receive PC regimen with a successful clinical result. Consensus regarding this treatment was achieved between Chinese and European experts.

Patient 2 did not receive conventional radiotherapy after surgery. He received only TMZ chemotherapy, which deviated from the standard treatment protocol. Although this application is relatively rare in China, it still occurs in real-world management because patients may refuse treatment suggestions for any reason. In fact, in Europe and the United States, real-world treatment may also deviate from the normal treatment modes for various personal reasons. According to the medical history, Patient 2 did not undergo radiotherapy after surgery, and the rapid tumor regrowth was not surprising. After application of the rescue treatment regimen, the tumor was relieved to some extent as shown by imaging, but bevacizumab may have played a greater role. Bevacizumab is an anti-angiogenic agent for glioblastoma. In China, as in Europe and the United States, although it is not routinely used after the initial diagnosis, it is often used for recurrence/progression of glioma. However, this patient's condition improved after the use of bevacizumab, which mainly acted to eliminate brain edema; tumor reduction was not significant as shown by T2 flair MRI. A consensus was reached regarding the subsequent treatment of Patient 2 between the Chinese and European experts. At the time of this consultation, the tumor exhibited a wide range of invasion and the patient's condition was relatively poor; thus, he was no longer suitable for surgical treatment or radiotherapy. Continuation of TMZ and bevacizumab was suggested until further deterioration. Continued deterioration of the patient's condition indicated that the treatment was not providing more benefits and that active antitumor treatment should therefore not be considered. Instead, only symptomatic supportive treatment should be given. If any other molecular targeted agents can be tried for this patient, European experts suggest that VEGFR tyrosine kinase inhibitors such as regorafenib may be tried if bevacizumab is considered ineffective. However, the adverse effects of regorafenib, such as fatigue and hand–foot syndrome, have a great impact on patients' quality of life. Apatinib is a similar targeted drug available in China.[5] It can selectively inhibit VEGFR and may have a similar antivascular effect. However, although the effectiveness of this drug is unknown, it may be considered after bevacizumab fails.

In Europe, if the patient has a similar condition (terminal cancer) for which existing standard regimens cannot provide further benefits but the patient can still communicate normally, the doctor will consider directly communicating with the patient about the prognosis and the next treatment options, including palliative therapy only. The doctor must confirm that the patient is making the choice with full knowledge. In China, however, some family members will hide the illness from the patient, and their family will choose active treatment even in the later stage of disease despite a low chance of success. The concepts of “fighting for slim hope” and “always do something” are common. At the same time, because patients are not limited by insurance (most of them pay their own expenses), patients are likely to choose active treatment.


  Conclusion Top


In clinical practice, following treatment guidelines, patients with glioma should be managed on a case-by-case basis to meet each individual patient's specific requirements. The final treatment regimen requires informed consent from the patient and his or her family members. Thus, in clinical practice, some cases may deviate from the established guidelines. Patient 2 in this report did not receive standard radiotherapy and chemotherapy after surgery, but instead received selected chemotherapy alone. Although this situation is rare in China, it occasionally occurs in clinical practice. At the time of this report, Patient 2 was continuing to be followed up, and related clinical symptoms were still gradually emerging. We also respect his family's opinions regarding active treatment (including the use of bevacizumab and TTF therapy). European (German) scholars in this case suggested focusing on symptomatic treatment and discontinuing active antitumor treatment. Although treatment philosophies for patients with glioma are slightly different between Eastern and Western medical experts, any treatment strategies should satisfy the patient.

Financial support and sponsorship

Nil.

Institutional review board statement

The ethics approval is not applied since the case consultations with experts were arranged through Meeting organizer.

Declaration of participant consent

The need for written informed consent was waived owing to the retrospective nature of the study.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Li D, Chen Y, Guo C, Zhang X, Sai K, Ke C, et al. Real-world management and survival outcomes of patients with newly diagnosed gliomas from a single institution in China: A retrospective cohort study. Glioma 2019;2:96-104.  Back to cited text no. 1
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2.
Dubbink HJ, Atmodimedjo PN, van Marion R, Krol NM, Riegman PH, Kros JM, et al. Diagnostic detection of allelic losses and imbalances by next-generation sequencing: 1p/19q Co-deletion analysis of Gliomas. J Mol Diagn 2016;18:775-86.  Back to cited text no. 2
    
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van den Bent MJ, Brandes AA, Taphoorn MJ, Kros JM, Kouwenhoven MC, Delattre JY, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: Long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol 2013;31:344-50.  Back to cited text no. 3
    
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Lombardi G, De Salvo GL, Brandes AA, Eoli M, Rudà R, Faedi M, et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): A multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol 2019;20:110-9.  Back to cited text no. 4
    
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Zhang H, Chen F, Wang Z, Wu S. Successful treatment with apatinib for refractory recurrent malignant gliomas: A case series. Onco Targets Ther 2017;10:837-45.  Back to cited text no. 5
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]



 

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