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    -  Oktay K
    -  Güzel E
    -  Kaya V
    -  Güzel A
    -  Yıldırım M

 
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ORIGINAL ARTICLE
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Reoperation does not provide a survival advantage in patients with recurrent Glioblastoma treated with irinotecan/bevacizumab treatment


1 Department of Internal Medicine and Medical Oncology, Gaziantep University School of Medicine, Gaziantep, Turkey
2 Department of Neurosurgery, Medicalpark Gaziantep Hospital, Gaziantep, Turkey
3 Department of Radiology, Medicalpark Gaziantep Hospital, Gaziantep, Turkey
4 Department of Radiation Oncology, Medstar Antalya Hospital, Antalya, Turkey
5 Department of Medical Oncology, Medicalpark Gaziantep Hospital, Gaziantep, Turkey

Date of Submission21-Nov-2018
Date of Decision24-Mar-2019
Date of Acceptance24-Mar-2019

Correspondence Address:
Ozlem Nuray Sever,
Department of Internal Medicine and Medical Oncology, Gaziantep University School of Medicine, Gaziantep
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_758_18

  Abstract 


Background: Treatment options for recurrent glioblastoma (GBM) have limited efficacy. Although reoperation is useful for both the confirmation of the diagnosis of recurring disease and the relief of the symptoms, its effect on survival is unknown. The aim of this study was to evaulate the impact of second surgery in recurrent GBM.
Methods: Patients with GBM followed in our center between January 2015 and April 2018 were analyzed retrospectively based on the treatment options.
Results: 25 patients diagnosed with recurrent GBM were analyzed. Ten patients (40%) were treated with chemotherapy following reoperation, and 15 patients (60%) were treated with only chemotherapy. No benefits of reoperation were observed in the univariate analysis.
Conclusion: The second surgery in recurrent GBM has limited effect in clinical course.


Keywords: Glioblastoma, recurrence, reoperation, survival
Key Message: Repeat surgery does not contribute to improved survival in patients receiving irinotecan/bevacizumab regimen.



How to cite this URL:
Sever ON, Oktay K, Güzel E, Kaya V, Güzel A, Yıldırım M. Reoperation does not provide a survival advantage in patients with recurrent Glioblastoma treated with irinotecan/bevacizumab treatment. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 30]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297034





  Background Top


Glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults.[1] Surgical treatment followed by radiotherapy with concurrent temozolomide and adjuvant temozolamide (Stupp Protocol) is the standard treatment for newly diagnosed patients. It is considered as the most effective treatment for progression-free survival (PFS) and overall survival (OS).[2],[3] However, despite the optimal treatment, the progression is observed in almost all the patients, and median survival does not exceed 12–15 months.[1],[2],[3],[4] The 5-year survival rates are around 10%.[1],[2],[3],[4] Reoperation, systemic chemotherapy, and/or bevacizumab treatment options are available for the treatment of recurrent disease, but the efficacy is still low.

Reoperation is useful for both, the confirmation of the recurrent disease and to provide symptoms' relief, but its effect on survival is unknown. Due to ethical reasons, conducting randomized studies that compare between performing reoperation and chemotherapy in cases of recurrence is not possible. Therefore, the studies evaluating the benefit of the second surgery can only be performed retrospectively. Retrospective studies in the literature are also limited.[5],[6],[7],[8],[9],[10]

Therefore, the effect of the second surgery in patients with recurrent GBM treated at our center was analyzed retrospectively in this study.


  Patients and Methods Top


Patients with histopathologically diagnosed GBM between January 2015 and April 2018 at our institution were included in the study. Patient medical history files were retrospectively reviewed to obtain information about the progression and treatment of the disease. Patients who were not administered Stupp Protocol in first-line treatment, patients receiving nonirinotecan (IRI)/bevacizumab (BEV) treatment in the second-line treatment, and patients diagnosed with high-grade glial tumor other than GBM were excluded from the study. After the recurrence, patients were treated with further chemotherapy (IRI/BEV) or considered for surgery depending on general conditions, extent, and site of the recurrence. After the surgery, all patients received further chemotherapy (IRI/BEV).

Statistical analysis was carried out using SPSS version 15.0 software program. The single-variable analysis of survival was carried out with log-rank test. Survival rates were calculated using Kaplan–Meier survival analysis method. P value less than 5% was considered meaningful.


  Results Top


A total of 25 patients were included in the study. Ten of 25 (40%) were female and 15 (60%) were male. The mean age of the patients was 58.5 ± 16.3 years (range 16–93 years). Based on patients' Eastern Cooperative Oncology Group (ECOG) performance score, ECOG 1 was determined in 18 (72%) patients, ECOG 2 in 5 (20%), and ECOG 3 in 2 (8%) patients. Eight of the total patients also had comorbid diseases. The most common comorbid diseases were hypertension (observed in four patients) and type 2 diabetes mellitus (observed in two patients).

When evaluating the patients based on first clinical presentation, headache was most commonly determined accounting for 13 patients (52%). It was followed by five patients (20%) with neurological deficit and four patients (16%) with epileptic attack. In 8 of the total patients (32%), the tumor was located on the left, while in 17 patients (68%) it was located on the right. Nineteen patients (76%) were determined to have epileptic attack in the follow-up. Seven of the patients (28%) underwent total excision, 17 (68%) underwent sub-total excision, and 1 patient underwent biopsy.

All patients received standard Stupp Protocol in the primary care. All the patients in the study received adjuvant temozolomide. Patients received a median of three and an average of four cycles of temozolomide while they received minimum 1 cure and maximum 11 cures. PFS of the patients was 8.3 ± 7.1 (range 2.14–30.9). Following the progression, 10 patients (40%) underwent a second surgery, while 15 patients did not have any secondary surgery.

All patients received IRI/BEV treatment during the secondary care. The OS of the patients was 20.5 ± 1.9 months (95% confidence interval, 16.78–23.4) [Figure 1].
Figure 1: Overall survival of the patients

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Patients were grouped based on whether the surgery was performed after initial progression. They were also compared in terms of age, ECOG performance score, and survival. There was no difference between the two groups in terms of age and ECOG performance score as well as no statistical difference in survival between the two groups (P = 0.98) [Figure 2].
Figure 2: Survival differences between the groups

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In terms of side effects associated with chemotherapy, one patient had grade 2 neutropenia and one patient had grade 1 mucositis. No surgical complications were observed in any patient.


  Discussion Top


Despite radical surgery and adjuvant radiotherapy/temozolomide treatment, disease progression and relapse still occur in a majority of patients with GBM. Interestingly, a small fraction (less than 10%) of patients with GBM survive longer than 36 months and several studies have been conducted to explain this. Among them, some studies performed genome-wide gene expression analyses. For example, in an ex vivo study by Mangiola et al.,[11] tumor tissue of patients with GBM and peritumoral proximal tissue were found to be similar in terms of gene expression profile. In that study, they concluded that the outcome could be explained by a dilution of genes expressed from tumor cells infiltrating the peritumor tissue. Alternatively, these findings could be sustained by a relevant amount of apparently normal cells presenting a gene profile compatible with a precancerous state or even quiescent cancer cells. Otherwise, the recurrent tumor may arise from both infiltrating tumor cells and an interaction and recruitment of apparently normal cells in the peritumor tissue by infiltrating tumor cells.[11] Similar to this study, Fazi et al.[12] found a grey zone represented by the area surrounding the tumor, which they show to be characterized by the expression of several molecules shared with proper tumor mass.[12] With the results of a recent meta-analysis, Olson et al.[13] found that methylguanine methyltransferase (MGMT) methylation status was a statistically significant independent predictor of OS in patients with primary GBM, with >50% lower relative risk of death for methylated patients, compared with unmethylated patients.[13] Thus, MGMT methylation status may be useful in clinical decision-making.[14] However, it is not clear why some GBM patients live longer than others.

Today, various chemotherapy options are available in the treatment of the recurrent disease. These include lomustine (CCNU),[15] fotemustine,[16] and carboplatin/etoposide.[17] Although these agents provide an objective response, their effects on symptom control and survival are limited. Another promising agent, BEV, is used both in newly diagnosed patients and in the recurrent disease.[18],[19],[20] In newly diagnosed patients, BEV increases PFS, but does not provide OS contribution.[21],[22] In phase 2 BELOB study,[20] when BEV or CCNU was used alone in the recurrent disease, OS was 8 months, whereas OS was found to be 12 months when CCNU/BEV combination was used. After this study, phase 3 study of this combination was initiated (EORTC 26101, NCT01290939; TAMIGA, NCT01860638). But in this study, BEV treatment in patients with progressive GBM despite prolonged PFS does not confer a survival advantage.

Whether reoperation in recurrent GBM brings a survival advantage is still not clear.[23] There were limited numbers of retrospective studies focusing on the role of the second surgery. In a majority of these studies, it was observed that a second surgery did not provide any survival benefit.[6-8,10] In the retrospective study conducted by De Bonis et al.,[9] 76 patients with recurrent GBM were analyzed by dividing the patients into the following groups: patients who received only chemotherapy, patients who did not receive treatment, and patients administered with chemotherapy following reoperation. The results of the study showed that survival advantage was only observed in the latter group.[9] Furthermore, performance status (PS) was determined to be an independent prognostic factor in this study. In a study by Michaelsen et al.,[24] patients with recurrent GBM following the standard treatment were analyzed for prognosis based on the treatment administered.[24] The patients who were included in the study were grouped as those who underwent surgery, those who received BEV/IRI treatment, those who were treated with surgery + BEV/IRI combination, and those who received no treatment. Patients in the surgical and systemic chemotherapy group showed better survival than those who received no treatment. However, there was no statistical difference between surgery + BEV/IRI group and only BEV/IRI group. The combination of surgery and systemic chemotherapy showed better results than surgery alone. In another study, Gorlia et al.[10] analyzed data from 300 patients and found that 12% of the patients underwent reoperation due to recurrence. They found no survival difference (P = 0.25).[10] Most studies concluded that reoperation does not provide any advantage in survival, while only in a small number of studies, reoperation appears to be advantageous in some patient subgroups (such as those with good PS, patients who underwent radical or near radical surgery).[9],[25]

Taking all into consideration, if reoperation is thought to have no effect on the survival, the purpose of reoperation should be confirming the diagnosis and preventing symptoms due to mass effect. Whether the second surgery is necessary should be carefully assessed, and each patient should be assessed as a separate case. Moreover, the second surgery should be planned as a reserved option for young patients with large tumor masses and pressure symptoms. The MGMT methylation status may be useful in selecting patients for the second surgery since these patients may benefit less from chemotherapy. Therefore, the second surgery may be a more appropriate treatment option.

One of the most important questions still to be answered is how to decide on which patients are to be treated with surgery and which of them are to be treated systemically. In 2013, Park et al.[23] recommended using a scale based on prognostic factors to determine whether surgical treatment would be beneficial in patients with recurrent GBM.[23] On this scale, three prognostic groups (good: median OS, 18 months, moderate: median OS, 10 months, and poor: median OS, 4 months) were determined according to Karnofsky Performance Score (KPS) and the degree of ependymal involvement. Researchers have discussed that patients in good prognostic group may benefit more from surgery, while chemotherapy and surgery are equally effective in the moderate prognostic group, but the patients in the poor prognostic group do not benefit much from surgery. That study was an observational study in which a small number of patients were evaluated. Thus, the outcomes should be validated with prospective studies. Another complicated scoring system is based on the data of 34 patients reoperated with recurrent GBM. According to this scoring system, the involvement of the critical/vital brain area (P = 0.021), KPS <80 (P = 0.030), and tumor volume ≥50 cm3 were defined as the factors associated with poor postoperative survival. Based on the combination of these factors, the authors divided patients into poor, moderate, and good postoperative risk groups.[8] In another study conducted in North America, prognostic factors in patients with recurrent high-grade GBM were examined. A total of 333 patients were analyzed in the New Approaches to Brain Tumor Therapy (NABTT) study in which age, ECOG PS, shorter time from initial diagnosis (DxTime), and initial steroid use were found to be the most important prognostic factors in the survival of patients with GBM.[26] In that study, patients were divided into four groups based on the median survival time, ranging from median 10.4 months (younger than 50 years of age, KPS 90–100) to 4.9 months (older than 50 years of age, initially requiring steroids). In the North Central Cancer Treatment Group- North American Brain Tumor Consortium (NCCTG-NABTC) study, 596 patients were analyzed similarly. Age, PS, initial steroid use, and period until the disease recurrence were found to be the most important factors affecting survival.[27] The European Organisation for Research and Treatment of Cancer (EORTC) study, in which data from 300 patients with recurrent GBM were evaluated, also confirms the earlier results.[10] In the study, poor PS and multiple target lesions were identified as the most effective negative prognostic factors for both PFS and survival. Patients with tumors greater than 42 mm in diameter and initially in need of steroid use have the worst prognosis, but the prognosis for frontal tumors is better. These models help the physician, patient, and patient's relatives to discuss the options of optimal treatment in case of recurrence.

The recent advances in the surgical technique of awake craniotomy with intraoperative brain mapping and neuropsychological monitoring, together with the elucidation of new concepts of network organization of brain functions and neural plasticity, have allowed a new opportunity for the development of surgery in “eloquent areas.”[28] The Glioma Outcome Project is the study prospectively analyzing the morbidity of the second surgery. The data of this study revealed that 33% of the patients had perioperative complications, 18% of the patients had neurological deterioration, 10% had seizures, 4% had intracranial hemorrhages, and 4% had systemic infections. About 20% of the total patients had depression, and the perioperative mortality rate was 2.2%.[29] However, the study analyzed the postoperative early results. Thus, it could be a limitation since postoperative complications may also occur later. The study also indicates that some complications may be prevented by chemotherapy administered, while some of the patients with recurrent GBM may benefit from the second surgery.


  Conclusion Top


In this study, we showed that reoperation did not contribute to survival in patients who received IRI/BEV as secondary care. The most important limitation of our study is that it was a retrospective study from a single center and the number of patients evaluated was limited. Second, the methylation status of the MGMT gene was not assessed in our study.

As a result, our study is in good agreement with many early studies in the literature. The role of reoperation in recurrent GBM is still controversial and this treatment option seems to be only suitable for selected patient groups.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from participants included in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Park JK, Hodges T, Arko L, Shen M, DelloIacono D, McNabb A, et al. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 2010;28:3838-43.  Back to cited text no. 8
    
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Gorlia T, Stupp R, Brandes AA, Rampling RR, Fumoleau P, Dittrich C, et al. New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials. Eur J Cancer 2012;48:1176-84.  Back to cited text no. 10
    
11.
Mangiola A, Saulnier N, De Bonis P, Orteschi D, Sica G, et al. Gene expression profile of glioblastoma peritumoral tissue: An ex vivo study. PLoS ONE 2013;8:e57145.  Back to cited text no. 11
    
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Fazi B, Felsani A, Grassi L, Moles A, D'Andrea D, et al. The transcriptome and miRNome profiling of glioblastoma tissues and peritumoral regions highlights molecular pathways shared by tumors and surrounding areas and reveals differences between short-term and long-term survivors. Oncotarget 2015;6:22526-52.  Back to cited text no. 12
    
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Olson RA, Brastianos PK, Palma DA. Prognostic and predictive value of epigenetic silencing of MGMT in patients with high grade gliomas: A systematic review and meta-analysis. J Neurooncol 2011;105:325-35.  Back to cited text no. 13
    
14.
Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M,et al. Personalized care in neuro-oncology coming of age: Why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol 2012;14(Suppl. 4):iv100-8.  Back to cited text no. 14
    
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Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 2010;28:1168-74.  Back to cited text no. 15
    
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Brandes AA, Tosoni A, Franceschi E, Blatt V, Santoro A, Faedi M, et al. Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: A phase II trial of Gruppo Italiano Cooperativo di Neuro-oncologia (GICNO). Cancer Chemother Pharmacol 2009;64:769-75.  Back to cited text no. 16
    
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Franceschi E, Cavallo G, Scopece L, Paioli A, Pession A, Magrini E, et al. Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma. Br J Cancer 2004;91:1038-44.  Back to cited text no. 17
    
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Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40.  Back to cited text no. 18
    
19.
Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:4722-9.  Back to cited text no. 19
    
20.
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial. Lancet Oncol 2014;15:943-53.  Back to cited text no. 20
    
21.
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014;370:709-22.  Back to cited text no. 21
    
22.
Gilbert MR, Dingnam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370:699-708.  Back to cited text no. 22
    
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24.
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29.
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