Summary

METHODS
Different scenarios and situations were prepared for a web-based online questionnaire emailed to radiation oncologists.

RESULTS
A total of 195 radiation oncologists responded to the survey. There was a consensus for concurrent adjuvant chemoradiotherapy for patients younger than 70 years old with good performance. However, physicians disagreed on the course of adjuvant temozolomide, whereas they administered the chemotherapy six courses (44%), 12 courses (34%), or until progression (19%). For patients older than 70 years and with good performance, most physicians (80%) preferred the standard treatment approach. However, standard approaches differed among the physicians for older adults with poor status, and diverse strategies were recommended for managing this patient group. Stereotactic approaches (73%) are recommended for reirradiation in progression. The systemic treatment recommendation was bevacizumab (87%) in the patient who progressed after standard chemoradiotherapy. Surgery was requested for younger patients who have good performance and small tumors. In symptomatic radionecrosis, steroids, bevacizumab, and surgery were the alternatives, respectively.

CONCLUSION
Physicians take different approaches to treatment, such as adjuvant chemotherapy cycles in younger patients, radiotherapy schemes in older adults, and treatment choices for progression. Despite the continuing investigations in high-grade gliomas, it may be suggested that the guidelines include detailed clinical scenarios for optimal management.

Introduction

Another question is the optimal treatment and treatment sequences in terms of the progression of glioblastoma. Unlike de novo disease, there is no standard of care in treating recurrent disease, and the preferred treatments are not superior. Options include resection, reirradiation, chemotherapy, and systemic therapies (i.e., bevacizumab).[6] However, more evidence-based, highquality knowledge is required in recurrent situations.

There is a need for more data about managing various scenarios and for more consensus on managing patients with glioblastoma. Hence, through a nationwide survey, we aimed to determine the prevailing clinical practice patterns in radiotherapy for glioblastoma management.

Methods

Results

Table 1: Participants" professional features, treatment time, planning, and fractionation preferences

Radiotherapy Time and Planning Details
Approximately 60% of the participants initiated postoperative radiotherapy for glioblastoma patients either three weeks after surgery or immediately following suture removal. Most participants favored the two-phase approach for defining target volumes in radiotherapy planning (61%). Phase I was described as tumor and/or the cavity and edema, and phase II was defined as the same but without edema. The rest of the physicians defined the target volume in a single phase as tumor and/or cavity ± edema (21%) or tumor and/ or cavity ± edema with a simultaneous integrated boost technique (Table 1).

The Scenarios and Situations
Table 2 provides all scenarios and situations, and Figure1 sketches the results. Among the physicians, the Karnofsky Performance Status Scale (KPS) (96.9%), the patient"s age (53.6%), and tumor characteristics (45.9%) were factors in deciding the radiotherapy fraction scheme.

Table 2: Survey scenarios and situations

Fig. 1: Results from all the scenarios and situations provided from Table 2.
KPS: Karnofsky Performance Status Scale; RT: Radiotherapy; TMZ: Temozolomide.

The Patient Younger Than 70 Years and KPS More Than 60 After Resection or Biopsy
All participants agreed on the standard adjuvant treatment, which included 60 Gy radiotherapy and concurrent temozolomide. However, following the concurrent therapy, the number of adjuvant chemotherapy courses administered varied: 44% of physicians prescribed six courses, 34% opted for 12 courses, and 19% continued treatment until disease progression.

The Patients Older Than 70 Years After Resection or Biopsy
The physicians preferred the standard approach (80%) rather than the short fraction scheme (20%) in elderly patients who have good performance status (KPS≥60). However, the standard approach (8.8%), short fraction radiotherapy (24.7%), temozolomide (28.4%), or short fraction and chemotherapy (37.1%) were administered to patients with KPS<60.

Treatment Decisions in Progress
Considering re-irradiation in recurrence after standard treatments in patients younger than 70 years and KPS more than 60, stereotactic radiosurgery (73%) was the most common treatment preference, and the systemic treatment recommendation was bevacizumab (87%) in the patients who progressed. Surgical consultation was requested for patients who had good performance (95%), had limited tumors (84%), and were younger (64%). In these patients, re-irradiation was applied to the cavity following surgery (43.5%).

Treatment Decisions for Radionecrosis
In symptomatic radionecrosis, steroids (86%), bevacizumab (60%), and surgery (64%), respectively, were recommended. The decision not to administer radiotherapy was based on performance (96%), age (54%), tumor characteristics (46.6%), and methylation status (21.5%).

Discussion

The optimal time from surgery to the beginning of radiotherapy is uncertain, and guidelines vary widely. In our study, participants also suggested varying waiting times before initiating radiotherapy following surgery. According to the Dutch Cancer Society Glioma Guideline, radiotherapy should begin up to 6 weeks after surgery.[6] Laureiro et al.,[7] in a meta-analysis of 19 retrospective studies published between 1974 and 2014, examined the effect of prolonging the time from surgery to radiotherapy. No significant correlation was observed between the prolongation of the time from surgery to radiotherapy and overall survival (OS). (HR=0.98; 95% CI 0.90-1.08; p=0.70). However, this meta-analysis included studies published before the Stupp regime era. A more recent study showed that delayed postop chemoradiotherapy may result in worse survival.[8,9] Seidlitz et al.[8] published their retrospective cohort study; 369 patients treated between 2001 and 2014 were included, and the effect of waiting time was investigated. In this large series of patients, the time between surgery and adjuvant radiotherapy (median 27 days, range 11-112 days), duration of radiation therapy (median 45, range 40-71 days), and total time from surgery to the end of radiotherapy (median 54, range 71-154 days) did not show any effect on OS or progression-free survival (PFS). Buszek et al.[9] analyzed 45,942 glioblastoma patients archived in the National Cancer Database. They revealed that delays of more than eight weeks in patients with a gross total resection and delays of less than four weeks in patients with a subtotal resection or biopsy resulted in worse survival. They concluded that the impact of time delay from surgery to radiotherapy, in conjunction with the extent of resection, should be considered in the clinical management of patients and future designs of clinical trials.

Several studies compare the efficacy and safety of standard and extended adjuvant temozolomide following concurrent chemoradiotherapy in patients with newly diagnosed glioblastoma multiforme. Attia et al.,[10] in a retrospective study evaluating a total of 121 patients, showed that extended temozolomide therapy was safe and tolerable but did not significantly improve PFS or OS compared to the standard cycle course. Feldheim et al.[11] showed that temozolomide causes loss of methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation and triggers migratory behavior. After temozolomide administration, cells with the unmethylated MGMT promoter showed more aggressive behavior.[11] GEINO-14-01, a randomized trial comparing prolonged adjuvant temozolomide (n=80) and six courses of temozolomide (n=79) treatment according to MGMT status and the presence or absence of residual disease in 159 patients, found no difference in OS or PFS.[12] In our study, we observed that the participants had different approaches regarding adjuvant treatment duration. No patients were without adjuvant treatment, but the application times differed. Extensive, randomized studies in which patients are categorized according to MGMT and other molecular markers are needed to elucidate the current issue.

There is no clear standard of care or salvage treatment when recurrence occurs in glioblastoma patients. Treatment guidelines make recommendations for these patients, such as surgery, re-administration of temozolomide, nitrosoureas, bevacizumab, and reirradiation.[13] Neither of these methods is superior to the other. In our study, the participants stated that they recommend bevacizumab-based systemic treatment at a rate of 86% in cases of recurrence.

In our study, 84% of the participants recommended resection if the patient was suitable for surgery in case of progression. Here, the determining factors were performance, a small tumor, a location far from risky areas, and patients younger than 70. A prospective, randomized, multicenter study, DIRECTOR, compared a 2-dose intensified temozolomide regimen in relapsed glioblastoma patients.[14] In this study, a total of 61 patients were examined, and a difference in post-recurrence survival was found between surgery with total resection (12.9 mo [95% CI: 11.5-18.2] vs. 6.5 mo [95% CI: 3.6-9.9], p<0.001). In a study examining current models of care in the Australian population for recurrent glioblastoma, 76% of patients received re-resection, and 24% received medical therapy.[15] Surgery may contribute to symptomatic and large lesions, but this patient group should be carefully selected. There are also publications trying to develop algorithms for choosing between re-irradiation and second surgery for relapsed glioblastoma.[16]

In our study, the determining factor in the radiotherapy recommendations of the radiation oncologists was primarily the patients" performance. In addition, the patient"s MGMT status and age were also influential. In elderly patients with poor performance, hypofractionated treatments were chosen in addition to the standard fraction. Similarly, the patient"s performance status was the definitive factor for hypofractionated regimes. In the study of 488 patients with a diagnosis of glioblastoma, Malakhov et al.[17] showed better outcomes for patients receiving chemoradiotherapy rather than radiation alone, regardless of the performance status. In another study, among the 70 glioblastoma patients who were 60 years old or older, gross total resection provided significantly longer overall survival, and patients who received postoperative adjuvant therapy had more prolonged overall survival than those with no postoperative adjuvant therapy.[18]

For patients with symptomatic radionecrosis, corticosteroids were the first choice (76%), followed by surgery (64%) and bevacizumab (60%) in our survey. Corticosteroids reduce inflammatory signals and cytokines from necrotic tissue and reduce blood-brain barrier leakage.[19] Bevacizumab, the vascular endothelial growth factor inhibitor, is also widespread and is an essential mediator in radionecrosis.[20] In a study evaluating 71 patients diagnosed with radionecrosis, bevacizumab administration showed a 97% radiographic response rate, 79% clinical improvement, and a mean 6 mg reduction in dexamethasone.[20,21] Previous publications have demonstrated that surgical application in treating radionecrosis carries the risk of morbidity.[22] The approach to treating radiation necrosis, a complication of radiation therapy, varies depending on the severity of the necrosis and the individual patient"s symptoms and may involve a combination of the treatments.

Limitations
Our survey has some limitations. Although almost 1000 radiation oncologists work in our country, 195 participants responded to our survey. Given this number, the actual clinical practice may not be fully reflected in these results, and physicians with a particular interest and neurooncological experience may have been overrepresented in our survey. Beyond the limitations, our survey provides essential insights into how care is delivered nationally for glioblastoma. More research to examine the effects of preferred treatments on patients" quality of life will be of great importance in the future.

Conclusion

Ethics Committee Approval: The study was approved by the Marmara University Faculty of Medicine Ethics Committee (no: 09.2021.921, date: 02/07/2021).

Conflict of Interest: All authors declared no conflict of interest.

Financial Support: None declared.

Use of AI for Writing Assistance: No AI technologies utilized.

Authorship Contributions: Concept - B.M.A., Z.A., U.A., K.O.; Design - B.M.A., Z.A., U.A., K.O.; Supervision - B.M.A., Z.A., U.A., K.O.; Materials - B.M.A., Z.A., U.A., K.O.; Data collection and/or processing - B.M.A., Z.A., U.A., K.O.; Data analysis and/or interpretation - B.M.A., Z.A., U.A., K.O.; Literature search - B.M.A., Z.A., U.A., K.O.; Writing - B.M.A., Z.A.; Critical review - B.M.A., Z.A., U.A., K.O.

Peer-review: Externally peer-reviewed.

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