A randomized phase III study of shortcourse radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII)

- A randomized phase III study of short- course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma.
- Makoto Ohno 8 , Yoshinori Ito 9 , Ryo Nishikawa 10 , Haruhiko Fukuda 2 , Yasumasa Nishimura 11 , Yoshitaka Narita 8 and Brain Tumor Study Group and Radiation Therapy Study Group of the Japan Clinical Oncology Group.
- Background: The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide.
- In recent studies, 40 Gy in 15 fractions vs.
- 60 Gy in 30 fractions, 34 Gy in 10 fractions vs.
- 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs.
- 25 Gy in 5 fractions have been reported as non-inferior.
- The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions.
- Full list of author information is available at the end of the article.
- Methods: This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m 2 /day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m 2 /day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma.
- Patients 71 years of age or older, or 71 – 75 years old with resection of less than 90% of the contrast- enhanced region, will be registered and randomly assigned to each group with 1:1 allocation.
- Discussion: If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma..
- The incidence of glio- blastoma peaks among patients in their 60s to 70s and is increasing with the growth of the elderly population [1 – 3].
- The present standard treatment for patients younger than 70 years old with glioblastoma is radiotherapy com- prising 60 Gy in 30 fractions with concomitant and adju- vant temozolomide [4, 5].
- Most clinical trials for glioblastoma have excluded elderly patients because of their poor prognosis, comorbidity and sensitivity of the aging brain to radiation [6].
- Several studies of elderly pa- tients with glioblastoma evaluating radiotherapy as 60 Gy in 30 fractions with concomitant and adjuvant temo- zolomide showed prolonged OS in patients with good performance status but treatment-related toxicities such as greater deterioration of mental status [6 – 9].
- In 2017, the Canadian Cancer Clinical Trials Group (CCTG) and the European Organization for Research and Treatment of Cancer (EORTC) reported that me- dian OS was longer with short-course radiotherapy com- prising 40 Gy in 15 fractions plus concomitant (75 mg/.
- m 2 , daily from first to last day of radiation) and adjuvant mg/m 2 , days 1 – 5, every 4 weeks, 12 cycles) temozolomide than with 40 Gy in 15 fractions alone (9.3 months vs.
- In a back- ground with fewer enrolled patients 65 to 70 years old than 71 to 75 years old, patients 65 to 70 years old with satisfactory performance status are generally treated with radiotherapy as 60 Gy in 30 fractions plus concomitant and adjuvant temozolomide.
- Based on these consider- ations, a regimen of radiotherapy as 40 Gy in 15 frac- tions plus temozolomide could be an appropriate standard treatment for newly diagnosed glioblastoma pa- tients 71 years old or above..
- Three other phase III trials were conducted for further hypofractionated radiotherapy in elderly patients with newly diagnosed glioblastoma.
- 40 Gy in 15 fractions vs.
- 60 Gy in 30 fractions [11], 34 Gy in 10 fractions vs.
- 60 Gy in 30 fractions [12], and 40 Gy in 15 fractions vs.
- 25 Gy in 5 fractions [13] and re- ported non-inferior results in terms of safety and efficacy for elderly patients with newly diagnosed glioblastoma (Table 1 [10–15.
- In August 2020, the Brain Tumor Study Group and the Radiation Therapy Study Group of the Japan Clinical Oncology Group (JCOG) started a multicenter random- ized controlled phase III trial in elderly patients with newly diagnosed glioblastoma (JCOG1910, AgedGlio- PIII)..
- The purpose of this study was to confirm the non- inferiority of radiotherapy as 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolo- mide in terms of OS in elderly patients with newly diag- nosed glioblastoma..
- Methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter region is examined using surgical specimens before the second registration.
- ≥70%) and methylation status of the MGMT promoter region (methylated vs.
- OS is defined as the time from registration to death from any cause, censored as of the last day when the pa- tient is known to be alive.
- PFS is defined as the time from registration to either the first event of tumor pro- gression or death from any cause, censored as of the lat- est day when the patient is alive without any evidence of progression.
- Table 1 Randomized controlled trials in elderly patients with glioblastoma.
- Roa et al., 2004 [11.
- Keime-Guibert et al ANOCEF ≥ 70 42 Best supportive care 1.2 3.9.
- Wick et al NOA-08 >.
- Malmström et al Nordic study >.
- Roa et al., 2015 [13.
- Perry et al CE Gy/15 fr 3.9 7.6.
- (5) Tumor present in the supratentorial region on preoperative contrast-enhanced MRI of the brain..
- (6) Preoperative contrast-enhanced MRI of the brain reveals no dissemination..
- (1) Second registration within 21 days of the first registration..
- (1) 40 Gy in 15 daily fractions with temozolomide..
- day, 5 days/week, 15 times and 40 Gy in total).
- (1) 25 Gy in 5 daily fractions with temozolomide..
- Gadolinium-enhanced MRI of the brain will be evaluated at least every 8 weeks until disease progression or death.
- This study is designed as a multi-institutional, random- ized controlled trial to confirm the non-inferiority of radiotherapy of 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolomide in terms of OS in elderly patients with newly diagnosed glioblast- oma.
- Stratified Cox re- gression analysis with extent of surgical resection, Kar- nofsky performance status and methylation status of the MGMT promoter region will be performed for primary analysis..
- The interim analysis will be conducted after half of the planned number patients have been enrolled.
- The Lan-DeMets method with an O’Brien and Fleming-type alpha spending function will be used to adjust the multiplicity of the interim analysis and the primary analysis [17]..
- The disadvantages of the standard treatment are prolonged gastrointestinal symptoms caused by temozolomide, pro- longed hospitalization for about 2 months, and deterior- ation of QOL due to hospitalization.
- Based on the CE.6 trial results, the regimen of radio- therapy comprising 40 Gy in 15 fractions plus temozolo- mide is the standard treatment for newly diagnosed glioblastoma patients 65 years old or older.
- As the definition of maximal tumor resection is resection exceeding 90%, patients with 71–75 years and resection of less than 90% of the contrast-enhanced re- gion has been set as an inclusion criterion for this study..
- In the analysis of the CE.3 trial, patients with a methylated MGMT promoter showed a survival benefit from temozolomide (median OS, 21.7 months vs.
- Radiotherapeutic regimens of 40 Gy in 15 fractions, 34 Gy in 10 fractions, and 25 Gy in 5 fractions have been shown to offer similar efficacy and safety for elderly pa- tients with glioblastoma according to the three earlier phase III studies [11–13].
- On the basis of the estimated α/β value 1.2 Gy, EQD2s of 40 Gy in 15 fractions and 25 Gy in 5 fractions were consid- ered equivalent for glioblastoma in elderly patients, sug- gesting similar efficacy.
- Meanwhile, the EQD2 of 25 Gy in 5 fractions is less than that of 40 Gy in 15 fractions for normal brain tissue, meaning less damage would be incurred by 25 Gy in 5 fractions.
- These estimates are supported by study results finding no differences in OS, PFS, or QOL between patients receiving the two radio- therapy regimens of 40 Gy in 15 fractions and 25 Gy in 5 fractions [13]..
- Based on the prediction of radiobiological response from the results of clinical trials, the aim of this study is to confirm the non-inferiority of radiotherapy compris- ing 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomi- tant and adjuvant temozolomide in terms of OS among elderly patients with newly diagnosed glioblastoma.
- If the primary endpoint is met, radiotherapy as 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be established as a standard of care for elderly pa- tients with newly diagnosed glioblastoma.
- We would like to thank all members of the JCOG Data Center/Operation office, Brain Tumor Study Group and Radiation Therapy Study Group of the Japan Clinical Oncology Group, and Ms.
- The Brain Tumor Study Group and the Radiation Therapy Study Group of the Japan Clinical Oncology Group..
- KS, JM, YS, and HF contributed to the design and logistics of the protocol, proofread the manuscript, and will undertake statistical analyses.
- TO, MK, MO, YI, RN, YN, and YN contributed to the design and logistics of the protocol and conducted initiation of the study.
- Perry et al CE.6 40 Gy/15 fr .
- Roa et al Gy/5 fr .
- Malmström et al Nordic study 34 Gy/10 fr .
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