Comparative Analysis of Hypofractionated Short-Course Versus Standard Radiation Therapy in Elderly Patients with Glioblastoma: Analysis of Nationwide Database

doi:10.21203/rs.3.rs-5002386/v1

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Case Report

Comparative Analysis of Hypofractionated Short-Course Versus Standard Radiation Therapy in Elderly Patients with Glioblastoma: Analysis of Nationwide Database

https://doi.org/10.21203/rs.3.rs-5002386/v1

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Journal Publication

published 21 Oct, 2024

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Purpose

Hypofractionated short-course radiation therapy (SCRT) is an alternative treatment option for elderly or frail patients with newly diagnosed glioblastoma (GBM) post-surgery. This study compares survival outcomes and treatment costs between patients receiving SCRT and those undergoing standard long-course radiation therapy (LCRT).

Methods

This retrospective study utilized health insurance claims and national cancer registry data from Korea to compare overall survival (OS) and treatment costs between patients receiving SCRT and LCRT across all ages and sub-group analysis within the subgroup of cases aged 65 and older from 2016 onwards, a period when intensity-modulated radiotherapy (IMRT) was widely adopted.

Results

A total of 1,598 patients were included. Median OS since the first day of radiation therapy was 10.4 months (95% CI [9.6; 12.8]) for SCRT (n=197) versus 16.2 months (95% CI [15.5; 16.9]) for (n=1401) for LCRT respectively. Subgroup analysis using stabilized inverse probability of treatment weighting (S-IPTW) showed indicating non-inferiority in elderly patients in median OS for elderly patients (≥65) with 10.6 months (95% CI [8.9; 14.0]) for SCRT (n=147) versus 13.2 months (95% CI [8.9; 14.0]) for LCRT (n=541). Treatment costs were significantly lower for SCRT, with a median saving of 6000 USD. Compliance with the standard TMZ regimen post-radiation significantly improved OS across all age groups.

Conclusion

SCRT is a viable, cost-effective alternative to LCRT for elderly GBM patients, with similar OS outcomes, supporting its adoption of SCRT in appropriate patient populations.

Glioblastoma

Adjuvant radiotherapy

Elderly patients

Temozolomide

Overall survival

Cost-effectiveness

Glioblastoma (GBM), the most common type of brain tumor in adults, is a highly aggressive malignant neoplasm with a very poor prognosis [1]. GBM accounts for approximately 14.2% of all newly diagnosed brain tumors and 50.9% of all malignant brain tumors [2]. There are disparities in the incidence of this disease, among different racial groups, with non-Hispanic whites having an incidence rate of 22.31 per 100,000 people, while Black and Hispanic populations have a rate of 14.44 per 100,000 [2]. Asian populations generally have lower prevalence rates of GBM, with recent data from Korea reporting an incidence rate of 7.47 per 100,000 for malignant gliomas, including GBM [3]. The prognosis for GBM remains poor, with a median overall survival (OS) of about eight months, shorter than the OS for those with other solid tumors [1, 2]. After years of evolving treatment modalities, the current standard of care has been established as surgical resection followed by adjuvant concurrent chemoradiation therapy with temozolomide (TMZ) and additional TMZ therapy after concurrent chemoradiation therapy [4, 5].

Standard radiation therapy (RT) for GBM typically involves administering 60 Gray (Gy) or more doses of radiation after surgical resection with more than 30 fractions of treatment sessions [4–6]. However, this high-dose regimen presents significant challenges for elderly and frail patients, who often cannot complete the prescribed radiation treatment schedule. To address this issue, hypofractionated short-course radiation therapy (SCRT) has been developed. Clinical trials conducted by the Nordic Clinical Brain Tumour Study Group [7] and Roa et al. [8, 9] have validated the efficacy and safety of this SCRT schedule. It is now considered an alternative treatment option for elderly and frail patients according to major treatment guidelines [4, 5].

Despite these results of clinical trials, there is not much information available about how effective hypofractionated SCRT is in real-world settings. Some studies based on real-world evidence (RWE) [10, 11] have found that patients treated with SCRT have a lower OS rate than those treated with standard long-course radiation therapy (LCRT). Thus, more research is needed. However, it is important to note that previous studies have been mostly conducted during the 2-dimensional or 3-dimensional radiation therapy (RT) era. As a result, their findings did not consider recent advancements in radiotherapy technology, such as intensity-modulated radiotherapy (IMRT) and associated improvements in RT-induced toxicity [12].

We have confirmed that health insurance claims data in Korea (Republic of Korea), operating under a unified public health insurance system, can effectively be used to analyze treatment outcomes for SCRT [13]. By integrating this health insurance claims data with the national cancer registry, which uses pathologic confirmation to identify GBM patients and accurately gathers survival data through government-managed death registration [14], this study aims to evaluate the OS and radiation treatment costs of the patients with GBM treated with SCRT schedule compared to those treated with standard LCRT. The analysis will utilize data from 2016 onwards, when IMRT was universally reimbursed in Korea and widely adopted in hospitals. In addition, we have conducted a specific analysis focused on the elderly patient group aged 65 and over to assess their eligibility for SCRT based on current treatment guidelines.

Data sources and access process

A retrospective data analysis was performed based on national health insurance claims data and patient registry data of Korea rather than clinical data from individual medical institutions. To ensure public interest and anonymity, data integration from related institutions was conducted through an application review by the Korea Healthcare Bigdata Service (https://hcdl.mohw.go.kr/), an affiliated organization of Korea Health Information Service (KHIS) of the Ministry of Health and Welfare, Republic of Korea. Before submitting the application, the researcher obtained IRB review and approval from the affiliated institution. Data analysis could only be performed at the closed network computing room located at the KHIS. Only the results were allowed to be exported and utilized for this study after KHIS’s review.

Study population

The initial case selection was based on the Korean National Cancer Registry, managed by the Korea National Cancer Center (KNCC). This database, required by law, contains diagnosis and related data for all cancer patients in the country. It includes the morphological code based on the International Classification of Diseases for Oncology (ICD-O) [15], which enables identification of GBM patients (coded of 944_._ in ICD-O) among those diagnosed with C71 in the International Statistical Classification of Diseases (ICD). We selected cases registered in the database between January 1, 2016, and December 31, 2021 who had both C71 in ICD and a morphological code starting with 944_._ in IDC-O. To ensure data integration with another database, we generated anonymized linkage keys for these cases. We established a starting point for recruiting in 2016 because selected cases treated with IMRT became fully reimbursed by national health insurance in mid-2015. Furthermore, KNCC expanded its cancer registration to include all institutions in the early 2010s, which ensured that the selected group received consistent radiotherapy with accurate diagnosis.

The second database was the Health Insurance Review and Assessment Service (HIRA) database which included records of treatments administered and billed to health insurance. From previously obtained cases, we identified patients who received appropriate surgery by a neurosurgeon and RT session by examining claims data for the type and date of surgery, the number of RT sessions (fractions) administered, and their schedule.

Patients who were considered not to be treated with standard RT in HIRA data were excluded from this study. Those who received fewer than 12 sessions of radiotherapy were also excluded because it was determined that they either did not complete their radiotherapy or received fewer than 10 sessions with a palliative aim. While some SCRT studies were conducted with 5 to 10 sessions of radiation therapy, these were rarely done in Korea. Therefore, they were excluded from this research. Patients with an interval of more than 30 days between RT sessions were also excluded because this suggested that the RT session was interrupted or there was a possibility of re-irradiation rather than continuous treatment. These patients were excluded regardless of their total number of sessions. Patients who started their first radiotherapy session more than 90 days after surgery were also excluded from the analysis. In GBM, standard treatment typically started RT within six weeks after surgery. Even in cases of delayed recovery, it was rare to extend beyond eight weeks. Therefore, radiotherapy initiated after 90 days was not considered to be an adjuvant treatment. Additionally, cases treated with proton radiation therapy were excluded to ensure homogeneity of RT among cases.

After the above process, eligible cases were selected, and survival data were collected from these cases. Data were obtained from the National Health Insurance Service (NHIS) database regularly updated by the government. This database provides accurate information on both survival status and date of death. Collected data were then integrated for the analysis of OS (Fig. 1).

Study variables

Demographic data on age and gender were obtained from the HIRA database. Treatment details included the date and category of surgery (such as craniectomy or craniotomy), dates of each RT session and the total number of RT sessions, whether temozolomide was prescribed or not, prescribed dates and duration of treatment periods, and the total cost of all treatments claimed for C71 disease. To analyze overall survival (OS), we used data on survival status from the NHIS database, including the date of death if applicable.

Statistical methods

Demographics are reported using medians, standard deviations (SDs), and 95% confidence intervals for continuous variables. Normality was assessed by the Shapiro–Wilk test for continuous variables. Since continuous variables did not follow a normal distribution in this study, they were compared using the Mann–Whiney U test. Demographics for categorical variables are presented as counts and proportions. They were analyzed using the chi-square test. Due to the retrospective study design, we identified an imbalance in the distribution of age and chemotherapy status between the two treatment groups (SCRT vs LCRT) in the original dataset using the standardized mean difference (SMD). To adjust for confounders, we utilized the Propensity Score method and applied Stabilized Inverse Probability of Treatment Weighting (S-IPTW) to minimize any imbalance of confounding variables between SCRT and LCRT groups [16, 17]. Thus, a statistical analysis comparing the two treatment groups was done with data after the S-IPTW analysis.

The primary endpoint was OS from the date of the first day of RT to evaluate outcomes focusing on RT. It was estimated by the Kaplan-Meier (K-M) methods. Given the short survival duration of GBM resulting in early formation of the median survival, the Gehan-Breslow test was introduced to determine the statistical difference. The log-rank test was also used. We conducted non-inferiority and consistency tests of HR using the Cox proportional hazards regression model.

The secondary endpoint was the total cost of treatment. The total claimed costs during RT did not follow a normal distribution, as determined by the Shapiro-Wilk test for normality. Therefore, comparisons between courses were performed using the Mann-Whitney U-test. For comparison of mean values, a 2-sample t-test was also used.

Exploratory endpoints were primarily related to concurrent temozolomide, investigating changes in treatment outcome and cost with or without temozolomide during RT. Additionally, changes in treatment outcome due to adjuvant temozolomide treatment after the completion of RT were explored for the group that received temozolomide during RT. To adjust for an imbalanced distribution between the two groups, S-IPTW was also applied before survival analysis.

All statistical analyses were performed using R Studio (version 4.2.2 2022, RStudio, PBC, Boston, MA, USA), with packages of ‘survival' and ‘survminer’ for survival analysis, ‘survey’ for IPTW and 'ggplot2' for data visualization.

Accrual

A total of 2,851 cases were detected in the KNCC database by disease code and morphological code. Among them, throughout the database joining process, a total of 1,598 GBM cases diagnosed between January 1, 2016, and December 31, 2021, were selected as final eligible cases. They were treated with surgery and appropriate RT (Fig. 1). Among them, 197 cases were treated with SCRT. Their median age was 70 years (mean ± SD: 68.76 ± 9.97 years) older than the median age of the LCRT group at 60 years (mean ± SD: 57.03 ± 13.53 years). A total of 693 cases were ≥ 65 years old and 79.2% (156/197) of those in the SCRT group aged ≥ 65 years (demographics of elderly and non-elderly group, Tables S1 and S2). Men accounted for 60.6%. In addition, 65% of cases were prescribed temozolomide during the treatment period. A weighted population was created using S-IPTW for statistical analysis (Table 1).

Table 1

Characteristics among SCRT and LCRT group
Baseline Characteristics	Original population (n = 1598)			Weighted population after IPTW (n = 1641)
	SCRT (n = 197)	LCRT (n = 1401)	SMD	SCRT (n = 242)	LCRT (n = 1399)	SMD
Age, Years
Median	70	60	0.987	55	60	0.371
Mean ± SD	68.76 ± 9.97	57.03 ± 13.53		52.82 ± 16.60	58.44 ± 13.58
Elderly, n (%)			0.772			0.127
≥ 65 years	156 (79.2)	537 (38.3)		147 (60.7)	541 (38.7)
Gender, n (%)			0.133			0.293
Male	108 (54.8)	860 (61.4)		112 (46.2)	848 (60.6)
Female	89 (45.2)	541 (38.6)		130 (53.8)	551 (39.4)
Temozolomide, n (%)			0.240			0.250
Treated	108 (54.8)	932 (66.5)		128 (52.9)	911 (65.1)
Untreated	79 (45.2)	469 (33.5)		114 (47.1)	488 (34.9)
RT fraction, n
Median	15	30	4.803	15	30	4.723
Mean ± SD	14.92 ± 0.75	28.94 ± 4.06		14.85 ± 0.87	28.86 ± 4.10
SCRT: Hypofractionated short-course radiation therapy, LCRT: Standard long-course radiation therapy, SD: Standard deviation, SMD: Standardized mean difference

Characteristics of RT session

This study examined the number of RT sessions (fractions) that distinguished SCRT from LCRT. It was observed that the majority (n = 156) of the SCRT group received 15 treatment sessions. In LCRT, common treatment schedules included 25, 30, and 33 sessions, with 30 sessions being the most frequent (n = 951). This confirms that 30 sessions are currently considered the standard number of RT sessions for GBM in Korea. Treatment schedules with more than 30 sessions were reviewed for treatment dates and identified as cases of recurrence where re-irradiation was performed. Additionally, it was noted that treatment courses of 10 or 5 sessions, known as alternative SCRT schedules, were rarely administered. Treatments with fewer than 12 sessions were excluded from the analysis in this study (Fig. 2).

The interval between the date of surgery and the start of RT was also investigated (Table S3). While there was no significant difference in the median interval, the third interquartile was higher in the SCRT group, particularly among those under the age of 65 who were receiving SCRT. In the histogram that categorized participants by interval, SCRT in the group aged 65 and over frequently started between 25 to 35 days after planning. However, in the group under 65, there was no consistent pattern observed with many cases having intervals exceeding 40 days (Figure S2).

Overall survival

A survival analysis was performed on 1,598 cases. The overall median OS for all 1,598 subjects, starting from the date of the first radiation treatment, was 15.6 months (95% CI: 14.9–16.4 months). When categorized by age group, the median OS for the elderly group was 12.7 months (95% CI: 11.7–13.7 months). For the non-elderly group, the median OS was 18.2 months (95% CI: 16.9–19.7 months). Regarding the RT course, cases who received SCRT (n = 197) had a median OS of 10.4 months (95% CI: 9.6–12.8 months), while those who received LCRT (n = 1401) had a median OS of 16.2 months (95% CI: 15.5–16.9 months). To account for potential confounding factors (age, temozolomide treatment, gender) that could affect OS, a statistical analysis comparing SCRT and LCRT was conducted using pseudo-data generated by S-IPTW (Table S1 for SCRT and Table S2 for LCRT). In the entire age group, the median OS was 12.8 months (95% CI: 10.7–13.7 months) for the SCRT group (n = 242) compared to 15.9 months (95% CI: 15.1–16.6 months) for the LCRT group (n = 1399), yielding a hazard ratio (HR) of 1.296 (95% CI: 0.937–1.726). The non-inferiority HR margin was set at 1.32. The non-inferiority p-value was 0.4498, indicating that the inferiority could not be rejected, thus revealing a statistically significant difference in OS among all cases (Fig. 3A). However, in patients aged 65 or more, the median OS was 10.6 months (95% CI: 8.9–14.0 months) for the SCRT group (n = 147) compared to 13.2 months (95% CI: 12.1–14.0 months) for the LCRT group (n = 541), yielding an HR of 1.043 (95% CI: 0.8545–1.273). The p-value for the non-inferiority test was 0.0152, indicating rejection of inferiority and confirming no statistical difference in OS among elderly patients. Moreover, the Kaplan-Meier analysis using the Gehan-Breslow test showed a p-value of 0.220 (Fig. 3B). In patients under the age of 65, the difference in median OS between SCRT (n = 40) and LCRT (n = 864) was more pronounced. It was 10.9 months (95% CI: 9.9–18.4 months) for SCRT versus 18.7 months (95% CI: 17.3–20.2 months) for LCRT. The hazard ratio (HR) was 1.846 (95% CI: 1.117–2.894). The p-value for the non-inferiority test was 0.9280. The Kaplan-Meier (K-M) plot visually demonstrated differences between the two groups (Fig. 3C).

Treatment cost

Treatment cost included all expenses claimed to HIRA during RT. This encompassed the fee for each daily RT session, charges for computed tomography (CT) simulation, planning fees, and all reimbursed costs during RT sessions. These costs also included the price of temozolomide, and the cost of inpatient treatment if patients were admitted to a hospital or healthcare facility. However, due to limitations of this database, it was not possible to investigate costs that fell outside the scope of reimbursement. As expected, there was a statistically significant difference (p < 0.001) in total treatment costs of approximately 6,000 USD between SCRT and LCRT groups. Furthermore, a median cost difference of about 10,000 USD was observed between those who received temozolomide treatment and those who did not (Table 2).

Table 2

Total treatment cost based on claimed to HIRA during RT
	SCRT	LCRT	p-value^*
All cases Cost, KRW(USD)^†
Median	26,144,800 (19,367)	34,893,280 (25,847)	< 0.001
IQR	17,905,660–56,075,260	31,626,680–62,036,020
Case treated with Temozolomide Cost, KRW(USD)^†
Median	32,934,290 (24,396)	48,028,220 (35,576)	< 0.001
IQR	20,532,245–60,460,840	32,672,880–77,424,270
Case treated without Temozolomide Cost, KRW(USD)^†
Median	19,447,860 (14,405)	32,457,970 (24,043)	< 0.001
IQR	16,775,760–39,897,500	28,525,925–34,582,305
≥ 65 years Cost, KRW(USD)^†
Median	26,970,800 (19,978)	35,465,320 (26,271)	< 0.001
IQR	17,905,660–56,602,440	31,396,460–60,559,560
< 65 years Cost, KRW(USD)^†
Median	25,170,660 (18,645)	34,755,790 (25,745)	< 0.001
IQR	18,211,220–46,353,040	31,743,975–64,046,055
*: from Mann-Whitney U-test, †: 1 US dollar (USD) = 1350 Korean Won (KRW)

Effect of temozolomide

Survival analysis was conducted separately by age group to examine the impact of concurrent temozolomide treatment. However, S-IPTW was not applied in this analysis. In the elderly group (aged 65 years or more), there was no statistically significant difference in OS between those with concurrent temozolomide and those without. The median OS for the elderly group with concurrent temozolomide was 13.4 months (95% CI: 11.8–14.3 months), which was not statistically different from the median OS of the group without concurrent temozolomide (12.2 months, 95% CI: 10.2–13.9 months). In the group under 65, although there was a statistically significant difference in OS based on the Log-rank test (p-value = 0.026), the difference was only 7 days, which was considered clinically insignificant. The median OS for those with concurrent temozolomide was 18.1 months (95% CI: 16.7–19.7 months), compared to 18.4 months (95% CI: 16.0–21.2 months) for those without concurrent temozolomide. When the Gehan-Breslow test reflecting differences during the early observation period, was conducted, the p-value was 0.126, indicating no significant difference (Figure S3).

Among the 1039 cases with concurrent temozolomide treatment history, 366 cases who did not have temozolomide treatment after RT had a median OS of 13.4 months (95% CI: 11.7–15.9 months), while 673 cases who received temozolomide prescription at least once after RT had a median OS of 16.5 months (95% CI: 15.3–17.3 months). Kaplan-Meyer analysis did not show a statistical difference between the two groups in the log-rank test (p-value = 0.094). However, the Gehan-Breslow test did show a statistically significant difference (p-value < 0.001) (Figure S4). Among cases with a temozolomide prescription history, an in-depth analysis was conducted on the standard temozolomide treatment which entailed at least five five-day temozolomide administration cycles after RT. According to this benchmark, 307 cases were categorized as the standard group with a prescription history of at least 25 days (5 cycles x 5-day) following RT (Figure S5). After S-IPTW, the median OS for the group that completed standard treatment was 22.5 months (95% CI: 20.2–24.6 months), compared to 12.3 months (95% CI: 11.4–13.6 months) for the group with incomplete standard treatment. The hazard ratio (HR) was 0.521 (95% CI: 0.439–0.617, p-value < 0.001) by the Cox proportional hazard model (Figure S6A). Both elderly (median OS 22.1 months vs. 11.5 months, Figure S6B) and non-elderly (median OS: 23.6 vs. 13.2 months, Figure S6C) groups showed similar results, demonstrating that patients who completed standard temozolomide therapy had a statistically significant increase in OS.

In this study, the median OS of all eligible cases was 15.6 months, relatively longer than the previously reported OS of 8 months for all GBM patients [2]. However, the median OS in this study was similar to the previously reported OS of treated patients, which was 14 ~ 16 months [18], although there was about 1-month difference in the start date of OS calculation (diagnosis date vs. the 1st day of RT in this study). The primary endpoint of this study was to the effect of SCRT on survival. In entire cases, SCRT showed significantly worse results in OS than LCRT. However, results were different when limited to cases aged 65 and older. There was no statistically significant difference in OS between SCRT and LCRT groups in the elderly group. This result was consistent with key randomized trial results [7, 8], suggesting that for patients over 65, following guidelines that recommend SCRT could yield comparable results to those of LCRT.

This study showed a median OS of 12.7 months for cases aged 65 years or more. The choice of defining "elderly" at 65 years old in this study might be subject to some disagreement, as some consider 70 years to be the threshold for elderly patients [11]. We used a cut-off of 65 years for elderly patients based on benchmark studies by Perry et al. [19], Wick et al. [20], and Roa et al. [9] using 65 years as a cut-off for elderly patients.

The OS result of this study contrasted with previous Real-World Evidence (RWE) studies. Haque et al. [10] have investigated 5126 patients aged 65 years or more from 2006 to 2012 and found a statistically significant difference in OS (6.2 months for SCRT vs. 10.7 months for LCRT, p < 0.001). Mak et al. [11] have conducted a similar study on the elderly aged 70 years or more and obtained similar results (4.9 months for SCRT vs. 8.9 months for LCRT). We hypothesize that this significant difference on OS between SCRT and LCRT might be due to two main reasons. First, the difference in the RT method. The two previous studies were conducted before the era of IRMT. SCRT inevitably increases the radiation dose per fraction. Three-dimensional RT has a larger treatment field in the non-target brain than IMRT, increasing radiation therapy toxicity. This might have contributed to the poorer outcome of the SCRT group. Second, there were significant differences in proportions of SCRT and LCRT patients. In both studies, the number of LCRT cases was more than 10 times greater than that of SCRT cases. Besides the numerical difference in frequency, this potentially indicated that the SCRT group was assigned to patients who were more fragile or difficult to treat. This possibility cannot be ruled out. Taking these points into consideration, results of this study suggest that SCRT can be considered at least as a non-inferior treatment method for patients aged over 65 years or more. Furthermore, Trone et al. [21] have conducted a meta-analysis and found that SCRT can result in comparable survival outcomes with an added benefit of a shortened duration of treatment. The advantage of this shortened duration was also shown to have cost-benefit as confirmed by the secondary endpoint in the present study.

Another debate that may arise regarding this study was the definition of SCRT in terms of fraction numbers. Our database research confirmed that a 15-fraction treatment schedule was predominantly used, while 5- or 10-fraction treatments, which were not investigated in this study, were also administered in real-world settings in Korea, although they were rare (Fig. 2). However, several studies have defined SCRT as a shorter schedule consisting of only 5 or 10-fractions of RT. A phase 3 study conducted by Roa et al. [9] has compared a 15-fraction schedule with a total radiation dose 40Gy to a 5-fraction schedule with a total radiation dose of 25Gy. Their study reported no difference in OS between the two schedules. Furthermore, a meta-analysis of four studies on SCRT schedules also found no significant difference among evaluated schedules [22]. Ongoing research is being conducted to explore increasing the total treatment dose even within the a 15-session schedule [23]. Some investigators have defined 25 sessions as moderately hypofractionated SCRT [24]. Therefore, further research is warranted to determine the optimal hypofractionation of the RT schedule.

To the best of our knowledge, studies comparing the cost of SCRT and LCRT have not been reported yet. However, this study showed a significant reduction in total treatment cost for SCRT compared to LCRT. It was observed that there was a median cost saving of USD 6,000 per case. In South Korea, the billing structure for radiation therapy is on a per-fraction basis, rather than charging for all treatment sessions. This means that the reduced number of radiation therapy fractions directly leads to a cost reduction. In addition to cost savings, SCRT also offers several other benefits from the patient's perspective, including reduced traveling expenses, decreased cost of hospitalization, and allowing for a faster return to daily life. Therefore, assuming that there is no disadvantage in terms of survival, SCRT may be a favorable treatment option. It can help reduce overall treatment costs while also potentially improving patient convenience and the overall medical experience. These findings provide valuable information for healthcare policymakers and offer important criteria for selecting efficient and cost-effective treatment methods.

Regarding the effect of standard temozolomide as an exploratory endpoint, treatment for five or more cycles after completion of RT showed a statistically significant effect on OS in all age groups (Figure S6). Although there was no difference in OS in the initial analysis based solely on the history of temozolomide treatment, the above results confirmed the importance of compliance with standard temozolomide after RT. From the introduction of temozolomide, the role of adjuvant temozolomide after RT has been well known [25, 26]. It has also improved survival outcomes in SCRT [19, 27]. Results of this study indicate that completing the standard, including the adjuvant temozolomide schedule, is associated with improved survival outcomes.

Despite the above results, this study also has limitations. Firstly, the availability of qualitative demographics regarding patients' overall performance status and medical conditions was severely restricted, which posed challenges in analyzing the impact of these related factors. Secondly, it was difficult to identify pathologic characteristics beyond the diagnosis of GBM. Distinguishing whether GBM was secondary GBM from another glioma was difficult and crucial prognostic factors such as IDH (isocitrate dehydrogenase) mutation status and O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation status remained unknown. The absence of detailed genetic and molecular profiling limited our ability to stratify cases based on prognostic and therapeutic markers.

Despite these limitations, one of the most significant aspects of this study was its ability to evaluate actual real-world treatment outcomes in the era of widespread use of IMRT. This was accomplished by utilizing seamless cancer registry data and actual mortality registration data from all patients across various medical institutions. This approach allowed for a comprehensive analysis of treatment efficacy and patient survival in a real-world setting, providing valuable insights into the effectiveness of IMRT and its impact on patient care. Recently, researchers have been attempting to address limitations by adding missed information and combined big data from individual medical institutions after joining process. It is anticipated that further insights can be gained by applying this same approach to the database used in this study in the future.

In conclusion, real-world evidence (RWE) showed that SCRT was associated with similar OS rates for elderly patients aged 65 or more when compared to LCRT. Furthermore, SCRT was found to reduce health insurance claims costs by over 20%. Additionally, completing the standard temozolomide treatment after RT improved the OS of patients with GBM. This evidence strongly supports the wider implementation of SCRT, particularly in elderly GBM patients, as a cost-effective and efficient treatment option.

Conflict of interest:

The authors declare that none of them have any conflicts on interest in relation to the present publication.

Author Contribution

Author contributionsConception and design: Y.K.W, E.S.K, I.Y.J, H.J.O, S.M.L, I.D.Y, S.P.H, J.W.L, J.H.S, H.S.JCollection and assembly of data: Y.K.W, I.N.Y, N.Y.K Data analysis and interpretation: Y.K.W, H.J.O, J.H.S, N.Y.K, H.S.JManuscript writing: All authorsFinal approval of manuscript: All authors

Acknowledgement

Statistical analysis was supported by CC&I Research. This research was supported by data from the Korea Healthcare Bigdata of the Ministry of Health and Welfare in 2022. (NO. 2022-00081)

Data Availability

The anonymized joint database used in this study was analyzed within Korea Healthcare Bigdata’s computing facilities where external data removal was prohibited. Researchers only possessed results allowed for external release. Data access and reanalysis are possible within 2024. Any inquiries regarding this study's data and statistics should be directed to the first author at [email protected].

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Comparative Analysis of Hypofractionated Short-Course Versus Standard Radiation Therapy in Elderly Patients with Glioblastoma: Analysis of Nationwide Database

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