Comparison of Quality of Life in Postoperative High-Grade Glioma Patients Treated Using EORTC and RTOG Target Delineation Techniques for Postoperative Radiotherapy

Keywords

glioma - high-grade - brain - radiotherapy - quality of life - neurocognitive functions - FACT-Br

Introduction

High-grade gliomas (HGGs) are primary brain tumors arising from abnormal glial cells with a global incidence of 3.56 per 1 lakh population, with a male preponderance (GLOBOCAN).[1] HGGs include World Health Organization (WHO) grade IV glioma (glioblastoma multiforme [GBM]), anaplastic astrocytoma (AA), and anaplastic oligodendroglioma (AO) histologies. Treatment of HGGs involve a multimodality approach involving maximal safe resection and adjuvant chemoradiation (CTRT) to a dose of 60 Gy/30 fractions with temozolomide (TMZ) followed by at least 6 months of TMZ. Despite this trimodality treatment, the estimated 2-year overall survival (OS) has remained dismal with a median survival of 2, 3, and 5 years, respectively, for GBM, AA, and AO.[2] [3]

Brain Tumour Co-operative Group trial 6901(BTCG) and Scandinavian Glioblastoma Study Group (SGSG) landmark trials by Walker et al and Kristiansen et al were the first to establish the role of adjuvant CTRT over best supportive care postsurgery.[4] [5] Historically, radiation treatment of HGGs involved using conventional whole brain radiotherapy (WBRT), which was associated with reduced OS due to large brain volume irradiated. Over the years, the two-dimensional technique gave way to more conformal techniques like the 3D conformal radiotherapy (RT) and currently intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT) using computed tomography (CT)-based treatment planning system with fusion of magnetic resonance imaging (MRI). This leads to better target delineation; decreasing normal tissue volume receiving high doses, in turn decreasing adverse effects like deterioration in neurocognitive functions (NCFs) and quality of life (QOL) while enabling better radiation dose coverage to the tumor and lesser dose to the organs at risk (OARs).[5] [6] [7] [8] [9] [10]

With imaging in target delineation, an important question posed was what should be taken as a disease. RT volume gradually evolved from WBRT to focal irradiation after the incorporation of MRI in RT planning in the 1980s.[11] There is conflicting data regarding presence of tumor cells in the peritumoral edema surrounding the enhancing postoperative cavity. Therefore, two target volume delineation guidelines are in practice—the European Organization for Research and Treatment of Cancer (EORTC), where the resection cavity and residual enhancing lesion with a margin is treated, and the Radiotherapy and Oncology Group (RTOG), where the same along with peritumoral edema (T2 fluid-attenuated inversion recovery [FLAIR] abnormality) with margin is treated. Treating a larger area can be hypothesized to cause more toxicity, while avoiding peritumoral edema might lead to disease being left behind. Both techniques are used according to physicians' discretion.[12] [13] [14] [15] [16] [17] [18] [19] [20] The retrospective series by Paulsson et al did not show any difference in pattern of failure in patients with different clinical target volume (CTV) margins ranging from 5 to 20 mm.[21] There has been no prospective data comparing these two techniques.

During the disease process, treatment, or both, patients develop neurocognitive deficits, subsequently affecting their QOL. NCF in glioma patients can be affected by the tumor due to tumor-related epilepsy, surgery, RT, chemotherapy, antiepileptics, corticosteroids, and patient-related factors including age and psychological distress.[22] [23] [24] Treatment overall was found to improve QOL, and the RTOG 0525 study showed that changes in QOL could act as useful markers of response and/or progression.[25] QOL is being recognized as an important yardstick for assessment of treatment and interventions in brain tumors like gliomas as opposed to only survival data as ensuring patients' general well-being becomes more important in such cases with poor survival. QOL measurement involves a multidimensional measurement including physical, functional, social, and emotional well-being of an individual.[26] QOL in the central nervous system tumors is underreported in comparison to sites like breast, lung, or prostate cancer.[27] Multiple tools for assessment of QOL are available, for example, Functional Assessment of Cancer Therapy Brain (FACT-Br), EORTC, and Functional Living Index. In this study, we have used the FACT-Br questionnaire for QOL assessment.[28] There has not been many studies comparing QOL in glioma pre- and post-RT, retrospective studies have shown either minimal improvement or deterioration posttreatment.[29] [30] [31] This study is one of the initial attempts to prospectively compare QOL outcomes of HGG patients treated using EORTC or RTOG delineation guidelines.

Materials and Methods

Study Design

This was a single-center, open-label, randomized trial conducted between January 2020 and April 2022.

Patients

Patients included were those with histologically proven WHO grade III and IV tumors, age between 18 and 70 years with normal pretreatment blood parameters, kidney (KFT) and liver function tests (LFT), and Eastern Cooperative Oncology Group Performance Status 1 to 2. Exclusion criteria included proven 1p19q co-deleted AO, multicentric glioblastoma, cases of previously treated primary brain tumors, those with visual disturbances who were not able to read the questionnaires provided, history of Alzheimer's disease, Parkinson's disease, any form of dementia, those with contraindications for MRI examination or gadolinium agent use, and pregnant or nursing mothers. The study was started after institutional ethics committee approval. Informed written consent was taken from the patients, after explaining the detailed plan, purpose, and duration of the study in their own language

Randomization and Masking

Sample size of 50 was planned according to yearly registration data in our institute. This sample size was planned based on an exploratory nature and not based on statistical power calculation. These patients were randomized into two groups—EORTC and RTOG arm based on computer-generated randomization table.

Procedure

All patients underwent pretreatment evaluation, which included history and physical examination, hemogram, KFT, LFT, and contrast-enhanced MRI (CE-MRI) brain (postop and planning MRI). QOL assessment was done before starting RT using self-administered FACT-Br questionnaire consisting of a group of self-administered tools measuring QOL in patients with cancer. In addition to the core questionnaire (FACT-General [FACT-G]), tumor-specific assessments are available for supplementation with this general cancer questionnaire. The FACT-Br is specific to brain tumors and metastasis, consisting of 50 questions covering five multi-item domains, namely, physical (PWB), social (SWB), functional (FWB) (each having scores ranging from 0 to 28), and emotional (EWB) (0–24) well-being, as well as 23 single-item questions regarding brain-specific QOL concerns as Brain Cancer Subscale (BCS) (0–92), which is specially designed for patients with brain tumors. The Trial Outcome Index (TOI) (0–148), FACT-G (0–108), and FACT-Br (0–200) total scores are obtained through calculations of the domains mentioned above. A higher score indicates a better QOL. Contrast-enhanced CT for RT planning was done on GE Optima machine and the image was imported on to a treatment planning system (MONACO or Eclipse). Postcontrast T1-weighted contrast and fat-saturated T2-weighted sequences were acquired in treatment position using a customized head and neck thermoplastic cast and the same neck rest used for CT scan for positional replication. MRI images obtained in Digital Imaging and Communications in Medicine format was imported to the planning system and registered with CT images. Target delineation was done according to the group allocated. According to the EORTC guideline the postoperative cavity with surrounding contrast enhancement as noted in MRI was given a CTV margin of 2 cm edited according to anatomical barriers, and was treated to 60 Gy in 30 fractions after addition of planning target volume (PTV) margin. In the RTOG group, perilesional edema was delineated on T2 FLAIR sequence and given a margin of 2 cm. This volume is treated to 46 Gy in 23 fractions, with additional PTV. The postoperative cavity with surrounding contrast enhancement was given a margin of 2 cm and was contoured as boost volume and received a boost dose of 14 Gy in 7 fractions. Planning was done by the IMRT/VMAT technique. The radiation dose was prescribed according to the International Commission on Radiation Units and Measurements guidelines to 100% at the isocenter, ensuring 95% isodose surface coverage to at least 95% of the PTV. The dose to the OARs was evaluated to ensure constraint limits and was not crossed in providing a good plan. All patients received RT, 5 days a week with concurrent capsule TMZ 75 mg/m² before RT with necessary supportive medications; TMZ was given all 7 days a week. Patients were monitored for complaints and reviewed weekly with hemogram/KFT/LFT during treatment. All patients received six cycles of adjuvant TMZ 150 to 200 mg/m² starting 4 weeks post-RT from days 1 to 5 of a 28-day cycle after ensuring normal blood investigations for at least 6 months. At 3 and 6 months patients underwent response assessment CE-MRI and QOL evaluation with FACT-Br questionnaire.

Statistical Analysis

Data collection was done on Microsoft Excel. At the end of the study, data obtained was analyzed using the IBM SPSS 23 software. Descriptive statistics were used to convey demographic data, proportions for categorical variables, and mean, median, range, and standard deviation (SD) for continuous variables. Effect size was assessed using partial eta squared test where values of 0.01, 0.06, and 0.14 signify small, medium, and large effect size, respectively. Repeated measures analysis of variance test was used for comparison of means and assessment of QOL between the EORTC and RTOG groups at 6 months. Mauchly's test of sphericity was used to test for sphericity. Absolute volume of PTV receiving 46 and 60 Gy in each arm were described, PTV 46/60 was also described in terms of % of whole brain volume. The absolute volume of the body receiving 46 and 60 Gy was described.

Results

Between January 2020 and August 2021, 28 patients were recruited according to the inclusion and exclusion criteria. Due to the coronavirus disease 2019 (COVID-19) pandemic, we could recruit only 28 patients in the study. Final analysis included 18 patients ([Fig. 1]). The EORTC (group 1) and the RTOG (group 2) arm each had 9 patients who were planned to receive RT according to the respective target delineation guidelines. All patients recruited were contoured, planned for treatment, and underwent QOL assessment before the treatment and received concurrent TMZ and at least six cycles of adjuvant TMZ. Their age ranged from 29 to 57 in the EORTC arm and 31 to 67 in the RTOG arm with the most common age group overall being 41 to 50 years in both groups. The median age in the EORTC arm was 42 years and in the RTOG arm was 41 years. The ratio of male to female patients was 14:4, out of the 4 female patients 2 each were in the EORTC and RTOG arm. WHO grade IV was the most common histology with the most common site of tumor being the frontal region ([Table 1]). The T1contrast enhancing postoperative cavity (residual volume or gross tumor volume) in the EORTC arm ranged from 22.6 to 102 mL while in the RTOG arm the residual volume of disease ranged from 25.7–to 121 mL.

Fig. 1 Consort diagram.

Table 1 Patient characteristics

	EORTC group (no. of patients)	RTOG group (no. of patients)
Age group (y)
< 30	3	0
31–40	1	4
41–50	3	4
51–60	2	0
> 60	0	1
Tumor location
Frontal	3	5
Parietal	3	0
Temporal	2	4
Occipital	0	1
Tumor grade
Grade III	2	4
Grade IV	5	5
Gliosarcoma	2	0
Duration of treatment
< 42	4	5
43–46	3	4
47–50	1	0
> 50	1	0
Extent of resection
GTR	4	3
NTR	3	1
STR	2	5

Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; GTR, gross total resection; NTR, near-total resection; RTOG, Radiotherapy and Oncology Group; STR, subtotal resection.

In our study, we had two PTV volumes of irradiation. PTV46 circumscribed the perilesional edema contoured in the RTOG group and was prescribed a dose of 46 Gy. The absolute PTV46 volume in RTOG varied from 298.2 to 622 mL and is described in [Table 2]. The mean PTV 46 Gy volume in the RTOG arm was 466.13 mL (SD of ± 138.6).

Table 2 Absolute PTV 46 and PTV 60 volumes

Absolute PTV 46 volumes received by number of patients		Absolute PTV 60 volumes received by number of patients
PTV 46 (in mL)	RTOG	PTV 60 (in mL)	RTOG	EORTC
< 300	1	< 300	4	4
300–450	3	300–450	4	4
450–600	4	450–600	1	0
> 600	1	> 600	0	1

Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; PTV, planning target volume; RTOG, Radiotherapy and Oncology Group.

PTV 60 Gy is the volume which is prescribed a dose of 60 Gy and is common to both the EORTC and RTOG groups. The absolute PTV 60 Gy volume values are represented in [Table 2]. PTV 60 Gy volume of more than 40% was irradiated in 11% of the patients in the EORTC arm while none of the patients in the RTOG arm. The mean PTV 60 Gy volume in EORTC was 335 mL (SD ± 131.2) and in the RTOG arm was 318.8 mL (SD ± 81.2). The PTV 46 volume was higher in the RTOG versus the EORTC group while the PTV 60 volumes were comparable.

Significant improvement was noted in posttreatment in PWB (p = 0.007, large effect size), though there was no significant difference between the two arms posttreatment (p = 0.2).

As per the line diagrams ([Figs. 2] and [3A–D]) comparing the mean differences in QOL between the EORTC and RTOG arms at 0 and 6 months, the baseline values were lower in the EORTC arm compared with RTOG in PWB, FWB, EWB, BCS, TOI, FACT-G, and FACT-Br total score. Improvement was noted posttreatment in the EORTC arm in all parameters; differences in points ranging from 0.7 to 19 except SWB, which showed a deterioration of 3 points posttreatment. In the RTOG arm improvement was noted in PWB, SWB, and EWB (0.6–5 points) while all other parameters showed deterioration. The only significant improvement was noted in the overall posttreatment values in PWB (p = 0.007, large effect size). ([Table 3]).

Fig. 2 (A–D) Comparison of quality of life (QOL) at baseline vs. 6 months European Organization for Research and Treatment of Cancer (EORTC) vs. Radiotherapy and Oncology Group (RTOG).

Fig. 3 (A–D) Comparison of quality of life (QOL) at baseline vs. 6 months European Organization for Research and Treatment of Cancer (EORTC) vs. Radiotherapy and Oncology Group (RTOG).

Discussion

Due to the poor survival associated with HGGs even after treatment, it has become important to find a solution wherein treatment also considers the QOL and NCF status of patient along with survival. Overall, we found a statistically significant improvement posttreatment in PWB of the entire cohort of patients. The volume of brain irradiated is an important factor determining the NCF decline and thus the overall QOL. This study did not show any statistically significant difference in any of the QOL parameters between the two different CTV delineation guidelines. It is noteworthy that the magnitude of improvement in the EORTC arm was higher in comparison to the RTOG arm without statistical significance.

With the advent of more conformal techniques of RT like IMRT there is significant decrease in the volume of normal tissue treated to high dose, in turn reducing radiation-related adverse effects, but there is no consensus in terms of the precise volume to be irradiated. This is because of the two schools of practices in place—the EORTC and RTOG guidelines target delineation both of which are used according to physician discretion, patient, and disease characteristics. The present study is an endeavor to compare the superiority of target delineation guidelines of EORTC and RTOG in terms of differences in the QOL posttreatment.

The extent of tumor resection is an important prognostic factor as gross tumor resection (GTR) is associated with longer survival while subtotal resection (STR) and absence of surgery are associated with poor prognosis. In our study, most patients had GTR (7 patients) and STR (7 patients). The volume of the residual tumor present before RT start is an important factor of prognosis. Lesser the volume, the better the progression-free survival and QOL.

No comparative study has evaluated the volume of brain irradiated between the two groups. According to the study by Kumar et al,[32] which compared the volume of irradiation between the RTOG and MD Anderson Cancer Center (MDACC) guidelines of target delineation, which has a smaller volume of irradiation, V60 volume was much lower in the MDACC arm, which was associated with better survival outcomes and QOL. In the present study, more than 40% of the brain was irradiated to at least 46 Gy in 20% of patients in the RTOG arm versus 10% in the EORTC arm. In terms of V60 volume, more than 40% of the brain irradiated to 60 Gy was present in only 11% of the patients in the EORTC arm and none in the RTOG arm. The volume of the brain receiving 60 Gy was similar in both groups. This finding was similar to what was noted in a study by Yan et al.[33]

Though it has been established that QOL is an important parameter to assess in patients with HGG, there is no universal standard for it.[25] There has not been much literature comparing change in QOL with treatment in HGGs. The study by Haraldseide et al[34] noted that most QOL assessments were done postsurgery. Though the QOL tool was not found to correlate with survival, the authors advocated recording it presurgery to assess treatment impact. A longitudinal cohort study by Drewes et al followed up and assessed QOL in patients postsurgery for 6 months, which was found to deteriorate.[31] The study by Bitterlich and Vordermark,[35] compared QOL in all patients with brain tumors before and after treatment, found only minimal improvement in the overall QOL posttreatment, while earlier studies showed deterioration in QOL posttreatments, which have been attributed to the declining NCF when irradiating large volume of the brain as in the RTOG delineation technique. In this study, statistically significant improvement was noted posttreatment in PWB (p = 0.007). Though there were no significant differences noted posttreatment between the two arms, it should be noted that patients in the EORTC group had lower baseline values compared with RTOG; EORTC showed larger values of improvement in 7 of the 8 domains at 6 months compared with patients in RTOG who showed only minimal improvement from baseline in 3 out of the 8 domains. We also believe that the COVID-19 pandemic affected diagnosis, treatment, and follow-up adversely due to disruption of oncological services in the dire times, which not only affected patient recruitment but also QOL findings in our study. No earlier study has systematically assessed QOL post-RT during follow-up. To the best of our knowledge, this study is the first of its kind to prospectively compare EORTC and RTOG target delineation techniques in terms of improvement in QOL and herein lies its importance.

Several factors affect QOL like patient, tumor, and treatment-related factors.[6] The higher QOL scores in RTOG at baseline probably reflect this fact. The main focus of our study was RT volume and this baseline difference in factors could have affected our results. In conclusion, we believe that QOL is multifactorial and the RT volume as such does not contribute much to the QOL of HGG patients. The major limitation of this study is its small sample size making it difficult to make a meaningful conclusion.

Conclusion

In conclusion, a statistically significant improvement was seen in PWB with treatment irrespective of the treatment arm. Though no significant differences were noted between the findings in both the groups, the mean differences in improvement were higher in the EORTC group. A large sample size is required to detect a meaningful difference in QOL. Considering the multifactorial nature of QOL and the relative rarity of these tumors, it may not be possible to recruit such a large population of patients to detect any such difference. Both CTV delineation techniques seem to yield comparable QOL.

Table 3 Comparison of pre- and posttreatment scores—overall and EORTC vs. RTOG

	Pre- vs. post-6 months treatment for all patient cohort				Pre- vs. post-6 months treatment EORTC vs. RTOG over time
Quality of life (QOL)	p-Value	F-Value	Partial eta squared	Effect size	p-Value	F-Value	Partial eta squared	Effect size
Physical well-being (PWB)	0.007	9.46	0.37	Large	0.215	1.67	0.09	Small
Social well-being (SWB)	0.207	1.73	0.10	Medium	0.090	3.16	0.17	Large
Emotional well-being (EWB)	0.166	2.11	0.12	Medium	0.424	0.67	0.04	Small
Functional well-being (FWB)	0.881	0.02	0.001	Small	0.599	0.29	0.02	Small
Brain Cancer Subscale (BCS)	0.258	1.38	0.08	Small	0.157	2.20	0.12	Medium
FACT-Br-Trial Outcome Index (TOI)	0.226	1.58	0.09	Small	0.167	2.10	0.12	Medium
FACT-G total score	0.849	0.04	0.002	Small	0.304	1.13	0.07	Small
FACT-Br total score	0.190	1.87	0.11	Medium	0.177	1.99	0.11	Medium

Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; FACT-Br, Functional Assessment of Cancer Therapy Brain; FACT-G, Functional Assessment of Cancer Therapy General; PTV, planning target volume; RTOG, Radiotherapy and Oncology Group.

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