AbstractPurposeTo evaluate recurrence patterns of and survival outcomes in glioblastoma treated with intensity-modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3D-CRT).
Materials and MethodsWe retrospectively examined 91 patients with glioblastoma treated with either IMRT (n = 60) or 3D-CRT (n = 31) between January 2013 and December 2019. Magnetic resonance imaging showing tumor recurrence and planning computed tomography scans were fused for analyzing recurrence patterns categorized as in-field, marginal, and out-of-field based on their relation to the initial radiation field.
ResultsThe median overall survival (OS) was 18.9 months, with no significant difference between the groups. The median progression-free survival (PFS) was 9.4 months, with no significant difference between the groups. Patients who underwent gross total resection (GTR) had higher OS and PFS than those who underwent less extensive surgery. Among 78 relapse cases, 67 were of in-field; 5, marginal; and 19, out-of-field recurrence. Among 3D-CRT-treated cases, 24 were of in-field; 1, marginal; and 9, out-of-field recurrence. Among IMRT-treated cases, 43 were of in-field; 4, marginal; and 10, out-of-field recurrence. In partial tumor removal or biopsy cases, out-of-field recurrence was less frequent in the IMRT (16.2%) than in the 3D-CRT (36.3%) group, with marginal significance (p = 0.079).
ConclusionIMRT and 3D-CRT effectively managed glioblastoma with no significant differences in OS and PFS. The survival benefit with GTR underscored the importance of maximal surgical resection. The reduced rate of out-of-field recurrence in IMRT-treated patients with partial resection highlights its potential utility in cases with unfeasible complete tumor removal.
IntroductionGlioblastoma, the most aggressive and prevalent form of primary brain tumor accounting for 14.2% of all intracranial neoplasms in United States [1], continues to pose a formidable challenge. The key pathologic feature of glioblastoma is the infiltration of tumor cells into the surrounding normal brain parenchyma. Due to its extensive infiltrative nature, the standard treatment protocol includes maximal safe surgical resection followed by radiotherapy with significant margins, along with concomitant and adjuvant chemotherapy [2-5]. Despite advancements in surgical techniques and adjuvant therapies, the prognosis of patients with glioblastoma remains poor with a median survival of approximately 13 to 15 months [2-4].
Two techniques are predominantly used in radiotherapy: three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). The 3D-CRT has been the mainstay treatment for glioblastoma, providing a high degree of conformality while sparing normal tissues [6]. However, the advent of IMRT has introduced the potential for further dose optimization, allowing for more precise dose delivery to the tumor volume while minimizing exposure to surrounding normal tissues [7,8]. Compared with 3D-CRT, IMRT reduced the percent brain volume receiving >45 Gy by 40% [9]. There exists an ongoing debate regarding its clinical superiority over 3D-CRT in treating glioblastoma. Concerns persist that the sharp dosimetric fall-off characteristic of IMRT might contribute to higher marginal recurrence rates, which is a significant issue given the infiltrative nature of glioblastomas [10]. Therefore, this study aimed to compare the failure patterns of IMRT and 3D-CRT in treating glioblastomas and contribute to the body of evidence guiding clinical decision-making in managing this challenging disease.
Materials and Methods1. Patient selectionWe retrospectively examined 91 patients with glioblastomas treated with radiation therapy between January 2013 and December 2019 at Seoul St. Mary’s Hospital. The inclusion criteria were histologically confirmed glioblastoma classified according to the 2016 World Health Organization Classification of Tumors of the Central Nervous System [11], following surgery or biopsy studies, and received adjuvant radiation therapy. The exclusion criteria were previous brain radiation therapy, radiation therapy discontinued midway, no follow-up diagnostic images after radiation therapy, and diagnosed with another primary cancer within 5 years before glioblastoma diagnosis (exceptions were made for primary cancers not affecting the treatment and follow-up of glioblastomas).
2. Treatment protocolBrain magnetic resonance imaging (MRI) and computed tomography (CT) were performed to determine tumor location. All patients underwent surgery or biopsy studies for histological confirmation. All received adjuvant radiation therapy either with or without concurrent temozolomide. Concurrent chemoradiation therapy involved the administration of temozolomide (TMZ) at a dose of 60-80 mg/m2/day throughout the radiation therapy period. Adjuvant TMZ was administered at 150–200 mg/m2 for 5 days in 28-day cycles, for up to six cycles. The detailed chemotherapy regimen and dosage are summarized in Table 1. CT simulation was conducted with the head secured using thermoplasty. The gross target volume (GTV) was defined as the surgical resection cavity plus any residual tumor identified in post-contrast T1-weighted MRI scans. The clinical target volume (CTV) was defined as the GTV with an added 2 cm margin. The planning target volume was defined as the CTV with an additional 3–5 mm margin, in accordance with the ESTRO-ACROP guidelines [12]. Both 3D-CRT and IMRT were performed using CT-based treatment planning. The radiation therapy dose for all patients was 59.4–60 Gy, administered in 30–33 fractions (1.8–2.0 Gy daily fraction).
3. Dosimetric analysis of recurrenceTo analyze recurrent tumor dosimetry, the initial radiotherapy-planning CT scan was fused with the follow-up brain MRI scan using MIM software (version 7.1.0; MIM Software, Cleveland, OH, USA). The radiation oncologist then defined and contoured the recurrent tumor volume based on the T1-weighted enhancing mass on brain MRI.
Recurrence patterns were classified as follows [13-16] (Fig. 1). In-field recurrence: 80%–100% of the recurrent gross tumor volume (rGTV) intersects with the prescribed 95% isodose line of the radiation target field volume. Marginal recurrence: 20%–80% of the rGTV intersects with the prescribed 95% isodose line of the radiation target field volume. Out-of-field recurrence: <20% of the rGTV intersects with the prescribed 95% isodose line of the radiation target field volume.
4. Statistical analysisStatistical analyses were performed using R version 4.3 (https://www.r-project.org) and Statistical Package for Social Sciences version 18 (SPSS Inc., Chicago, IL, USA). The primary endpoints were overall survival (OS) and progression-free survival (PFS). Survival rates were estimated using the Kaplan–Meier method, and differences between groups were tested using the log-rank test. Cox proportional hazards model was used to perform univariate analysis. Categorical variables were compared using the chi-square or Fisher exact test. Statistical significance was set at p < 0.05.
Results1. Patient outcomesThe median follow-up time was 18.9 months (range, 4.9 to 121.7). The median age was 59 years, with a balanced distribution between the two treatment groups. IMRT (n = 60) and 3D-CRT (n = 31) were the treatment modalities. Patient characteristics are summarized in Table 1. The median OS was 18.9 months. The median PFS was 9.4 months. For patients treated with 3D-CRT, the median OS and PFS were 19.3 and 10.8 months, respectively. For patients treated with IMRT, the median OS and PFS were 18.4 and 8.9 months, respectively. The p-values for OS and PFS between the two treatment groups were 0.363 and 0.731, respectively (Fig. 2). Patients who underwent gross total resection (GTR) had a median OS and PFS of 25.8 and 12 months, respectively. Patients who did not undergo GTR had a median OS and PFS of 17.3 and 8.3 months, respectively. The p-values for OS and PFS between GTR and non-GTR groups were 0.003 and 0.001, respectively. In patients with MGMT (O6-methylguanine-DNA-methyltransferase) methylation, the median OS and PFS were 25.1 and 15.2 months, respectively. The p-values for OS and PFS between MGMT methylated and non-methylated groups were 0.094 and 0.075, respectively (Fig. 3).
2. Recurrence patternSeventy-eight patients experienced recurrence. Twelve patients did not experience recurrence. The recurrent cases were as follows: 67 (73.6%), in-field; 5 (5.5%), marginal; and 19 (20.9%), out-of-field (Table 2). Multiple recurrence types were observed in 12 cases. Among 3D-CRT-treated cases, 24 (70.6%) were in-field; 1 (2.9%), marginal; and 9 (26.5%) out-of-field recurrence. Among IMRT-treated cases, 43 (75.5%) were in-field, 4 (7.0%) had recurrence, and 10 (17.5%) had out-of-field recurrence. The IMRT group had a higher marginal recurrence rate (7.0%, four cases) than the 3D-CRT group (2.9%, one case).
Notably, out-of-field recurrence was more frequent in IMRT-treated patients who underwent GTR than 3D-CRT-treated patients (20.0% vs. 8.3%). However, the odds ratio (OR) was 0.37 (range, 0.01 to 4.49) without statistical significance (p = 0.626). Among patients who did not underwent GTR, out-of-field recurrence was observed in 16.2% of IMRT-treated and 36.3% of 3D-CRT-treated patients with OR of 2.95 (range, 0.86 to 10.12) with marginal significance (p = 0.079) (Tables 2, 3).
Discussion and ConclusionThis study presents an in-depth analysis of recurrence patterns and survival outcomes in glioblastoma treated using IMRT versus 3D-CRT. Despite advancements in radiotherapy, the challenge of effectively managing glioblastoma is underscored by the lack of significant differences in OS and PFS between these two modalities [17]. Our findings demonstrated that IMRT, known for its precision, does not confer a significant survival benefit over 3D-CRT (p = 0.356 for OS; p = 0.728 for PFS), consistent with the broader literature that acknowledges the refractory nature of glioblastoma to various treatment strategies [4,6].
1. Analysis of recurrence patternsIn-field recurrence remains the predominant challenge, consistent with previous studies, suggesting that even with dose escalation, local control of glioblastoma is not substantially improved [14]. This is indicative of the aggressive biological behavior of glioblastoma, which often extends beyond radiographically defined tumor margins and remains elusive even with the most targeted radiation techniques [13].
Marginal recurrence, although less frequent, is a concern, particularly in the context of IMRT. Our data showed a non-significant trend toward higher marginal recurrence rates with IMRT (6.7%) than with 3D-CRT (3.2%). This marginal difference, although not significant (OR = 0.41; p = 0.647), invites a re-evaluation of the IMRT planning processes to ensure that treatment margins are adequate (Fig. 4, Table 3). This trend emphasizes the need for a nuanced understanding of glioblastoma infiltration patterns and perhaps supports a more aggressive margin delineation strategy in line with the ESTRO-ACROP guidelines [12].
2. Impact of surgical extent on recurrence and survivalPatients who underwent GTR showed better survival outcomes, echoing the principle that the extent of surgical resection plays a critical role in glioblastoma management. This is substantiated by significant differences in OS and PFS in favor of GTR (p = 0.003 and p = 0.001, respectively) (Fig. 3) and by existing evidence suggesting that maximal tumor resection is associated with improved survival [1,18]. When comparing the impact of GTR between 3D-CRT and IMRT, the benefit of GTR remains evident. For the 3D-CRT group, GTR had a hazard ratio (HR) of 1.732 for OS (p = 0.176) and 1.796 for PFS (p = 0.141), while for the IMRT group, GTR had an HR of 2.294 for OS (p = 0.004) and 2.413 for PFS (p = 0.004). These results suggest that the advantage of GTR is consistent across different radiotherapy modalities, but it is more statistically significant in the IMRT group (Table 4).
Interestingly, the study found a trend toward higher out-of-field recurrence with IMRT in patients undergoing GTR, although the difference was not significant (OR = 0.37; p = 0.626). This suggests that 3D-CRT is more effective than IMRT in controlling the disease spread outside the primary treatment zone in this subgroup. However, the lack of significance warrants a cautious interpretation. After GTR, the surgical cavity and surrounding tissues may harbor residual microscopic glioma cells not visible on imaging [19]. The less conformal nature of 3D-CRT may cover these regions more effectively, despite the potential for slightly increased toxicity [8,9]. Conversely, the study found a trend toward lower out-of-field recurrence with IMRT in patients who did not receive GTR (OR = 2.95; p = 0.079), although this did not reach conventional levels of significance (p = 0.079). This implies that without complete surgical removal of the tumor, 3D-CRT may not be as effective in managing potential tumor spread. The near-significant p-value suggests that there is an approximately 195% increase in the odds of out-of-field recurrence with 3D-CRT compared with IMRT, which may be clinically relevant, indicating that IMRT could be a better option in cases where GTR is not achieved. Buglione et al. [20] analyzed the pattern of recurrence in patients treated with the Stupp protocol. They found only one case of out-field recurrence in those treated with 3D-CRT, and no out-field recurrence was observed in the IMRT group. Moreover, Morganti et al. [21] specifically analyzed IMRT in a cohort where 12 patients underwent GTR and seven patients did not receive GTR. The out-field recurrence rate was 13.3%, which is lower than our study. The results indicated that IMRT was more effective in reducing out-field recurrences compared to 3D-CRT, highlighting its advantage in non-GTR cases.
3. Comparison of recurrence patterns across studiesOur study's comparison of recurrence patterns (Table 5) is essential for evaluating the effectiveness of radiotherapy in glioblastoma treatment. In our study, the in-field recurrence rate for 3D-CRT was 70.6%, which aligns with historical data from Wallner et al. [22] and Minniti et al. [23], who reported rates of 78% and 81%, respectively. For IMRT, our study showed an in-field recurrence rate of 75.5%, similar to the findings of Langhans et al. [16] and Zheng et al. [24], who reported rates of 75.4% and 83.6%, respectively. Faustino et al. [18] reported an even higher in-field recurrence rate of 83% for their mixed technique group (IMRT of 57%, 3D-CRT of 43%).
In our study, the marginal recurrence rates were 2.9% for 3D-CRT and 7.0% for IMRT. These rates are consistent with those reported by Oppitz et al. [25] for 3D-CRT (3%). However, the marginal recurrence rates reported by Minniti et al. [23] for 3D-CRT (5.7%) and Faustino et al. [18] for their mixed group (9.7%) are broader than our study's definitions, which could explain the higher rate of marginal recurrence. However, although 3D-CRT appears to have a lower tendency for marginal recurrence compared to IMRT, it is difficult to interpret the statistical correlation due to the varying definitions of marginal recurrence in each study.
The out-field recurrence rates in our study were different between 3D-CRT (26.5%) and IMRT (17.5%), even though lacking statistical significance. The out-field recurrence rate is consistent with Morganti et al. [21], who reported a 13.3% out-field recurrence rate for their IMRT group. Faustino et al. [18] reported a lower out-field recurrence rate of 7.3%, which could be attributed to differences in patient selection and treatment protocols.
4. Novelty and limitations of the studyAlthough previous studies have explored various aspects of glioblastoma recurrence patterns [13,16,18,22,23,25-27], our study is the first to specifically compare the recurrence patterns of glioblastoma treated using IMRT and 3D-CRT.
While our findings are promising, they are tempered by certain inherent limitations. The retrospective design, while expedient, is susceptible to biases inherent to post hoc analyses and may not provide the control and randomization offered by prospective studies. The sample size, although adequate for initial observations, requires expansion in future studies to confirm these findings across broader demographic and clinical settings. The single-institution study design may have affected the generalizability of the results, underscoring the need for multicenter studies to validate and extend our findings.
5. Future directionsFuture research should be directed toward enhancing the precision of targeted radiation therapy for glioblastoma. This involves not only improving imaging technologies for tumor delineation but also potentially integrating biomarker-driven strategies to personalize treatment. Such advancements could lead to a reduction in both marginal and out-of-field recurrence, paving the way for improved glioblastoma management and outcomes.
6. ConclusionThe data presented in this study provide a nuanced perspective on the recurrence patterns of glioblastoma treated with radiotherapy. Despite technological advancements in radiotherapy, such as IMRT, our results did not reveal a significant advantage in terms of OS or PFS compared with 3D-CRT. This suggests that factors beyond the scope of radiation technique is instrumental in influencing patient outcomes.
The observed recurrence patterns reinforce the notion that the aggressive biological behavior of glioblastoma may diminish the potential benefits of more precise radiation modalities. In-field recurrence rate remains a principal concern, highlighting the necessity for therapeutic strategies that extend beyond dose escalation. Our study reported slightly higher marginal recurrence rates with IMRT, indicating that even with advanced targeting techniques, achieving complete margin coverage is challenging.
Furthermore, patients who underwent GTR had better survival outcomes, echoing the principle that the extent of surgical resection plays a critical role in glioblastoma management. Conversely, for patients who did not receive GTR, our findings indicated a trend toward lower out-of-field recurrence with IMRT, albeit not significant.
In conclusion, our study provides valuable insights into the collective understanding that personalized and flexible treatment planning are crucial for glioblastoma management. Future research should aim to harness new developments in imaging, radiation planning, and targeted therapies to improve glioblastoma treatment. Our ongoing pursuit is to better manage this challenging cancer and improve patients' quality of life.
Statement of Ethics This study was approved by the Institutional Review Board of Seoul St. Mary's Hospital (No. KC24RASI0363). Table 1.Values are presented as mean ± standard deviation or number (%). 3D-CRT, three-dimensional conformal radiation therapy; IMRT, intensity-modulated radiation therapy; GTR, gross total resection; PTR, partial tumor resection; MGMT, O6-methylguanine-DNA-methyltransferase promoter methylations; CCRT, concomitant chemoradiation therapy; TMZ, temozolomide. Table 2.Table 3.Table 4.OS, overall survival; PFS, progression-free survival; 3D-CRT, three-dimensional conformal radiation therapy; IMRT, intensity-modulated radiation therapy; GTR, gross total resection; MGMT, O6-methylguanine-DNA-methyltransferase promoter methylations; CCRT, concomitant chemoradiation therapy; HR, hazard ratio. Table 5.
References1. Ostrom QT, Price M, Neff C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2016-2020. Neuro Oncol 2023;25:iv1–99.
2. Nam HR, Lim DH, Ahn YC, et al. Outcome of glioblastoma patients treated with surgery and radiation therapy. Radiati Oncol J 2004;22:91–7.
3. Lee SW, Kim GE, Suh CO, Kim WC, Keum KC, Chang SK. Analysis of prognostic factors in glioblastoma multiforme. J Korean Soc Ther Radiol 1996;14:181–90.
4. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96.
5. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ 2021;374:n1560.
7. Xu S, Frakulli R, Lin Y. Comparison of the effectiveness of radiotherapy with 3D-CRT, IMRT, VMAT and PT for newly diagnosed glioblastoma: a Bayesian network meta-analysis. Cancers (Basel) 2023;15:5698.
8. Thibouw D, Truc G, Bertaut A, Chevalier C, Aubignac L, Mirjolet C. Clinical and dosimetric study of radiotherapy for glioblastoma: three-dimensional conformal radiotherapy versus intensity-modulated radiotherapy. J Neurooncol 2018;137:429–38.
9. MacDonald SM, Ahmad S, Kachris S, et al. Intensity modulated radiation therapy versus three-dimensional conformal radiation therapy for the treatment of high grade glioma: a dosimetric comparison. J Appl Clin Med Phys 2007;8:47–60.
10. Khoo VS, Oldham M, Adams EJ, Bedford JL, Webb S, Brada M. Comparison of intensity-modulated tomotherapy with stereotactically guided conformal radiotherapy for brain tumors. Int J Radiat Oncol Biol Phys 1999;45:415–25.
11. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016;131:803–20.
12. Niyazi M, Brada M, Chalmers AJ, et al. ESTRO-ACROP guideline "target delineation of glioblastomas". Radiother Oncol 2016;118:35–42.
13. Lee SW, Fraass BA, Marsh LH, et al. Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 1999;43:79–88.
14. Chan JL, Lee SW, Fraass BA, et al. Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 2002;20:1635–42.
15. Chang EL, Akyurek S, Avalos T, et al. Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma. Int J Radiat Oncol Biol Phys 2007;68:144–50.
16. Langhans M, Popp I, Grosu AL, et al. Recurrence analysis of glioblastoma cases based on distance and dose information. Radiother Oncol 2023;183:109600.
17. Chen YD, Feng J, Fang T, Yang M, Qiu XG, Jiang T. Effect of intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy on clinical outcomes in patients with glioblastoma multiforme. Chin Med J (Engl) 2013;126:2320–4.
18. Faustino AC, Viani GA, Hamamura AC. Patterns of recurrence and outcomes of glioblastoma multiforme treated with chemoradiation and adjuvant temozolomide. Clinics (Sao Paulo) 2020;75:e1553.
19. Eidel O, Burth S, Neumann JO, et al. Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: a correlation with histopathology. PLoS One 2017;12:e0169292.
20. Buglione M, Pedretti S, Poliani PL, et al. Pattern of relapse of glioblastoma multiforme treated with radical radio-chemotherapy: could a margin reduction be proposed? J Neurooncol 2016;128:303–12.
21. Morganti AG, Balducci M, Salvati M, et al. A phase I dose-escalation study (ISIDE-BT-1) of accelerated IMRT with temozolomide in patients with glioblastoma. Int J Radiat Oncol Biol Phys 2010;77:92–7.
22. Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 1989;16:1405–9.
23. Minniti G, Amelio D, Amichetti M, et al. Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol 2010;97:377–81.
24. Zheng L, Zhou ZR, Yu Q, et al. The definition and delineation of the target area of radiotherapy based on the recurrence pattern of glioblastoma after temozolomide chemoradiotherapy. Front Oncol 2020;10:615368.
25. Oppitz U, Maessen D, Zunterer H, Richter S, Flentje M. 3D-recurrence-patterns of glioblastomas after CT-planned postoperative irradiation. Radiother Oncol 1999;53:53–7.
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