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ACTA ONCOLOGICA https://doi.org/10.1080/0284186X.2023.2200150 ORIGINAL ARTICLE Transitioning from conventional photon therapy to proton therapy for primary brain tumors a b c,d a b,e f Hanna Ek , Ingrid Fagerstrom Kristensen , Lars Stenberg , Sara Kinhult , Hunor Benedek , Simon Ek , g a b,e Svend Aage Engelholm , Silke Engelholm and Per Munck af Rosenschold a b Oncology, Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden; Radiation Physics, Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden; Section of Neuroradiology, Department of Medical Imaging and Physiology, Skåne University Hospital, Lund, Sweden; Department of Diagnostic Radiology, Lund e f University, Lund, Sweden; Medical Radiation Physics, Lund University, Lund, Sweden; Department of Physics, Lund University, Lund, Sweden; Department of Oncology, Rigshospitalet, Copenhagen, Denmark ABSTRACT ARTICLE HISTORY Received 3 November 2022 Introduction: Proton radiation therapy (PT) has become a treatment option alongside photon therapy Accepted 4 April 2023 (XRT) for lower-grade gliomas (LGG). In this single-institution retrospective study, we investigate the patient characteristics and treatment outcomes, including pseudo-progression (PsP), for LGG patients KEYWORDS selected for PT. Glioma; proton radiation Method: Adult patients with grade 2–3 glioma consecutively treated with radiotherapy (RT) from May therapy; pseudoprogression; 2012 to December 2019 were retrospectively included in this cohort study. Tumor characteristics and radiotherapy; fatigue treatment data were collected. The groups treated with PT and XRT were compared regarding treat- ment characteristics, side effects, occurrence of PsP, and survival outcomes. PsP was defined as new or growing lesions followed by either decrease or stabilization during a 12 month-period with no treatment. Results: Out of 143 patients meeting the inclusion criteria, 44 were treated with PT, 98 with XRT and one with mixed PTþ XRT. The patients receiving PT were younger, had a lower tumor grade, more oli- godendrogliomas and received a lower mean brain and brainstem dose. PsP was observed in 21 out of 126 patients, with no difference between XRT and PT (p¼ .38). The rate of fatigue in immediate connection to RT (zero to three months after) was higher for XRT than for PT (p¼ .016). The PT patients had a significantly better PFS and OS than the XRT patients (p¼ .025 and .035), but in multi- variate analysis radiation modality was non-significant. Higher average dose to both brain and brain- stem was associated with inferior PFS and OS (p< .001). Median follow-up time were 69 months and 26 months for XRT and PT patients, respectively. Conclusion: Contrary to previous studies, there was no difference in risk of PsP for XRT and PT. PT was associated with lower rates of fatigue <3 months after RT. The superior survival outcomes for PT indicates that the patients with the best prognosis were referred to PT. Introduction The majority of lower-grade gliomas (LGG) are diffuse gliomas WHO grade 2–3, i.e., less aggressive, diffusely infil- Modern radiation therapy (RT) of brain tumors can be given trating primary brain tumors (astrocytomas and oligodendro- either as proton therapy (PT) or as conventional x-ray ther- gliomas). A minor part of the patients have circumscribed apy (XRT). The use of intensity modulated proton therapy gliomas (e.g., pleomorphic xantoastrocytomas and ganglio- has been used for pediatric patients with brain tumors since gliomas) with less infiltrative nature. the early 2000s . In the setting of RT, a beneficial charac- When treating LGG, it is particularly important to minim- teristic of a proton beam is that it deposits most of its ize long term side effects, due to the long expected overall energy just before the protons come to a halt, resulting in a, survival (OS). To avoid late toxicity, the EANO  and so called, Bragg peak  and meaning that PT can be tail- Swedish national guidelines recommend that PT might be ored to target a tumor at a very precise depth, keeping the considered either if the tumor is close to organs at risk exit dose to a minimum. In practice, this means that for PT (OAR), or if the prognosis of the patient is deemed favorable, the radiation can be limited to a smaller volume, which may i.e., gliomas grade 1–2 and grade 3 with favorable prognostic lead to less damage to healthy brain tissue . factors (IDH-mutation and 1p/19q codeletion. Additionally, CONTACT Per Munck af Rosenschold email@example.com Skane University Hospital, Klinikgatan 5, 222 42 Lund, Sweden Supplemental data for this article can be accessed online at https://doi.org/10.1080/0284186X.2023.2200150 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 H. EK ET AL. two studies have shown acceptable acute and late toxicity Clinical data collection for PT [6,7], and a single arm prospective trial of PT for LGG Patients were found using treatment planning and record found no decrease in cognitive function over time . In and verify software (Eclipse/Aria, Varian Medical Systems, agreement with these clinical studies, a considerable amount Palo Alto, US). Follow-up images were retrieved from the of treatment planning simulation studies suggest dosimetric local picture archiving and communication system (PACS). advantages for brain cancer patients treated with PT, Medical records were scanned for demographics, tumor hist- compared to standard XRT [9–11]. Only one clinical study ology, prior surgery and chemotherapy, clinical condition, comparing side effects of PT and XRT of glioblastomas side effects, PFS, and OS. The WHO 2016 classification was in adults, have been conducted , showing reduced used  and for patients diagnosed earlier than 2016, the toxicity and fatigue after PT, compared to XRT . Two tumors were reclassified based on the pathology reports, ongoing randomized studies for grade 2–3 gliomas are accordingly. We did not reclassify all tumors per the WHO ongoing [14,15]. 2021 criteria , since the necessary biomarkers were miss- With increasing use of PT, concerns have been raised ing for several of the early patients. We classified ‘fatigue’ as regarding the frequency of pseudoprogression (PsP) com- the highest degree of either physical or mental fatigue. Side pared to XRT. A meta-analysis of the few studies performed effects were scanned for retrospectively according to CTCAE found no difference in pediatric LGG, but a significant het- v5.0, from the end of RT to progression/lost follow up. erogeneity between PT and XRT for adult LGG . An add- Extent of resection was estimated from the postoperative itional problem is that there are no standardized diagnostic magnetic resonance imaging MRI, acquired within 48 h from criteria for PsP in LGG , contrary to high grade glioma surgery, and the following multidisciplinary conference, (HGG), where PsP is well studied  and there are RANO cri- where gross total resection was defined as no evidence of teria for the definition of PsP . Differentiation of PsP and tumor on the MRI, confirmed by a neuroradiologist at a true progression with indication for salvage treatment is a multidisciplinary conference. Tumor location could be in sev- common and important clinical problem. eral lobes. Insula and other deep structures were categorized The overall purpose of this study was to describe charac- as central tumor locations. teristics and report outcomes for all patients treated primar- ily for lower grade glioma at Skåne University Hospital Radiation therapy during the period when PT was introduced at the Department of Oncology. More specifically, the study aimed Starting in 2016, patients were considered for PT if they at retrospectively investigating what characterized the either had a grade 2 tumor or a oligodendroglioma or pleo- patients that were selected for PT, whether PsP is more com- morphic xantoastrocytoma grade 3. IDH-mutated anaplastic mon in that group, manifestation of acute and late side astrocytomas were in exceptional cases considered for PT, effects, progression-free survival (PFS) and OS in the group mainly younger patients or tumors with only minor parts selected for PT, compared to the entire cohort. with grade 3 characteristics. For patients referred for PT, comparative treatment plans were created, see Figure 1, and were used to select the treatment of choice. The comparison Methods took the following aspects into consideration for selecting treatment modality: target coverage, dose to OAR, as well as Selection and description of participants the dose to the entire brain volume minus the PTV. The pro- In this retrospective cohort study all adult patients with ton and photon plans were discussed at a national multidis- grade 2–3 gliomas that were planned for radiotherapy at the ciplinary conference where representatives from all university Department of Oncology at Skåne University Hospital from hospitals participated, and where the decision was made. May 2012 to December 2019 were included. The patients There were no exact criteria for choosing PT. Throughout the were scanned and delineated at Skåne University Hospital, study the following definitions concerning the tumor volume and subsequently received either PT at the Skandion Clinic, are used. Gross tumor volume (GTV) is the actual tumor vol- Uppsala during 2016–2019 or XRT at Skåne University ume, as observed on MRI. In a postoperative setting, this Hospital during 2012–2019. The patients were followed up equals the sum of the surgical cavity and residual tumor vol- until March 31, 2021. In this study, we included patients sev- umes. In grade 2 tumors, GTV is defined on FLAIR and in eral years before the introduction of proton therapy. In this grade 3 tumors on T1 with contrast. Furthermore, the clinical way, patients with favorable clinical prognostic factors who target volume (CTV) is defined as the GTV plus a margin of were treated using both XRT and PT were studied and 1.0–2.0 cm depending on tumor grade, not including natural included in the multivariate analysis. Thus, we hope to reveal barriers and the planning target volume (PTV) is the CTV any differences related to the therapy rather than intrinsic plus a 3 mm margin. PT robust optimization was utilized, bias in the selection of PT patients. We followed the with range uncertainties of 3 mm/3.5%. For 51 of the XRT EQUATOR guidelines for reporting, using the STROBE check- treatments, one or two Volumetric Modulated Arc Therapy list for observational studies (checklist included in the (VMAT) co- or non-coplanar arcs with 6 MV was used. For 47 Supplementary File) . The study was approved by the XRT patients, Helical Tomotherapy (Accuray Inc, Sunnyvale, Swedish Ethical Review Authority (2020-04164). CA, USA) with 1 cm or 2.5 cm field with 6 MV was used. For ACTA ONCOLOGICA 3 Figure 1. Comparison between PT (left) and VMAT (right) for a patient with glioma. The patient was selected for PT based on lower doses to OARs, and a lower dose to the parts of the brain not including the PTV (brain-PTV); PT 6.7 Gy RBE vs VMAT 15.2 Gy. PT, two to three beams were used. Beam configuration was symptoms and/or death. PsP was defined as new or enlarged selected to avoid OAR, metal material such as surgical clips, lesions with abnormal contrast enhancement in the radiation but also to avoid spots from all beams accumulating dose in field on post-RT MRIs mimicking tumor progression, which the same volume of a sensitive OAR, hence considering the either decreased or stabilized for a period of 12 months with- possible Relative Biological Effectiveness (RBE) variation at out new oncologic therapy or was confirmed with biopsy. the end of the Bragg peak, not to overdose in sensitive PsP was not only considered within a certain time frame fol- OARs. RBE for PT was set to 1.1. A range shifter was used in lowing radiotherapy. Date of PsP and progression were back- cases where the target volume was close to the patient out- dated to the first date at which a lesion met the criteria for line. Energies that can be used ranges from 60 MeV to respective condition. The time to disease-related outcomes 230 MeV. Single Field Uniform Dose was preferred but was calculated from the end date of RT. Patients without evi- Multifield Optimization was used when needed. Mainly dence of progression were censored from PFS analysis at 0.5 cm spotspacing was used. date of last follow-up. The date of death was collected from The constraints and objectives used are specified in the the Swedish Cause of Death Register, using the record and Swedish national guidelines , which are based on the ICPU verify software (Aria). reports . Chiasm/optic nerve has the highest priority, fol- lowed by brainstem, GTV, PTV, retina, lenses, cochlea, pituit- ary, lacrimal gland and hippocampus in written order. Treatment planning and dosimetry data were extracted from the treatment planning software using the scripting API Statistics (Eclipse). The statistical analyses were performed with SPSS software (version 28, IBM, US) and Matlab (R2020b). All clinical data Follow up were descriptively summarized and compared by a non-para- metric test and the pretreatment variables were analyzed Standard follow up practice for both therapy modalities with a spearman correlation test. PFS and OS were estimated included MRI scans every three months during the first year using the Kaplan–Meier method. Cox regression analysis was after therapy, and subsequently every three months for grade used to investigate the association of different variables with 3 tumors and every six months for grade 2 tumors, if stable. outcome metrics. Fatigue over time was analyzed with the This study includes examination of all subsequent post-RT Wilcoxon rank sum test at each time-point, comparing the MRIs until progression. An experienced neuroradiologist (LS) distribution over dichotomized data for PT and XRT, respect- was involved in the examination to assess whether progres- ively. Missing data were censored. All the confidence inter- sion or PsP had occurred. Progression was defined by local standard, i.e., deemed present if one or more of the follow- vals were set to 95%, pvalue cutoff for significance was set to <.05 and all tests were two-sided in this explorative, retro- ing criteria were met: findings resulting in new oncologic therapy, tissue diagnosis following surgery, worsened clinical spective study. 4 H. EK ET AL. Table 1. Patient characteristics. Patient characteristic Photon (n¼ 98) Proton (n¼ 44) Parameter Count (median) Share (min–max) Count (median) Share (min–max) Statistic p Value Age [y] (56) (22–74) (44) (23–67) MW <.001 Sex Female 40 41% 27 61% v .023 Male 58 59% 17 39% WHO grade 2 40 41% 29 66% v .006 3 58 59% 15 34% Histology Astrocytoma 58 59% 16 36% v .008 Oligodendroglioma 33 34% 25 57% Oligoastrocytoma 4 4% 0 0% Other 33% 3 7% IDH mutation Yes 26 27% 36 82% v .019 No 15 15% 6 14% 1p/19q co-deletion Yes 29 30% 22 50% No 15 15% 9 20% Ki-67 <5% 26 27% 11 25% 5–10 % 28 29% 19 43% 11–15 % 7 7% 3 7% 16–20% 11 11% 3 7% >20% 8 8% 2 5% Presenting symptom Seizure 64 65% 28 64% Focal deficits 22 22% 6 14% Cognitive sympt. 13 13% 1 2% v .049 Pressure sympt. 12 12% 4 9% Headache 3 3% 2 5% Asymptomatic 2 2% 2 5% ECOG PS at start of RT 0 64 65% 34 77% 1 22 22% 10 23% 2 9 9% 0 0% 3 3 3% 0 0% Memory impairment at start of RT [grade ] 0 85 87% 40 91% 1 11 11% 3 7% 2 2 2% 1 2% Fatigue at start of RT [grade ] 0 74 76% 34 77% 1 15 15% 9 20% 2 8 8% 1 2% 3 1 1% 0 0% Tumor location Frontal 54 55% 29 66% Temporal 38 39% 18 41% Parietal 26 27% 9 20% Occipital 8 8% 2 5% Central 40 41% 16 36% Brainstem 4 4% 3 7% Cerebellum 1 1% 0 0% Multifocality Yes 7 7% 1 2% No 91 93% 42 95% Crossing midline Yes 12 12% 6 14% No 86 88% 38 86% Extent of resection Gross total 8 8% 4 9% Subtotal 53 54% 30 68% Biopsy 35 36% 9 20% Prior chemotherapy Yes 1 1% 2 5% No 97 99% 42 95% Concomitant chemotherapy Temozolomide 49 50% 3 7% v <.001 No 49 50% 41 93% Maintenance chemotherapy Yes 62 63% 32 73% v .033 No 36 37% 7 16% Time from last surgery to RT [months] (1.3) (0.7–82.5) (1.9) (1–38) MW <.001 Prescription dose [Gy] (59) (54–64) (54) (54–60) MW <.001 Planned number of fractions (30) (28–33) (30) (25–33) MW <.001 GTV [cm ] (45) (2–522) (45) (8–270) CTV [cm ] (192) (23–672) (215) (56–538) Mean brain dose (RBE 1.0) [Gy] (27.5) (7.2–46.6) (16.6) (8.4–33.9) MW <.001 D2% brain dose [Gy] (60.7) (43.1–66.0) (55.0) (16.5–63.2) MW <.001 Mean brainstem dose (RBE 1.0) [Gy] (21.5) (0.8–53.6) (8.1) (0.0–44.6) MW <.001 D2 % brainstem dose [Gy] (51.0) (1.1–64.9) (48.3) (0.0–60.8) Note: GTV: gross tumor volume; CTV: clinical target volume; RBE: relative biological effectiveness; v : chi-square; MW: Mann Whitney. Others: pleomorph xantoastrocytoma, ganglioglioma. More than one symptom is possible. According to CTCAE v 5.0. Tumor localization could be in several lobes. ACTA ONCOLOGICA 5 imminent herniation followed by acute surgery, and pleuro- Results pneumonia in need of draining, respectively. All 142 patients A total of 143 patients, treated during 2012–2019, were were, however, included in pretreatment analyses (dosimetry retrospectively identified, out of which 44 were treated with and treatment planning data). The patients receiving 5.4, PT (2016–2019), and 98 were treated with XRT (2012–2019). respectively, 18 Gy of radiation were excluded in analyses of One patient received PT and XRT consecutively, and data outcomes (PsP, side effects, PFS and OS) but the patient about that patient was missing. The most common diagnosis receiving 46.8 Gy of radiation was included, since most of was astrocytoma followed by oligodendroglioma, pleo- the treatment was given. Seven patients were lost to follow- morphic xantoastrocytoma, oligoastrocytoma, and ganglio- up, and side-effect data were not available for another five glioma. Patient characteristics are shown in Table 1. Three patients receiving XRT. patients (1 PT, 2 XRT) were discontinued after 5.4 Gy, 18 Gy, At baseline the patients receiving PT were younger and 46.8 Gy of radiation due to lowering of consciousness, (p< .001), more often women (p¼ .023), had a lower tumor grade (p¼ .006), more IDH mutations (p¼ .019) and more Table 2. Univariate Cox-models for pseudoprogression. commonly oligodendrogliomas (p¼ .008). They received less Univariate Cox models: pseudoprogression (21 events) concomitant (p< .001) and more maintenance (p¼ .033) chemotherapy and received a lower mean brain (p< .001) Parameter N HR p Value and brainstem dose (p< .001). Patients with cognitive symp- High age 126 0.983 .334 Male sex 126 1.197 .685 toms at diagnosis received XRT to a greater extent. The WHO grade 2 (vs grade 3) 126 1.128 .783 median prescription dose for XRT and PT was 59.4 Gy and Oligodendroglioma (vs astrocytoma) 117 0.557 .196 IDH mutation 73 0.331 .093 54.0 Gy, respectively. The XRT patients had an average fol- 1p/19q codeletion 67 0.863 .832 low-up time of 69 months (95% CI 62–77 months) and the PT Frontal tumor location 126 2.817 .064 patients 26 months (95% CI 20–31 months), estimated using Central tumor location 126 0.851 .742 Multifocal 126 0.045 .463 the Kaplan–Meier method. See supplementary figure 1. Less extensive resection 124 1.137 .651 Patients with astrocytomas were more frequently men Large GTV 122 0.996 .492 (Spearman’s q¼0.18, p¼ .041) and had centrally located High prescription dose 126 1.020 .792 54.0 Gy (vs >54.0 Gy) 126 1.091 .843 tumors (q¼0.18, p¼ .038). 1p/19q codeletion correlated High mean brain dose 119 0.988 .649 with a better ECOG performance status (q¼0.26, p¼ .023). High D2% brain dose 119 0.885 .061 High mean brainstem dose 116 0.991 .585 IDH mutation was more common in younger patients High D2% brainstem dose 119 0.991 .387 (q¼0.24, p¼ .032) and was negatively correlated with both Boost 121 1.241 .639 focal (q¼0.23, p¼ .043) and cognitive symptoms (q¼0.24, PT (vs XRT) 126 0.611 .380 Concomitant chemotherapy 126 1.264 .284 p¼ .032) at diagnosis. Worse EGOC performance status was Maintenance chemotherapy 126 1.824 .287 more frequently observed in patients with centrally located Note: GTV: gross tumor volume. tumors (q¼ 0.20, p¼ .017). Figure 2. Actuarial rate of fatigue, graded according to CTCAE for patients treated with photons (color) versus protons (black), before and after treatment. The groups are compared with Wilcoxon rank sum test. 6 H. EK ET AL. Figure 3. Kaplan–Meier curves of progression-free survival (PFS) and overall survival (OS). (a) PFS for patients with astrocytoma vs oligodendroglioma; (b) PFS for patients treated with photons vs protons; (c) OS for patients with astrocytoma vs oligodendroglioma; (d) OS for patients treated with photons vs protons. PsP was observed in 21 of 126 patients, out of which 17 was significantly longer for PT than for XRT (log-rank patients were treated with XRT and 4 with PT. PsP occurred p¼ .025), see Figure 3. Patients with astrocytoma had a at a median of 4.5 months from the last day of RT (1.6– shorter PFS than those with oligodendroglioma (11 months 71 months). No significant difference in rate of PsP between (95% CI 4–19) and 44 months (95% CI could not be counted) XRT and PT was found using the Kaplan–Meier estimate (log respectively (p¼ .003)). OS in the whole cohort was rank, p¼ .38). Additional Cox regression analyses revealed no 51 months (95% CI 33–69 months), 45 months (95% CI 31– association between mean dose to the brain or GTV with 59 months) for XRT patients, while median OS was not yet reached for PT (p¼ .035). OS was 41 months (95% CI 22– PsP, see Table 2. The association between fatigue and other variables is 61 months) and 80 months (95% CI 58–102 months, log rank reported in Supplementary Table 1 and the fatigue status is p< .001) for astrocytoma and oligodendroglioma, respect- shown in Figure 2, where we found that the rate of fatigue ively. The Cox regression analyses are summarized in as an acute side effect (zero to three months after RT) was Supplementary Table 2. In multivariate analysis, radiation greater after XRT than after PT (Wilcoxon, p¼ .016), but modality was non-significant. thereafter no difference was found. No difference was seen between PT and XRT for memory impairment after RT. A Discussion total of 12 patients experienced alopecia grade 2 at three months after RT (7 PT and 5 XRT). One XRT patient In this paper we report on our experience of transitioning developed cognitive disturbance grade 2 after RT, one PT from conventional XRT to PT for primary gliomas. We found patient got tinnitus grade 1 and one PT patient got that the patients receiving PT compared to XRT were decreased range of motion in left temporomandibular joint younger, had a lower tumor grade, more oligodendrogliomas grade 1. and more IDH mutations, all of which are good prognostic Recurrence occurred in 79 patients and 64 patients died factors [20,21]. This is consistent with the Swedish national during follow up. The median PFS was 24 months (95% CI guidelines  and hence as could be expected. Furthermore, 15–33) in the whole cohort and 17 months (95% CI 8–27) for they received less concomitant and more maintenance XRT. Median PFS for PT had not been reached, though PFS chemotherapy in accordance with former local guidelines ACTA ONCOLOGICA 7 with different treatment strategies due to histology. The and mean radiation brainstem dose had a significant correl- mean brain and brainstem doses were lower for PT than ation with OS, a correlation also found previously for glio- XRT, due to lower prescription dose and the inherently blastoma . We did find that the PT patients had a better improved sparing offered by the low exit dose in PT. PFS and OS, as expected since patients with better prognos- Curiously, more women than men received PT (X2, p¼ .023), tic factors should be referred to PT. However, in multivariate even though gliomas are more common in men [22,23]. In analyses, radiation modality was no significant prognostic our cohort, more women had oligodendrogliomas, which factor. IDH mutation was strongly associated with a better could be a part of the explanation. PFS and OS but was not included in multivariate analysis We found no association between PT and PsP. Previous due to missing data in several cases, and today, the IDH wild trials have shown conflicting results for relationship between type-tumors would have been diagnosed as glioblastomas, PsP and PT [24–26], higher radiation dose and concomi- according to the WHO 2021 classification. Our study cannot tant temozolomide [25,27]. In our study, no correlation was answer the question whether radiation modality affects sur- seen between chemotherapy and PsP. We found no signifi- vival. There is an ongoing prospective Nordic study  cant prognostic factors for PsP, consistent with some studies where LGG patients are randomized to either photon or pro- [24,26] and there appears to be no consensus on this ques- ton radiation therapy, that hopefully will help to answer the tion. As a recent meta-analysis shows, different definitions of question whether treatment modality do affect survival. PsP in the various studies give difficulties in clinical interpret- The retrospective nature of this study is a major limitation, ation of data and outcomes , only two trials studied PsP e.g., since tumors were reclassified according to the WHO after PT and one of those showed higher incidence. We 2016 guidelines if the diagnosis was made before its release. chose no time limit in our analysis since PsP seems to appear We have chosen not to reclassify the tumors according to later in LGG than HGG . Increasing T2/FLAIR changes the WHO 2021 classification  mainly because molecular were not considered an indication of PsP in HGG nor in our data is missing in many cases, and thus IDH wild type study . It would be desirable to find a common definition tumors are included in the study. Side effects were graded of PsP in order to be able to more reliably compare different retrospectively from the medical records, probably leading to studies, and even better prospective studies to further under-reporting. Also, PsP was graded retrospectively, which understand this phenomenon. means that if a patient was assessed as having a true pro- Fatigue is a considerable problem for patients with gli- gression and thus starts salvage treatment, it is inherently oma, affecting quality of life, with a prevalence of 20– impossible to find out whether the lesion would have stabi- 77%, occurring before, during and after treatment lized into a PsP. Follow up was missing in a noticeable num- [31,32]. In our study, acute fatigue (zero to three months ber of the PT patients which might introduce bias. Note that after RT) occurred more frequently after XRT than after PT, the prevalence of risk factors in the XRT cohort may change but no difference was observed for long term fatigue. Since during the study period due to access of PT during the latter radiotherapy-induced fatigue declines over time [33,34], the part of the period. In addition, the PT and XRT groups dif- impact of treatment modality may mostly affect the rate of fered widely and comparisons between the groups should fatigue early after treatment. The difference in onset of be made with caution. fatigue is probably multifactorial, but the radiation dose to In summary, we found significant lower rates of fatigue the brain is known to affect the rate of fatigue  and the up to three months following therapy for patients treated PT patients did receive a lower radiation dose to the brain with PT than for patients treated with XRT. The difference in and brainstem. The radiation modality could be part of the fatigue appears to be associated with the performance status explanation, due to dosimetric advantage of PT . The XRT before therapy and/or potentially due to better dosimetry for group had worse PFS and OS, which is indeed associated proton patients. The difference in fatigue was not persistent with a higher degree of fatigue [36,37]. In addition, the over time., patients receiving XRT had more concomitant and less main- A noteworthy result in this study is that no significant dif- tenance chemotherapy, which could also affect the onset of ference in PsP was found between the radiation modalities. fatigue [34,38]. In our study, worse ECOG performance status This result contrasts with previous studies and indicates that and fatigue before RT were the only factors that predicted further investigation is required. fatigue after RT, which is consistent with other studies The superior PFS and OS outcomes for PT indicates that [36,39]. the patients with best prognosis were selected for PT. In In our cohort, only age, ECOG performance status and multivariate analysis, we found that older patients, astrocyto- histology were prognostic factors for both PFS and OS in mas (vs oligodendrogliomas) and poor performance status multivariate analyses, consistent with earlier studies [21,40– were associated with inferior outcomes. Increased average 45]. We found tumor located in the brainstem and multifocal dose to the brain was associated with inferior progression- tumor to be negative prognostic factors. Tumor location free survival but increased mean brainstem dose with inferior close to eloquent structures makes a gross total resection overall survival. challenging which might partly explain the observed inferior outcome . Acknowledgments In multivariate analyses, mean brain dose was found to be a significant predictor for PFS, while brainstem location We thank Hannes Mogensen for assisting radiotherapy data collection. 8 H. EK ET AL.  Louis DN, Perry A, Reifenberger G, et al. 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Acta Oncologica – Taylor & Francis
Published: Apr 3, 2023
Keywords: Glioma; proton radiation therapy; pseudoprogression; radiotherapy; fatigue
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