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Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced glioma

Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced... Background: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). Methods: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. Results: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9–30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemo- therapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. Conclusions: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Deter- mining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma. *Correspondence: mohno@ncc.go.jp; yonarita@ncc.go.jp Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ohno et al. Radiation Oncology (2022) 17:85 Page 2 of 11 Keywords: Radiation-induced glioma, IDH1/2 mutations, Secondary neoplasms, Long-term survivors of malignancies, Reirradiation Background strategy, especially for the role of ReRT. We also investi- Radiotherapy is used for cancer treatments, including gated genetic alterations in 8 patients and evaluated the pediatric brain tumors and hematological malignancies, diagnostic impact of isocitrate dehydrogenase (IDH) 1 such as glioma, medulloblastoma, germ cell tumors, and and 2 mutation status on establishing RIG diagnosis. leukemia. Despite an overall improvement in the sur- vival rates of patients with these tumors, patients treated Methods and materials with radiotherapy are at risk of long-term neurologi- Patient characteristics cal complications such as the development of progres- This study was a retrospective observational study. We sive leukoencephalopathy, arteritis, hypopituitarism, reviewed our departmental database between 2001 and and hypothalamic insufficiency [1]. One of the most 2021. We included patients who satisfied Cahan’s criteria, serious late consequences of radiotherapy is secondary which were as follows: (1) the tumor must originate in a neoplasms, which occur in rare cases but represents a previously irradiated region (but not necessarily in the major cause of mortality in long-term survivors of child- full-dose region), (2) there must be a sufficient latency hood malignancies [2–6]. Among radiation-induced time between irradiation and the onset of the postra- brain tumors, meningiomas and gliomas are the most diation tumor, (3) the tumor histology must be differ - frequently reported secondary neoplasms [1]. The cumu - ent from that of the primary tumor, and (4) the patient lative risk of secondary brain tumors occurring after radi- must not have pathologies that favor the development of ation therapy for pituitary adenomas is 2.0% at 10  years tumors: Li-Fraumeni’s disease, von Recklinghausen’s dis- and 2.4% at 20  years, which is 10.5 times higher than ease, tuberous sclerosis, xeroderma pigmentation, or ret- that seen in the general population [3]. The cumulative inoblastoma [5, 16, 17]. risk of secondary brain tumors occurring among long- The clinical, operative and radiological records of the term acute lymphoblastic leukemia survivors is 0.8% at patients were reviewed, and data on the following vari- 10 years and 1.87% at 20 years [2]. ables were collected: clinical and treatment history before Radiation-induced gliomas (RIGs) are typically high- RIG diagnosis, clinical and treatment history after RIG grade tumors. The median latency period for develop - diagnosis, Karnofsky performance status (KPS) at the ing RIGs is 8–11  years [4–6]. The overall standardized time of RIG diagnosis, presence or absence of comor- incidence ratio (SIR) for RIG in childhood cancer sur- bidities and leukoencephalopathy at the time of RIG vivors is 10.8, and the SIR is different according to the diagnosis, date of operation for RIG, postoperative follow-up period; 20.6 in 0–4  years follow-up, 7.5 in therapy for RIG, date of tumor recurrence of RIG, date 5–9 years follow-up, 11.0 in 10–14 years follow-up, 12.5 of death or last hospital visit, the extent of resection of in 15–19  years follow-up, 7.2 in 20–29  years follow- RIG, and treatment after tumor recurrence of RIG. The up, and 5.0 in 30  years follow-up [7]. The treatments leukoencephalopathy was evaluated by magnetic reso- of RIGs are usually challenging, and the clinical out- nance images (MRI) and graded based on the Common comes are generally poor [3–5, 8]. The median survival Terminology Criteria for Adverse Events version 5.0. The time (MST) of patients with RIGs is 11  months, with extent of resection of the RIGs was determined based on a 2-year survival rate of 20.2% [5]. Several studies and the surgeon’s operative notes and postoperative imaging review articles have proposed a combination therapy studies and classified as follows: total if 100% of the con - of reirradiation (ReRT) and chemotherapy as a poten- trast-enhanced lesion was resected; subtotal, if 95–99% tial treatment option; however, there are few reports of the lesion was resected; partial, if < 94% of the lesion on the details of the combined therapy and their treat- was resected, or removed as a biopsy [18]. All patients ment outcomes. Thus, the optimal therapeutic approach were re-diagnosed by neuropathologists at our hospital for RIGs is not well defined [5 ]. Moreover, few stud- according to the World Health Organization 2016 clas- ies investigated genetic alterations in RIGs [9–15], and sification [19]. their clinical impact remains unclear. In this study, we retrospectively analyzed the clinical Genetic analysis characteristics and treatment outcomes in 11 patients Tumor DNA was extracted from frozen tumor tissues in 8 with RIG to clarify the optimal follow-up period from cases using a DNeasy Blood & Tissue Kit (Qiagen; Tokyo, the treatment of the primary disease and therapeutic Japan). The presence of hotspot mutations in the IDH1 Ohno  et al. Radiation Oncology (2022) 17:85 Page 3 of 11 (R132) and IDH2 (R172) genes was assessed by Sanger using the Kaplan–Meier method by JMP ver. 15.1.0 sequencing and/or pyrosequencing, as described previ- software for Mac (SAS Institute Japan; Tokyo, Japan) and ously [20, 21]. Pyrosequencing assays were designed to GraphPad Prism ver. 9.2.0 for Mac (GraphPad Software; detect all known mutations in these genes [20]. The two La Jolla, CA, USA). mutation hotspots in the telomerase reverse transcriptase (TERT) gene promoter were analyzed in 8 tumors using Results Sanger sequencing and/or pyrosequencing, as reported Patient characteristics of primary disease previously [22]. The mutation hotspots at codons 27 We identified 11 patients who satisfied Cahan’s criteria and 34 of the histone H3.3 (H3F3A) gene, and those at and had RIG [5, 16, 17]. The patient characteristics of the codon 600 of the B-Raf (BRAF) gene, were analyzed in 6 primary disease are summarized in Table  1. The median tumors using Sanger sequencing and/or pyrosequencing age of the 11 patients was 12  years (range: 1–39  years), [21]. The methylation status of the O-6-methylguanine and there was no sex predominance (male: 6, female: DNA methyltransferase (MGMT) promoter was analyzed 5). The primary diseases included germinomas (n = 2), in 8 tumors using bisulfite modification of the tumor acute lymphoblastic leukemias (n = 2), medulloblastomas genomic DNA, followed by pyrosequencing, as previ- (n = 3), diffuse astrocytoma with IDH2 mutant (n = 1), ously described [22]. The MGMT promoter methylation pilocytic astrocytoma (n = 1), pituitary adenoma (n = 1), status was defined as hypermethylation when its mean and a metastatic brain tumor from lung cancer (n = 1). level at the 16 CpG sites was 16% and greater than 16%, All patients received cranial radiation. In Case 1, received and hypomethylation when less than 16% [18, 22]. continuous intraarterial bromodeoxyuridine combined with radiotherapy of 41  Gy in 23 fractions at 15-year- Statistical analysis old and of 60 Gy in 34 fractions at 17-year-old [23]. The The latency period was defined as the interval between median latency time between the primary disease and the date of diagnosis of the primary disease and that of RIG was 17 years (range: 9–30 years) (Table 1). RIG. Overall survival time (OS) was defined as the inter - val between the date of RIG surgery and death or the last Patient characteristics and treatment of RIGs follow-up, whichever occurred first. Progression-free The characteristics of the 11 patients with RIG are sum - survival time (PFS) was defined as the period between marized in Table 2. The median age of the patients was the date of RIG surgery and the detection of progression, 34  years (range: 10–49  years). The RIGs included glio - death, or last follow-up. These times were calculated blastoma (GBM) with IDH1/2 wild type (n = 7), GBM Table 1 Characteristics of patients with primary diseases Case no. Sex Age at primary Primary disease Location Therapy Chemotherapy Latency disease (years) (years) Radiation therapy Radiation dose (Gy) a a 1 M 15 Germinoma SuprasellarLocal, Local41, 60 Yes 30 2 M 25 Pituitary adenoma Sellar Local 60 No 20 3 M 1 Acute lymphoblastic Systemic TB 18 Yes 9 lymphoma 4 M 20 Germinoma Suprasellar WB 50 Yes 13 5 F 12 Pilocytic astrocytoma Hypothalamus Local 54 No 22 6 F 9 Medulloblastoma Cerebellum CS WB: 35.6, Local: 66, Yes 30 WS: 31.9 7 F 10 Medulloblastoma Cerebellum CS WB: 40, Local: 60, Yes 13 WS: 30 8 M 2 Acute lymphoblastic Systemic TB 12 Yes 15 lymphoma 9 F 15 Diffuse astrocytoma, Left Frontal Local 60 Yes 17 IDH2-mutant 10 F 39 Metastatic brain tumor Multiple Local, WB CK: 22, WB: 30 Yes ( TKI) 10 from Lung cancer 11 M 6 Medulloblastoma Cerebellum CS WB: 23.4, Local: 55.8, Yes 22 WS: 23.4 M male, F female, IDH isocitrate dehydrogenase, TB total body, CS craniospinal, WB whole brain, WS whole spine, CK cyberknife, TKI tyrosine kinase inhibitor This patient received radiotherapy of 41 Gy in 23 fractions at 15-year-old and of 60 Gy in 34 fractions at 17-year-old Ohno et al. Radiation Oncology (2022) 17:85 Page 4 of 11 Table 2 Characteristics of patients with radiation-induced gliomas Case Sex Age Secondary Karnofsky Location Leukoenceph Comorbidity Initial treatment Recurrent Treatment at first recurrence PFS OS Status no. (years) disease performance alopathy pattern (months) (months) Operation Chemotherapy Radiation Operation Chemotherapy Radiation status therapy therapy 1 M 45 GBM, NOS 80 Rt. insula Grade I Visual dys- Partial ACNU No Local BSC 28.1 34.5 Dead function removal 2 M 45 AA, NOS 70 Rt. temporal No No Partial TMZ No Local BSC 3.0 8.4 Dead removal 3 M 10 GBM, 80 Lt. frontal Lt. No Short stature Biopsy ACNU Local RT Local No Carboplatin, No 3.8 11.0 Dead IDH1/2- parietal 40 Gy/20fr Etoposide Wildtype 4 M 33 GBM, 60 Rt. Cerebel- Grade II Hypopituita- Biopsy Carboplatin, No Dissemina- BSC 2.5 4.6 Dead IDH1/2- lum Pons rism Etoposide tion Wildtype (dissemina- tion) 5 F 34 GBM, 80 Lt. temporal No Hypopitui- Total TMZ No Local Subtotal TMZ Local RT 11.3 27.5 Dead IDH1/2- tarism Visual removal removal 45 Gy/25f Wildtype dysfunction 6 F 39 AA, IDH1/2- 60 Rt. Parietal No Mild cognitive Rt. parietal: TMZ No Local Rt. Parietal: TMZ Local RT 8.8 27.3 Dead Wildtype Rt. occipital impairment partial Total 60 Gy/30fr removal Rt. removal Rt. occipital: Occipital: partial Total removal removal 7 F 23 GBM, 90 Rt. frontal No Mild cognitive Subtotal TMZ No Local No TMZ SRT 7.4 29.1 Dead IDH1/2- impairment removal 40 Gy/10fr Wildtype 8 M 17 GBM, NOS 90 Rt. parietal No No Total TMZ Local RT Local No No GKS 17.0 30.8 Dead removal 66 Gy/33fr 9 F 32 GBM, 80 Lt. frontal- Grade II No Biopsy TMZ Local RT Distant No TMZ SRT 23.0 35.1 Dead IDH1/2- parietal 60 Gy/30fr 42 Gy/7fr Wildtype 10 F 49 GBM, 90 Rt. frontal No No Total TMZ, Bev Local RT Distant Biopsy Bev SRT 15.9 28.3 Dead IDH1/2- removal 50 Gy/25fr 42 Gy/7fr Wildtype 11 M 28 GBM, 60 Lt. cerebel- No Mild cognitive Biopsy TMZ, Bev Local RT No recur- No recur- 9.8 9.8 Alive IDH1/2- lum impairment 40 Gy/15fr rence rence Wildtype M male, F female, GBM glioblastoma, NOS not otherwise specified, AA anaplastic astrocytoma, IDH isocitrate dehydrogenase, Rt right, Lt left, ACNU nimustine hydrochloride, TMZ temozolomide, Bev bevacizumab, RT radiation therapy, BSC best supportive care, GKS gamma knife radiosurgery, SRT stereotactic radiotherapy Ohno  et al. Radiation Oncology (2022) 17:85 Page 5 of 11 ReRT regimens were as follows: 40  Gy in 15 fractions, not otherwise specified (n = 2), anaplastic astrocytoma 40 Gy in 20 fractions, 50 Gy in 25 fractions, 60 Gy in 30 with IDH1/2 wild type (n = 1), and anaplastic astro- fractions, and 66 Gy in 33 fractions. cytoma not otherwise specified (n = 1). All patients Ten patients had tumor recurrences, and 7 patients underwent tumor removal or biopsy and were diag- received further treatments for recurrent tumors. All the nosed based on histopathological examination. Two patients were treated with chemotherapy. Four patients patients had multiple intraparenchymal lesions (Case received ReRT at the initial location at the time of recur- 3 and Case 6), and one had right cerebellar and pon- rence. Two patients with supratentorial tumors (Case tine lesions with cerebrospinal dissemination (Case 4). 9 and Case 10)  had tumor recurrence in the cerebellum Three patients showed leukoencephalopathy at the time at a distance from the initial location and received ste- of RIG diagnosis: Grade II in 2 patients and Grade I in reotactic radiotherapy consisting of 42  Gy in 7 fractions 1 patient. Seven patients (63.6%) suffered from comor - (Table 2). bidities, which were related to primary therapy: 3 had mild cognitive impairment, 2 had hypopituitarism, 2 had visual dysfunction, and 1 had short stature. No Treatment outcomes of RIGs patient with leukoencephalopathy was associated with The median PFS and median survival time (MST) in 11 cognitive impairment. The median KPS at the time of patients with RIG were 11.3  months and 28.3  months, RIG diagnosis was 80. respectively (Fig. 1A, B). The median PFS in patients ini - For postoperative treatment, 5 patients received tially treated with ReRT combined with chemotherapy ReRT combined with chemotherapy, including ReRT/ (n = 5) was 17.0  months; this was longer than that of temozolomide (TMZ) (n = 2), ReRT/TMZ/bevaci- patients treated with chemotherapy alone (8.1  months, zumab (Bev) (n = 2), and ReRT/nimustine hydrochlo- n = 6) (Fig.  1C). The MST in patients initially treated ride (ACNU) (n = 1); 6 patients were treated with with ReRT combined with chemotherapy (n = 5) and chemotherapy alone, including TMZ (n = 4), ACNU those receiving chemotherapy alone (n = 6) were 29.6 and (n = 1), and carboplatin and etoposide (n = 1). The 27.4 months (Fig. 1D). A B C D Fig. 1 Kaplan–Meier curves of progression-free survival time (PFS) and overall survival time. A The median PFS was 11.3 months. B The median survival time was 28.3 months. C The median PFS in patients treated initially with reirradiation (ReRT ) combined with chemotherapy (n = 5) was 17.0 months, and that in patients receiving chemotherapy alone was 8.1 months (n = 6). D The median survival times of patients treated initially with ReRT combined with chemotherapy (n = 5) was 29.6 months, and that in patients receiving chemotherapy alone (n = 6) was 27.4 months Ohno et al. Radiation Oncology (2022) 17:85 Page 6 of 11 The tumor recurrence pattern after initial treatment patient presented with dizziness; an MRI revealed a for RIGs was evaluated by radiological examinations in left cerebellar contrast-enhanced lesion (Fig.  2A, B). 9 patients, excluding 1 patient who presented with cere- He underwent a biopsy and was diagnosed as having brospinal dissemination and 1 patient who did not have a GBM with IDH1/2 wild-type. He received ReRT at a recurrence. Among 4 patients treated initially with ReRT dose of 40 Gy in 15 fractions combined with TMZ/Bev combined with chemotherapy, 2 had local recurrence, and maintenance TMZ/Bev therapy. The tumor showed and 2 had distant recurrence; all 5 patients treated with a complete response, and the patient did not develop chemotherapy alone had local recurrence. tumor recurrence 9.8  months after the treatment for None of the patients was observed to develop sympto- GBM with IDH1/2 wild-type (Fig. 2C, D). matic radiation necrosis, which could be caused by a high cumulative radiation dose during the follow-up period. Case presentation 2 Genetic alterations of RIGs A 12-year-old female patient (Case 9) initially presented The genetic alterations of 8 patients whose tumor samples with a cataplectic attack; 3  years later, an MRI exam were available for analysis are summarized in Table  3. revealed a left frontal non-contrast-enhanced tumor There were no alterations in the IDH1/2 or TERT pro- (Fig.  3A). She underwent subtotal resection and was moters in the 8 cases, and no BRAF or H3F3A mutations diagnosed with diffuse astrocytoma. After the opera - were found in the 6 cases for which data was available. tion, she received radiation therapy at a dose of 60  Gy Two tumors had hypermethylated MGMT promoters, in 30 fractions and chemotherapy with ACNU. Seven- whereas the other six had hypomethylated promoters. teen years after treatment for the diffuse astrocytoma, she developed a contrast-enhanced lesion just posterior Illustrative cases to the primary tumor, which was included within the We presented 2 illustrative cases; one case showed the prior radiation field (Fig.  3B). She underwent a biopsy, favorable therapeutic effect of ReRT/TMZ/Bev (Case and the secondary tumor was diagnosed as GBM with presentation 1:  Case 11), and the other case showed the IDH1/2 wild-type (Fig.  3C). We performed Sanger usefulness of IDH1/2 mutational status evaluation in sequencing analysis of the IDH1/2 gene in the primary establishing the RIG diagnosis (Case presentation 2: Case tumor and found that the tumor had an IDH2 mutation 9). (Fig. 3D). Because IDH1/2 mutations maintain through tumor recurrence [24], the secondary tumor with Case presentation 1 IDH1/2 wild-type was no recurrence from the primary A 6-year-old boy (Case 11) initially presented with tumor with IDH2 mutation but was a de novo tumor headache, vomiting, and conscious disturbance and that was most likely to be related to the previous expo- underwent total removal of a right cerebellar tumor. sure. Therefore, we diagnosed the secondary tumor as The tumor was diagnosed as a medulloblastoma, and RIG. The patient received ReRT at a dose of 60  Gy in combined chemotherapy was performed with cranio- 30 fractions combined with TMZ; however, the patient spinal radiation of 23.4  Gy in 13 fractions and local had a distant recurrence in the cerebellum 23.0 months radiation up to 55.8  Gy in 31 fractions. Twenty-two after the treatment for GBM with IDH1/2 wild-type years after the treatment for medulloblastoma, the (Fig. 3E) and died 12.1 months thereafter. Table 3 Summary of genetic alterations in radiation-induced gliomas Case no. Secondary disease IDH1/2 BRAF H3F3A TERT MGMT 3 GBM, IDH1/2 Wild-type WT ND ND WT Hypomethylation 4 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 5 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 6 AA, IDH1/2 Wild-type WT WT WT WT Hypermethylation 7 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 9 GBM, IDH1/2 Wild-type WT ND ND WT Hypomethylation 10 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 11 GBM, IDH1/2 Wild-type WT WT WT WT Hypermethylation GBM glioblastoma, AA anaplastic astrocytoma, WT wild-type, ND not determined, IDH isocitrate dehydrogenase, BRAF B-Raf, H3F3A histone H3.3, TERT telomerase reverse transcriptase, MGMT O-6-methylguanine DNA methyltransferase Ohno  et al. Radiation Oncology (2022) 17:85 Page 7 of 11 A B C D Fig. 2 Representative patient treated with reirradiation, temozolomide, and bevacizumab (ReRT/TMZ/Bev) showing a favorable response (Case 11). A Preoperative T1-weighted magnetic resonance image with gadolinium enhancement and B fluid-attenuated inversion recovery (FLAIR) image showing an enhanced tumor in the left cerebellum (black arrow). C T1-weighted magnetic resonance image with gadolinium enhancement and D FLAIR image obtained 9.8 months after ReRT/TMZ/Bev treatment showing a favorable response (white arrow) Previous studies reported that the median latency period Discussion was 8–11  years, and the incidence of RIG largely disap- In this study, we observed a median latency time of peared after 15–20  years [4–6]. However, in our cohort, 17  years, with a range of 9 to 30  years. Among the the median latency time from the primary cancer treat- 11 patients with RIG, ReRT combined with chemo- ment to the development of RIG was 17  years, with a therapy was performed in 5 patients at the initial range of 9 to 30  years, and 5 out of 11 patients (45.5%) treatment of RIG and for 6 patients at the time of recur- had a latency period of 20 years or more. Nakao et al. also rence; the median PFS and MST were 11.3  months and reported that the latency period was more than 20 years 28.3 months, respectively. Local recurrence was observed in 4 patients [13]. The French Childhood Cancer Survivor in all 5 patients initially treated with chemotherapy alone, Study showed that a latency period of more than 25 years whereas in 2 patients among 4 patients treated initially was observed in 25 (53.2%) patients among 47 patients with ReRT combined with chemotherapy. We identi- with RIG [26]. These results indicate that pediatric fied no genetic alterations in the IDH1/2 and TERT patients with primary diseases treated successfully with promoters or in the H3F3A and BRAF genes. Moreover, radiation therapy have a risk of developing RIG more we found that the IDH1/2 mutational status evaluation than 20  years after the initial treatment. Regular imag- helped establish RIG diagnosis in cases whose IDH1/2 ing surveillance is not recommended due to financial and mutational states differed between the primary and sec - emotional stress, rarity of incidence and lack of evidence ondary glioma. that early identification of RIG could improve outcome The optimal screening frequency or follow-up time [27]. However, based on our results, we conclude it is of childhood cancer survivors remains unclear [25]. Ohno et al. Radiation Oncology (2022) 17:85 Page 8 of 11 A E C D Fig. 3 Representative patient treated with reirradiation and temozolomide (ReRT/TMZ) showing the usefulness of IDH1/2 mutational status evaluation in establishing the RIG diagnosis (Case 9). A T2-weighted magnetic resonance image at the initial presentation showing a hyperintense lesion in the left medial frontal lobe (black arrow). B T1-weighted magnetic resonance image with gadolinium enhancement obtained 17 years after the primary tumor showing a contrast-enhanced lesion just posterior to the primary tumor, which was included within the prior radiation field. C Sanger sequencing analysis of the secondary tumor (glioblastoma) showing the homozygous G nucleotide at codon 515 of the IDH2 gene, indicating the IDH2 gene was wild-type. D Sanger sequencing analysis of the primary tumor (diffuse astrocytoma) showing the heterozygous G and A nucleotides at codon 515 of the IDH2 alleles, indicating the IDH2 gene was mutant. E T1-weighted magnetic resonance images with gadolinium enhancement were obtained 23.0 months after the secondary tumor diagnosis showing a distant recurrence in the cerebellum (white arrow) important to inform cancer survivors about the long- chemotherapy on local tumor control and emphasize the term risk of developing RIG beyond 20  years and the importance of ReRT in RIG treatment. need for timely neuroimaging evaluation when they pre- A serious concern of ReRT in the treatment of RIG is sent neurological symptoms. the risk of radiation necrosis. Fetcko et  al. reported that ReRT is a primary treatment option in RIG manage- 5.9% of patients developed radiation necrosis, and 3.3% ment [4, 5]. Paulino et  al. reported that patients who had major neurological deficits after stereotactic radio - underwent ReRT for RIG showed better survival rates surgery (SRS) treatment for recurrent high-grade glio- than those who did not (13 vs. 8  months; p = 0.0009), mas [29]. Shanker et  al. also reported that the radiation suggesting that ReRT was efficacious in treating these necrosis rates after ReRT for recurrent high-grade glio- tumors [4]. Yamanaka et  al. reported that the MST of mas were 7.1% for fractionated stereotactic radiotherapy, patients who received surgery, chemotherapy, and ReRT 6.1% for SRS, and 1.1% for conventional radiotherapy was 18  months, whereas the remainder of patients who [30]. Paulino et  al. reported from literature reviews that did not receive combined modality therapy had an MST the risk of developing necrosis is less than 10% in the of 9  months (p = 0.0006), suggesting that the combina- patients who underwent ReRT treatment for RIG [4]. In tion of ReRT and chemotherapy is a potentially effective this study, we did not observe radiation necrosis in any treatment option for RIG [5]. In our study, the median patient. One possible reason for the low rate of radia- PFS and MST were 11.3 and 28.3  months, better than tion necrosis is that the period between the first and those reported in previous studies [4, 5, 28]. We also second radiation sessions is usually more than 10  years, showed that patients initially receiving ReRT combined and most patients with RIG die within 3 years; therefore, with chemotherapy tended to have a longer PFS and late complications related to ReRT might not be clini- more favorable local control than those initially receiv- cally relevant. To minimize the risk of radiation necro- ing chemotherapy alone. These are key findings, as they sis, the addition of Bev to ReRT may be a promising suggest the potential effect of initial ReRT combined with option. Cuneo et  al. observed radiation necrosis in 19% Ohno  et al. Radiation Oncology (2022) 17:85 Page 9 of 11 of patients who received SRS without bevacizumab, and difference in the IDH1/2 mutational states between the in 5% of those who received SRS with Bev, indicating Bev primary and secondary tumors, we could conclude that may reduce the risk of developing radiation necrosis [31]. secondary tumor with IDH1/2 wild-type did not develop The two patients (Cases 10 and 11) received Bev com - from the primary tumor with IDH2 mutation, but the bined with postoperative ReRT and TMZ, and they did secondary tumor was a de novo tumor that was related to not develop symptomatic radiation necrosis during the the previous radiation therapy. Furthermore, the obser- follow-up period with 28.3 and 9.8  months. In addition, vation that secondary tumor had IDH1/2 wild-type was as shown in Case 11, ReRT combined with TMZ/Bev consistent with prior studies that RIGs do not harbor could have significant therapeutic effect (Fig.  2). It will be IDH1/2 mutations [12–14]. We recommend evaluating of interest to investigate the efficacy of combined ReRT the IDH1/2 mutational status between the primary and and TMZ/Bev therapy in larger patient cohort with RIG. secondary tumors when the primary tumor was glioma. Treatment-related comorbidities might influence the Our study had certain limitations. First, this was a ret- management and make the treatment challenging in rospective study, and the indications or dose/fraction patients with RIG. We found 7 patients (63.6%) who had regimens of ReRT were heterogeneous. The indications comorbidities, which were related to primary therapy. or dose/fraction regimens of ReRT might have depended Family support was needed to safely perform chemo- on the previous radiation field or regimen or period from therapy in patients with mild cognitive impairment or the previous radiation; thus, heterogeneity was inevita- visual dysfunction and to maintain hormone replacement ble. Second, we did not investigate the genetic status in in those with hypopituitarism. In treating patients with three patients because tissue samples were unavailable. these comorbidities, careful monitoring is mandatory to u Th s, further studies are needed to elucidate the genetic avoid treatment-related complications. characteristics of RIG. Third, our cohort was too small We investigated genetic alterations in 8 patients whose to draw definitive conclusions. We acknowledge that the tumor samples were available. We found no alterations in power of the survival analysis regarding the usefulness of the IDH1/2 or TERT promoters or in the H3F3A or BRAF ReRT, and the ReRT-related toxicity, was limited by the genes. Two patients had a hypermethylated MGMT sample size; therefore, our results need to be confirmed promoter; the other 6 patients had a hypomethylated in larger cohort studies. MGMT promoter. These results are consistent with those of previous reports and confirm the genetic characteris - Conclusions tics of RIG [10–15, 32]. Recent comprehensive molecu- RIG can occur beyond 20 years after successful treatment lar analyses revealed that RIGs had recurrent PDGFR of the primary disease using radiotherapy; thus, cancer amplification, loss of CDKN2A/B and absence of histone survivors should be informed of the long-term risk of 3 and IDH1/2 mutations and also showed that their DNA developing RIG and the need for timely neuroimaging methylation patterns closely resembled those of spo- evaluation when they present neurological symptoms. radic pediatric GBM RTK1 tumors [14, 15, 32]. These ReRT combined with chemotherapy appears to be fea- observations suggest that RIGs are molecularly distinct sible and has favorable outcomes. ReRT combined with from adult diffuse gliomas and aberrant activation of the TMZ/Bev could be a promising therapeutic approach. MAPK/ERK pathway together with loss of cell cycle con- Determining the IDH1/2 mutational status is useful trol facilitates the tumorigenesis of RIG [14, 15, 32]. to establish RIG diagnosis when the primary tumor is To establish the diagnosis of RIG, the tumor histol- glioma. ogy of the secondary tumor must be different from that of the primary tumor [5, 16, 17]. However, when the pri- mary tumor is diffuse glioma, differentiating the second - Abbreviations RIG: Radiation-induced glioma; ReRT: Reirradiation; GBM: Glioblastoma; TMZ: ary tumor from the recurrence of the primary tumor or Temozolomide; Bev: Bevacizumab; ACNU: Nimustine hydrochloride; IDH: de novo tumor that was related to the previous radia- Isocitrate dehydrogenase; OS: Overall survival; MST: Median survival time; PFS: tion exposure is difficult. In that situation, if the IDH1/2 Progression-free survival time; MGMT: O-6-methylguanine DNA methyltrans- ferase; TERT: Telomerase reverse transcriptase; BRAF: B-Raf; H3F3A: Histone mutational status is different between the primary and H3.3; MAPK/ERK: Mitogen-activated protein kinase/extracellular signal-regu- the secondary tumors, the tumor origin is thought to be lated kinase. different between these two tumors. Thus, the IDH1/2 Acknowledgements mutational status difference between the primary and A part of this study was presented at the 19th International Symposium on secondary tumors could help differentiate the second - Pediatric Neuro-Oncology meeting. ary tumor from the recurrence of the primary or de novo Author contributions tumors. In Case 9, the primary tumor had IDH2 muta- M.O. and Y.N. designed the study. M.O., Y.M., M.T., S.Y., Y.T., D.K., M.K., H.I., tion, and the secondary tumor did not. Based on the and Y.N. contributed to the patient management and treatment. A.Y. and Ohno et al. Radiation Oncology (2022) 17:85 Page 10 of 11 K.S. contributed to the diagnoses. M.O., Y.M., M.T., S.Y., Y.T., Y.M., K.I., and Y.N. 7. Taylor AJ, Little MP, Winter DL, Sugden E, Ellison DW, Stiller CA, et al. Pop- contributed to sample collection, molecular analyses, data acquisition, and ulation-based risks of CNS tumors in survivors of childhood cancer: the interpretation. M.O. conducted the statistical analyses. M.O. and Y.N. wrote British Childhood Cancer Survivor Study. J Clin Oncol. 2010;28:5287–93. the manuscript. All the authors reviewed, edited, and approved the final 8. Pettorini BL, Park YS, Caldarelli M, Massimi L, Tamburrini G, Di Rocco C. manuscript. Radiation-induced brain tumours after central nervous system irradiation in childhood: a review. Childs Nerv Syst. 2008;24:793–805. Funding 9. Hiraki T, Fukuoka K, Mori M, Arakawa Y, Matsushita Y, Hibiya Y, et al. Appli- Not applicable. cation of genome-wide DNA methylation analysis to differentiate a case of radiation-induced glioblastoma from late-relapsed medulloblastoma. J Availability of data and materials Neuropathol Exp Neurol. 2021;80:552–7. The datasets used and/or analyzed during the current study are available from 10. Izycka-Swieszewska E, Bien E, Stefanowicz J, Szurowska E, Szutowicz- the corresponding author upon reasonable request. Zielinska E, Koczkowska M, et al. Malignant gliomas as second neoplasms in pediatric cancer survivors: neuropathological study. Biomed Res Int. 2018;2018:4596812. Declarations 11. Kajitani T, Kanamori M, Saito R, Watanabe Y, Suzuki H, Watanabe M, et al. Three case reports of radiation-induced glioblastoma after complete Ethics approval and consent to participate remission of acute lymphoblastic leukemia. Brain Tumor Pathol. All procedures performed in this study were in accordance with the ethical 2018;35:114–22. standards of the institutional review board and the 1964 Helsinki Declara- 12. Lopez GY, Van Ziffle J, Onodera C, Grenert JP, Yeh I, Bastian BC, et al. The tion and its later amendments. This study was approved by the Institutional genetic landscape of gliomas arising after therapeutic radiation. Acta Review Board of the National Cancer Center (2004-066 or 2007-086). For this Neuropathol. 2019;137:139–50. retrospective study, a waiver of informed consent was obtained through 13. Nakao T, Sasagawa Y, Nobusawa S, Takabatake Y, Sabit H, Kinoshita M, the Institutional Review Board of the National Cancer Center (2004-066 or et al. Radiation-induced gliomas: a report of four cases and analysis of 2007-086). molecular biomarkers. Brain Tumor Pathol. 2017;34:149–54. 14. Deng MY, Sturm D, Pfaff E, Sill M, Stichel D, Balasubramanian GP, et al. Consent for publication Radiation-induced gliomas represent H3-/IDH-wild type pediatric Not applicable. gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B. Nat Commun. 2021;12:5530. Competing interests 15. DeSisto J, Lucas JT Jr, Xu K, Donson A, Lin T, Sanford B, et al. Comprehen- HI received grants from HekaBio, Elekta KK, and CICS, a consulting fee from sive molecular characterization of pediatric radiation-induced high-grade HekaBio, and lecture fees from Varian, Itochu, and CICS. All authors report no glioma. Nat Commun. 2021;12:5531. disclosures relevant to the manuscript. 16. Cahan WG. Radiation-induced sarcoma–50 years later. Cancer. 1998;82:6–7. Author details 17. Cahan WG, Woodard HQ, et al. Sarcoma arising in irradiated bone; report Department of Neurosurgery and Neuro-Oncology, National Cancer Center of 11 cases. Cancer. 1948;1:3–29. Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Department of Radia- 18. 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Abstract

Background: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). Methods: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. Results: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9–30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemo- therapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. Conclusions: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Deter- mining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma. *Correspondence: mohno@ncc.go.jp; yonarita@ncc.go.jp Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ohno et al. Radiation Oncology (2022) 17:85 Page 2 of 11 Keywords: Radiation-induced glioma, IDH1/2 mutations, Secondary neoplasms, Long-term survivors of malignancies, Reirradiation Background strategy, especially for the role of ReRT. We also investi- Radiotherapy is used for cancer treatments, including gated genetic alterations in 8 patients and evaluated the pediatric brain tumors and hematological malignancies, diagnostic impact of isocitrate dehydrogenase (IDH) 1 such as glioma, medulloblastoma, germ cell tumors, and and 2 mutation status on establishing RIG diagnosis. leukemia. Despite an overall improvement in the sur- vival rates of patients with these tumors, patients treated Methods and materials with radiotherapy are at risk of long-term neurologi- Patient characteristics cal complications such as the development of progres- This study was a retrospective observational study. We sive leukoencephalopathy, arteritis, hypopituitarism, reviewed our departmental database between 2001 and and hypothalamic insufficiency [1]. One of the most 2021. We included patients who satisfied Cahan’s criteria, serious late consequences of radiotherapy is secondary which were as follows: (1) the tumor must originate in a neoplasms, which occur in rare cases but represents a previously irradiated region (but not necessarily in the major cause of mortality in long-term survivors of child- full-dose region), (2) there must be a sufficient latency hood malignancies [2–6]. Among radiation-induced time between irradiation and the onset of the postra- brain tumors, meningiomas and gliomas are the most diation tumor, (3) the tumor histology must be differ - frequently reported secondary neoplasms [1]. The cumu - ent from that of the primary tumor, and (4) the patient lative risk of secondary brain tumors occurring after radi- must not have pathologies that favor the development of ation therapy for pituitary adenomas is 2.0% at 10  years tumors: Li-Fraumeni’s disease, von Recklinghausen’s dis- and 2.4% at 20  years, which is 10.5 times higher than ease, tuberous sclerosis, xeroderma pigmentation, or ret- that seen in the general population [3]. The cumulative inoblastoma [5, 16, 17]. risk of secondary brain tumors occurring among long- The clinical, operative and radiological records of the term acute lymphoblastic leukemia survivors is 0.8% at patients were reviewed, and data on the following vari- 10 years and 1.87% at 20 years [2]. ables were collected: clinical and treatment history before Radiation-induced gliomas (RIGs) are typically high- RIG diagnosis, clinical and treatment history after RIG grade tumors. The median latency period for develop - diagnosis, Karnofsky performance status (KPS) at the ing RIGs is 8–11  years [4–6]. The overall standardized time of RIG diagnosis, presence or absence of comor- incidence ratio (SIR) for RIG in childhood cancer sur- bidities and leukoencephalopathy at the time of RIG vivors is 10.8, and the SIR is different according to the diagnosis, date of operation for RIG, postoperative follow-up period; 20.6 in 0–4  years follow-up, 7.5 in therapy for RIG, date of tumor recurrence of RIG, date 5–9 years follow-up, 11.0 in 10–14 years follow-up, 12.5 of death or last hospital visit, the extent of resection of in 15–19  years follow-up, 7.2 in 20–29  years follow- RIG, and treatment after tumor recurrence of RIG. The up, and 5.0 in 30  years follow-up [7]. The treatments leukoencephalopathy was evaluated by magnetic reso- of RIGs are usually challenging, and the clinical out- nance images (MRI) and graded based on the Common comes are generally poor [3–5, 8]. The median survival Terminology Criteria for Adverse Events version 5.0. The time (MST) of patients with RIGs is 11  months, with extent of resection of the RIGs was determined based on a 2-year survival rate of 20.2% [5]. Several studies and the surgeon’s operative notes and postoperative imaging review articles have proposed a combination therapy studies and classified as follows: total if 100% of the con - of reirradiation (ReRT) and chemotherapy as a poten- trast-enhanced lesion was resected; subtotal, if 95–99% tial treatment option; however, there are few reports of the lesion was resected; partial, if < 94% of the lesion on the details of the combined therapy and their treat- was resected, or removed as a biopsy [18]. All patients ment outcomes. Thus, the optimal therapeutic approach were re-diagnosed by neuropathologists at our hospital for RIGs is not well defined [5 ]. Moreover, few stud- according to the World Health Organization 2016 clas- ies investigated genetic alterations in RIGs [9–15], and sification [19]. their clinical impact remains unclear. In this study, we retrospectively analyzed the clinical Genetic analysis characteristics and treatment outcomes in 11 patients Tumor DNA was extracted from frozen tumor tissues in 8 with RIG to clarify the optimal follow-up period from cases using a DNeasy Blood & Tissue Kit (Qiagen; Tokyo, the treatment of the primary disease and therapeutic Japan). The presence of hotspot mutations in the IDH1 Ohno  et al. Radiation Oncology (2022) 17:85 Page 3 of 11 (R132) and IDH2 (R172) genes was assessed by Sanger using the Kaplan–Meier method by JMP ver. 15.1.0 sequencing and/or pyrosequencing, as described previ- software for Mac (SAS Institute Japan; Tokyo, Japan) and ously [20, 21]. Pyrosequencing assays were designed to GraphPad Prism ver. 9.2.0 for Mac (GraphPad Software; detect all known mutations in these genes [20]. The two La Jolla, CA, USA). mutation hotspots in the telomerase reverse transcriptase (TERT) gene promoter were analyzed in 8 tumors using Results Sanger sequencing and/or pyrosequencing, as reported Patient characteristics of primary disease previously [22]. The mutation hotspots at codons 27 We identified 11 patients who satisfied Cahan’s criteria and 34 of the histone H3.3 (H3F3A) gene, and those at and had RIG [5, 16, 17]. The patient characteristics of the codon 600 of the B-Raf (BRAF) gene, were analyzed in 6 primary disease are summarized in Table  1. The median tumors using Sanger sequencing and/or pyrosequencing age of the 11 patients was 12  years (range: 1–39  years), [21]. The methylation status of the O-6-methylguanine and there was no sex predominance (male: 6, female: DNA methyltransferase (MGMT) promoter was analyzed 5). The primary diseases included germinomas (n = 2), in 8 tumors using bisulfite modification of the tumor acute lymphoblastic leukemias (n = 2), medulloblastomas genomic DNA, followed by pyrosequencing, as previ- (n = 3), diffuse astrocytoma with IDH2 mutant (n = 1), ously described [22]. The MGMT promoter methylation pilocytic astrocytoma (n = 1), pituitary adenoma (n = 1), status was defined as hypermethylation when its mean and a metastatic brain tumor from lung cancer (n = 1). level at the 16 CpG sites was 16% and greater than 16%, All patients received cranial radiation. In Case 1, received and hypomethylation when less than 16% [18, 22]. continuous intraarterial bromodeoxyuridine combined with radiotherapy of 41  Gy in 23 fractions at 15-year- Statistical analysis old and of 60 Gy in 34 fractions at 17-year-old [23]. The The latency period was defined as the interval between median latency time between the primary disease and the date of diagnosis of the primary disease and that of RIG was 17 years (range: 9–30 years) (Table 1). RIG. Overall survival time (OS) was defined as the inter - val between the date of RIG surgery and death or the last Patient characteristics and treatment of RIGs follow-up, whichever occurred first. Progression-free The characteristics of the 11 patients with RIG are sum - survival time (PFS) was defined as the period between marized in Table 2. The median age of the patients was the date of RIG surgery and the detection of progression, 34  years (range: 10–49  years). The RIGs included glio - death, or last follow-up. These times were calculated blastoma (GBM) with IDH1/2 wild type (n = 7), GBM Table 1 Characteristics of patients with primary diseases Case no. Sex Age at primary Primary disease Location Therapy Chemotherapy Latency disease (years) (years) Radiation therapy Radiation dose (Gy) a a 1 M 15 Germinoma SuprasellarLocal, Local41, 60 Yes 30 2 M 25 Pituitary adenoma Sellar Local 60 No 20 3 M 1 Acute lymphoblastic Systemic TB 18 Yes 9 lymphoma 4 M 20 Germinoma Suprasellar WB 50 Yes 13 5 F 12 Pilocytic astrocytoma Hypothalamus Local 54 No 22 6 F 9 Medulloblastoma Cerebellum CS WB: 35.6, Local: 66, Yes 30 WS: 31.9 7 F 10 Medulloblastoma Cerebellum CS WB: 40, Local: 60, Yes 13 WS: 30 8 M 2 Acute lymphoblastic Systemic TB 12 Yes 15 lymphoma 9 F 15 Diffuse astrocytoma, Left Frontal Local 60 Yes 17 IDH2-mutant 10 F 39 Metastatic brain tumor Multiple Local, WB CK: 22, WB: 30 Yes ( TKI) 10 from Lung cancer 11 M 6 Medulloblastoma Cerebellum CS WB: 23.4, Local: 55.8, Yes 22 WS: 23.4 M male, F female, IDH isocitrate dehydrogenase, TB total body, CS craniospinal, WB whole brain, WS whole spine, CK cyberknife, TKI tyrosine kinase inhibitor This patient received radiotherapy of 41 Gy in 23 fractions at 15-year-old and of 60 Gy in 34 fractions at 17-year-old Ohno et al. Radiation Oncology (2022) 17:85 Page 4 of 11 Table 2 Characteristics of patients with radiation-induced gliomas Case Sex Age Secondary Karnofsky Location Leukoenceph Comorbidity Initial treatment Recurrent Treatment at first recurrence PFS OS Status no. (years) disease performance alopathy pattern (months) (months) Operation Chemotherapy Radiation Operation Chemotherapy Radiation status therapy therapy 1 M 45 GBM, NOS 80 Rt. insula Grade I Visual dys- Partial ACNU No Local BSC 28.1 34.5 Dead function removal 2 M 45 AA, NOS 70 Rt. temporal No No Partial TMZ No Local BSC 3.0 8.4 Dead removal 3 M 10 GBM, 80 Lt. frontal Lt. No Short stature Biopsy ACNU Local RT Local No Carboplatin, No 3.8 11.0 Dead IDH1/2- parietal 40 Gy/20fr Etoposide Wildtype 4 M 33 GBM, 60 Rt. Cerebel- Grade II Hypopituita- Biopsy Carboplatin, No Dissemina- BSC 2.5 4.6 Dead IDH1/2- lum Pons rism Etoposide tion Wildtype (dissemina- tion) 5 F 34 GBM, 80 Lt. temporal No Hypopitui- Total TMZ No Local Subtotal TMZ Local RT 11.3 27.5 Dead IDH1/2- tarism Visual removal removal 45 Gy/25f Wildtype dysfunction 6 F 39 AA, IDH1/2- 60 Rt. Parietal No Mild cognitive Rt. parietal: TMZ No Local Rt. Parietal: TMZ Local RT 8.8 27.3 Dead Wildtype Rt. occipital impairment partial Total 60 Gy/30fr removal Rt. removal Rt. occipital: Occipital: partial Total removal removal 7 F 23 GBM, 90 Rt. frontal No Mild cognitive Subtotal TMZ No Local No TMZ SRT 7.4 29.1 Dead IDH1/2- impairment removal 40 Gy/10fr Wildtype 8 M 17 GBM, NOS 90 Rt. parietal No No Total TMZ Local RT Local No No GKS 17.0 30.8 Dead removal 66 Gy/33fr 9 F 32 GBM, 80 Lt. frontal- Grade II No Biopsy TMZ Local RT Distant No TMZ SRT 23.0 35.1 Dead IDH1/2- parietal 60 Gy/30fr 42 Gy/7fr Wildtype 10 F 49 GBM, 90 Rt. frontal No No Total TMZ, Bev Local RT Distant Biopsy Bev SRT 15.9 28.3 Dead IDH1/2- removal 50 Gy/25fr 42 Gy/7fr Wildtype 11 M 28 GBM, 60 Lt. cerebel- No Mild cognitive Biopsy TMZ, Bev Local RT No recur- No recur- 9.8 9.8 Alive IDH1/2- lum impairment 40 Gy/15fr rence rence Wildtype M male, F female, GBM glioblastoma, NOS not otherwise specified, AA anaplastic astrocytoma, IDH isocitrate dehydrogenase, Rt right, Lt left, ACNU nimustine hydrochloride, TMZ temozolomide, Bev bevacizumab, RT radiation therapy, BSC best supportive care, GKS gamma knife radiosurgery, SRT stereotactic radiotherapy Ohno  et al. Radiation Oncology (2022) 17:85 Page 5 of 11 ReRT regimens were as follows: 40  Gy in 15 fractions, not otherwise specified (n = 2), anaplastic astrocytoma 40 Gy in 20 fractions, 50 Gy in 25 fractions, 60 Gy in 30 with IDH1/2 wild type (n = 1), and anaplastic astro- fractions, and 66 Gy in 33 fractions. cytoma not otherwise specified (n = 1). All patients Ten patients had tumor recurrences, and 7 patients underwent tumor removal or biopsy and were diag- received further treatments for recurrent tumors. All the nosed based on histopathological examination. Two patients were treated with chemotherapy. Four patients patients had multiple intraparenchymal lesions (Case received ReRT at the initial location at the time of recur- 3 and Case 6), and one had right cerebellar and pon- rence. Two patients with supratentorial tumors (Case tine lesions with cerebrospinal dissemination (Case 4). 9 and Case 10)  had tumor recurrence in the cerebellum Three patients showed leukoencephalopathy at the time at a distance from the initial location and received ste- of RIG diagnosis: Grade II in 2 patients and Grade I in reotactic radiotherapy consisting of 42  Gy in 7 fractions 1 patient. Seven patients (63.6%) suffered from comor - (Table 2). bidities, which were related to primary therapy: 3 had mild cognitive impairment, 2 had hypopituitarism, 2 had visual dysfunction, and 1 had short stature. No Treatment outcomes of RIGs patient with leukoencephalopathy was associated with The median PFS and median survival time (MST) in 11 cognitive impairment. The median KPS at the time of patients with RIG were 11.3  months and 28.3  months, RIG diagnosis was 80. respectively (Fig. 1A, B). The median PFS in patients ini - For postoperative treatment, 5 patients received tially treated with ReRT combined with chemotherapy ReRT combined with chemotherapy, including ReRT/ (n = 5) was 17.0  months; this was longer than that of temozolomide (TMZ) (n = 2), ReRT/TMZ/bevaci- patients treated with chemotherapy alone (8.1  months, zumab (Bev) (n = 2), and ReRT/nimustine hydrochlo- n = 6) (Fig.  1C). The MST in patients initially treated ride (ACNU) (n = 1); 6 patients were treated with with ReRT combined with chemotherapy (n = 5) and chemotherapy alone, including TMZ (n = 4), ACNU those receiving chemotherapy alone (n = 6) were 29.6 and (n = 1), and carboplatin and etoposide (n = 1). The 27.4 months (Fig. 1D). A B C D Fig. 1 Kaplan–Meier curves of progression-free survival time (PFS) and overall survival time. A The median PFS was 11.3 months. B The median survival time was 28.3 months. C The median PFS in patients treated initially with reirradiation (ReRT ) combined with chemotherapy (n = 5) was 17.0 months, and that in patients receiving chemotherapy alone was 8.1 months (n = 6). D The median survival times of patients treated initially with ReRT combined with chemotherapy (n = 5) was 29.6 months, and that in patients receiving chemotherapy alone (n = 6) was 27.4 months Ohno et al. Radiation Oncology (2022) 17:85 Page 6 of 11 The tumor recurrence pattern after initial treatment patient presented with dizziness; an MRI revealed a for RIGs was evaluated by radiological examinations in left cerebellar contrast-enhanced lesion (Fig.  2A, B). 9 patients, excluding 1 patient who presented with cere- He underwent a biopsy and was diagnosed as having brospinal dissemination and 1 patient who did not have a GBM with IDH1/2 wild-type. He received ReRT at a recurrence. Among 4 patients treated initially with ReRT dose of 40 Gy in 15 fractions combined with TMZ/Bev combined with chemotherapy, 2 had local recurrence, and maintenance TMZ/Bev therapy. The tumor showed and 2 had distant recurrence; all 5 patients treated with a complete response, and the patient did not develop chemotherapy alone had local recurrence. tumor recurrence 9.8  months after the treatment for None of the patients was observed to develop sympto- GBM with IDH1/2 wild-type (Fig. 2C, D). matic radiation necrosis, which could be caused by a high cumulative radiation dose during the follow-up period. Case presentation 2 Genetic alterations of RIGs A 12-year-old female patient (Case 9) initially presented The genetic alterations of 8 patients whose tumor samples with a cataplectic attack; 3  years later, an MRI exam were available for analysis are summarized in Table  3. revealed a left frontal non-contrast-enhanced tumor There were no alterations in the IDH1/2 or TERT pro- (Fig.  3A). She underwent subtotal resection and was moters in the 8 cases, and no BRAF or H3F3A mutations diagnosed with diffuse astrocytoma. After the opera - were found in the 6 cases for which data was available. tion, she received radiation therapy at a dose of 60  Gy Two tumors had hypermethylated MGMT promoters, in 30 fractions and chemotherapy with ACNU. Seven- whereas the other six had hypomethylated promoters. teen years after treatment for the diffuse astrocytoma, she developed a contrast-enhanced lesion just posterior Illustrative cases to the primary tumor, which was included within the We presented 2 illustrative cases; one case showed the prior radiation field (Fig.  3B). She underwent a biopsy, favorable therapeutic effect of ReRT/TMZ/Bev (Case and the secondary tumor was diagnosed as GBM with presentation 1:  Case 11), and the other case showed the IDH1/2 wild-type (Fig.  3C). We performed Sanger usefulness of IDH1/2 mutational status evaluation in sequencing analysis of the IDH1/2 gene in the primary establishing the RIG diagnosis (Case presentation 2: Case tumor and found that the tumor had an IDH2 mutation 9). (Fig. 3D). Because IDH1/2 mutations maintain through tumor recurrence [24], the secondary tumor with Case presentation 1 IDH1/2 wild-type was no recurrence from the primary A 6-year-old boy (Case 11) initially presented with tumor with IDH2 mutation but was a de novo tumor headache, vomiting, and conscious disturbance and that was most likely to be related to the previous expo- underwent total removal of a right cerebellar tumor. sure. Therefore, we diagnosed the secondary tumor as The tumor was diagnosed as a medulloblastoma, and RIG. The patient received ReRT at a dose of 60  Gy in combined chemotherapy was performed with cranio- 30 fractions combined with TMZ; however, the patient spinal radiation of 23.4  Gy in 13 fractions and local had a distant recurrence in the cerebellum 23.0 months radiation up to 55.8  Gy in 31 fractions. Twenty-two after the treatment for GBM with IDH1/2 wild-type years after the treatment for medulloblastoma, the (Fig. 3E) and died 12.1 months thereafter. Table 3 Summary of genetic alterations in radiation-induced gliomas Case no. Secondary disease IDH1/2 BRAF H3F3A TERT MGMT 3 GBM, IDH1/2 Wild-type WT ND ND WT Hypomethylation 4 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 5 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 6 AA, IDH1/2 Wild-type WT WT WT WT Hypermethylation 7 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 9 GBM, IDH1/2 Wild-type WT ND ND WT Hypomethylation 10 GBM, IDH1/2 Wild-type WT WT WT WT Hypomethylation 11 GBM, IDH1/2 Wild-type WT WT WT WT Hypermethylation GBM glioblastoma, AA anaplastic astrocytoma, WT wild-type, ND not determined, IDH isocitrate dehydrogenase, BRAF B-Raf, H3F3A histone H3.3, TERT telomerase reverse transcriptase, MGMT O-6-methylguanine DNA methyltransferase Ohno  et al. Radiation Oncology (2022) 17:85 Page 7 of 11 A B C D Fig. 2 Representative patient treated with reirradiation, temozolomide, and bevacizumab (ReRT/TMZ/Bev) showing a favorable response (Case 11). A Preoperative T1-weighted magnetic resonance image with gadolinium enhancement and B fluid-attenuated inversion recovery (FLAIR) image showing an enhanced tumor in the left cerebellum (black arrow). C T1-weighted magnetic resonance image with gadolinium enhancement and D FLAIR image obtained 9.8 months after ReRT/TMZ/Bev treatment showing a favorable response (white arrow) Previous studies reported that the median latency period Discussion was 8–11  years, and the incidence of RIG largely disap- In this study, we observed a median latency time of peared after 15–20  years [4–6]. However, in our cohort, 17  years, with a range of 9 to 30  years. Among the the median latency time from the primary cancer treat- 11 patients with RIG, ReRT combined with chemo- ment to the development of RIG was 17  years, with a therapy was performed in 5 patients at the initial range of 9 to 30  years, and 5 out of 11 patients (45.5%) treatment of RIG and for 6 patients at the time of recur- had a latency period of 20 years or more. Nakao et al. also rence; the median PFS and MST were 11.3  months and reported that the latency period was more than 20 years 28.3 months, respectively. Local recurrence was observed in 4 patients [13]. The French Childhood Cancer Survivor in all 5 patients initially treated with chemotherapy alone, Study showed that a latency period of more than 25 years whereas in 2 patients among 4 patients treated initially was observed in 25 (53.2%) patients among 47 patients with ReRT combined with chemotherapy. We identi- with RIG [26]. These results indicate that pediatric fied no genetic alterations in the IDH1/2 and TERT patients with primary diseases treated successfully with promoters or in the H3F3A and BRAF genes. Moreover, radiation therapy have a risk of developing RIG more we found that the IDH1/2 mutational status evaluation than 20  years after the initial treatment. Regular imag- helped establish RIG diagnosis in cases whose IDH1/2 ing surveillance is not recommended due to financial and mutational states differed between the primary and sec - emotional stress, rarity of incidence and lack of evidence ondary glioma. that early identification of RIG could improve outcome The optimal screening frequency or follow-up time [27]. However, based on our results, we conclude it is of childhood cancer survivors remains unclear [25]. Ohno et al. Radiation Oncology (2022) 17:85 Page 8 of 11 A E C D Fig. 3 Representative patient treated with reirradiation and temozolomide (ReRT/TMZ) showing the usefulness of IDH1/2 mutational status evaluation in establishing the RIG diagnosis (Case 9). A T2-weighted magnetic resonance image at the initial presentation showing a hyperintense lesion in the left medial frontal lobe (black arrow). B T1-weighted magnetic resonance image with gadolinium enhancement obtained 17 years after the primary tumor showing a contrast-enhanced lesion just posterior to the primary tumor, which was included within the prior radiation field. C Sanger sequencing analysis of the secondary tumor (glioblastoma) showing the homozygous G nucleotide at codon 515 of the IDH2 gene, indicating the IDH2 gene was wild-type. D Sanger sequencing analysis of the primary tumor (diffuse astrocytoma) showing the heterozygous G and A nucleotides at codon 515 of the IDH2 alleles, indicating the IDH2 gene was mutant. E T1-weighted magnetic resonance images with gadolinium enhancement were obtained 23.0 months after the secondary tumor diagnosis showing a distant recurrence in the cerebellum (white arrow) important to inform cancer survivors about the long- chemotherapy on local tumor control and emphasize the term risk of developing RIG beyond 20  years and the importance of ReRT in RIG treatment. need for timely neuroimaging evaluation when they pre- A serious concern of ReRT in the treatment of RIG is sent neurological symptoms. the risk of radiation necrosis. Fetcko et  al. reported that ReRT is a primary treatment option in RIG manage- 5.9% of patients developed radiation necrosis, and 3.3% ment [4, 5]. Paulino et  al. reported that patients who had major neurological deficits after stereotactic radio - underwent ReRT for RIG showed better survival rates surgery (SRS) treatment for recurrent high-grade glio- than those who did not (13 vs. 8  months; p = 0.0009), mas [29]. Shanker et  al. also reported that the radiation suggesting that ReRT was efficacious in treating these necrosis rates after ReRT for recurrent high-grade glio- tumors [4]. Yamanaka et  al. reported that the MST of mas were 7.1% for fractionated stereotactic radiotherapy, patients who received surgery, chemotherapy, and ReRT 6.1% for SRS, and 1.1% for conventional radiotherapy was 18  months, whereas the remainder of patients who [30]. Paulino et  al. reported from literature reviews that did not receive combined modality therapy had an MST the risk of developing necrosis is less than 10% in the of 9  months (p = 0.0006), suggesting that the combina- patients who underwent ReRT treatment for RIG [4]. In tion of ReRT and chemotherapy is a potentially effective this study, we did not observe radiation necrosis in any treatment option for RIG [5]. In our study, the median patient. One possible reason for the low rate of radia- PFS and MST were 11.3 and 28.3  months, better than tion necrosis is that the period between the first and those reported in previous studies [4, 5, 28]. We also second radiation sessions is usually more than 10  years, showed that patients initially receiving ReRT combined and most patients with RIG die within 3 years; therefore, with chemotherapy tended to have a longer PFS and late complications related to ReRT might not be clini- more favorable local control than those initially receiv- cally relevant. To minimize the risk of radiation necro- ing chemotherapy alone. These are key findings, as they sis, the addition of Bev to ReRT may be a promising suggest the potential effect of initial ReRT combined with option. Cuneo et  al. observed radiation necrosis in 19% Ohno  et al. Radiation Oncology (2022) 17:85 Page 9 of 11 of patients who received SRS without bevacizumab, and difference in the IDH1/2 mutational states between the in 5% of those who received SRS with Bev, indicating Bev primary and secondary tumors, we could conclude that may reduce the risk of developing radiation necrosis [31]. secondary tumor with IDH1/2 wild-type did not develop The two patients (Cases 10 and 11) received Bev com - from the primary tumor with IDH2 mutation, but the bined with postoperative ReRT and TMZ, and they did secondary tumor was a de novo tumor that was related to not develop symptomatic radiation necrosis during the the previous radiation therapy. Furthermore, the obser- follow-up period with 28.3 and 9.8  months. In addition, vation that secondary tumor had IDH1/2 wild-type was as shown in Case 11, ReRT combined with TMZ/Bev consistent with prior studies that RIGs do not harbor could have significant therapeutic effect (Fig.  2). It will be IDH1/2 mutations [12–14]. We recommend evaluating of interest to investigate the efficacy of combined ReRT the IDH1/2 mutational status between the primary and and TMZ/Bev therapy in larger patient cohort with RIG. secondary tumors when the primary tumor was glioma. Treatment-related comorbidities might influence the Our study had certain limitations. First, this was a ret- management and make the treatment challenging in rospective study, and the indications or dose/fraction patients with RIG. We found 7 patients (63.6%) who had regimens of ReRT were heterogeneous. The indications comorbidities, which were related to primary therapy. or dose/fraction regimens of ReRT might have depended Family support was needed to safely perform chemo- on the previous radiation field or regimen or period from therapy in patients with mild cognitive impairment or the previous radiation; thus, heterogeneity was inevita- visual dysfunction and to maintain hormone replacement ble. Second, we did not investigate the genetic status in in those with hypopituitarism. In treating patients with three patients because tissue samples were unavailable. these comorbidities, careful monitoring is mandatory to u Th s, further studies are needed to elucidate the genetic avoid treatment-related complications. characteristics of RIG. Third, our cohort was too small We investigated genetic alterations in 8 patients whose to draw definitive conclusions. We acknowledge that the tumor samples were available. We found no alterations in power of the survival analysis regarding the usefulness of the IDH1/2 or TERT promoters or in the H3F3A or BRAF ReRT, and the ReRT-related toxicity, was limited by the genes. Two patients had a hypermethylated MGMT sample size; therefore, our results need to be confirmed promoter; the other 6 patients had a hypomethylated in larger cohort studies. MGMT promoter. These results are consistent with those of previous reports and confirm the genetic characteris - Conclusions tics of RIG [10–15, 32]. Recent comprehensive molecu- RIG can occur beyond 20 years after successful treatment lar analyses revealed that RIGs had recurrent PDGFR of the primary disease using radiotherapy; thus, cancer amplification, loss of CDKN2A/B and absence of histone survivors should be informed of the long-term risk of 3 and IDH1/2 mutations and also showed that their DNA developing RIG and the need for timely neuroimaging methylation patterns closely resembled those of spo- evaluation when they present neurological symptoms. radic pediatric GBM RTK1 tumors [14, 15, 32]. These ReRT combined with chemotherapy appears to be fea- observations suggest that RIGs are molecularly distinct sible and has favorable outcomes. ReRT combined with from adult diffuse gliomas and aberrant activation of the TMZ/Bev could be a promising therapeutic approach. MAPK/ERK pathway together with loss of cell cycle con- Determining the IDH1/2 mutational status is useful trol facilitates the tumorigenesis of RIG [14, 15, 32]. to establish RIG diagnosis when the primary tumor is To establish the diagnosis of RIG, the tumor histol- glioma. ogy of the secondary tumor must be different from that of the primary tumor [5, 16, 17]. However, when the pri- mary tumor is diffuse glioma, differentiating the second - Abbreviations RIG: Radiation-induced glioma; ReRT: Reirradiation; GBM: Glioblastoma; TMZ: ary tumor from the recurrence of the primary tumor or Temozolomide; Bev: Bevacizumab; ACNU: Nimustine hydrochloride; IDH: de novo tumor that was related to the previous radia- Isocitrate dehydrogenase; OS: Overall survival; MST: Median survival time; PFS: tion exposure is difficult. In that situation, if the IDH1/2 Progression-free survival time; MGMT: O-6-methylguanine DNA methyltrans- ferase; TERT: Telomerase reverse transcriptase; BRAF: B-Raf; H3F3A: Histone mutational status is different between the primary and H3.3; MAPK/ERK: Mitogen-activated protein kinase/extracellular signal-regu- the secondary tumors, the tumor origin is thought to be lated kinase. different between these two tumors. Thus, the IDH1/2 Acknowledgements mutational status difference between the primary and A part of this study was presented at the 19th International Symposium on secondary tumors could help differentiate the second - Pediatric Neuro-Oncology meeting. ary tumor from the recurrence of the primary or de novo Author contributions tumors. In Case 9, the primary tumor had IDH2 muta- M.O. and Y.N. designed the study. M.O., Y.M., M.T., S.Y., Y.T., D.K., M.K., H.I., tion, and the secondary tumor did not. Based on the and Y.N. contributed to the patient management and treatment. A.Y. and Ohno et al. Radiation Oncology (2022) 17:85 Page 10 of 11 K.S. contributed to the diagnoses. M.O., Y.M., M.T., S.Y., Y.T., Y.M., K.I., and Y.N. 7. Taylor AJ, Little MP, Winter DL, Sugden E, Ellison DW, Stiller CA, et al. Pop- contributed to sample collection, molecular analyses, data acquisition, and ulation-based risks of CNS tumors in survivors of childhood cancer: the interpretation. M.O. conducted the statistical analyses. M.O. and Y.N. wrote British Childhood Cancer Survivor Study. J Clin Oncol. 2010;28:5287–93. the manuscript. All the authors reviewed, edited, and approved the final 8. Pettorini BL, Park YS, Caldarelli M, Massimi L, Tamburrini G, Di Rocco C. manuscript. Radiation-induced brain tumours after central nervous system irradiation in childhood: a review. Childs Nerv Syst. 2008;24:793–805. Funding 9. Hiraki T, Fukuoka K, Mori M, Arakawa Y, Matsushita Y, Hibiya Y, et al. 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Journal

Radiation OncologySpringer Journals

Published: May 3, 2022

Keywords: Radiation-induced glioma; IDH1/2 mutations; Secondary neoplasms; Long-term survivors of malignancies; Reirradiation

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