Herein, we have chronicled the medical course a childhood cancer survivor, including 32 years of follow-up after surgery and radiotherapy for MB and similar treatment imposed by a rare RIGB of later adult life. In this instance, PBT afforded access to high-dose, second-phase postoperative radiotherapy.

For survivors of childhood cancer, the cumulative incidence of SPTs arising within 30 years after initial tumor diagnoses ranges from 3 to 10% [3]. This is roughly 3–6 times higher than comparable rates in the general population. The most common SPTs encountered are breast cancer for female survivors, ranging from 12 to 20%; thyroid cancer, estimated at 2–7%; and skin cancer, exceeding general population risk by 2–6 times [7, 8]. GB is a relatively rare SPT as such, but it is a recognized risk, particularly for recipients of cranial radiotherapy. More so than chemotherapy, irradiation is usually associated with a higher incidence of SPT (9.5% vs. 2.4%) [3], given its capacity to alter DNA methylation and methyltransferase activity and its deregulation of mRNA.

MB is a common childhood tumor, the overall survival of which has improved through combined use of radiotherapy, chemotherapy, and surgery. Current survival rates are ~ 80–85% for standard risk groups and ~ 65–70% for high-risk groups. However, long-term toxic effects (especially SPTs) are increasing as a result. In the aftermath of MB, CNS is reportedly the most common site of SPTs (63/146, 43.2%), followed by endocrine and hematologic systems. Similar outcomes have been documented during the Childhood Cancer Survivor Study and its British counterpart probe, likely due to whole brain and spinal axis targeting during CSI [7, 9]. The unique physical properties entailed have broadened the usage of PBT in treating childhood cancer. Proton doses are characterized by abrupt surges in energy release, called Bragg peaks. Such rapid dosing decays reduce radiation to nearby healthy tissues by a factor of 2–3. However, monitoring of treated patients for potential SPTs is a long-term proposition, and available research on SPT incidence by mode of MB treatment (proton vs. photon therapy) is currently lacking.

Raymond [10] has generated estimates of secondary cancer incidence using a model derived from Publication No. 60 of the International Commission on Radiologic Protection. Compared with intensity-modulated or conventional X-ray plans, proton beams lowered the expected incidence of radiation-induced secondary cancers after MB treatment by a factor of 8–15. An analysis of the SEER database from mid-2000s forward, ostensibly marked by greater PBT use, has also confirmed fewer SPTs as late effects [3]; and in another assessment according to treatment time frames (1973–1995 vs. 1995–2014), the SPT rate proved higher during earlier years (1973–1995) of more limited PBT use [11]. Matched adult populations (n = 558 each) receiving proton or photon therapy have been followed as well (median interval: proton group, 6.7 years; photon group, 6.0 years) [12], recording SPT rates of 5.2% and 7.5%, respectively. Above findings imply a lower incidence of SPT after PBT of childhood MB. On the other hand, most present-day survivors of pediatric tumors have received photon therapy over a decade ago, so longer follow-up periods may be needed to ascertain SPT incidence in relation to PBT.

Classification of a second primary GB as radiation induced (rather than recurrent second primary) [13,14,15] is based on the following criteria: (1) tumor situated within the irradiated field; (2) sufficient latency between irradiation and tumor occurrence; (3) histological type different from that of original neoplasm; and (4) no pathology, such as Von Recklinghausen disease, favoring tumor development. The most common malignancies associated with RIGB are nasopharyngeal carcinoma (37%), primary intracranial germinoma (21%), and MB (16%) [16]. At 9 years of age, our patient with MB received postoperative CSI only. In analyzing 2771 patients with MB from the SEER-18 database, there were 146 patients (5.27%) who developed SPTs at 15 years. Rates of SPTs after radiotherapy only, radio- and chemotherapy, and chemotherapy only were 9.5%, 4.3%, and 2.4%, respectively [3]. Several studies have shown a 14-year mean latency between radiotherapy and diagnosis of RIGB, unlike the 32-year span in our patient that surpassed most previously published intervals [11, 14]. It is a widely held concept that the younger a patient is at primary treatment, the greater the risk of RIGB will be. Younger onset may therefore render patients especially vulnerable to radiation-induced gliomagenesis in later years due to an abundance of neurogenic stem cells and increased growth factor activity [17].

RIGB is a relatively rare SPT, with a molecular profile that distinguishes it from primary GB and recurrent secondary GB. Clinicians focus more on recurrent secondary GB, tending to overlook the specific and individualized treatment of RIGB. IDH mutation is a critical marker in glioma classification that helps differentiate recurrent and radiation-induced forms of secondary GB (Tables 1 and 2). IDH mutations are largely features of less ominous tumors (WHO grade II-III), whereas the IDH wild type primarily reflects aggressive disease (WHO grade IV), signaling a worse prognosis. In 2021, the latest WHO revision of GB grading was substantial, stipulating that only IDH wild-type lesions warrant a GB diagnosis [5]. Still, there are perhaps some GBs with IDH mutations. The latter have chiefly presented as secondary GBs, morphologically similar to primary GB but imparting a more favorable prognosis [18]. In patients with IDH-mutant GBs, median OS may be ~ 31 months, as opposed to 15 months for those with IDH-wildtype GBs [18, 19].

Among 39 patients with secondary GBs, the IDH mutation rate was found to be 60%, and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation rate was 68.8% [20]. MGMT is a direct DNA repair enzyme that eliminates the TMZ-produced genotoxic O6-methylguanine adduct in a single-step process. Because this restores the genomic integrity of tumors, MGMT promoter methylation denotes a better prognosis. An earlier meta-analysis has determined a median OS (mOS) of 10 months in patients with RIGBs [Peter Y. M]. Across the spectrum of grade IV GBs, survival in patients with RIGBs (mOS, 4.8 months) was shorter than in instances of de novo GB (mOS, 19.2 months; p < 0.001). These findings may be explained by the fact patients with IDH wild type were involved, and there was a lower percentage of MGMT promoter methylation [14]. Our patient with WHO grade IV GB exhibited both IDH mutation and MGMT promoter methylation, thus suggesting TMZ sensitivity and a better prognosis than anticipated for primary or recurrent secondary GB of IDH wild type.

Currently, there is no consensus on oncologic treatment in instances of RIGB. Studies have concluded that patients with secondary GBs experience significantly longer survival times if repeat resection is elected, instead of foregone [20]. Patients with good KPS scores and proper suitability for surgery should subsequently consider second-phase resection as a primary treatment option, although decisions on postoperative adjuvant therapy are comparatively more difficult. Physicians must weigh the perceived benefit of reirradiation against the risk of related brain damage.

In the past, the conventional dose limit for partial brain radiotherapy has been 60 Gy. Some sources have challenged this view, suggesting that reirradiated brain tissue may tolerate a fractionated (2 Gy/fr) cumulative normalized total dose of 100 Gy before necrosis ensues [13]. Paulino et al. have noted that among patients with radiotherapy-induced high-grade gliomas, those who received reirradiation of 50 Gy (35/85, 41%) displayed a 2-year overall survival (OS) rate of 21%. This was significantly better than the 3% rate recorded at 2 years in the absence of reirradiation [21]. Similarly, a meta-analysis has found that reirradiation (mean dose, 48 Gy) conferred a better 2-year OS rate (24%) than the rate achieved (9%) through different treatment. Upon examining factors linked to survival in the setting of grade III-IV RIGB, multimodality combination therapy (including radiotherapy) was identified as an independent prognostic factor (p = 0.002) [16]. These observations suggest that in some patients with radiation-induced gliomas, a therapeutic strategy of reirradiation may serve to prolong disease control. However, the tolerance threshold is changing due to advances in radiotherapy technology, such as PBT. These improvements stand to mitigate the risk of late radiation effects. Despite a scarcity of data on PBT use for reirradiation of RIGB, we are encouraged by its successful application in patients with recurrent gliomas or other brain tumors. Scartoni et al. [22] have investigated 33 patients who completed questionnaires before starting PBT, on last day of treatment, and at every follow-up visit until disease progression. It appears that PBT is safe and well tolerated, ensuring stable quality-of-life parameters for the duration.

The Proton Collaborative Group (PCG) has examined 45 patients from 12 PBT centers in the United States, all receiving photon radiotherapy initially at doses of 60 Gy. The median time between original diagnosis and recurrence was only 20 months, and the median total reirradiation dose was 46.2 Gy (range, 25–60 Gy), with a median of 2.2 Gy per fraction. Of these 45 patients, 40 (88.9%) had received an equivalent dose in 2 Gy fractions (EQD2) of > 39 Gy. All patients had GB as their primary diagnosis. Median progression-free survival (PFS) time was 13.9 months, and median OS was 14.2 months. In terms of side effects, a total of five patients experienced grade 3 toxicity. One showed acute toxicity (ataxia), whereas late toxicity (neuropathy, cognitive disturbance, optic nerve disorder, or seizure) surfaced in the other four. No acute or delayed grade 4 or 5 toxicities were observed.

During a similar multicenter study, patients with GB were reirradiated at high dose, without serious side effects over a year’s time, highlighting the utility of PBT for this purpose [23]. Another 20 patients who received proton reirradiation for recurrent gliomas also registered acceptable outcomes after high-dose radiotherapy. The mean initial dose was 59.4 Gy, and the mean reirradiation dose after a median of 15.3 months (range, 5.3-152.6 months) was 54 Gy [24]. Several earlier investigations have further reinforced the prospect of high-dose irradiation enabled by PBT.

When irradiating our patient (32 years after initial radiotherapy), we used a standard postoperative dose of 60 Gy, delivering a low dose to brainstem and hippocampus. The Dmax of brain scan was 53.5 Gy, the Dmean of left hippocampus was 33 Gy, and the Dmean of right hippocampus was 0.95 Gy. Although the prognosis of a grade IV RIGB is poor, lessening our concerns over later clinically significant necrosis, it is important for physicians to optimally protect a patient’s cognitive function. The incidence of radiation necrosis typically peaks around 1–3 years after radiotherapy [25]. At 1 year after reirradiation, no signs of tumor recurrence or radiation necrosis have been detected as yet.

In summary, RIGB is a rare SPT determined by strategic molecular profiling and requiring individualized management. PBT is the preferred postoperative treatment.