Outcomes following radiotherapy for atypical teratoid/rhabdoid tumor in combination with surgery and intensive chemotherapy: A report from Children’s Oncology Group study ACNS0333

Abstract

Background:

Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI).

Methods:

Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression.

Results:

Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06–1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13–1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment).

Conclusions:

RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

Lay summary

Atypical teratoid/rhabdoid tumor (ATRT) represents a rare brain tumor that unfortunately often occurs in very young children. While often deadly, intensive treatment consisting of surgery, high-dose chemotherapy, and radiation has been shown to improve the chance of disease control and survival. Radiation is given as either directed to the primary brain tumor or to the whole brain and spine. However, directing radiation to the primary brain tumor is preferred due to long-term side effects on brain development associated with whole brain radiation. This article reports on the radiation aspects of a prospective clinical trial where the majority of kids received focal brain radiation with very good control of the primary brain tumor.

Introduction

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant infant CNS tumor with generally poor outcomes. However, prognosis can improve with aggressive surgery, chemotherapy, and radiotherapy (RT).^1–3 Although the molecular landscape is increasingly well-defined, efforts to stratify treatment based on genomic subgroups, or to effectively incorporate targeted systemic therapy agents, remain investigational.⁴ Several database,^5,6 retrospective series,^7,8 and registry studies^9,10 support improved survival with the use of RT. Nonetheless, significant concerns persist regarding neurocognitive impact^11,12 and risk of radiation necrosis^13,14 associated with RT in very young patients with brain tumors. These challenges continue to complicate the pursuit of optimal treatment strategies.

Focal RT to the primary site, administered post-chemotherapy and designed to avoid large-volume irradiation of uninvolved brain, was required for limited stage disease (M0) as part of intensive systemic therapy for the 2 largest prospective ATRT trials to date: DFCI 02–294¹ and Children’s Oncology Group (COG) ACNS0333.¹⁵ The encouraging long-term survival rates reported include 5-year OS of 49.6% in DFCI 02–294 (N = 20) and 4-year OS of 43% in ACNS0333 (N = 65), indicating that further investigation into the contribution of RT to these outcomes is warranted. Notably in DFCI 02–295, all long-term survivors had received RT for M0 disease, and represented an older cohort (40% were older than 36 months) compared to ACNS0333.¹⁶ ACNS0333 met its primary endpoint of improved EFS for young children (age <36 months) compared to historical controls; however, the very young age of the cohort (31% aged 12–35 months and 52% <11 months) may have contributed to RT refusal in 20% of patients (n = 13).

The present study reports outcomes for the 40 patients who received RT on ACNS0333, in order to explore efficacy and morbidity of RT in ATRT when combined with surgery and intensive chemotherapy, as directed in a protocol-specified analysis of outcomes and failure patterns following RT.

Materials and methods

Protocol therapy

Patients were prospectively enrolled and treated according to the COG study ACNS0333, the primary results of which have been reported.¹⁵ ACNS0333 was conducted by the COG in accordance with FDA, NCI, and institutional requirements. Written informed consent was obtained from parents or legal guardians. Protocol therapy consisted of maximal safe tumor resection with optional second-look surgery following induction chemotherapy, consolidation, and RT. Induction consisted of 2 cycles of vincristine/methotrexate/etoposide/cyclophosphamide/cisplatin followed by consolidation with 3 cycles of carboplatin/thiotepa with peripheral blood stem cell (PBSC) support. RT guidelines are shown in Table 1. M0 patients received mandatory protocol-specified focal RT to the primary tumor site. Patients with metastatic disease (M+) at enrollment were allowed, at physician discretion, to receive either craniospinal irradiation (CSI; recommended dose: 2340 cGy for age ≤36 months or 3600 cGy for age >36 months; plus boost) or focal primary site RT. The timing of RT was determined by disease stage, patient age, and tumor location. M0 patients aged ≥6 months old with infratentorial tumors and those aged ≥12 months with supratentorial tumors received RT after induction and before consolidation (RT-first). All other patients (M+ of any age, M0 < 6 months and infratentorial, M0 < 12 months and supratentorial) received RT after completing both induction and consolidation chemotherapy (consolidation-first). This analysis reports outcomes for patients who received RT as part of protocol-specified therapy. Patients who did not begin post-induction therapy, did not receive RT, or received off-study RT were excluded. Molecular ATRT subgrouping was conducted with global methylation profiling analyses as previously reported.^15,17

Table 1.

Children’s Oncology Group (COG) ACNS0333 Radiation Guidelines.

Age at RT (months)	M stage	Primary Site	Radiation target	CSI dose (cGy)	Primary site dose, total (cGy)	Metastatic site dose, total (cGy)
6≤Age <36	M0	IT	Focal	0	5040	-
12≤Age ≤36	M0	ST	Focal	0	5040	-
>36	M0	IT or ST	Focal	0	5400	-
≤36	M+	IT or ST	Focal OR, CSI + Boosta	2340	5040	4500–5400b
>36	M+	IT or ST	Focal OR, CSI + Boosta	3600	5400	4500–5400b

Abbreviations: CSI, craniospinal radiation; Focal, Focal Primary Site RT; IT, infratentorial, M0, no evidence of metastasis at enrollment; M+, evidence of metastasis at enrollment; RT, Radiation therapy; ST, supratentorial.

^aCSI was recommended and administered at the discretion of the treating physician.

^bSupplemental boost radiation of metastatic sites (4500–5040cGy total dose) was administered at the discretion of the treating physician.

Radiology review

All patients underwent retrospective central reviews of neuro-radiology imaging at protocol specified timepoints: pre-surgery, post-surgery, prior to RT (either before or after consolidation), 4 weeks after the end of therapy, and at progression. For the previously reported primary analysis, the treating institution’s determination of relapse—categorized as local, distant, or combined local and distant—was used.¹⁵ In the present analysis, central radiology review was used to determine the presence and location of treatment failure. In cases of data discrepancies between institutional and central review, a consensus confirmation of central review findings was obtained through a conference call with the neuro-radiology team. All central reviews were completed prior to the initiation of patterns of failure analysis.

Outcome measures

Post-RT event free survival (RT-EFS) was defined as the time from the initiation of RT until the detection of a relapse or second malignant neoplasm (SMN), death, or last patient contact, whichever occurred first. A patient who experienced a relapse, SMN or died was considered to have experienced an EFS-event; otherwise the patient was considered censored at last contact. Post-RT overall survival (RT-OS) was defined as the time from the initiation of RT until death regardless of cause or last patient contact. Patients whose RT-OS follow-up was terminated because of death were considered to have experienced an OS-event; otherwise the patient was considered censored at last contact. The details of the statistical methods are described in the Data Analysis Supplement (Appendix S1). All statistical analyses were performed using SAS 9.4 (Cary NC).

Results

Study cohort

Between December 2008 and April 2013, 70 patients were enrolled from 41 COG institutions; of these, 65 were evaluable. The Consort Diagram (Figure 1) demonstrates therapy received, number of patients stratified on each treatment arm according to age, tumor location, and extent of disease, as well as points at which patients were removed from protocol therapy. Data current to June 30, 2017—the cutoff used for the primary manuscript¹⁵ and the date of submission to the National Clinical Trails Network (NCTN) database—were used for this analysis. Twenty-five patients were removed from protocol therapy prior to the initiation of RT for the following reasons: (1) physician/parent choice—6 M0 and 7 M+ patients; (2) progressive disease—5 M0 patients and 4 M+ patients; (3) inadequate stem-cell collection—2 M+ patients; and (4) attributable to treatment toxicity—1 M+ patient. RT modality included photon intensity modulated radiation therapy (IMRT) in 25 patients, photon 3D conformal in 1 patient, and passively scattered proton therapy in 14 patients. This analysis includes 40 patients who received RT (29 M0, 11 M+; see Table 2). The median primary site dose was 5040 cGy (range 4500–5400 cGy) with 8 patients receiving 5400 cGy to the primary site. All 29 M0 patients received focal RT. Among the 11 M+ patients, 5 received either focal RT only and 6 received CSI + boost. Additionally, 3 M+ patients who received metastatic site-directed RT in addition to focal primary RT (1 patient) or CSI (2 patients).

Figure 1.

Consort diagram of patients who received radiation (RT) on ACNS0333 (n = 40).

Table 2.

Characteristics of patients who received radiation therapy (RT) on COG ACNS0333 (n = 40).

Age, enrolled
Median	17 months
Range	2–165 months
<6 months	2 (5%)
6 to <12 months	8 (20%)
≥12 to <36 months	22 (55%)
≥36 months	8 (20%)
Sex
Female	23 (58%)
Male	17 (42%)
Primary location
Infratentorial brain	21 (53%)
Supratentorial brain	19 (47%)
M stage
M0	29 (73%)
M1	1 (2%)
M2	4 (10%)
M3	6 (15%)
Surgery
GTR yes	16 (40%)
GTR no	24 (60%)
Group molecular class
ATRT-SHH	9 (23%)
ATRT-TYR	15 (37%)
ATRT-MYC	10 (25%)
Not available	6 (15%)
Order of therapy
RT-first	28 (70%)
Consolidation-first	12 (30%)
Primary dose
4500 cGy	1 (2%)
4860 cGy	2 (5%)
5040 cGy	29 (73%)
5400 cGy	8 (20%)
RT target/stage
Focal RT/M0	29 (73%)
Focal RT/M+	5 (12%)
CSI + Boost/M+	6 (15%)

Abbreviations: cGy, centigray; consolidation-first, consolidation prior to radiation therapy; CSI, craniospinal radiation; focal RT, focal radiation therapy; GTR, gross total resection; RT, radiation therapy; RT-first, radiation therapy prior to consolidation.

RT-EFS and RT-OS

With a median follow-up of 4.49 years (95% CI: 3.78–4.66 years), the 4-year RT-EFS was 56.84% and the 4-year RT-OS was 58.8% (Figure 2). Sixteen (40%) achieved gross total resection (GTR) of the primary tumor, while 24 (60%) had less than GTR (Table 2). The impact of treatment variables on RT-EFS and RT-OS is presented in Table 3. Extent of surgery less than GTR was not significantly correlated with RT-EFS (P = .709) or RT-OS (P = .305). The 4-year RT-EFS was 47.82% for M0 and 80.81% for M+ with a trend toward reduced EFS-event risk among M+ patients (P = .0625). The 4-year RT-OS was 50.55% for M0 and 80.81% for M+ patients, with no statistically significant difference in survival according to disease stage (P = .101). Among M+ patients (n = 11), there were no significant differences in RT-EFS (P = .842) or RT-OS (P = .842) when comparing M1 (n = 1), M2 (n = 4), or M3 (n = 6) stage patients.

Figure 2.

Event free survival (EFS) and overall survival (OS) of patients receiving radiation therapy (RT) on Children’s Oncology Group ACNS0333.

Table 3.

Event free survival (RT-EFS) and overall survival (RT-OS) following radiation according to patient and treatment characteristics.

Factor	Category	Number	4-Year RT-EFS	P a	RHRb (95% CI)	4-Year RT-OS	P c	RHRd (95% CI)
Radiation type–M+ at enrollment	Focal RT	5	0.80	0.89	1	0.80	0.89	1
	CSI	6	0.80		0.82 (0.05–13.1)	0.80		0.82 (0.05–13.1)
Stage–M+ at enrollment	M1	1	1.0	0.84	-e	1.0	0.84	-e
	M2	4	0.75		-	0.75		-
	M3	6	0.80		-	0.80		-
Extent of resection prior to radiation therapy	Gross total resection	16	0.62	0.71	1	0.67	0.31	1
	Not gross total resection	24	0.53		1.21 (0.45–3.3)	0.53		1.73 (0.60–5.0)
Timing of radiation therapy	After consolidation	12	0.81	0.037	1	0.81	0.067	1
	Prior to consolidation	28	0.46		4.3 (0.97–18.6)	0.49		3.7 (0.83–16)
Disease status prior to radiation therapy	Complete	16	0.74	0.031	1	0.80	0.0069	1
	response
	Partial response	21	0.51		2.3 (0.73–7.5)	0.51		3.2 (0.88–12)
	Stable disease	3	0		6.5 (1.4–30)	0		10 (2.0–53)
Extent of disease at enrollment	M0	29	0.48	0.091	1	0.51	0.10	1
	M+	11	0.72		0.36 (0.11–1.3)	0.81		0.31 (0.07–1.4)
Molecular subgroup	ATRT-SHH	9	0.78	0.23	1	0.78	0.26	1
	ATRT-TYR	15	0.46		3.1 (0.44–15)	0.53		2.3 (0.47–11)
	ATRT-MYC	10	0.40		3.7 (0.73–18)	0.40		3.6 (0.72–18)

^aP value for the null hypothesis of equal risk for RT-EFS-event across the categories of the factor of interest.

^bRelative hazard rate (RHR) for risk of RT-event and 95% confidence interval.

^cP value for the null hypothesis of equal risk for RT-death across the categories of the factor of interest

^dRHR for risk of RT-death and 95% confidence interval

^eRHR and 95% confidence interval cannot be estimated because no events were observed in at least one category of the factor of interest

Outcomes according to RT therapy sequencing (RT-first or consolidation-first) and pre-RT chemotherapy response are shown in Figure 3. Patients treated with RT-first had inferior RT-EFS compared to consolidation-first RT (RHR 4.3; 95% CI 0.97–18.6; P = .037). A similar statistical trend was observed for RT-OS, with a trend for increased risk of death associated with RT-first sequencing (RHR 3.7; 95% CI 0.83–16; P = .067). Disease status prior to radiation (pre-RT chemotherapy response) was categorized as complete response (CR; 16 patients), partial response (PR; 21 patients), or stable disease (SD; 3 patients). Favorable pre-RT chemotherapy response was significantly associated with lower risk for both EFS-event (P = .0306) and death (P = .0069). Molecular grouping was available for 34 patients: 9 in group ATRT-SHH, 15 in group ATRT-TYR, and 10 in group ATRT-MYC. The risk for RT-EFS event and RT-related death was not significantly associated with molecular subgroup. Of the 16 patients in CR prior to RT, 12 were M0 patients who achieved GTR.

Figure 3.

Event free survival (EFS) and overall survival (OS) of patients receiving radiation therapy (RT) on Children’s Oncology Group ACNS0333. According to order of therapy (A, B) and pre-radiation chemotherapy response (C, D). Order of therapy RT sequencing is either following consolidation (consolidation-first) or prior to consolidation (radiation-first). Pre-radiation chemotherapy response is either complete response (CR), partial response (PR), or stable disease (SD).

Patterns of failure and radiation delivery

Among all patients, the 4-year cumulative incidence of RT-local relapse (RT-CILR) was 7.84% (Figure S1). No significant difference was observed in RT-CILR when comparing patients who received a RT dose of ≥5400 cGy to the primary site (n = 8) with those who received < 5400 cGy (n = 32, P = .3827). The 4-year RT-CILR was 0% for patients receiving ≥5400 cGy, compared to 9.74% for those receiving <5400 cGy. The 4-year RT-CILR was 0% for patients who achieved GTR, versus 14.8% for those with less than GTR (P = .0961), representating a statistical trend for increased RT-CILR with less than GTR. No significant difference in RT-CILR was observed between M0 and M+ stages (P = .8519). The 4-year CILR rate for M0 patients was 6.9% and was 10.1% for M+ patients.

Among M0 patients (n = 29) all of whom received focal RT, the 4-year cumulative incidence of distant relapse (RT-CIDR) was 31.3% (Figure S2). For M+ patients (n = 11) who received either CSI or focal RT, the 4-year RT-CIDR was 19.2%. Among M+ patients (CSI: 6 patients, Focal RT: 5 patients), there was no significant difference in CIDR based on radiation field (CSI vs. focal RT; P = .886). Similarly, there were no observed differences in risk for EFS-event of death among M+ patients according to whether they received focal RT or CSI.

Radionecrosis

An initial report confirmed radiographic RT-related treatment changes are a common finding (23.8%) during follow-up of ACNS0333 patients.¹⁸ Among these, there were 3 cases where symptomatic radionecrosis was associated with patient death, and all occurred in patients who received RT prior to consolidation (Patient #1, Patient #2, and Patient #3). Two of these cases (Patient #1 and Patient #2) were reported in the primary publication,¹⁵ whereas Patient #3 was previously reported as local failure by institution and later identified as radionecrosis by central radiology review.

Patient #1 (enrollment age 16 months) had GTR, induction chemotherapy with pre-RT CR, and focal passive scatter proton RT (5040 cGy) followed by consolidation. The patient expired from CNS necrosis with a complex clinical history of active viral encephalitis and sepsis at the time of death. Patient #2 (enrollment age 50 months) had subtotal resection, induction chemotherapy with pre-RT PR, and photon IMRT (5400 cGy) followed by consolidation. At 1 month following therapy completion the patient had CR at the primary site with enhancement and T2/FLAIR abnormalities in the brainstem. The patient expired of fatal radionecrosis 1.61 months post-therapy completion. Patient #3 had subtotal resection, induction chemotherapy with pre-RT PR, and focal photon IMRT (5400 cGy) followed by consolidation. Three months after therapy completion she presented with fever, altered mental status, and extensive T2/FLAIR abnormalities in the brainstem and bifrontal white matter. The patient expired 4.60 months after therapy completion with autopsy revealing extensive treatment-related leukoencephalopathy with no evidence of tumor.

Taken together, all 3 patients with fatal radionecrosis had RT-first therapy order (3/28 patients treated with RT-first sequencing) compared with 0 cases among 12 patients receiving consolidation-first RT. Total primary dose was 5400 cGy in 2 cases (2 out of 8 patients receiving 5400 cGy) compared with 1 case out of 32 patients who received 5040 cGy. Notably, planning tumor volume (PTV) target size (range 10.9–502cc, entire cohort) among all 3 cases of fatal necrosis was larger (214cc, 319cc, and 502cc) than both the median PTV (137cc) and mean PTV (163cc) of the cohort.

Additionally, 1 patient with asymptomatic radionecrosis was initially thought to have local progression prior to surgery, but pathological analysis revealed only radiation changes. This patient (age 38 months at enrollment, M0/5400 cGy focal RT) received RT prior to consolidation and is NED at last follow-up (>5 years).

Discussion

The COG ACNS0333 study mandated focal RT for all patients with the option of CSI for M+ patients, and demonstrated significantly reduced risk for EFS-event compared to historical controls (primary study endpoint). Protocol therapy was intensive including 2 courses induction chemotherapy and 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue. Notably, 25 patients (38.5%) did not receive protocol specified RT. The present study was conducted as a pre-planned analysis of outcomes of patients who largely received focal RT for a tumor that has propensity for disseminated CNS failure. Among 40 patients receiving RT 4-year RT-EFS was 56.84% and 4-year RT-OS was 58.80%, which while measured from RT start was numerically higher than the overall cohort (4-year EFS 37%, 4-year OS 43%). There were important demographic differences: in the RT subgroup (RT-ACNS0333) where 85% received consolidation chemotherapy as compared to 64.6% of all eligible patients. Among the 25 patients who did not receive RT, the most common reasons were physician/parent choice (13 patients) and progressive disease (9 patients), both of which would be expected to contribute to poorer outcomes in the entire cohort as compared to those who received RT. The impact of lack of reporting outcomes for progressive disease patients who did not receive RT in this analysis is not directly evaluable for how it pertains to either M0/M+ or RT-first/consolation first comparisons. However it is outside of study aims of RT-ACNS0333, and does represent a study limitation. However, protocol removal for progressive disease occurred fairly similarly in M0 patients who largely receive RT-first (5 of 41 M0 enrolled) as compared to M+ patients who largely received consolidation first (4/24 M+ enrolled).

Patients who received consolidation-first RT (12 patients) showed improved RT-EFS as well as a trend for RT-OS compared to radiation-first patients, and 9 patients who received consolidation-first prior had M+ disease. While patient and disease characteristics determined the sequence of therapy (consolidation-first or RT-first), there was less opportunity to discontinue treatment or suffer progression in this cohort if RT was delivered prior to consolidation (RT-first). While this may have contributed to a more favorable prognosis cohort in the consolidation-first group, delaying RT until after consolidation is compelling and recommended by the ACNS0333 study team for patients receiving this therapy considering the risk of radionecrosis. There were 3 cases of fatal radionecrosis all of which occurred in patients who received RT-first prior to consolidation although in 1 patient this occurred at an unconventional time period (16.22 months after therapy completion), and with other confounding factors including severe systemic viral sepsis. Each case of fata radionecrosis also resulted following treatment of large PTV sizes (all >200cc), compared to with a median PTV for the cohort of 137cc. Importantly, no cases of fatal radionecrosis were observed in patients who received RT post consolidation (consolidation-first). As opposed to predicting an inferior outcome, M+ patients (82% received consolidation-first RT) had non-significantly higher RT-EFS and RT-OS than M0 patients (10.3% received consolidation-first RT). Furthermore, the receipt of consolidation-first RT was significantly associated with improved RT-EFS and RT-OS. Patient selection may have contributed to these differences, as patients receiving RT post-consolidation had to demonstrate at least continued stable disease throughout induction and consolidation as well as well as having tolerated treatment sufficiently to proceed. While 3 M0 patients and 9 M+ patients received RT post-consolidation, protocol discontinuation occurred in 2 M0 (both MD/parent choice) and 6 M+ other patients (3 MD/parent choice, 3 progressive disease) immediately prior to planned RT. On ACNS0333 RT, M0 and RT-first patients (most M0 received RT-first) had lower percentages of patients receiving consolidation (M0: 69%, RT-first: 79%), compared to 100% completing consolidation among either M+ or consolidation-first patients (see Figure 1). This finding may have contributed to improved outcomes in both consolidation-first or M+ patients.

A higher primary RT dose (≥5400 cGy) did not show significant differences in RT-CILR, RT-EFS, or RT-OS; however, these comparisons are limited by low patient numbers receiving higher dose in this very young cohort. Although no local failures were observed among 8 patients receiving ≥5400 cGy, 2 of the 3 cases of fatal necrosis occurred with 5400 cGy photon focal RT; the third case involved a patient who received 5040 cGy proton focal RT. There is no universally accepted standard for primary RT dose in ATRT, and dosing¹⁹ can typically vary based on tumor location (supratentorial, infratentorial brain location, or spinal). In the recently reported Proton/Photon Consortium Registry analysis (n = 68), all patients received proton RT, with a similar proportion receiving either 5040 cGy (42.6%) or 5400 cGy (41.2%). Consistent with the present analysis, no differences were observed in Local Relapse, EFS, or OS according to primary radiation dose. In the currently enrolling SIOPE ATRT-01 study, the primary dose is 5400 cGy regardless of patient age, with optional boost to a cumulative dose of 5940 cGy for residual disease. The ESTRO-SIOPE consensus guidelines, however, allow for consideration of 5040 cGy, particularly in very young patients.²⁰ In the present study, 14 patients (35%) received proton RT. It is expected that this proportion would be much higher in a contemporary cohort, as access to proton beam has expanded significantly in North America and worldwide.²¹

The extent of disease by MRI prior to RT on ACNS0333 was centrally reviewed, and patients in CR or PR prior to start of RT were at significantly reduced risk for subsequent EFS-event or death. This finding is valuable for families and caregivers when considering the inclusion of RT after demonstrating a positive response to chemotherapy. Importantly, all patients in the present series with favorable outcomes according to pre-RT chemotherapy response also received RT. Conversely, seven patients whose disease responded favorably to chemotherapy but who were removed from protocol before completing RT all died of disease.¹⁵ Similarly, the Head Start III experience of 19 children underscores the risks of withholding RT after intensive systemic therapy, reporting, respectively, 3-year EFS and OS rates of 21 and 26%.²² The ongoing SIOPE-ATRT-01 trial is expected to provide further insights, as patients with age 12–35 months with at least stable disease after induction will be randomized to either high-dose chemotherapy with stem cell rescue or focal RT.²⁰

For patients with disseminated disease, achieving either a PR or CR to systemic therapy prior to RT may support the consideration of lower dose craniospinal RT or focal RT to the primary (with or without metastatic boost/site directed RT). Although the present study included only 11 M+ patients and no differences between focal RT or CSI, ACNS0333 patients were included in a recent meta-analysis of published studies of M+ ATRT patients who received RT.²³ On this multivariate analysis consisting of 25 studies and a total of 96 patients with M+ ATRT receiving RT, pre-RT chemotherapy response (P = .02) and GTR (P = .012) were associated with improved RT-OS. Among patients achieving either CR or PR prior to RT, there was a a non-significant statistical trend favoring focal RT over CSI for RT-OS (P = .089). The role of RT in disseminated ATRT is planned for evaluation through prospective study by the Children’s Oncology Group ATRT Study Team.

In the SJYC07 and SJMB03 trials for pediatric ATRT radiotherapy was a critical component of multimodal therapy, tailored by age and risk.¹⁹ Infants (<3 years, SJYC07) with non-metastatic disease received focal RT to the primary site, after surgery and 4 cycles of chemotherapy, while children (≥3 years, SJMB03) received CSI post-operatively. Outcomes demonstrated that radiotherapy, particularly CSI in children with non-metastatic disease, contributed to markedly improved survival—5-year overall survival reached 81.8% in non-metastatic patients age >3 years, compared to 51.8% in non-metastatic patients age <3 years. In contrast, patients with metastatic disease in either age group had poor survival. Those treated with craniospinal irradiation had 5-year OS of approximately 25% whereas for the youngest patients with metastatic disease and for whom radiotherapy was not a planned part of the treatment regimen, there were no reported survivors.

Compared to the outcomes reported in the current study, the SJYC07 and SJMB03 results showed higher survival rates for older children with non-metastatic disease when CSI was used and similar results for younger patients treated with focal irradiation. Older age at enrollment (≥3 years) represented a minority for both cohorts: 8 patients (20%) on ACNS0333 RT and 22 patients (30%) on SJYC07/SJMB03 (11 M0, 11 M+). Like the current study, the presence or absence of metastatic disease and residual tumor at the time of irradiation were critical factors, and highlighted the impact of risk-adapted, age-specific radiotherapy strategies, and the necessity of balancing survival benefits with long-term toxicity, especially in younger children.

In summary, patients with ATRT who received RT on ACNS0333 demonstrated encouraging survival and primary site disease control for this rare and unfortunately often lethal embryonal CNS tumor. Patients without detectable disease prior to RT (pre-RT chemotherapy CR), and those who received consolidation prior to RT had the best outcomes. Caution is warranted when considering early RT for regimens including myeloablative chemotherapy with stem cell rescue, as 3 cases of fatal brain necrosis were observed, all occurring with RT-first treatment sequencing.

Supplementary Material

Supplementary material is available at Neuro-Oncology Pediatrics online.

Key points.

• Radiation therapy as a component of surgery and intensive chemotherapy on Children’s Oncology Group ACNS0333 for Atypical Teratoid/Rhabdoid Tumor was associated with low risk of primary site relapse.

• Patients with Stabledisease at pre-radiation assessment were at highest risk for EFS-event and death compared to Complete or Partial response.

• Future infant embryonal tumor protocols should consider the risk of sequencing radiation therapy prior to myeloablative chemotherapy with stem cell rescue, as cases of fatal brain radionecrosis were observed with this treatment sequencing.

Importance of the study.

Radiation therapy (RT) was a critical component of the ACNS0333 protocol for atypical teratoid/rhabdoid tumor (ATRT). The protocol included mandatory focal radiation RT for localized disease, while disseminated disease allowed for either focal RT or craniospinal irradiation. The sequencing of RT—either before or after consolidation with myeloablative chemotherapy followed by stem cell rescue—was determined based on patient age and disease location. The primary outcomes of the study, published for all evaluable patients, demonstrated improved event-free survival compared to historical controls. This report represents a protocol-specified analysis of treatment outcomes for patients who received radiation therapy. Given that ATRT typically occurs in very young children, focal RT is generally preferred to minimize neurocognitive sequelae associated with treatment. To our knowledge this is one of the largest reported prospective studies of patients receiving RT for ATRT.

Data availability

The data underling this article will be shared on reasonable request to the corresponding author, in concordance with the data sharing policies of the Children’s Oncology Group.