Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol

Patient characteristics

Twenty-nine adult medulloblastoma patients were registered in the Dutch rare tumors registry between January 1, 2010 and October 15, 2018. Eighteen patients were additionally identified in the PALGA-database. Six patients had to be excluded because they were treated in a hospital that followed another treatment protocol. Another 13 cases were excluded for multiple reasons (see Fig. 1B). Thirty-two patients were treated following the treatment protocol. We received the clinical information and tumor material of 28 and 20 patients, respectively, from 10 neuro-oncology centers. The selection process is shown in Fig. 1B.

Baseline and treatment characteristics are shown in Table 1. Eighteen patients were male (64%). Median age was 29.5 years (range 18–46). At time of diagnosis, twenty-three patients (82%) had a good performance status (Karnofsky performance score 70–100). The histological variants were mainly classic (43%) and desmoplastic (36%). Twelve patients (43%) were classified as high-risk. One patient was 17 weeks pregnant at time of diagnosis.

Table 1 Baseline and treatment characteristicsMethylation profiling

Upon methylation profiling the calibrated score for three tumors was below 0.84: one patient had a rare histological subtype, medullomyoblastoma, and was included in our cohort despite the lower Classifier score (0.72). The molecular results of the other two patients were not included. The CNV plot was noisy in one of them suggesting low-quality/technical issues. The most frequent molecular subtype was SHH-activated (60%), followed by non-WNT/non-SHH (25%) and WNT-activated (5%). All desmoplastic medulloblastomas belonged to the SHH-activated subtype. The single WNT-activated tumor had a classic phenotype. The correlation between molecular and histological subtype is shown in Fig. 2. Patients with SHH-activated medulloblastomas were generally older (median 30 years; range 18–44) compared to those with non-SHH-activated tumors (median 23 years, range 18–28), although this difference was not statistically significant (p = 0.07).

Fig. 2figure 2

Clinical and histomolecular profiles

Two SHH-activated medulloblastomas (17%) had subclonal loss of chromosome 10q and chromosome 17p loss. One of them had additional chromosome 3p loss (8%). No non-WNT/non-SHH tumors had chromosome 8p or 8q losses (Fig. 2). Additional NGS was performed of 10 SHH-activated medulloblastomas. The NGS result of one tumor was unreliable. A TP53 mutation was found in one of the SHH-activated medulloblastomas. Of additional mutations in SHH-activated tumors, TERT promoter mutation was most frequently observed (90%), followed by PTCH1 (40%), DDX3X (30%) and SMO mutation (20%; Fig. 2).

Treatment and toxicitiesTreatment

Four of the 28 patients underwent a second operation due to residual tumor. Twenty-six of the 28 patients received the advised radiotherapy dose. Two patients received a lower radiation dose than advised in the treatment protocol without reported reason. In one high-risk patient treatment order was changed due to pregnancy (carboplatin/etoposide courses followed by one course carboplatin/vincristine/cyclophosphamide and, after childbirth, radiotherapy), while one high-risk patient refused all chemotherapy. Neoadjuvant chemotherapy was given to 10 of the 12 high-risk patients. One patient with postoperative meningitis was not given neoadjuvant chemotherapy due to long treatment delay. Eight high-risk patients received vincristine during the radiation phase (67%). Besides the already mentioned pregnancy or chemotherapy refusal, in two other patients no reason for omitting vincristine was given. Adjuvant chemotherapy was started according to treatment protocol in 10 (83%) high-risk patients. We excluded the pregnant and chemotherapy refusing patients for postoperative time to treatment and dose delays/reductions evaluation. Table 1 shows the median treatment intervals. In one of four patients with a second operation, this could be performed within the per-protocol specified treatment window. Half of them had a high-risk subtype. Neoadjuvant chemotherapy started within 21 days of surgery in 30% of the patients (median 27, range 17–52). Radiotherapy started within the per-protocol specified treatment window in only 25% of the standard-risk and 30% of the high-risk patients. Median time between surgery and radiotherapy was 40 days (range 20–161) for standard-risk and 71 days (range 38–94) for high-risk patients, with delay mostly brief (median delay for standard-risk 12 days vs. high-risk 8 days). Postoperative infections were the cause of longer delays. In 70% of the patients who received adjuvant chemotherapy, this was started within the per-protocol specified treatment window [median 75 days after start radiotherapy (range 67–98)].

Dose delays/reductions

The neoadjuvant chemotherapy dose was reduced in one (11%) and 1-week delayed in two (22%) patients. The dose of the second course was not reported in one patient. Seven of the eight patients receiving vincristine during the chemo-radiation phase received the advised three administrations. Radiotherapy was 1-week delayed in one patient (4%). Only one of 10 patients received the total dose of adjuvant chemotherapy as prescribed in the treatment protocol. The dose was reduced or a part of the chemotherapy was discontinued during the adjuvant chemotherapy due to adverse events in nine patients (90%): treatment reductions were made for two patients in the first course (20%), for five patients in the second course (50%) and for eight patients in the third and fourth courses (80%). Adjuvant chemotherapy was completely discontinued after course three in one patient due to toxicity (10%). Especially vincristine was reduced or stopped early due to neuropathy during adjuvant courses. The delays in adjuvant chemotherapy varied between 0 and 5 weeks (median 1 week).

Toxicity

Toxicity could be evaluated in 27 of the 28 patients (Table 2). In one high-risk patient, the radiotherapy phase was not reported. The pregnant patient was only included for the neoadjuvant phase, as the treatment changed afterwards. Hematological toxicity, especially leukopenia (33%) and thrombocytopenia (26%), were most frequently reported CTCAE (v4.0) grade 3–4 toxicity in the whole cohort, thereafter gastro-intestinal toxicity (22%) and infections (15%) were reported. In the high-risk group, hematological toxicity was the only high-grade toxicity reported during the neoadjuvant chemotherapy (leukopenia in 20% and thrombocytopenia in 10%).

Table 2 Reported hematological and non-hematological toxicity grades 1/2 and 3/4

Especially high-grade gastro-intestinal toxicity, due to radiotherapy, was reported in the standard-risk group (gastrointestinal toxicity 27%, leukopenia 7% and infection 7%). Whereas in the high-risk group treated with chemoradiation, more high-grade (hematological) toxicity occurred (leukopenia 10%, thrombocytopenia 30%, gastrointestinal toxicity 20% and fatigue 10%). Most adverse events were reported during the adjuvant chemotherapy; in 100% of the patients at least one adverse event was reported at that stage. Grade 3–4 thrombocytopenia and leukopenia were reported in 50% and 80% of the patients, respectively. Eighty percent of the patients had at least one high-grade adverse event during treatment. No fatal adverse events occurred.

Survival

The median follow-up time was 67 months (range 8–111). 5-years PFS was 69% for the standard-risk and 90% for the high-risk group (p = 0.248). 5-years OS was 81% for the standard-risk and 90% for the high-risk group (p = 0.358). Survival for standard-risk patients seemed worse than for high-risk patients, although this difference was not statistically significant. Also, no significant differences were found for the risk group per methylation subgroup (Fig. 3). All patients with either a WNT-activated or high-risk SHH-activated tumor were still alive and without progression at the end of the study period. Three of the five patients with non-WNT/non-SHH tumors had no progression after 5 years (Fig. 3B). Disease progression was seen in one of four patients with a PTCH1 mutation (25%) and in one of three patients with a SMO mutation (33%) after 25 and 32 weeks, respectively. The only patient with a SHH-activated/TP53-mutant medulloblastoma showed progression after 4 years.

Fig. 3figure 3

Progression-free survival and overall survival for A standard-risk and high-risk groups (log rank PFS p = 0.248 and OS p = 0.358), B by risk group per molecular subgroup (log rank PFS p = 0.338 and OS p = 0.120)

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