Therapy of adult MB is mostly based on pediatric studies and only small retrospective and few prospective adult trials are available [12]. Standard treatment comprises a combination of maximal safe resection, craniospinal irradiation (CSI), and chemotherapy (CT). A molecular classification of MB is starting to translate into clinics, and subgroup-specific approaches will ideally allow an accurate selection of radiation dosage or CT schedules, and specific targeted therapies [13]. However, the standard of care is still based on clinical classification.
Surgery
The first step of multimodal treatment is maximal safe resection. The prognostic relevance of extent of resection (EOR) in MB is still controversial. In pediatric population, EOR did not showed a significant survival benefit for WNT, SHH, or group 3. However, there was a progression-free survival (PFS) benefit in group 4. None of these studies have found an association between EOR and overall (OS). Evidence suggests that maximal safe resection should remain the aim of initial surgery [14] [Level III B].
Radiation therapy
The next step in the therapy for both standard-risk (SR) and high-risk (HR) patients is radiation therapy (RT), and it is commonly delivered as CSI with a boost to posterior fossa or the tumor bed [15] [Level I A]. RT represents a favorable prognostic factor in adult patients. Worse outcomes have been reported when RT was delayed more than 3–6 weeks after surgery [16]. Evidence from pediatric prospective randomized trials showed that a shorter time to completion of RT was associated with improved event-free survival (EFS). We recommend that RT should start 3–6 weeks after surgery with minimal disruptions.
RT dose in adults is not well established. These patients can experience acute side effects (hematologic and gastrointestinal for example) and also frequent neurocognitive deterioration. CSI is usually delivered with full dose (36 Gy) with a boost of 18.8 Gy to posterior fossa (up to 54–55.8 Gy) in addition to CT (17). RT alone is an option for unfit patients. In SR adult patients, dose-reduced CSI (23.4 Gy) in combination with CT is still under study, but it could be used based on pediatric studies (level IIIB). There are trials ongoing.
Another strategy to ameliorate toxicity of CSI could be proton beam therapy [18] [Level III B]. A decrease in hematologic toxicity would facilitate the use of chemotherapy in adults but there is no prospective evidence, and proton radiation is not widely available yet.
Systemic therapy
Chemotherapy (CT) recommendations for adult patients suffer from a lack of randomized studies. Treatment recommendations are based on retrospective analysis of adult cohorts within pediatric trials, few single arm adult studies and a meta-analysis.
In HR patients, the available evidence suggests that adjuvant CT is associated with improved survival compared with RT alone.
The Packer regimen consisting of eight doses of vincristine during RT, followed by eight cycles of lomustine, cisplatin and vincristine administered in 6-week cycles [15] is the most used protocol, but dose modifications are required in nearly all adult patients. The prospective single arm phase II NOA-07 trial evaluated feasibility and toxicity of Packer regimen in 33 patients older than 21. 70% of patients tolerated at least 4 cycles of chemotherapy, all of them with dose modifications. The 3-year event-free survival rate was 66.6%, and the 3-year overall survival rates were 70%. In the prospective analysis of adults over 21y with non-metastatic MB who were not meeting the inclusion criteria for the pediatric trial HIT 2000, 47 of 49 patients required dose modifications. The 4-year event-free and overall survival rates were 68 and 89%, respectively. To avoid the dose reductions caused by hematologic toxicity after radiation, some propose the use of CT pre-radiation. A non-comparative phase II study by Brandes et al., in which HR patients received chemotherapy before RT and low-risk patients RT alone. No significant difference in PFS and OS was observed [12].
In SR patients, it is less clear than in children, but a recent meta-analysis showed that chemotherapy (neo or adjuvant) given as first-line significantly improved survival and increased the chance for long-term survival in all patients [19].
We recommend adult patients are treated with CT in first line, in addition to surgery and radiotherapy, irrespective of their risk profile. [level IIA].