MB is the most common malignant brain tumor in children, accounting for about 15–20% of all pediatric brain tumors [3].
Despite progress in diagnostic techniques and treatment modalities, the cure rate for most relapsed pediatric brain tumor patients has not reflected this success [14] and outcomes for high-risk patients have shown minimal improvement, with relapses in approximately 30% of MB patients and median survival following relapse of less than one year[15].
Several salvage treatments, including various conventional drug combinations or HDCT, have been investigated for relapsed MB. However, these approaches have yielded discouraging outcomes, characterized by limited and short-lasting responses. The OS rates after MB recurrence are reported, in the largest observational studies involving 581 children, as 38.2% at 1 year, 16.9% at 3 years, and 12.4% at 5 years [16].
Among the strategies employed for MB relapse, oral TMZ stands out as one of the most commonly utilized options after conventional chemo-radiotherapy upfront treatment. An Italian multi-center study showed a PFS rate for all patients at 6 and 12 months of 30% and 7.5%, respectively. Their median OS rate at 6 and 12 months was 42.5% and 17.5%, respectively [17].
Grill et al.[18] demonstrated that not even the addition of irinotecan to TMZ changed the objective response rate of 32.6% with a median survival of 16.7 months.
Therefore, a definitive, impactful curative therapy for recurrent MB remains elusive, as evidenced by poor outcomes, short-lasting responses, and a high incidence of toxicity associated with different standard or intensive chemotherapies [3][19][20].
MC offers a novel approach in pediatric oncology, involving the repeated administration of low doses of chemotherapy to minimize toxicity and target the endothelium or tumor stroma [21].
In contrast to conventional cytotoxic therapy, which is classically given in a dose-intensive fashion to maximize cell kill, sustained suppression of endothelial cell proliferation requires a low continuous (metronomic) dosing. Indeed, this regimen stands apart from conventional treatment protocols due to its utilization of a metronomic antiangiogenic combination strategy targeting the tumor microenvironment.
These low, minimally toxic doses, without extended drug-free intervals, aim at disrupting vascular cells crucial for sustaining tumor cell proliferation, migration, and metastasis [22]. Besides its antiangiogenic effects, metronomic chemotherapy seems to influence other cell populations within the tumor microenvironment, potentially triggering immunogenic pathways capable of activating both innate and adaptive immune responses [23].
Several studies have explored various MC combinations, initially for palliative treatment and later extended to high-risk solid tumors in children who completed standard chemo and radiotherapy [24].
The MEMMAT protocol’s predecessor, the” 5-drug” phase II trial [25] published by Robison, aimed to establish an outpatient-based and oral treatment approach for children with various relapsed solid tumors, added fenofibrate, a PPAR-alpha agonist, to Celebrex, thalidomide, etoposide, and cyclophosphamide used in a prior “4-drug” pilot study Fenofibrate was introduced based on data obtained in a preclinical model that demonstrated synergistic effects of its antiangiogenic activity with COX2 inhibition and cytotoxic metronomic therapy [8].
Based on this preliminary experience, a retrospective observational study using a modified (no dose escalation of thalidomide) “5-drug” regimen augmented by IV bevacizumab every two weeks and alternating intraventricular therapy via an Ommaya reservoir consisting of etoposide and cytarabine, evaluated this alternative metronomic antiangiogenic strategy in recurrent medulloblastoma. The study conducted prior to the start of the formal MEMMAT trial, and termed “MEMMAT-like” included 29 patients with first or multiple MB recurrences and reported a median OS of 29.5 months. OS and PFS at three years were 48.3 ± 9.3% and 42.0 ± 9.5%, respectively [10].
Another study that corroborated the improvement of survival in patients treated with a MEMMAT/ modified MEMMAT protocol was published by the French Society for Children with Cancer and highlighted a median OS of 26 months in children with various relapsed brain tumors [26].
Finally, Peyrl et al. recently published the formal phase II results of the international transatlantic MEMMAT trial (ClinicalTrials.gov Identifier: NCT01356290)[27].The multicenter study evaluated the activity and toxicity profile of the combinatorial metronomic approach in pediatric patients who had previously been irradiated and experienced first or consecutive medulloblastoma recurrences. With a mean OS of 43.6% at 3 years and 22.6% at 5 years, the study supported the potential of MC in improving outcomes for pediatric patients with recurrent MB. The median OS of 25.5 months also favorably compared to the OS of 19 months in the better arm, including the addition of bevacizumab to TMZ and irinotecan, reported by the Children’s Oncology Group study [19].
Our study aimed to prolong survival for patients with recurrent medulloblastoma while at the same time reducing treatment-associated morbidity and maintaining QoL. Our analysis therefore, reports a real-life experience of 14 patients with relapsed MB treated with a modified MEMMAT regimen, the combination demonstrated to be safe, prolonged median PFS and OS compared to historical controls, and did not impact QoL, neither in a second-line treatment setting nor in third or beyond line. The entire treatment for all patients was carried out on an outpatient basis. Our modified MEMMAT regimen omitted thalidomide from the oral drug combination because its antiangiogenetic mechanism is similar to bevacizumab [28].
In addition, we chose to use intralumbar topotecan once every four weeks instead of intraventricular etoposide/cytarabine since our patients did not have Ommaya reservoirs and ventricular peritoneal shunts were no exclusion criteria as in the formal MEMMAT study. For the entire population median OS from the date of start of the “modified MEMMAT” regimen was 18.27 (8.1–34) months and median PFS 12.8 (6.2–32.3) months. OS at 12 and 24 months were 78.6% (IC 95% 47.2%-92.5%) and 14.3% (IC 95% 2.3%-36.6%), respectively. PFS at 12 and 24 months were 55.0% (95% IC: 25.8%-76.8%) and 15.7% (95% IC 2.5%-39.4%), respectively. Analysis of OS and PFS according to the number of treatment lines (second line, A, or third and beyond, B) showed that OS and PFS had no difference between survival distributions of A and B (p = 0.441).
Results appear to be less encouraging than in the above-cited MEMMAT studies (Table 3). Major key differences between our series and all three other studies reside probably in both cohort characteristics and drugs used and may explain our comparatively shorter OS. Compared with the studies by Peyrl et al. and Slavc et al [10][27] a higher percentage of patients in our patient cohort received metronomic therapy from the third line onward; moreover, we did not exclude patients with ventriculoperitoneal shunts which was an exclusion criterion in two of the other studies [10][26] because of inconsistent drug distribution in cases with a VP-shunt in place. Furthermore, we used topotecan instead of etoposide/cytarbine for intrathecal therapy and applied it via lumbar puncture rather than via an Ommaya reservoir. Additionally, in order to avoid repeated anesthesias, time intervals for intralumbar topotecan were extended to once every 4 weeks. In addition, the MEMMAT strategy allows for additional focal radiotherapy to persistent tumors after response evaluation which was used in a proportion of the patients in all three above-mentioned studies[10][26][27].
Table 3
Comparison of MEMMAT and “Modified-MEMMAT” studies
Study | Type of malignancy | Line of treatment | PFS months (%) | Median PFS (months) | OS months (%) | Median OS (months) |
Winnicki 2023 MEMMAT | MB 22 pts ATRT 8 pts Ependymoma 5 pts Others 6 pts | II-line 13 pts III - V line 28 pts | 12 (46.4) 24 (28.9) | 9.7 | 12 (68.6) 24 (54.8) | 26 |
Slavc 2022 MEMMAT-like | MB 29 pts | II-line 19 pts III - V line 10 pts | 12 (64.7) 24 (58) | 22.1 | 12 (79.3) 24 (69) | 29.5 |
Peyrl 2023 MEMMAT | MB 40 pts | II-line 30 pts III - V line10 pts | 12 (38) 24 (31) | 8.5 | 12 (68) 24 (54) | 25.5 |
Bambino Gesù Children Hospital 2024 Modified-MEMMAT | MB 14 pts | II-line 8 pts III - V line 6 pts | 12 (55) 24 (15.7) | 14.3 | 12 (78.6) 24 (14.3) | 18.6 |
Our data confirmed that the “modified-MEMMAT” regimen is well tolerated and safe, predominantly demonstrating grade 2–3 hematological toxicity, with only one patient experiencing grade 3 pancreatitis.
Any correlation between time of survival and molecular subgroup has been highlighted [10][27], though the pattern of relapse seemed to show association with the tumor’s biology in other series [29]. Our cohort, too heterogeneous and small to lend itself to analysis, comprised a WNT patient, usually the subgroup less involved in the relapse occurrence. This patient was the oldest of the cohort (26 years old), and it is commonly shared that, unlike those arising in children, adults with WNT tumors are postulated to have a worse prognosis [30][31]. Moreover, the patient presented a germline pathogenetic gene APC mutation (well known for its negative regulator role of the WNT pathway) [32].
Quality of life during metronomic therapy has rarely been reported but is even more important for patients with an overall poor prognosis. QoL, low at the baseline, due to prior therapy and associated sequelae didn’t worsen during Modified-MEMMAT treatments[26][27].
According to the literature, our study revealed that the “modified-MEMMAT” regimen did not significantly compromise patients' QoL, highlighting a minor load in nausea, probably due to the daily use of ondansetron due to continuative oral chemotherapy. While documentation of the QoL during metronomic therapy has been limited, its significance is amplified for patients confronting a challenging overall prognosis[33].
Although our results in terms of PFS and OS appear comparatively inferior to those reported in the literature[10][27][26], this account emphasizes the treatment's efficacy and tolerability, with the overarching goal of extending survival through outpatient care.
In conclusion, there is a lack of standardization in treatment protocols for progressive and relapsed MB, presenting a challenge in determining the optimal approach for affected children. Our primary objective has been to assess the effectiveness and tolerance of a metronomic schema administered in children with recurrent MB. Our study confirms that the “modified-MEMMAT” regimen represents a promising approach for patients with relapsed/refractory MB. The substantial clinical advantages it offers to this patient population underscore the rationale for further assessment of this combination. These findings provide valuable real-life data on a homogeneous group of patients. It is clear that a metronomic chemotherapy combination not only induces responses but also supports the continuity of PFS in patients with a history of multiple intensive prior treatments. Additionally, it is crucial within this patient cohort, where curative options are lacking, to preserve their QoL and enable them to continue residing in their homes.