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Pediatric protocols applicable for adult patients with metastatic medulloblastoma
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The intensified pediatric HIT2000 protocol appeared feasible and safe for the treatment of adult patients with metastatic medulloblastoma, according to study results.
Limited knowledge exists regarding the effects of intensified chemotherapy and radiotherapy on adult patients with metastatic medulloblastoma due to the relative scarcity of adults with the disease.
André O. von Bueren, MD, PhD, of the department of pediatric hematology and oncology at University Medical Center Goettingen in Germany, and colleagues registered adults with disseminated medulloblastoma as observational patients in the HIT2000 clinical trial for children and adolescents.
The trial included 23 adult patients (median age, 30.7 years).
The researchers assigned patients to treatment with the sandwich strategy MET-HIT2000AB4 (n = 14) — which consisted of postoperative chemotherapy, hyperfractionated craniospinal radiotherapy and maintenance chemotherapy — or the HIT’91 maintenance strategy (n = 9), which consisted of postoperative craniospinal radiotherapy and maintenance chemotherapy.
Eighteen patients survived initial treatment. The median follow-up for surviving patients was 3.99 years (range, 1.04-7.69).
Surviving patients had a 4-year EFS rate of 52% ± 12% and a 4-year OS rate of 91% ± 6%. Researchers reported similar survival rates in both treatment groups.
Results showed improved survival among adults with classic medulloblastoma (n = 11; EFS = 71% ± 14%; OS = 91% ± 9%) and desmoplastic medulloblastoma (n = 10; EFS = 48% ± 16%; OS = 100%) than patients with large cell/anaplastic medulloblastoma (n = 2; EFS = 0%; OS = 0%; P for OS = .033).
Eleven patients experienced tumor progression at a median time of 1.26 years (range, 0.25-4.91) after primary surgery. Relapsed patients treated with the HIT2000AB4 protocol (n = 7) experienced a median time to progression of 0.47 years (range, 0.25-3.85), whereas relapsed patients in the HIT’91 cohort (n = 4) had a median time to progression of 1.92 years (range, 1.02-4.91), similar to previous study findings in children and adolescents.
Fifty percent of patients experienced treatment-related neurotoxicity. The researchers had access to professional data from 10 survivors, of whom six definitively stopped working, three worked adapted jobs after treatment and one worked with no employment modification.
“Our results confirm that the treatment of adults with metastatic medulloblastoma according to the pediatric protocol HIT2000 is possible,” the researchers wrote. “Toxicity [is] acceptable, and EFS rates achieved by both strategies are similar and appear to be inferior to the EFS in older children and adolescents with metastatic disease.
“Because metastatic medulloblastoma in adulthood is rare, prospective randomized multicenter trials seem not to be feasible. Due to the rarity, we recommend central review of the diagnostic procedures [and] treatment according to the guidelines of large registries in order to increase the standard of care and learn more about treatment efficiency and toxicity in adults.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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James Symanowski, PhD
The authors investigated outcomes associated with two treatment regimens in adult patients with metastatic medulloblastoma. This disease is rare in adults, and the authors report that limited information about treatment efficacy and safety is available. Moreover, interpretation of this limited data is further hampered by the fact that most studies have been retrospective and included small patient sample sizes. The current study is a prospective observational study and includes 23 patients aged older than 21 years who did not meet eligibility criteria for the HIT2000 trial. The two treatments evaluated included the HIT’91 maintenance regimen and a more intense regimen from the HIT2000 trial (MET-HIT2000AB4). Although only 23 patients were included in the current study, the authors clarify that this represents one of the largest series reported on. Therefore, it is important and informative to make such a data disclosure on patients in this rare-disease setting. The authors appropriately state — what I consider to be the most important conclusion — that the more intense regimen from the HIT2000 trial was feasible and showed an acceptable toxicity profile.
However, the article — including the supplemental tables — includes extensive results that readers should evaluate with caution. The primary efficacy outcomes are EFS and OS. The power associated with time-to-event endpoints is based on the number of events, and in this study, there were 11 EFS events and 5 deaths. Clearly, these small event numbers do not support comparative analyses. The authors did appropriately indicate that all P-values are considered explorative and that no significance level was fixed. However, results from statistical comparisons of numerous subgroup analyses are presented, and inferences are made where subgroups are different when the P-value is less than .05 and subgroups are not different when the P-value is greater than .05. For example, it is stated that classic and desmoplastic subtypes had better OS than patients with large cell/anaplastic subtype, presumably because the log-rank P-value was .033. Moreover, the large cell/anaplastic subgroup included only two events for both the EFS and OS endpoints. Additionally, the cross-study comparison of OS between metastatic and non-metastatic patients was said to be not different because the P-value was .237. Referring to P-values in such comparisons is problematic not only because they are under powered, but also because they are prone to false positives due to a small number of highly influential observations that can skew results. The inferences made in this article regarding EFS and OS are difficult to interpret and should be evaluated with caution. This study does, however, contribute important information about treatments, toxicity and outcomes in this rare disease in adults where level one evidence is lacking.
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