Date Published: June 20, 2019
Publisher: Public Library of Science
Author(s): Andrés F. Cardona, Alejandro Ruiz-Patiño, Zyanya Lucia Zatarain-Barrón, Fernando Hakim, Enrique Jiménez, Juan Armando Mejía, Juan Fernando Ramón, Nicolás Useche, Sonia Bermúdez, Diego Pineda, Hernando Cifuentes, Leonardo Rojas, Luisa Ricaurte, Luis Eduardo Pino, Carmen Balaña, Oscar Arrieta, Jung Weon Lee.
To compare the effectiveness of octreotide/everolimus vs. sunitinib for the systemic treatment of recurrent aggressive meningiomas.
31 patients with recurrent or refractory WHO II or WHO III meningiomas were examined in two reference centers in Colombia. Patients who had systemic treatment (sunitinib, everolimus/octreotide) and a complete follow-up were included. Overall survival (OS), progression-free survival (PFS) and toxicities were evaluated. Additionally, tissue samples were examined for PDGFRβ and VEGFR2, their expression was correlated with outcomes.
Twenty-two patients (72%) were female with a median age of 55 years (SD±15.3). The most prevalent histology was anaplastic meningioma in 20 patients (65%) with 48% of patients suffering from three previous relapses before the start of systemic treatment. A total of 14 patients received combination therapy with octreotide/everolimus, 11 received sunitinib and the remaining 6 received other second-line agents. Median OS was 37.3 months (95%CI 28.5–42.1) and the PFS during the treatment with everolimus/octreotide (EO) and sunitinib (Su) was 12.1 months (95%CI 9.2–21.1) and 9.1 months (95%CI 6.8–16.8); p = 0.43), respectively. The OS of the group treated with the EO→Su→Bev sequence (1st/2nd/3rd line) was 6.5 months longer than the Su→EO→Bev sequence (36.0 vs. 29.5 months) (p = 0.0001). When analyzing molecular markers, the positive PDGFRβ and negative VEGFR2 expression were associated with longer survival both in OS and PFS.
Sunitinib and octreotide/everolimus have similar efficacy and safety in the systemic management of refractory meningioma. VEGFR2 and PDGFRβ expression are associated with better outcomes.
Meningiomas are the most common type of intracranial tumor, with an estimated prevalence of around 97.5 cases for each 100.000 individuals in the United States [1, 2]. Tumor grading is performed according to the World Health Organization (WHO) classification for tumors of the central nervous system (CNS), which has been continuously revised in 2000, 2007 and 2016 [3, 4]. Almost all cases (95%) are considered benign (WHO I), whereas the remaining are cataloged as either atypical (WHO II) or anaplastic meningiomas (WHO III) [1, 4]. Grading is strongly correlated with clinical outcomes; tumors catalogued as WHO grade II and III carry a 5 to 10-fold increase in recurrence with 59% and 28% of patients free of relapse at 5 years, respectively . Other endpoints such as median overall survival (OS) and quality of life (QoL) are also strongly affected [6, 7]. Interestingly, higher-grade meningiomas, particularly WHO II, have been increasingly diagnosed in the last years, likely due to improvements in classification criteria stemming from a better understanding of tumor biology [3, 5].
Aggressive meningiomas continue to be a difficult to treat pathology. Due to its low frequency, few systemic treatment options have been proven to be effective. Similar to other tumors, a better understanding of the molecular mechanisms involved in tumor growth and progression has increased the probability of identifying successful treatment targets. To the authors´ knowledge this is the first study evaluating the comparative effectiveness of octreotide and everolimus vs. sunitinib, reaching similar results in terms of volumetric response and both clinical effectiveness and safety profiles with similar conclusions to the one arm, phase II studies of each individual treatment modality.
In conclusion, the present study did not find any statistically significant differences in terms of survival depending on medication administered as first line treatment. However, our data favor the hypothesis of better performance in terms of OS for the sequence E→Su→Bev. Furthermore, it also validates the prognostic significance of VEGFR and PDGFRβ. These results should be validated in a larger randomized controlled trials in order to overcome limitations of the present study.