Читать книгу Intracranial Gliomas Part II - Adjuvant Therapy - Группа авторов - Страница 54

Historically, WHO grade III gliomas were included in clinical studies dominated by patients with GBM [16]. Laramore et al. [17] specifically reviewed patients with anaplastic astrocytoma enrolled onto four early RTOG trials evaluating photon therapy, photon therapy with various chemotherapy combinations, and photon therapy with a neutron radiation boost. Median survival diminished with the addition of chemotherapy or neutron radiation boost in comparison to the photon-only controls [17]. Subsequent clinical studies conducted in the 1990s were conflicting on the possible role of chemotherapy in patients with anaplastic gliomas [18–20]. As such, the RTOG and EORTC conducted parallel randomized controlled trials evaluating the addition of chemotherapy to FRT in such population.

The EORTC 26951 study randomized patients to receive FRT alone (59.4 Gy in 33 fractions) or FRT followed by 6 cycles of PCV (procarbazine, CCNU, and vincristine) chemotherapy [21]. Adjuvant treatment with PCV was found to improve progression-free survival (PFS) but not overall survival. Patients with tumors characterized by combined complete loss of the chromosomal arms 1p and 19q (1p/19q co-deletion) had improved outcome but this was not considered a predictive factor on initial analysis [21]. In the RTOG 9402 study, patients were randomized to FRT alone or FRT preceded by 4 cycles of PCV chemotherapy [22]. The initial results showed improved PFS but no overall survival benefit. However, long-term results were subsequently published and an unplanned analysis showed a doubling in the median survival for those patients with 1p/19q co-deleted tumors who received PCV and FRT vs. FRT alone (14.7 vs. 7.3 years) [23]. Patients with 1p/19q non-codeleted gliomas did not show a difference in median survival with the addition of PCV (2.6 vs. 2.7 years) [23]. Long-term results were also then published from the EORTC 26951 trial wherein adjuvant chemotherapy with PCV improved overall survival for the entire cohort with a trend towards differential benefit for those with 1p/19q co-deleted tumors [24]. Finally, the NOA-04 phase III trial randomized patients with anaplastic gliomas to receive upfront FRT alone vs. upfront chemotherapy (PCV or TMZ) alone [25]. At the first sign of progression, patients were allowed to cross over. No difference in time-to-treatment failure (TTF), PFS, and overall survival was noted at both early and long-term follow-up.

Based on these results, at present FRT alone is not considered an acceptable therapeutic approach for patients with 1p/19q co-deleted anaplastic gliomas (i.e., anaplastic oligodendrogliomas). The optimal regimen of chemotherapy may be clarified upon completion of the CODEL study (EORTC 26081-22086; clinicaltrials.gov identifier NCT00887146) randomizing patients with 1p/19q co-deleted WHO grade III and “high-risk” grade II tumors to receive either FRT followed by 6 cycles of PCV chemotherapy, or FRT with concurrent and adjuvant (6–12 cycles) TMZ. Role of chemotherapy in the management of 1p/19q non-codeleted neoplasms is evaluated in a separate intergroup phase III clinical trial (CATNON study), which randomized patients to receive FRT alone, FRT with concurrent TMZ, FRT followed by adjuvant TMZ, or FRT with both concurrent and adjuvant TMZ. Interim analysis of results demonstrated strong impact of adjuvant TMZ both on PFS and overall survival in this population.