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Choosing appropriate chemotherapy for diffusely infiltrating WHO grade II gliomas in adults

New advances have been made in understanding the biology and treatment of diffuse gliomas, but a number of controversies regarding the management following surgery are still open. According to WHO 2016 the combination of two different molecular markers, such as IDH-1 and −2 mutation and 1p/19q codeletion, allows the stratification of lower grade gliomas into three different subtypes (oligodendroglioma IDH-1 and −2 mutated with 1p/19q codeletion, diffuse astrocytoma IDH-1 and-2 mutated lacking 1p/19 codeletion, and diffuse astrocytomas IDH wild-type) with different outcome in terms of overall survival (OS) [1]. Thus far, clinical trials on WHO grade II gliomas, including RTOG 9802 and EORTC 22033–26033, used clinical factors only to define the highrisk status (age ≥ 40, neurological symptoms, astrocytoma histology, tumor >4 cm of diameter, and incomplete resection), but did not include the assessment of the aformentioned molecular factors. With a modern approach, that includes these molecular markers, low-risk patients are considered those with IDH-1 and −2 mutations, with or without 1p/19 codeletion, who underwent a gross total or a supratotal resection: in these tumors, a watch-and-wait approach is still the standard of care. Conversely, IDH wild-type diffuse astrocytomas are often aggressive tumors and are now treated with adjuvant radiotherapy (RT) and chemotherapy regardless of the extent of resection: this applies in particular to the subgroup showing molecular alterations of glioblastoma, such as EGFR amplification and/or TERT promoter mutation an/or 7 +/10q[2]. An adjuvant treatment in high-risk diffuse grade II gliomas is generally considered, but the impact differs within the molecular subtypes. The phase III RTOG 9802 [3] reported a significant advantage for the combination of RT and procarbazine, CCNU, and vincristine (PCV) chemotherapy: a subsequent secondary analysis has shown that oligodendrogliomas IDH mutated and 1p19q codeleted had the maximum benefit as compared to IDH mutated and 1p19q non codeleted diffuse astrocytomas, while no benefit for the addition of chemotherapy was observed in IDH wild-type diffuse astrocytomas [4]. An issue that will be investigated in EORTC 1635IWOT trial (NCT03763422) is the role of watch-and-wait versus early radiation and chemotherapy in high-risk diffuse astrocytomas IDH mutated lacking 1p/19q codeletion. Temozolomide (TMZ) is increasingly considered a replacement for PCV due to the lower myelotoxicity. A phase III CATNON trial in newly-diagnosed 1p/19 not-codeleted anaplastic (grade III) gliomas has demonstrated a benefit in OS when TMZ is administered in the adjuvant setting following RT as compared to radiation alone [5]. Thus far, it is still unclear whether TMZ is equal in terms of disease control as compared with PCV in lower grade gliomas [6]. This issue will be investigated in the phase III CODEL trial (NCT00887146), which is randomizing IDH mutated and 1p/ 19q codeleted oligodendrogliomas of both grade II and III to receive RT + PCV versus RT + TMZ. The risk of neurocognitive impairment in long-term survivors after 8–12 years following RT has led a number of clinicians to postpone the use of RT in favor of an up-front chemotherapy. A retrospective study of the US National Cancer Database has reported that chemotherapy alone may confer a similar OS compared with chemoradiation [7], but the median follow-up is too short (4.6 years) to reveal a late effect of chemoradiation. Two phase II single arm studies have investigated the role of up-front TMZ in high-risk grade II gliomas. Wahl and colleagues reported a median PFS and OS of 4.2 and 9.7 years, respectively [8]. Similarly, the phase II AINO (Italian Association for Neuro-Oncology) study showed a PFS of 4.2 years and an OS of 9.8 years in oligodendrogliomas IDHmutated and 1p/19q codeleted [9]. Interestingly, both studies demonstrated a median time of delay to RT of 5.8 and 8.2 years, respectively, suggesting that TMZ alone as initial treatment after incomplete surgery may represent an option in high-risk patients with oligodendroglioma. The majority of patients treated with up-front TMZ in the Italian study, who were MGMT methylated at first surgery, became unmethylated at reoperation, suggesting a chemotherapy-induced shift toward a more chemoresistant phenotype. Moreover, TMZ has been shown to increase the mutation rate of low grade gliomas [10], but thus far this does not seem to increase the risk of a malignant transformation.