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The optimal management of high risk WHO grade II gliomas after surgery is debated including the role of initial temozolomide to delay radiotherapy and risk of cognitive defects.A post-hoc analysis of a phase II multicenter study on high risk WHO grade II gliomas, receiving initial temozolomide alone, has re-evaluated the long-term results within the molecular subgroups of WHO 2016. The primary endpoint of the study was response according to RANO, being seizure response, PFS and OS secondary endpoints.Response rate among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency 50% was observed in 87% of patients and a seizure freedom in 72%. The probability of seizure reduction 50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Sixty-seven percent of patients with oligodendroglioma IDH mutant and 1p/19q codeleted did not recur with a median follow up of 9.3 years, while 59% did not receive radiotherapy at recurrence with a median follow up of 8.2 years.The beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery alone, or with intractable seizures, should receive temozolomide as initial treatment with salvage radiotherapy and/o reoperation and/or second-line chemotherapy at recurrence.

BACKGROUND The optimal management of high risk WHO grade II gliomas after surgery is still debated. The efficacy of initial temozolomide to delay radiotherapy and risk of cognitive defects could vary across the molecular subgroups of WHO 2016, but information on this issue are lacking. PATIENTS AND METHODS A post-hoc analysis has been performed on a cohort of high risk WHO grade II gliomas, who received initial temozolomide alone in phase II multicenter study, with the objective of re-evaluating the long-term results across the different molecular subgroups of the WHO 2016 classification. The primary endpoint of the study, carried out between 2007 and 2010, was response rate according to RANO, being seizure response, PFS and OS secondary endpoints. RESULTS Response rate (partial and minor responses) among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency >50% was observed in 87% patients and a seizure freedom in 72%. The probability of seizure reduction >50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were all significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Of patients who did not recur or delay radiotherapy at recurrence for a median follow-up of 8.2 years, 67% and 59%, respectively, were oligodendrogliomas IDH-mutant and 1p/19q codeleted. CONCLUSIONS The post-hoc analysis of this phase II trial suggests that the beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery, especially when suffering from pharmacoresistant seizures, could receive temozolomide as initial treatment with radiotherapy and chemotherapy at recurrence. The trial was registered with EU Clinical Trials Register, EudraCT n. 2007/000386-38.

The third and fourth authors' affiliation was incorrectly specified in the original publication. It is correctly shown here.

INTRODUCTION: Initial chemotherapy with temozolomide (TMZ) may provide some benefit in high-risk low-grade gliomas. No standard treatment is validated at progression. The aim of the study was to investigate which is the optimal salvage therapy after the first progression in terms of PFS and the overall survival (OS). PATIENTS AND METHODS: We evaluated 49 patients with grade II oligodendroglioma and oligoastrocytoma according to WHO 2007 included in a phase II AINO trial, who progressed following initial chemotherapy alone with TMZ. Molecular data were available in 48 patients: 29 patients were IDH 1/2 mutated, 23 1p/19q codeleted, and 36 MGMT methylated. Median follow up was 140 months. RESULTS: All patients had local tumor progression and patterns on MRI were as follows: a FLAIR lesion in 25 patients (51.0%), a mild patchy enhancing lesion in 14 (28.6%), and a nodular enhancing lesion in the other 10 (20.4%). Twenty-four patients (49%) underwent a second-line chemotherapy, 12 (24.5%) a salvage radiotherapy, 11 (22.4%) a second surgery (10 gross-total resection and 1 subtotal resection), and 2 (4.1%) palliative care. Responses (RANO criteria) following salvage radiotherapy or chemotherapy consisted in PR in 6/38 patients (15.8%), MR in 9/38 (23.7%), SD in 10/38 (26.3%), and PD in 13/38 (34.2%). Median PFS after first salvage therapy was 18 months (IC95% 11–27). Median PFS was 11 months (IC95% 8–74) after radiotherapy, 14 months after chemotherapy and 31 months after surgery (IC95% 18–51, p 0.013). Median OS from the first salvage therapy was 63 months (IC95% 4 - NR). Median OS was 44 months (IC95% 4 NR) after radiotherapy, 38 months (IC95% 22–80) after chemotherapy, and 87 months after surgery (IC95% 11-NR, p 0.09). CONCLUSIONS: Reoperation aiming at total or near/total resection seems to offer a probability of a longer PFS and OS compared with the other treatment options.

INTRODUCTION: About 40% of ALK-rearranged NSCLC patients develop brain metastases (BM), while leptomeningeal metastases (LM) occur in 5% of patients, and spinal intramedullary metastases in < 1%. Few data are available regarding the efficacy of ALK inhibitors in neoplastic spinal disease from NSCLC. CASE-REPORT: In March 2014 a 55 year-old woman developed multiple BM after 2 years from the diagnosis of an ALK-rearranged NSCLC who was receiving crizotinib. Crizotinib was continued associated with WBRT with a near-CR (RANO criteria) lasting 12 months. One year later a spinal MRI displayed multiple intramedullary enhancing lesions and diffuse leptomeningeal spread along the cauda equina, with CSF positivity for neoplastic cells. Ceritinib was started and a CR both on MRI and CSF was obtained lasting 18 months. In December 2017 the patient developed bladder dysfunction and paralytic ileus due to multiple intramedullary spinal and leptomeningeal recurrences. Considering the higher BBB penetration of lorlatinib, the patient started the drug and achieved a significant improvement of the urinary incontinence and intestinal transit after 3 months. Conversely, no change of the extent of spinal disease was observed on MRI. At this time, the patient is continuing treatment with lorlatinib and she is free of recurrence since 5 months. DISCUSSION: The development of CNS disease in ALK-rearranged NSCLC has been suggested to be a natural evolution of the disease and/or is correlated to low CNS penetration of the molecular drugs that control the systemic disease. The PROFILE trials have shown longer OS in patients with BM who received crizotinib beyond progression, but data are lacking on the activity of second- and third-generation ALK inhibitors. CONCLUSION: This is the first report of a prolonged clinical and radiological response using sequentially different ALK inhibitors in a patient with concurrent LM and spinal intramedullary metastases from an ALK-rearranged NSCLC.