Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study

Abstract

Summary Background The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. Methods This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0–2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150–200 mg/m2 temozolomide given on days 1–5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. Findings At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45–0·93). Overall survival at 5 years was 55·9% (95% CI 47·2–63·8) with and 44·1% (36·3–51·6) without adjuvant temozolomide. Grade 3–4 adverse events were seen in 8–12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. Interpretation Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. Funding Schering Plough and MSD.

Epidemiological trends, relative survival, and prognosis risk factors of WHO Grade III gliomas: A population‐based study

“…With the update of the WHO classification for CNS tumor in 2016, the diagnosis of gliomas shifted from histology to genetics, especially 1p/19q status and IDH mutations . A large number of studies have focused on the treatment options for grade III glioma with different molecular markers . However, the latest NCCN guidelines for anaplastic gliomas recommend early and maximal surgical resection as the first therapeutic option .…”

“…Some studies have shown radiotherapy may cause additional long‐term cognitive disability and a higher symptom burden . Several trials showed adding chemotherapy to radiotherapy improved outcome for anaplastic gliomas . Considering the damage of radiation and chemotherapy on patients, a strategy of “wait and see” has been adopted for patients with low grade gliomas who have had an extensive resection.…”

cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

“…It is noteworthy that temozolomide chemotherapy is less toxic than combined procarbazine, lomustine, and vincristine, and results from the CATNON trial (Concurrent and Adjuvant Temozolomide Chemotherapy in Non-1p/19q-Deleted Anaplastic Glioma) suggest that the use of temozolomide seems reasonable for both grade II and grade III tumors without co-deleted 1p/19q. 7 In the longer term, cognitive decline is an important side effect of radiotherapy. In a Dutch prospective cohort study, patients with low-grade glioma who received radiotherapy had progressive cognitive decline after a mean follow-up of 12 years, whereas those who did not receive radiotherapy did not have cognitive decline.…”

Reflecting on survivorship outcomes to aid initial decision making in patients treated for IDH‐mutated anaplastic glioma

“…Cancer October 1, 2019 Data from recent clinical trials in patients with anaplastic glioma (Radiation Therapy Oncology Group [RTOG] 9402, European Organization for Research and Treatment of Cancer [EORTC] 26951, and EORTC CATNON) conducted before IDH mutation data were available 6,7,9 have demonstrated an improved outcome with a more aggressive intervention using combined RT and chemotherapy, and a similar conclusion was reached in a study of low-grade gliomas (RTOG 9802). 10 Although the timing of the intervention remains uncertain, especially for patients with 1p19q codeleted tumors, the general conclusion has been for more aggressive combined adjuvant therapies to be performed earlier in the natural history of the tumor.…”