Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide

2 February 2009

Glas M, Happold C, Rieger J, Wiewrodt D, Bähr O, Steinbach JP, Wick W, Kortmann RD, Reifenberger G, Weller M, Herrlinger U.

Division of Clinical Neurooncology, Department of Neurology, University of Bonn; Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen; Dr. Senckenbergisches Institut of Neurooncology, University of Frankfurt, Frankfurt am Main; Department of Neurosurgery, University of Mainz; Department of Neurooncology, University of Heidelberg; Department of Radiation Oncology, University of Leipzig; and Department of Neuropathology, Heinrich-Heine-University of Duesseldorf, Germany; and Department of Neurology, University Hospital Zürich, Zürich, Switzerland.

PURPOSE: To evaluate long-term survival in a prospective series of patients newly diagnosed with glioblastoma and treated with a combination of lomustine (CCNU), temozolomide (TMZ), and radiotherapy. PATIENTS AND METHODS: Thirty-nine patients received radiotherapy of the tumor site only (60 Gy) and CCNU/TMZ chemotherapy (n = 31 received standard-dose CCNU, 100 mg/m(2) on day 1 and TMZ 100 mg/m(2)/d on days 2 to 6; n = 8 received intensified-dose CCNU 110 mg/m(2) on day 1 and TMZ 150 mg/m(2) on days 2 to 6) for up to six courses. RESULTS: In the whole cohort, the median overall survival (mOS) was 23.1 months; 47.4% survived for 2 years, and 18.5% survived for 4 years. After a median follow-up of 41.5 months, mOS had not been reached in the intensified group and was significantly higher than in the standard group (22.6 months; P = .024). In the intensified group, four of eight patients survived for at least 56 months, two of them without recurrence. O(6)-methylguanine-DNA methyltransferase (MGMT) gene promotor methylation in the tumor tissue was associated with significantly longer mOS (methylated, 34.3 months v nonmethylated, 12.5 months). A multivariate Cox proportional hazard model revealed MGMT status (methylated v nonmethylated; relative risk [RR] of death, 0.43; P = .003) and chemotherapy dose (intensified v standard; RR, 0.37; P = .012) as independent prognostic factors. WHO grade 4 hematoxicity was observed more frequently in the intensified group (57% v 16%). CONCLUSION: The combination of radiotherapy, CCNU, and TMZ yielded promising long-term survival data in patients with newly diagnosed glioblastoma. Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit, albeit with greater acute toxicity.

Commento Personale: Questo studio mette in luce uno straordinario aumento della sopravvivenza utilizzando due farmaci che, oggi, sono disponibili completamente anche in Italia. In fase di prima diagnosi, dopo la radioterapia e la craniotomia, occorrerebbe tentare di seguire questa combinazione di Temodal e lomustina a dose più elevata in coloro i quali hanno l’MGMT metilato. La maggioranza dei pazienti avevano più di 52 anni ed un KPS concentrato prettamente a quota 90. Molti di questi pazienti, ad onor del vero, sono comunque stati trattati in modo abbastanza aggressivo anche alla prima recidiva: radioterapia stereotassica alla recidiva ed altre chemioterapie successive più o meno sempre alchilanti fino ad una quarta linea. Altri passaggi importanti della ricerca sono i seguenti e mettono in luce quanto sia necessario tentare di introdurre, vista la tossicità accettabile dimostrata da questo studio, questa combinazione di farmaci ai nuovi diagnosticati (prima istanza). Questa combinazione è stata in qualche modo testata in Italia, ma per i GBM recidivanti ai quali si potrebbe chiedere se disposti ad applicarla (magari in una nuova sperimentazione) anche ai nuovi diagnosticati (chiederò).

In the whole cohort of 39 patients, the mPFS was 10 months (range, 1 to>=69 months). The mOS was 23.1 months. OS was 47.4% at 2 years, 26.4% at 3 years, 18.5% at 4 years, and 15.8% at 5 years.

Four of eight patients in the intensified group have currently survived for at least 56 months, and two of them have survived without any recurrence or signs of late neurotoxicity.

In the standard group, the mPFS was 9 months (range, 1.9 to >=54 months; Fig 3A) and themOSwas 22.6 months.2 The long-term survival analysisnowshows 41.9% of patients surviving 2 years, 16.9% of patients surviving 3 years, and 9.7% surviving 4 years

In contrast, the eight patients in the intensified group had an mPFS of 26 months, and mOS was not yet reached after a median follow-up time of 41.5 months (range, 1 to>=69 months).

The rate of long-term survivors of greater than 24 months is stunning, at almost 50% in the whole cohort. To our knowledge, this might be the best rate ever observed in a prospective glioblastoma analysis, and it does not appear to be bias driven. Patients with a nonmethylated MGMT promoter in our trial survived only 12.5 months, which is virtually identical to the median survival seen in previous trials, and this suggests that the patients in our series have not been selected for good therapy-independent prognostic factors. The increased 2-year survival rate is biologically meaningful in that patients who benefit from chemotherapy seem to have a potential for long-term survival. Although historical comparisons may not be legitimate, CCNU/TMZ almost doubled the percentage of survivors at 24 months (47.5%) compared with the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial that used TMZ monotherapy (26.5%).

With a survivor rate of 16% after 5 years, the rate of patients who are surviving long term and who are potentially cured is also increased, compared with the rate of 4% to 5% that is commonly reported for glioblastoma.

 Le immagini di questo intervento sono reperibili sempre qui.

Source J Clin Oncol. 2009 Feb 2