Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Efficacy of erlotinib in patients with relapsed gliobastoma multiforme who expressed EGFRVIII and PTEN determined by immunohistochemistry.

Epidermal growth factor receptor gene (EGFR) alteration is a common feature in most of glioblastoma multiforme (GBM). Robust response of anti-EGFR treatments has been mostly associated with the EGFR deletion mutant variant III (EGFRvIII) and expression of PTEN. We have performed a prospective trial in order to confirm the efficacy of erlotinib treatment in patients with relapsed GBM who expressed EGFRvIII and PTEN. All patients included in the trial were required to be PTEN (+++), EGFR (+++) and EGFRvIII (+++) positives by immunohistochemistry. This new phase II trial enrolled 40 patients and was design to be stopped in case of fewer than two responses in the first 13 patients. Patient eligibility included histopathology criteria, radiological progression, more than 18 years old, Karnofsky performed status, KPS > 50, and adequate bone marrow and organ function. There was no limit to the number of prior treatments for relapses. No enzyme-inducing antiepileptic drugs were allowed. The primary endpoints were response and progression-free survival at 6 months (PFS6). Thirteen patients (6 men, 7 women) with recurrent GBM received erlotinib 150 mg/day. Median age was 53 years, median KPS was 80, and median prior treatments for relapses were 2. There was one partial response and three stable diseases (one at 18 months). PFS at 6 months was 20 %. Dose reduction for toxicity was not needed in any patient. Dermatitis was the main treatment-related toxicity, grade 1 in 8 patients and grade 2 in 5 patients. No grade 3 toxicity was observed. Median survival was 7 months (95 % IC 1.41-4.7). As conclusion, monotherapy with erlotinib in GBM relapses patients with high protein expression for PTEN (+++), EGFR (+++), and EGFRvlII (+++) showed low toxicity but minimal efficacy and the trial stopped.

Influence of glioblastoma contact with the subventricular zone on survival and recurrence patterns.

BACKGROUND: There is growing evidence that the subventricular zone (SVZ) may be involved in both the initiation and progression of glioblastoma (GB). We aimed to assess tumor proximity to the SVZ as a potential prognostic factor in GB. METHOD: Retrospective study of 133 patients diagnosed with primary GB who underwent surgery followed by temozolomide-based chemoradiation between 2010 and 2016. All lesions were classified according to their anatomic relation with the SVZ. We determined the effect of tumor contact with the SVZ on progression-free survival (PFS), overall survival (OS), type, and patterns of recurrence. RESULTS: At a median follow-up of 18.6 months (95% CI 15.9-21.2), PFS and OS were 7.5 (95% CI 6.7-8.3) and 13.9 (95% CI 10.9-16.9) months, respectively. On the univariate analyses, initial contact with the SVZ was a factor for poor prognosis for both PFS (6.1 vs. 8.7 months; p = 0.006) and OS (10.6 vs. 17.9 months; p = 0.037). On the multivariate analysis, tumor contact with the SVZ remained statistically significant for PFS, but not OS. Patients with SVZ-contacting tumors presented a higher rate of aggressive clinical progression (30.9% vs. 11.3%; p = 0.007) and contralateral relapse patterns (23.4% vs. 9.1%; p = 0.048). CONCLUSIONS: Our results suggest that glioblastoma contact with the SVZ appears to be an independent prognostic factor for poor PFS. The presence of an SVZ-contacting tumor was associated with more aggressive recurrences and a higher rate of contralateral relapses. These findings suggest that this variable may be a new prognostic factor in glioblastoma.

Extended-schedule dose-dense temozolomide in refractory gliomas.

This multicenter phase II study conducted by the Spanish Neuro-Oncology Group evaluated the activity of an extended, dose-dense temozolomide regimen in patients with temozolomide-refractory malignant glioma. Adult patients (at least 18 years of age) with WHO grade III or IV glioma and a Karnofsky Performance Status of 60 or higher were treated with temozolomide (85 mg/m(2)/day) for 21 consecutive days every 28-day cycle until disease progression or unacceptable toxicity. All patients had developed progressive disease either during or less than 3 months after completing previous temozolomide treatment. Forty-seven patients were treated with a median of 2 (range, 1-13) cycles of temozolomide. Before study entry, patients had received a median of 6 cycles of temozolomide: 39 (83%) as part of initial therapy and 23 (49%) as second-line therapy. Three patients (6.4%) had a partial response with durations of 8.0, 3.5, and 3.2 months; 15 patients (31.9%) had stable disease with a median duration of 2.1 months, including 2 patients with stable disease (SD) for greater than 6 months (14 and 16 months). Median time to progression was 2 months, and median overall survival from study entry was 5.1 months. The 6-month progression-free survival rate was 16.7%. The most common hematologic toxicities were lymphopenia, thrombocytopenia, and leukopenia. Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no opportunistic infections occurred. In conclusion, this extended dose-dense schedule of temozolomide appears to have modest activity in patients refractory to previous treatment with temozolomide and is associated with manageable toxicity.

A comprehensive analysis of factors related to carmustine/bevacizumab response in recurrent glioblastoma.

PURPOSE: Patients with recurrent glioblastoma (rGBM) have a poor prognosis, with survival ranging from 25 to 40 weeks. Antiangiogenic agents are widely used, showing a variable response. In this study, we explored the efficacy of carmustine plus bevacizumab (BCNU/Bev) for treating rGBM. METHODS/PATIENTS: In this study, we assessed 59 adult patients with histologically confirmed rGBM who were treated with BCNU/Bev as second-line regimen. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated according to their molecular expression profile, including CD133 mRNA expression, MGMT methylation (pMGMT), PDGFR amplification, YKL40 mRNA expression, IDH1/2 condition, p53 and EGFRvIII mutation status. RESULTS: Median follow-up was 18.6 months, overall RR to the combination was 56.3%, and median PFS was 9.0 months (95% CI 8.0-9.9). OS from time of diagnosis was 21.0 months (95% CI 13.2-28.7) and from starting BCNU/Bev it was 10.7 months (95% CI 9.5-11.8). IDH1/2 mutations were found in 30.5% of the patients, pMGMT in 55.9% and high CD133 mRNA expression in 57.6%. Factors which positively affected PFS included performance status (p = 0.015), IDH+ (p = 0.05), CD133 mRNA expression (p = 0.009) and pMGMT+ (p = 0.007). OS was positively affected by pMGMT+ (p = 0.05). Meanwhile, YKL40 negatively affected PFS (p = 0.01) and OS (p = 0.0001). Grade ≥ 3 toxicities included hypertension (22%) and fatigue (12%). CONCLUSIONS: BCNU/Bev is a safe and tolerable treatment for rGBM. Patients with MGMT+/IDH+ derive the greatest benefit from the treatment combination in the second-line setting. Nonetheless, high YKL40 expression discourages the use of antiangiogenic therapy.

SEOM clinical guidelines for anaplastic gliomas (2017).

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

Correction to: SEOM clinical guidelines for anaplastic gliomas (2017).

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors.

2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary.

Cancer of unknown primary (CUP) is defined as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They differ from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2-9% of all cancer patients, mostly 60-75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP. The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Delay in starting radiotherapy due to neoadjuvant therapy does not worsen survival in unresected glioblastoma patients.

PURPOSE: We retrospectively examined the potential effect on overall survival (OS) of delaying radiotherapy to administer neoadjuvant therapy in unresected glioblastoma patients. PATIENTS AND METHODS: We compared OS in 119 patients receiving neoadjuvant therapy followed by standard treatment (NA group) and 96 patients receiving standard treatment without neoadjuvant therapy (NoNA group). The MaxStat package of R identified the optimal cut-off point for waiting time to radiotherapy. RESULTS: OS was similar in the NA and NoNA groups. Median waiting time to radiotherapy after surgery was 13 weeks for the NA group and 4.2 weeks for the NoNA group. The longest OS was attained by patients who started radiotherapy after 12 weeks and the shortest by patients who started radiotherapy within 4 weeks (12.3 vs 6.6 months) (P = 0.05). OS was 6.6 months for patients who started radiotherapy before the optimal cutoff of 6.43 weeks and 19.1 months for those who started after this time (P = 0.005). Patients who completed radiotherapy had longer OS than those who did not, in all 215 patients and in the NA and NoNA groups (P = 0.000). In several multivariate analyses, completing radiotherapy was a universally favorable prognostic factor, while neoadjuvant therapy was never identified as a negative prognostic factor. CONCLUSION: In our series of unresected patients receiving neoadjuvant treatment, in spite of the delay in starting radiotherapy, OS was not inferior to that of a similar group of patients with no delay in starting radiotherapy.

Medulloblastoma in young adults. Must we give adjuvant chemotherapy?

Medulloblastoma is a rare entity in adult patients. All data about treatment are from children, where this disease is the most common cerebral tumour. Reports of medulloblastoma in adults are scarce but in all of them the prognosis seems similar to the prognosis of children. We present our experience in five cases of medulloblastoma in young adults, treated at the University Hospital "Germans Trias i Pujol" from June 1994 to October 2003. This has not been a good experience as more than 50% of the patients had a recurrence in spite of the standard treatment. We have reviewed the literature, concluding that we have to adapt the findings in children to our adult patients, offering them adjuvant chemotherapy after surgery.

Clinical course of high-grade glioma patients with a "biopsy-only" surgical approach: a need for individualised treatment.

INTRODUCTION: 'Biopsy-only' high-grade glioma (HGG) patients get limited benefit from post-operative treatments, and as a group, negatively impact median survival outcomes. MATERIAL AND METHODS: We retrospectively evaluated clinical characteristics, treatment and overall survival of HGG patients with a 'biopsy- only' surgical approach diagnosed between 1997 and 2005 at a University Hospital in Spain. RESULTS: In 31% of 294 suspected gliomas, only a diagnostic biopsy was undertaken. Reasons for 'biopsy-only' for all patients were either location in eloquent areas: (motor area 18.7%, language area 25,3%, basal ganglia 7.7%, visual area 4.4%) or extension of the disease (corpus callosum invasion 14.3% and multicentricity/multifocality 28.6%). Seventy-four patients (80.4%) were HGG: 26% of all grade IV and 49% of all grade III tumours. For these patients, post-operative Karnofsky Performance Status of over 70%, median age and median survival were, respectively: 64 and 70%, 60.7 and 57 years old, and 23.1 and 42.7 weeks (p=0.0006). Patients lived longer if post-operative treatment was given, in all grades (p<0.0001). Nineteen patients (25.6%) died within 42 days after surgery. Only 60% of them initiated radiotherapy and 10% of them did not complete it. However, tumour grade, radiotherapy and temozolomide- based chemotherapy were independently associated with longer survival in multivariate analysis (p<0.05). CONCLUSION: Almost one third of HGG patients can undergo only a biopsy and not debulking surgery. Although radiotherapy improves survival, only 50% of them complete the treatment. An individualised approach to these patients is needed to facilitate a correct analysis of therapy results. New therapies must be investigated in these patients.

Results of a multicenter survey showing interindividual variability among neurosurgeons when deciding on the radicality of surgical resection in glioblastoma highlight the need for more objective guidelines.

PURPOSE: We assessed agreement among neurosurgeons on surgical approaches to individual glioblastoma patients and between their approach and those recommended by the topographical staging system described by Shinoda. METHODS: Five neurosurgeons were provided with pre-surgical MRIs of 76 patients. They selected the surgical approach [biopsy, partial resection, or gross total resection (GTR)] that they would recommend for each patient. They were blinded to each other's response and they were told that patients were younger than 50 years old and without symptoms. Three neuroradiologists classified each case according to the Shinoda staging system. RESULTS: Biopsy was recommended in 35.5-82.9%, partial resection in 6.6-32.9%, and GTR in 3.9-31.6% of cases. Agreement among their responses was fair (global kappa = 0.28). Nineteen patients were classified as stage I, 14 as stage II, and 43 as stage III. Agreement between the neurosurgeons and the recommendations of the staging system was poor for stage I (kappa = 0.14) and stage II (kappa = 0.02) and fair for stage III patients (kappa = 0.29). An individual analysis revealed that in contrast to the Shinoda system, neurosurgeons took into account T2/FLAIR sequences and gave greater weight to the involvement of eloquent areas. CONCLUSIONS: The surgical approach to glioblastoma is highly variable. A staging system could be used to examine the impact of extent of resection, monitor post-operative complications, and stratify patients in clinical trials. Our findings suggest that the Shinoda staging system could be improved by including T2/FLAIR sequences and a more adequate weighting of eloquent areas.

A phase II study of feasibility and toxicity of bevacizumab in combination with temozolomide in patients with recurrent glioblastoma.

PURPOSE: The aim of this prospective and multicentric phase II study was to evaluate the efficacy and safety of temozolomide (TMZ) and bevacizumab (BV) in patients (pts) with recurrent glioblastoma (GB), previously treated with chemoradiotherapy and at least three cycles of adjuvant TMZ. PATIENTS AND METHODS: Patients with GB at first relapse received BV 10 mg/kg day every 2 weeks and TMZ 150 mg/m(2) days 1-7 and 15-21, every 28 days. Patients underwent brain magnetic resonance imaging every 8 weeks. RESULTS: Thirty-two evaluable pts were recruited in 8 sites. Fourteen pts (44%) had gross total resection. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter was methylated in 12 pts, unmethylated in 6 pts, and missing in 14 pts. The estimated 6-month progression free survival (PFS) rate was 21.9% (95% CI 9.3-40.0%). The median PFS and overall survival (OS) were 4.2 months (95% CI 3.6-5.4 months) and 7.3 months (95% CI 5.8-8.8 months), respectively. No significant association with MGMT status was found in terms of OS or PFS. Six of 32 pts (19%; 95% CI 7.2-36.4) were long-term survivors, with a median PFS and OS (50% events) of 9.5 months (95% CI 7.9-23.6) and 15.4 (95% CI 8.9-NA), respectively: no differences in baseline characteristics were identified in comparison with total population. No unexpected toxicities or treatment-related deaths were observed. CONCLUSIONS: This regimen showed to be feasible and well tolerated in pts with recurrent GB pretreated with TMZ. Further investigation is warranted to identify subpopulations that are more likely to benefit from addition of BV to GB therapy.

The biology of non-small-cell lung cancer: identifying new targets for rational therapy.

Lung cancer, and in particular non-small-cell lung cancer (NSCLC), remains the leading cause of cancer death throughout the world. Almost three decades ago, the major concern was to identify whether cisplatin or cisplatin-based chemotherapy enhanced survival in metastatic NSCLC, and whether any survival benefit compensated for cisplatin-related toxicity. Over the last 10 years, significant advances have been achieved in molecular biology, including the identification of critical genes related to the pathogenesis of NSCLC, which have formed the basis for new targeted therapeutic approaches. These new approaches include novel agents against established chemotherapeutic targets such as thymidylate synthetase as well as agents that inhibit novel targets such as growth factor receptors and proteins important in angiogenesis. With the advent of genomic technologies that can identify patterns of gene expression, the hope is that therapy will be tailored to the genetic pattern of the patients's tumor, and individualized treatments that minimize toxicity and maximize efficacy can be developed.

[Rheumatoid arthritis and multiple neoplasms]. / Artritis reumatoide y neoplasia múltiple.

In patients with rheumatoid arthritis the appearance of neoplastic disease has been fundamentally described of lymphoproliferative origin. The case of a 59 year old woman with rheumatoid arthritis of a 4 year evolution is reported. The patient was treated with gold salts and methotrexate and presented successively a bronchogenic carcinoma and a non-Hodgkin lymphoma. The epidemiologic studies in the relation of rheumatoid arthritis-neoplasia are discussed and the pathogenic hypotheses to the immune alterations as well as the treatments employed are described.

[Induction chemotherapy in the treatment of head and neck cancer in advanced stages]. / Quimioterapia de inducción en el tratamiento del cáncer de cabeza y cuello en estadios avanzados.

Fifty patients with inoperable head and neck carcinomas were treated with Cisplatin-5-fluorouracil induction chemotherapy. After 3 years follow-up, characteristics of patients have been studied, that is: age, sex, stage, primary site, histological type, histological grade and performance status. The analysis of chemotherapy treatment and results on primary tumor and lymphatic areas are presented. A total response rate of 83.3% with 22.9% of complete response rate have been observed. Local treatment after chemotherapy is studied. Radiotherapy increased response in 33.4% of cases. Response duration and survival is to have a complete response after systemic and local treatment. Literature is revised.

Should we continue temozolomide beyond six cycles in the adjuvant treatment of glioblastoma without an evidence of clinical benefit? A cost analysis based on prescribing patterns in Spain.

PURPOSE: The standard adjuvant treatment for glioblastoma is temozolomide concomitant with radiotherapy, followed by a further six cycles of temozolomide. However, due to the lack of empirical evidence and international consensus regarding the optimal duration of temozolomide treatment, it is often extended to 12 or more cycles, even in the absence of residual disease. No clinical trial has shown clear evidence of clinical benefit of this extended treatment. We have explored the economic impact of this practice in Spain. MATERIALS AND METHODS: Spanish neuro-oncologists completed a questionnaire on the clinical management of glioblastomas in their centers. Based on their responses and on available clinical and demographic data, we estimated the number of patients who receive more than six cycles of temozolomide and calculated the cost of this extended treatment. RESULTS: Temozolomide treatment is continued for more than six cycles by 80.5 % of neuro-oncologists: 44.4 % only if there is residual disease; 27.8 % for 12 cycles even in the absence of residual disease; and 8.3 % until progression. Thus, 292 patients annually will continue treatment beyond six cycles in spite of a lack of clear evidence of clinical benefit. Temozolomide is covered by the National Health Insurance System, and the additional economic burden to society of this extended treatment is nearly 1.5 million euros a year. CONCLUSIONS: The optimal duration of adjuvant temozolomide treatment merits investigation in a clinical trial due to the economic consequences of prolonged treatment without evidence of greater patient benefit.