Nitrosourea-based Chemotherapy Research Articles

Brain Re-Irradiation Or Chemotherapy: a phase II randomised trial of re-irradiation and chemotherapy in patients with recurrent glioblastoma (BRIOChe) – protocol for a multi-centre open-label randomised trial

IntroductionGlioblastoma (GBM) is the most common adult primary malignant brain tumour. The condition is incurable and, despite aggressive treatment at first presentation, almost all tumours recur after a median of...

Palliative Carboplatin Chemotherapy in Previously Treated High-Grade Glioma: Real-World Efficacy and Safety

Abstract AIMS Effective third-line chemotherapy options for patients after temozolomide (TMZ) and nitrosourea-based chemotherapy for high-grade glioma (HGG) are not well defined. The use of carboplatin is limited due to uncertainly around its effectiveness and tolerability. METHOD Patients with HGG treated with single-agent carboplatin chemotherapy between 2005-2021 were identified from our institutional database. Patient and treatment-related details were acquired from electronic hospital records. SPSS Statistics for Windows, (Version 23.0, IBM Corp.) was used for data analysis. RESULTS A total of 16 HGG patients were identified. This included 9 glioblastoma (GBM) and 3 anaplastic astrocytomas (AA). These 12 patients were used for further analysis. The median age was 48 (22-73) years. All patients initially received a flat dose of 450 mg intravenous carboplatin every 3-4 weeks. All had previously received high dose RT (54-60 Gy), and temozolomide and lomustine-based chemotherapy. Carboplatin was used as 3rd or 4th line treatment. The median number of cycles given was 3 (range: 1-12). Five had rapid decline in performance status after 1-3 cycles. Five patients required dose/ cycle length adjustment due to grade 1 or 2 haematological toxicity. Other than cumulative fatigue, no other >/= grade 2 toxicities were reported. None required inpatient management for treatment toxicities. Median progression-free survival on carboplatin was 3 months (range 1-11 months) and overall survival was 8 months (range 1–26 months). CONCLUSION Carboplatin is a viable treatment option for HGG with acceptable toxicity rates. However, careful patient selection remains key to attaining maximum benefit.

Benefit with adjuvant chemotherapy in anaplastic astrocytoma

The role of chemotherapy for newly diagnosed anaplastic gliomas, particularly when combined with radiotherapy, has long been unresolved. Over the past few decades, despite no conclusive data, study findings have suggested that the addition of nitrosourea-based chemotherapy to radiotherapy could be beneficial. The NOA-04 trial 1 Wick W Hartmann C Engel C et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol. 2009; 27: 5874-5880 Crossref PubMed Scopus (668) Google Scholar revealed that initial treatment with chemotherapy (either temozolomide or procarbazine, lomustine, and vincristine [PCV]) or radiotherapy alone yielded similar results. Survival of patients with anaplastic glioma has been recognised as being strongly dependent on the presence or absence of the favourable 1p/19q co-deletion. This discovery resulted in secondary analyses of US and European trials, revealing improved survival in patients with co-deleted tumours who received combined radiation and PCV chemotherapy. 2 Cairncross G Wang M Shaw E et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J Clin Oncol. 2012; 31: 337-343 Crossref PubMed Scopus (777) Google Scholar , 3 van den Bent MJ Brandes AA Taphoorn MJ et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2012; 31: 344-350 Crossref PubMed Scopus (836) Google Scholar Separately, clear benefits were found with adding temozolomide to radiotherapy to treat newly diagnosed glioblastoma, 4 Stupp R Mason WP van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 2005; 352: 987-996 Google Scholar which led to investigations of whether radiation plus temozolomide would benefit patients with non-co-deleted anaplastic gliomas (ie, anaplastic astrocytomas). 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 studyAdjuvant 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. Full-Text PDF

Proposed therapeutic strategy for adult low-grade glioma based on aggressive tumor resection.

OBJECT There is no standard therapeutic strategy for low-grade glioma (LGG). The authors hypothesized that adjuvant therapy might not be necessary for LGG cases in which total radiological resection was achieved. Accordingly, they established a treatment strategy based on the extent of resection (EOR) and the MIB-1 index: patients with a high EOR and low MIB-1 index were observed without postoperative treatment, whereas those with a low EOR and/or high MIB-1 index received radiotherapy (RT) and/or chemotherapy. In the present retrospective study, the authors reviewed clinical data on patients with primarily diagnosed LGGs who had been treated according to the above-mentioned strategy, and they validated the treatment policy. Given their results, they will establish a new treatment strategy for LGGs stratified by EOR, histological subtype, and molecular status. METHODS One hundred fifty-three patients with diagnosed LGG who had undergone resection or biopsy at Tokyo Women's Medical University between January 2000 and August 2010 were analyzed. The patients consisted of 84 men and 69 women, all with ages ≥ 15 years. A total of 146 patients underwent surgical removal of the tumor, and 7 patients underwent biopsy. RESULTS Postoperative RT and nitrosourea-based chemotherapy were administered in 48 and 35 patients, respectively. Extent of resection was significantly associated with both overall survival (OS; p = 0.0096) and progression-free survival (PFS; p = 0.0007) in patients with diffuse astrocytoma but not in those with oligodendroglial subtypes. Chemotherapy significantly prolonged PFS, especially in patients with oligodendroglial subtypes (p = 0.0009). Patients with a mutant IDH1 gene had significantly longer OS (p = 0.034). Multivariate analysis did not identify MIB-1 index or RT as prognostic factors, but it did identify chemotherapy as a prognostic factor for PFS and EOR as a prognostic factor for OS and PFS. CONCLUSIONS The findings demonstrated that EOR was significantly correlated with patient survival; thus, one should aim for maximum tumor resection. In addition, patients with a higher EOR can be safely observed without adjuvant therapy. For patients with partial resection, postoperative chemotherapy should be administered for those with oligodendroglial subtypes, and repeat resection should be considered for those with astrocytic tumors. More aggressive treatment with RT and chemotherapy may be required for patients with a poor prognosis, such as those with diffuse astrocytoma, 1p/19q nondeleted tumors, or IDH1 wild-type oligodendroglial tumors with partial resection.

Survival effect of first- and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997-2010

Prospective follow-up studies of large cohorts of patients with glioblastoma (GBM) are needed to assess the effectiveness of conventional treatments in clinical practice. We report GBM survival data from the Brain Cancer Register of the Fondazione Istituto Neurologico Carlo Besta (INCB) in Milan, Italy, which collected longitudinal data for all consecutive patients with GBM from 1997 to 2010. Survival data were obtained from 764 patients (aged>16 years) with histologically confirmed primary GBM who were diagnosed and treated over a 7-year period (2004-2010) with follow-up to April 2012 (cohort II). Equivalent data from 490 GBM patients diagnosed and treated over the preceding 7 years (1997-2003) with follow-up to April 2005 (cohort I) were available for comparison. Progression-free survival (PFS) was available from 361 and 219 patients actively followed up at INCB in cohorts II and I, respectively. Survival probabilities were 54% at 1 year, 21% at 2 years, and 11% at 3 years, respectively, in cohort II compared with 47%, 11%, and 5%, respectively, in cohort I. PFS was 22% and 12% at 1 year in cohorts II and I. Better survival and PFS in cohort II was significantly associated with introduction of the Stupp protocol into clinical practice, with adjusted hazard ratios (HRs) of 0.78 for survival and 0.73 for PFS, or a 22% relative decrease in the risk of death and a 27% relative decrease in the risk of recurrence. After recurrence, reoperation was performed in one-fifth of cohort I and in one-third of cohort II but was not effective (HR, 1.05 in cohort I and 1.02 in cohort II). Second-line chemotherapy, mainly consisting of nitrosourea-based chemotherapy, temozolomide, mitoxantrone, fotemustine, and bevacizumab, improved survival in both cohorts (HR, 0.57 in cohort I and 0.74 in cohort II). Radiosurgery was also effective (HR, 0.52 in cohort II). We found a significant increase in overall survival, PFS, and survival after recurrence after 2004, likely due to improvements in surgical techniques, introduction of the Stupp protocol as a first-line treatment, and new standard protocols for second-line chemotherapy and radiosurgery after tumor recurrence. In both cohorts, reoperation after tumor recurrence did not improve survival.

Value of Nitrosourea-based Chemotherapy in Recurrent High Grade Glioma,NEMROCK Experience

Value of Nitrosourea-based Chemotherapy in Recurrent High Grade Glioma,NEMROCK Experience

Phase II trial of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of anaplastic astrocytoma

The efficacy and safety of adjuvant radioimmunotherapy with 125I-labeled anti-epidermal growth factor receptor 425 murine antibody (125I-425 mAb) in patients with newly diagnosed anaplastic astrocytoma (AA) is evaluated in this single-institution phase II study. Patients with newly diagnosed and histologically proven AA were eligible. A total of 80 patients received three weekly intravenous injections of 1.8 GBq of 125I-425 mAb following surgery and radiation therapy to a median dose of 60 Gy. Median overall survival was the primary endpoint and the secondary endpoint was toxicity. The median age was 43 years (range 22–75 years), and the median Karnofsky Performance Status was 80 (range 50–100). The percentage of patients who underwent surgical debulking, radiation therapy, temozolomide, and nitrosourea-based chemotherapy are 57.5, 99, 25, and 25 % respectively. The overall median survival was 55.6 months (95 % CI 42.7–68.5 months). The 2- and 5-year survivals were 74 and 47 %, respectively. There was no grade 3 or higher toxicity with the administration of 125I-425 mAb. Treatment with 125I-425 mAb in newly diagnosed AA patients was safe and well tolerated. Survival benefits are encouraging and warrant further study.

A retrospective pooled analysis of response patterns and risk factors in recurrent malignant glioma patients receiving a nitrosourea-based chemotherapy

BackgroundAt recurrence the use of nitrosoureas is widely-used as a therapeutic option for glioblastoma (GBM) patients. The efficacy of fotemustine (FTM) has been demonstrated in phase II clinical trials; however, these papers report a wide range of progression-free-survival (PFS-6 m) rates, ranging from 21% to 52%. We investigated whether FTM could have a different response pattern in respect to time to adjuvant temozolomide failure, or whether specific independent risk factors could be responsible for the wide range of response rates observed.MethodsRecurrent GBM patients have been treated with fotemustine 75-100 mg/sqm at day 1, 8, 15 and after 4/5 weeks of rest with 100 mg/sqm every 21 days. Patients were stratified in 4 groups according to time to temozolomide failure: before starting (B0), during the first 6 months (B1), after more than 6 months of therapy (B2), and after a treatment-free interval (B3). Primary endpoint was PFS-6 m. A multivariable analysis was performed to identify whether gender, time after radiotherapy, second surgery and number of TMZ cycles could be independent predictors of the clinical benefit to FTM treatment.Results163 recurrent GBM patients were included in the analysis. PFS-6 m rates for the B0, B1, B2 and B3 groups were 25%, 28%, 31.1% and 43.8%, respectively. The probability of disease control was higher in patients with a longer time after radiotherapy (p = 0.0161) and in those who had undergone a second surgery (p = 0.0306).ConclusionsFTM is confirmed as a valuable therapeutic option for patients with recurrent GBM and was active in all study patient groups. Time after the completion of radiotherapy and second surgery are independent treatment-related risk factors that were predictive of clinical benefit.

Efficacy of nitrosourea-based chemotherapy in recurrent malignant glioma according to time to adjuvant temozolomide failure: A pooled analysis.

2060 Background: Concomitant and adjuvant temozolomide (TMZ) is the standard of care of the first-line treatment in glioblastoma (GBM) patients. At recurrence patients have few therapeutic options and the use of nitrosoureas, alternative schedule of TMZ and new target therapy have been widely studied. Recently Perry and colleagues (JCO 2010;28:2051-2057) have demonstrated that time to adjuvant temozolomide failure seems to be predictable to dose-intense TMZ treatment. The aim of our pooled analysis was to assess the efficacy of nitrosourea in recurrent GBM patients according to time to adjuvant TMZ progression. Methods: Patients with GBM who failed the standard Stupp regimen have been treated with a nitrosoureas based regimen of fotemustine (FTM) 75-100mg/sqm at day 1, 8, 15 (induction phase) and after 4/5 weeks of rest 100 mg/sqm every 21 days. The primary endpoint of the study was 6-months progression free survival (PFS-6m), Overall survival at 1 year (OS1y), response rate (RR) and toxicity were secondary endpoints. Patients were stratified in 3 groups according to time to TMZ failure: GBM patients failing during the first 6 months of adjuvant TMZ (B1), those who failed after more than 6 months of therapy (B2) and GBM patients who recurred after a treatment-free interval (B3). Results: Six Italian centers participated in this study. At that time preliminary results are available: 119 patients with recurrent GBM have been evaluated. Results have been summarized in the table. Conclusions: Nitrosourea is a valuable therapeutic option for patients with recurrent GBM, not depending on time to adjuvant temozolomide failure and also patients recurred after 6 cycles of adjuvant TMZ (B2) seem to get a benefit from FTM treatment. A prospective randomized trial is warranted to define if TMZ and FTM have a different pattern of response in recurrent GBM. B1 (%) B2 (%) B3 (%) PSF-6m OS1y RR PSF-6m OS1y RR PSF-6m OS1y RR FTM 24.5 24.5 12.2 31.3 31.3 18.8 34.2 28.9 7.9 TMZ* 27.3 27.3 3 7.4 14.8 0 35.7 28.6 11.1

Temozolomide Versus Procarbazine, Lomustine, and Vincristine in Recurrent High-Grade Glioma

Temozolomide (TMZ) is an alkylating agent licensed for treatment of high-grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG. Four hundred forty-seven patients were randomly assigned to PCV (224 patients) or TMZ (sub-random assignment: TMZ-5 [200 mg/m(2) for 5 days, 112 patients] or TMZ-21 [100 mg/m(2) for 21 days, 111 patients]) for up to 9 months or until progression. The primary outcomes were survival (PCV v TMZ) and 12-week progression-free survival (PFS; TMZ-5 v TMZ-21). This study is registered as ISRCTN83176944. Percentages of patients completing 9 months of treatment in the PCV, TMZ-5, and TMZ-21 arms were 17%, 26%, and 13%, respectively. Major toxicity was similar across all three groups. With a median follow-up time of 12 months and 382 deaths, there was no clear survival benefit when comparing PCV with TMZ (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .350). For TMZ-5 versus TMZ-21, 12-week PFS rates were similar (63.6% and 65.7%, respectively; P = .745), but TMZ-5 improved overall PFS (HR, 1.38; 95% CI, 1.05 to 1.82; P = .023), survival (HR, 1.32; 95% CI, 0.99 to 1.75; P = .056), and global quality of life (49% v 19% improved > 10 points at 6 months, respectively; P = .005). Although TMZ (both arms combined) did not show a clear benefit compared with PCV, comparison of the TMZ schedules demonstrated that the 21-day schedule was inferior to the 5-day schedule in this setting. This challenges the current understanding of increasing TMZ dose-intensity by prolonged scheduling.

Favorable long-term outcome of low-grade oligodendrogliomas irrespective of 1p/19q status when treated without radiotherapy

Despite the accumulating evidences of high chemosensitivity especially in anaplastic oligodendrogliomas with loss of chromosomes 1p and 19q, the optimal management strategy for low-grade tumors using the 1p/19q information remains controversial. We have treated all low-grade oligodendrogliomas by a chemotherapy-preceding strategy without radiotherapy, and here we analyzed the survival outcomes of 36 consecutive patients in relation to 1p/19q status. The treatment protocol was as follows: (1) simple observation after gross total resection, and (2) modified PCV chemotherapy for postoperative residual tumors or recurrence after total resection. The 1p and 19q status were analyzed by fluorescence in situ hybridization. The median follow-up period was 7.5 years and no patient was lost during the follow-up periods. 1p/19q co-deletion was observed in 72% of the patients, and there was no significant association between 1p/19q co-deletion and chemotherapy response rate. The 5- and 10-year progression-free survival (PFS) rate was 75.1 and 46.9%, respectively, and the median PFS was 121 months for 1p/19q-deleted tumors and 101 months for non-deleted tumors (log-rank test: P = 0.894). Extent of surgery did not affect PFS (P = 0.685). In contrast, the elder patients (>50) had significantly shorter PFS (P = 0.0458). Recurrent tumors were well controlled by chemotherapy irrespective of 1p/19q status, and 35 out of 36 patients survived without receiving radiotherapy. The 5- and 10-year overall survival rates were 100 and 93.8%, respectively. Two of the patients in their sixties (29%) suffered from severe cognitive dysfunctions and marked brain atrophy following chemotherapy alone. These results show that low-grade oligodendrogliomas could be successfully treated by surgical resection and nitrosourea-based chemotherapy alone without radiotherapy irrespective of 1p/19q status.

Impact of adjuvant chemotherapy for gliomatosis cerebri

BackgroundGliomatosis cerebri (GC) is characterized by a diffuse infiltration of tumor cells throughout CNS, however, few details are available about the chemotherapeutic effect on GC. The aim of this study was to investigate its clinical course and to determine the efficacy of chemotherapy for GC.MethodsBetween Jan. 1999 and Dec. 2004, 37 GC patients were diagnosed by biopsy and treated with radiotherapy in a single institution. To determine the efficacy of chemotherapy for GC, we retrospectively reviewed their clinical courses. The study cohort was divided into 2 groups, those with and without receiving post-radiotherapy adjuvant chemotherapy such as temozolomide or nitrosourea-based chemotherapy.ResultsNineteen patients with adjuvant chemotherapy were assigned to the chemotreatment group and 18 with radiotherapy alone were assigned to the control group. Mean survival for chemotreatment group and control group were 24.2 and 13.1 months, respectively (p = 0.045). Time to progression for these groups were 16.0 and 6.0 months, respectively (p = 0.007). Overall review of the clinical course of patients with GC provided that early appearance of new contrast-enhancing lesions within 6 months from the initial diagnosis and higher histological grade were closely associated with poor survival (p < 0.001 and p = 0.008).ConclusionAdjuvant chemotherapy following radiotherapy could prolong the survival in patients with GC. In addition, newly developed contrast-enhanced lesions on the follow-up MR images indicate the progression of GC.

Can OS-6 replace PFS-6 as a primary endpoint in phase II studies on glioblastoma patients given antiangiogenetic drugs?

2022 Background: In the last decade, progression-free survival (PFS) at 6 months (PFS-6) has been considered the best endpoint in phase II trials on recurrent glioblastoma (GBM). However, since a new standard of care was established by the EORTC/NCIC phase III trial, no data have reported on the PFS-6 or overall survival (OS) obtained with second line treatment following combined RT/TMZ. Moreover, antiangiogenic agents might alter data on response by repairing the blood-brain barrier and diminishing contrast enhancement, thus precluding the accurate assessment of any reduction in the tumor burden. The issue of a robust primary endpoint for phase II studies is therefore still open. The aim of the study was to evaluate outcome endpoints for second line treatment at recurrence. Methods: A retrospective analysis was made using a database on 653 GBM patients (pts) followed prospectively between 5/2001 and 8/2008. Eligibility criteria: age ≥ 18 years; PS 0-2; histological diagnosis of GBM; cytotoxic treatment at disease progression after RT/TMZ. The log-rank test was used to evaluate the significance of the prognostic variables, and the Cox model to ascertain any association between PFS and OS. Results: 150 pts (median age: 52 years, [24–76 y]) were enrolled. MGMT methylation status, evaluable in 110 pts, was present in 38% of cases. Median OS was 18.5 months. At disease progression, 40 pts (27%) received temozolomide, 92 pts (61%), nitrosourea-based chemotherapy, and 18 pts (12%) other treatments. At the time of recurrence, mPFS was 2.5 months (95%CI: 2.0–3.1), PFS-6 15% (95%CI: 9.5%–21.3%, mOS 7.6 months (95%CI: 6.9–8.3) and OS-6 64% (95%CI: 56.6%–72.2%). In the Cox proportional hazard model, PFS with the second line treatment was correlated with OS measured as from the start of the second line treatment (p < 0.0001). Conclusions: The findings made in the present study, the first in literature to evaluate outcome endpoints for a second line treatment after RT/TMZ in GBM pts, confirm that a PFS-6 of 15% should be considered the cut-off for active cytotoxic drugs in phase II studies on recurrent GBM. For antiangiogenic compounds, OS-6 can be considered as a sound endpoint. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, OncoMethylome Sciences, Roche, Schering-Plough GlaxoSmithKline, Merck Sharp & Dohme, Roche, sanofi-aventis, Schering-Plough

Nitrosourea-based chemotherapy for low grade gliomas failing initial treatment with temozolomide

There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.

High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up R. Stupp, J.-C. Tonn, M. Brada & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group* Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, and Department of Oncology-Hematology Riveria-Chablais, Vevey, Switzerland; Department of Neurosurgery, Universitatsklinikum Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany; Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, Sutton, UK; Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

Efficacy of temozolomide as adjuvant chemotherapy after postsurgical radiotherapy alone for glioblastomas

Objectives The aim of this study was to assess the efficacy of adjuvant TMZ chemotherapy for newly diagnosed GBM patients who were treated with surgery followed by radiotherapy alone. Material and methods Between January 2003 and April 2005, 59 consecutive GBM patients underwent radiation therapy after surgical resection and subsequently received TMZ chemotherapy. For the comparative analysis, we selected 60 clinically matched GBM patients who underwent radiotherapy followed by nitrosourea-based chemotherapy (NUBC), at the same institution between June 1995 and April 2005. The study cohort was divided into two groups, those with adjuvant TMZ treatment and with NUBC. Results 59 patients with adjuvant TMZ treatment were assigned to the treatment group and 60 patients with NUBC to the control group. The median overall survival for the treatment group was 18.2 months (95% CI, 11.7–24.7 months), compared with the survival of 14.5 months (95% CI, 11.2–17.7 months) for the control group ( p = 0.019). The progression-free survival for the treatment group was 5.6 months (95% CI, 4.4–6.7 months), while the control group showed progression-free survival of 3.3 months (95% CT, 3.2–6.0 months) ( p = 0.030). Uni- and multivariate analysis revealed that extent of surgical resection, age ≥55 years and postoperative KPS were significantly associated with survival. Conclusion Adjuvant TMZ chemotherapy provided a clinically relevant benefit of survival, as compared with NUBC. Thus, we suggest that adjuvant TMZ chemotherapy may be effective even for patients who did not receive concomitant chemoradiotherapy for GBM.

Malignant glioma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Malignant glioma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

Phase I/II Trial of Erlotinib and Temozolomide With Radiation Therapy in the Treatment of Newly Diagnosed Glioblastoma Multiforme: North Central Cancer Treatment Group Study N0177

Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m(2) daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m(2) daily for 5 days every 28 days). The primary end point was survival at 1 year. Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

Mechanisms of Disease: temozolomide and glioblastoma—look to the future

Glioblastoma is both the most common and most aggressive primary brain tumor. Until recently, the standard of care involved maximal safe surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, the results of a large clinical trial examining the role of adjuvant chemotherapy in management of newly diagnosed glioblastoma were published. This study created a new standard of adjuvant treatment, using concurrent and sequential temozolomide in the initial therapy of glioblastoma. A companion tumor biology study identified the prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) status in patients with newly diagnosed glioblastoma. Several preliminary studies have been initiated to address the issue of resistance and suppression of MGMT activity, and have used alternative temozolomide dosing schedules and O(6)-guanine mimetic agents as substrates for MGMT. In addition, recent studies have attempted to define mechanisms responsible for the apparent synergy between temozolomide and radiotherapy. Lastly, an increased understanding of the molecular biology of glioblastoma has provided new leads for the adjuvant treatment of this disease. This Review summarizes new developments in treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer.

Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide

Temozolomide (TMZ) is active against newly diagnosed glioblastoma (GBM), and O(6)-methylguanine-DNA methyltransferase (MGMT) is implicated in resistance to TMZ and nitrosoureas. We evaluated the efficacy and safety of the standard 5-day TMZ regimen in patients with recurrent GBM after initial therapy including nitrosourea-based chemotherapy, in conjunction with an analysis of the prognostic value of MGMT protein expression regarding response to TMZ and survival. From September 2003 to January 2007, 30 patients having recurrent GBM received 150-200 mg/m(2)/day of TMZ for five consecutive days every 28 days. Tumor tissue from 19 patients was analysed for MGMT protein expression using western blotting, and 17 of them were assessable for a response. The overall response rate was 23.5% (one complete response and three partial responses). Six patients had stable disease (35.3%). Median progression-free survival (PFS) time was 2.2 months, and median overall survival (OS) time was 9.9 months from the initiation of TMZ therapy. Patients with low MGMT protein expression had a significantly improved PFS (P = 0.016) and OS (P = 0.019) compared to those with high expression. Both low MGMT expression (P = 0.040) and re-resection at relapse (P = 0.014) persisted as significant independent favorable prognostic factors for OS. The most common grade 3 and 4 hematological toxicity was lymphopenia (22.2%). The standard 5-day TMZ regimen resulted in moderate antitumor activity with an acceptable safety profile in patients with nitrosourea-pretreated recurrent GBM, and protein expression of MGMT is an important prognostic factor for patients treated with TMZ even after recurrence.