Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.

PURPOSE: Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS: Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS: A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION: The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.

Six year survival after prolonged temozolomide treatment in a 30-year-old patient with glioblastoma.

Glioblastoma (GBM) is the most malignant primary brain tumour in adults. Since 2005 surgery followed by radiotherapy with concomitant Temozolomide (TMZ) is the standard care for patients with a GBM. Despite these improved treatment strategies, survival of GBM-patients remains poor; and there are very few patients who survive for a long time. Also there is no standard therapeutic strategy after six cycles of TMZ, and further treatment is at the physician's discretion. We report a case of a young patient with a glioblastoma who, not only showed dramatic clinical and radiological improvement after TMZ treatment but who now also (under continued TMZ therapy) survives over 6 years, with complete remission clinically and radiologically. Up till now there are no studies describing TMZ treatment in GBM patients for as long as 6 years.

Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial.

PURPOSE: Little is known about the health-related quality of life (HRQOL) of patients treated for anaplastic oligodendrogliomas. The impact of combined procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy after radiotherapy (RT) compared with RT alone on HRQOL in the randomized European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial was studied. PATIENTS AND METHODS: Adult patients with anaplastic oligodendrogliomas received RT alone or RT plus PCV chemotherapy. HRQOL was assessed with the EORTC Quality of Life Questionnaire C30 and Brain Cancer Module. Seven prespecified HRQOL end points were selected. We hypothesized that chemotherapy would impair HRQOL during treatment but that there would be a similar HRQOL between treatment arms once off treatment. Assessments were performed at randomization, at the end of RT, and then every 3 to 6 months until progression. RESULTS: A total of 368 patients were randomly assigned to one of the two arms; overall, 58% were male, and the median age was 49 years. Compliance with HRQOL was 78% at baseline and dropped to 55% to 72% up to 2.5 years post-RT. Baseline scores demonstrated considerable impairments in HRQOL for both treatment groups. The longitudinal analysis showed a significant increase in nausea/vomiting in the RT plus PCV chemotherapy arm during and shortly after chemotherapy. Because of a difference in baseline scores for fatigue and physical functioning, the differences between treatment arms during PCV did not reach significance. The nonselected scales of appetite loss and drowsiness demonstrated significant differences between treatment arms during chemotherapy in favor of the RT arm. The long-term results showed no difference between arms. CONCLUSION: The major impact of PCV on HRQOL is on nausea/vomiting, loss of appetite, and drowsiness during and shortly after treatment. There are no long-term effects of PCV chemotherapy.

Prognostic value of health-related quality-of-life data in predicting survival in patients with anaplastic oligodendrogliomas, from a phase III EORTC brain cancer group study.

PURPOSE: This is one of a few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in patients with brain cancer. PATIENTS AND METHODS: Baseline HRQOL scores (from the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire C30 and the EORTC Brain Cancer Module) were examined in 247 patients with anaplastic oligodendrogliomas to determine the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap resampling procedure and the computation of C indexes and R2 coefficients were used to explore the stability of the models as well as better assess the potential benefit of using HRQOL to predict survival in clinical practice and research. RESULTS: Classical analysis controlled for major clinical prognostic factors selected emotional functioning (P = .0016), communication deficit (P = .0261), future uncertainty (P = .0481), and weakness of legs (P = .0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings and no single model was found to be preferable over all others. C indexes, which estimate the probability of a model to correctly predict which patient among a randomly chosen pair of patients will survive longer, and R2 coefficients, which measure the proportion of variability explained by the model, did not exhibit major improvement when adding selected or all HRQOL scores to clinical factors. CONCLUSION: While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor for patients with cancer.

Effect of carbogen breathing on the radiation response of a human glioblastoma xenograft: analysis of hypoxia and vascular parameters of regrowing tumors.

BACKGROUND AND PURPOSE: The aim of these experiments was to study the relationship between the previously demonstrated efficacy of carbogen breathing on tumor oxygenation status and the response to radiation assessed by a growth delay assay. This study was also developed to investigate the microenvironmental changes caused by combined treatment compared to irradiation only in regrowing tumors. MATERIAL AND METHODS: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without carbogen breathing. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after immunohistochemical staining. Tumor growth delay was monitored for up to 120 days after treatment. RESULTS: In general, there was no benefit of combined treatment. However, a small subgroup with good response to combined radiation and carbogen treatment was identified showing little hypoxia and mainly necrosis in the regrowing tumors. These microenvironmental characteristics were not seen in tumors of the other treatment groups. CONCLUSION: The observations suggest that a subgroup of patients, who could potentially benefit from the combined carbogen and radiation treatment, might be identified. However, the heterogeneous response to treatment illustrates the need for selection of patients before start of treatment.

Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial.

PURPOSE: Anaplastic oligodendrogliomas are more responsive to chemotherapy than high-grade astrocytomas. We investigated, in a multicenter randomized controlled trial, whether adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy improves overall survival (OS) in newly diagnosed patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas. PATIENTS AND METHODS: The primary end point of the study was OS; secondary end points were progression-free survival (PFS) and toxicity. Patients were randomly assigned to either 59.4 Gy of radiotherapy (RT) in 33 fractions only or to the same RT followed by six cycles of standard PCV chemotherapy (RT/PCV). 1p and 19q deletions were assessed with fluorescent in situ hybridization. RESULTS: A total of 368 patients were included. The median follow-up time was 60 months, and 59% of patients have died. In the RT arm, 82% of patients with tumor progression received chemotherapy. In 38% of patients in the RT/PCV arm, adjuvant PCV was discontinued for toxicity. OS time after RT/PCV was 40.3 months compared with 30.6 months after RT only (P = .23). RT/PCV increased PFS time compared with RT only (23 v 13.2 months, respectively; P = .0018). Twenty-five percent of patients were diagnosed with combined 1p/19q loss; 74% of this subgroup was still alive after 60 months. RT/PCV did not improve survival in the subgroup of patients with 1p/19q loss. CONCLUSION: Adjuvant PCV chemotherapy does not prolong OS but does increase PFS in anaplastic oligodendroglioma. Combined loss of 1p/19q identifies a favorable subgroup of oligodendroglial tumors. No genetic subgroup could be identified that benefited with respect to OS from adjuvant PCV.

Irradiation combined with SU5416: microvascular changes and growth delay in a human xenograft glioblastoma tumor line.

PURPOSE: The combination of irradiation and the antiangiogenic compound SU5416 was tested and compared with irradiation alone in a human glioblastoma tumor line xenografted in nude mice. The aim of this study was to monitor microenvironmental changes and growth delay. METHODS AND MATERIALS: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without SU5416. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after imunohistochemical staining. Tumor growth delay was monitored for up to 200 days after treatment. RESULTS: SU5416, when combined with irradiation, has an additive effect over treatment with irradiation alone. Analysis of the tumor microenvironment showed a decreased vascular density during treatment with SU5416. In tumors regrowing after reaching only a partial remission, vascular characteristics normalized shortly after cessation of SU5416. However, in tumors regrowing after reaching a complete remission, permanent microenvironmental changes and an increase of tumor necrosis with a subsequent slower tumor regrowth was found. CONCLUSIONS: Permanent vascular changes were seen after combined treatment resulting in complete remission. Antiangiogenic treatment with SU5416 when combined with irradiation has an additive effect over treatment with irradiation or antiangiogenic treatment alone.