Patrick Beauchesne

Temozolomide in Elderly Patients With Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial

PURPOSE The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken. PATIENTS AND METHODS Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition. RESULTS Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03). CONCLUSION Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.

Gonadotropic pituitary carcinoma: case report.

A 37-year-old man developed multiple intracranial, intraspinal, and general metastases from an invasive nonfunctioning pituitary adenoma after surgery and radiation therapy. This is the first gonadotropic pituitary carcinoma reported in literature.

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy

Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6-7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.

Gonadotropic Pituitary Carcinoma

: A 37-year-old man developed multiple intracranial, intraspinal, and general metastases from an invasive nonfunctioning pituitary adenoma after surgery and radiation therapy. This is the first gonadotropic pituitary carcinoma reported in literature.

Etoposide sensitivity of radioresistant human glioma cell lines

Purpose: Malignant gliomas display aggressive local behavior and are not cured by existing therapy. Etoposide, a topoisomerase-II-inhibitor agent, is one of the most active and useful antineoplastic agents. However, etoposide is not usually used on these tumors. We undertook an in vitro study to prove that etoposide is a useful drug for malignant gliomas. Methods: Five human glioma cell lines were the basis for this study. Following exposure to various concentrations of etoposide, the glioma cell lines were found to be sensitive; the median concentration inhibiting the number of cells by 50% (IC50) was 8.76 μg/ml (range 8–15.8 μg/ml). Since topoisomerase II is the critical target for etoposide, it was of interest to determine the topoisomerase II activity (decatenation of kinetoplast DNA isolated from Cryphtidia fasciculata) and the etoposide-induced inhibition of topoisomerase II activity. Results: The topoisomerase II activity was homogeneous in glioma cell lines (average of 50% decatenation with 7,000 cells), and topoisomerase II was the target of the etoposide. Conclusions: Our results suggest that topoiomerase II-reactive agents may prove to be clinically useful drugs for patients with malignant gliomas.

Phase II study of a radiotherapy/etoposide combination for patients with newly malignant gliomas

Purpose: Etoposide, a semisynthetic derivative of podophyllotoxine, is a topoisomerase II inhibitor. This drug is currently used in several types of human cancer. The aim of this study was to evaluate the efficacity and tolerance of a near-concurrent association of radiotherapy and etoposide for newly malignant gliomas. Methods: From May 1995 to December 1996, 30 malignant glioma patients were included in this phase II study; 16 patients underwent surgical tumor resection, and a stereotactic biopsy was performed in 14 patients. Standard cranial irradiation and six courses of etoposide (100 mg/m2, ×days 1–3) were administered. The first course of etoposide was administered on days 1–3 of radiotherapy and was resumed in the week following the end of radiotherapy. Treatment was consolidated by further courses of etoposide every 4 weeks. Results: Only 26 patients could be evaluated for the purpose of our study. The median age was 60.1 years, and the median Karnofsky performance score (KPS) was 80.2. The rate of objective response for evaluable patients was 34.6%, and four complete responses (CR) and five partial responses (PR) were noted. The median survival (MST) was 12 months, and the average overall survival was 12.5 months. Hematological toxicity was mild, and grade 3 or 4 neutropenia (white blood cell count <1500/ml) was noted in three patients, without any sepsis or bleeding. Conclusions: The results obtained in this study are comparable to the best reported results on the combination of radiotherapy and nitrosoureas. The near-concurrent combination of radiotherapy and etoposide seems to be effective and well tolerated in the treatment of newly malignant gliomas.

Letter to the editor: the natural history of extra-cranial metastasis from glioblastoma multiform [J Neurooncol DOI 10.1007/s11060-011-0575-8].

We read with interest the review by Lun et al. about the natural history of extra-cranial metastasis from glioblastoma multiform (GBM). The reports included were selected on the basis of a comprehensive electronic search for extra-cranial metastasis of glioblastoma case studies published in the English literature from 1928 to 2009; the data collected were: (1) survival time, (2) year of publication, (3) age of patient, (4) gender, (5) modern neuroimaging modality used, (6) site of glioblastoma, (7) site of metastasis, and (8) treatment received. The authors stated that they carefully reviewed the international literature, and 88 cases of extra-cranial metastasis from GBM (n = 83) and gliosarcoma (n = 5), were included. These totals are completely incorrect. The authors could not have reviewed the literature meticulously; the number of cases of extra-cranial metastasis of GBM is higher than they stated, and their analysis is questionable and open to discussion. The data obtained from their study must be interpreted with caution. We have published three articles in the English literature about extra-cranial metastases of GBM [1–3], and our last paper was a review of extra-neural metastases of malignant gliomas. Our first two case reports [1, 2] meet the criteria of the analysis of Lun et al. and should have been included in Lun’s study. This omission is unpardonable, and raises scientific criticism of the manner in which Lun et al. conducted this meta-analysis. The number of cases reported in the literature is approximately three times the number found by Lun et al. Indeed, we found, in the English literature, a total of 284 cases of extra-neural metastases from GBM and 19 cases from gliosarcoma [1–3]. Taking into account the methodology of the analysis and the use of comprehensive electronic search procedures, it is difficult to understand how these authors discovered only 88 case reports. Perhaps the authors decided to report a selection of the cases published in the literature, although there is no suggestion of this in their paper. Unfortunately, their study is not credible, and the data obtained from their meta-analysis do not represent the reality of this pathology. The authors asserted that extra-cranial metastases occurred in 0.4–0.5 % of all glioblastomas; again, this value is incorrect. The incidence of extra-cranial metastases of GBM is estimated to be approximately 2 % [1–3]. When they do occur, it is usually late in the course of the disease, a median of two years [3]. We would like to point out that we found the average age at diagnosis to be 40 years, and the mean survival time to be 17 months [3]. Extra-neural metastases usually occur in the lungs and pleural cavity (60 %), in the regional lymph nodes (51 %), especially in the cervical group, in the skeleton (31 %), where vertebral bodies are mainly involved, and in the liver (22 %) [1–3]. The scalp, kidney, orbit, spleen, and heart can also be involved [1–3]. The pathogenesis of extraneural dissemination is not well elucidated, but a few hypotheses have been proposed [3]. For example, dissemination could occur after neurosurgery and shunting, or direct communication between malignant glioma cells and extra-meningeal vessels and lymphatic channels could occur [3]. Hematological and lymphogenous routes are probably involved [3]. Genetic mutations could favor the emergence of sub-clones that are able to metastasize outside the central nervous system [3]. We believe these data and corrections should be shared with the oncology community. P. Beauchesne (&) Hopital Central, CHU de Nancy, Nancy, France e-mail: beauchesneP@wanadoo.fr

Upfront Bevacizumab and Temozolomide or Fotemustine before Radiotherapy for Patients with Glioblastoma and Severe Neurological Impairment at Diagnosis.

Unresectable glioblastomas with severe neurological impairment at diagnosis have a poor prognosis. The conventional approach using a temozolomide-based chemoradiotherapy has limited efficiency on patients in the RTOG RPA V–VI classes. The activity of the antiangiogenic monoclonal antibody bevacizumab is well defined in recurrent glioblastoma, despite the fact that its impact on survival is not yet established. We wondered if neoadjuvant bevacizumab, used as upfront treatment in combination with a cytotoxic agent, was tolerable and active on neurological signs in patients with severe alteration of the neurological status due to the tumor being located in functional areas. Eight patients received intravenous bevacizumab, 10 mg/kg every 2 weeks, and either oral temozolomide (150–200 mg/m2/day for 5 days every 4 weeks) or intravenous fotemustine (80 mg/m2 every 2 weeks). After an average of 5 cycles of bevacizumab, a clinical improvement of neurological functions was recorded in 8/8 patients who could then receive radiotherapy at a conventional dose (60 Gy in 30 fractions) with continuation of bevacizumab and the cytotoxic agent. Four out of the 8 patients benefited from a durable stabilization and experienced an unusually long survival in such a bad situation at diagnosis. In conclusion, neoadjuvant bevacizumab with chemotherapy appears to be feasible and efficient in a category of patients from the RTOG RPA V–VI classes, by allowing the completion of full-dose radiotherapy. A clinical trial is planned to confirm these retrospective observations.

Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG)

Abstract Lessons Learned. Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status. Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study. Background. The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70. Materials and Methods. Patients aged ≥70 years with a KPS <70 and biopsy‐proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130–150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks. Results. The trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval [CI], 19–27.6), and the median progression‐free survival (PFS) was 15.3 weeks (95% CI, 12.9–19.3). Twenty‐two (33%) patients became transiently capable of self‐care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%). Conclusion. This study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level.

A concurrent ultra-fractionated radiation therapy and temozolomide treatment: A promising therapy for newly diagnosed, inoperable glioblastoma.

We report on a phase II clinical trial to determine the effect of a concurrent ultra‐fractionated radiotherapy and temozolomide treatment in inoperable glioblastoma patients. A phase II study opened; patients over 18 years of age who were able to give informed consent and had histologically proven, newly diagnosed inoperable diagnosed and supratentorial glioblastoma were eligible. Three doses of 0.75 Gy spaced apart by at least 4 hr were delivered daily, 5 days a week for six consecutive weeks for a total of 67.5 Gy. Chemotherapy was administered during the same period, which consisted of temozolomide given at a dose of 75 mg/m2 for 7 days a week. After a 4‐week break, chemotherapy was resumed for up to six cycles of adjuvant temozolomide treatment, given every 28 days, according to the standard 5‐day regimen. Tolerance and toxicity were the primary endpoints; survival and progression‐free survival were the secondary endpoints. In total, 40 patients were enrolled in this study, 29 men and 11 women. The median age was 58 years, and the median Karnofsky performance status was 80. The concomitant ultra‐fractionated radiotherapy and temozolomide treatment was well tolerated. Complete responses were seen in four patients, and partial responses were reported in seven patients. The median survival from the initial diagnosis was 16 months. Several long‐term survivors were noted. Concurrent ultra‐fractionated radiation therapy and temozolomide treatment are well accepted by the patients. The results showed encouraging survival rates for these unfavorable patients.