Danica Grujicic

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial

BACKGROUND Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING Merck KGaA, Darmstadt, Germany.

Influence of extent of surgery and tumor location on treatment outcome of patients with glioblastoma multiforme treated with combined modality approach

SummaryBetween 1988 and 1991, eighty-six patients with glioblastoma multiforme were evaluated in order to define the influence of extent of surgery and tumor location on treatment outcome. Patients underwent surgery followed by postoperative hyperfractionated radiotherapy and chemotherapy delivered according to one of two consecutive protocols. Surgery consisted of biopsy in 25 (29%) patients and subtotal or gross total tumor resection in 61 (71%) patients. Frontally located tumors were noted in 26 (30%) patients and other tumor locations were noted in 60 (70%) patients. Patients having more radical surgery had longer median survival time (MST) and higher 1- and 2-year survival rates than those with biopsy only (56 vs 29 weeks, respectively; 62 % and 23 % vs 16% and 0%, respectively; p=0.00000). Patients having frontally located tumors had longer MST and higher 1- and 2-year survival rates than those with other tumor locations (101 vs 47 weeks, respectively; 76% and 44% vs 37% and 2.5%, respectively; p=0.00001). Multivariate analysis confirmed that extent of surgery and tumor location were independent prognostic factors in patients with glioblastoma multiforme. Regarding progression-free survival, patients having more radical surgery had longer median time to tumor progression (MTP) than those with biopsy only (33 weeks vs 21 weeks, respectively). Also, progression-free survival at 1 year was higher in radically resected group than in biopsy only group (20% vs 0%, respectively; p=0.00000). Patients with frontally located tumors had longer MTP (42 weeks) and higher progression-free survival at 1 year (42%) than those with other tumor location (28 weeks and 1.7%, respectively; p=0.00002). Multivariate analysis confirmed that the extent of surgery and tumor location are independent prognosticators in patients with glioblastoma multiforme treated with combined modality approach using progression-free survival as an endpoint.

Carboplatin and etoposide chemotherapy regimen for recurrent malignant glioma: a phase II study.

PURPOSE A phase II study that used combination chemotherapy with carboplatin (CBDCA) and etoposide (VP 16) (CE) was performed on patients with recurrent malignant glioma to investigate tumor control and toxicity. PATIENTS AND METHODS Thirty-eight patients were treated with CBDCA 300 mg/m2 on days 1 to 3 and VP 16 100 mg/m2 on days 1 to 5. A minimum of three courses were required unless the patient had a rapid progression of disease (PD). Courses were repeated every 4 weeks. RESULTS We observed partial responses (PRs) in eight of 38 patients (21%), stable disease (SD) in 12 of 38 (32%), whereas 18 of 38 (47%) patients had PD. The median time to tumor progression (TTP) for PR and SD patients was 42.5 weeks, whereas the median survival time (MST) for PR and SD patients was 47.5 weeks. Three groups of toxicities were observed: hematologic, gastrointestinal, and hepatic. No grade 4 Eastern Cooperative Oncology Group toxicity was observed. CONCLUSIONS This regimen has shown at least comparable results with other series that used platinum-based agents. Further studies that use these agents in various-dose schedules and drug combinations are warranted.

Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study

BACKGROUND Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Transfer of the medial pectoral nerve: myth or reality?

OBJECTIVE Transfer of the medial pectoral nerve is one of the most controversial procedures used to reinnervate the paralyzed upper arm because of brachial plexus spinal nerve root avulsion or directly irreparable proximal lesions of spinal nerves. The purpose of this study was to determine the value of this type of nerve transfer to the musculocutaneous and axillary nerves. METHODS The 25 patients included in the study comprised 14 patients who had nerve transfer to the musculocutaneous nerve and 11 who underwent nerve transfer to the axillary nerve. These patients’ functional recovery and the time course of their recovery were analyzed according to the type of transfer of one donor nerve or the donor nerve in combination with other donors. RESULTS Useful functional recovery was achieved in 85.7% of patients who had nerve transfer to the musculocutaneous nerve and in 81.8% of patients who underwent nerve transfer to the axillary nerve. There was no significant difference in results with regard to the type of nerve transfer and which recipient nerves were involved. A strong trend toward better results after procedures involving the use of a donor nerve combined with other donors was observed, however. CONCLUSION Our surgical results suggest that the transfer of the medial pectoral nerve to the musculocutaneous nerve and also to the axillary nerve may be a reliable and effective procedure.

Clinical prognostic factors in patients with malignant glioma treated with combined modality approach.

The impact of various clinical pretreatment prognostic factors in patients with malignant glioma treated with a combined modality approach was investigated in 229 patients treated on four consecutive prospective phase II studies. The median survival time for all 229 patients is 14 months, and 2- and 5-year survival rates are 34%, and 9%, respectively. The median time to tumor progression is 14 months, and 2- and 5-year progression-free survival rates are 32%, and 9%, respectively. Females did better than males, while patients 55 years or less did better than those more than 55 years. Patients with Karnofsky performance status (KPS) 80 to 100 did better than those with KPS 50 to 70 as well as did patients having preoperative tumor sizes 4 cm or less when compared to those with larger tumors. Frontal tumor location as well as more extensive surgery favorably influenced survival. Patients harboring anaplastic astrocytoma fared significantly better than those with glioblastoma multiforme. Both univariate and multivariate Cox analyses confirmed independent influence of these prognosticators. When progression-free survival was used as an endpoint, all seven variables remained independent prognosticators. This study showed that sex, age, KPS, tumor size, tumor location, histology, and extent of surgery are independent prognosticators in patients with malignant glioma treated with combined modality approach.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma and methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Key results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study.

LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). METHODS This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. RESULTS 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. CONCLUSIONS CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. CLINICAL TRIAL INFORMATION NCT00689221.

Combined treatment modality for anaplastic oligodendroglioma: a phase II study.

Purpose: To investigate feasibility, toxicity and antitumor activity of combined surgery, postoperative radiation therapy (RT) and adjuvant chemotherapy (CHT) in adult patients with pure anaplastic oligodendroglioma (PAO) or mixed anaplastic oligoastrocytoma (MAO).Methods: Between January 1988, and June 1993, 23 patients entered into a phase II study. After surgery, post-operative RT was administered with 60 Gy in 30 daily fractions in 30 treatment days in 6 weeks. Two weeks after RT, adjuvant ‘modified’ PCV (mPCV) (Procarbazine, 60 mg/m2, days 1–14; CCNU, 100 mg/m2, day 1; and vincristine, 1.4 mg/m2 (max. 2 mg), days 1 and 8) was administered every six weeks up to six cycles or until progression occurred.Results: Median survival time is not attained yet, while 1–5 year survival rates are 100%, 100%, 78%, 61%, and 52%, respectively. Median time to tumor progression is not attained yet, while 1–5 year progression-free survival rates are 100%, 100%, 70%, 52%, and 52%, respectively. On univariate analysis of potential prognostic factors, sex, tumor location (frontal versus other), and histology (pure versus mixed anaplastic oligodendroglioma) were not found to influence survival. Age of <50 years carried improved prognosis as well as Karnofsky performance status (KPS) 90–100 when compared to KPS of 70–80. Patients having tumors ≤4 cm did better than those with tumors >4 cm as well as those with total tumor resection when compared to those with subtotal tumor resection or biopsy only. Acute high-grade (≥3) CHT-related toxicity was mainly hematological with only 3 (13%) patients experiencing acute grade 4 toxicity.Conclusions: Combined treatment modality consisting of surgery, postoperative high-dose RT and mPCV chemotherapy for patients with anaplastic oligodendroglioma was effective with acceptable toxicity. Further studies are needed with more patients and longer follow-up to verify these results in this rare disease.

Hyperfractionated radiation therapy (hfx rt) followed by multiagent chemotherapy (CHT) in patients with malignant glioma: A phase II study☆

PURPOSE Forty-eight patients with malignant glioma were treated with hyperfractionated radiation therapy followed by multiagent chemotherapy to explore feasibility and toxicity of such combined modality treatment. METHODS AND MATERIALS There were 34 males and 14 females with a median age of 53 years (range, 32-74 years) and median Eastern Cooperative Oncology Group performance status score of 1 (range, 0-3). Histology included anaplastic astrocytoma in 11 patients and glioblastoma multiforme in 37 patients. Radiation was given at 1.2 Gy per fraction, two fractions per day, for a total dose of 72 Gy, with a reduction in field size after 52.8 Gy. Four weeks after completion of hyperfractionated radiation therapy multiagent chemotherapy was introduced with bischlorethyl nitrosourea (BCNU) 50 mg/m2, days 1-3, vincristine 1.4 mg/m2 (max. 2 mg), day 1, procarbazine 50 mg/m2, days 1-7 and cisplatin 20 mg/m2, days 1-3. Cycles were repeated every 4 weeks to a maximum of six cycles or until tumor progression was noted. RESULTS Median survival time for all patients was 52 weeks (range, 16-185 weeks) and median time to tumor progression was 30.5 weeks (range, 12-131 weeks). Besides age, histology, performance status, and extent of surgery, interfraction interval and location of tumor influenced survival in glioblastoma multiforms patients on univariate analysis: Patients treated with shorter intervals (4.5-5 h) did better than those treated with longer intervals (5.5-6 h); also, glioblastoma multiforme patients with frontal tumors did better than those with tumors of the other locations. Multivariate analysis confirmed that the performance status, interfraction interval, and tumor location were significant prognostic factors in glioblastoma multiforme patients. Acute toxicity was mild. No cases of brain necroses were observed. CONCLUSION Hyperfractionated radiation therapy followed by multiagent chemotherapy was well tolerated with mild acute and virtually no late toxicity. More patients and longer follow-up are needed for further evaluation of its activity and late effects in anaplastic astrocytoma patients.

Concurrent Accelerated Hyperfractionated Radiation Therapy and Carboplatin/etoposide in Patients With Malignant Glioma: Long-term break Results of A Phase II Study

AbstractPurpose: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. Material and methods: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60 Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200 mg/m2, and VP 16, 200 mg/m2, both given once weekly during the RT course. Results: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2-  and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2-  and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. Conclusions: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.