Hypofractionated intensity modulated radiotherapy with temozolomide in newly diagnosed glioblastoma multiforme

We conducted a phase I study to determine (a) the maximum tolerated dose of peri-radiation therapy temozolomide (TMZ) and (b) the safety of a selected hypofractionated intensity modulated radiation therapy (HIMRT) regimen in glioblastoma multiforme (GBM) patients. Patients with histological diagnosis of GBM, Karnofsky performance status (KPS) ⩾ 60 and adequate bone marrow function were eligible for the study. All patients received peri-radiation TMZ; 1 week before the beginning of radiation therapy (RT), 1 week after RT and for 3 weeks during RT. Standard 75 mg/m²/day dose was administered to all patients 1 week post-RT. Dose escalation was commenced at level I: 50 mg/m²/day, level II: 65 mg/m²/day and level III: 75 mg/m²/day for 4 weeks. HIMRT was delivered at 52.5 Gy in 15 fractions to the contrast enhancing lesion (or surgical cavity) plus the surrounding edema plus a 2 cm margin. Six men and three women with a median age of 67 years (range, 44–81) and a median KPS of 80 (range, 80–90) were enrolled. Three patients were accrued at each TMZ dose level. Median follow-up was 10 months (range, 1–15). Median progression free survival was 3.9 months (95% confidence interval [CI]: 0.9–7.4; range, 0.9–9.9 months) and the overall survival 12.7 months (95% CI: 2.5–17.6; range, 2.5–20.7 months). Time spent in a KPS ⩾70 was 8.1 months (95% CI: 2.4–15.6; range, 2.4–16 months). No instance of irreversible grade 3 or higher acute toxicity was noted. HIMRT at 52.5 Gy in 15 fractions with peri-RT TMZ at a maximum tolerated dose of 75 mg/m²/day for 5 weeks is well tolerated and is able to abate treatment time for these patients.     

Evaluation of <i>MGMT</i> Gene Methylation in Neuroendocrine Neoplasms

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.     

替莫唑胺胶囊治疗恶性脑胶质瘤30例疗效分析

目的评价替莫唑胺胶囊（TMZ）治疗人脑恶性胶质瘤的临床疗效及不良反应。方法2005年1月至2008年1月对一个单位30例术后确诊的恶性脑胶质瘤且使用TMZ化疗的患者进行随访,观察近期治疗反应、生存期,并分析常规病理和分子病理对治疗效果的影响。结果TMZ治疗结束时,30例患者客观有效率和疾病控制率分别为53．3％和80．0％,O^6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）对近期疗效无明显影响（P〉0．05）,而不同病理类型的近期疗效存在明显差异（P〈0．05）。随访期间共有12例患者死亡,生存期为0．7～3．7年,中位生存期为1．5年。MGMT阳性和阴性患者的中位生存期分别为1．3年和1．5年,无明显差异（P：0．31）。胶质母细胞瘤和间变型星形细胞瘤的中位生存期分别为1．3年和2．0年,亦无明显差异（P=0．28）。不良反应包括厌食、便秘等消化道症状11例（36．7％）,白细胞减少3例（10．0％）,假性进展2例（6．7％）。结论TMZ对恶性胶质瘤患者有较好的临床疗效,不良反应少,耐受性好,治疗方案简便,是一种理想的恶性胶质瘤术后辅助化疗药物。     

联合靶向治疗复发恶性脑胶质瘤的研究

目的 比较单独采用贝伐珠单抗治疗和贝伐珠单抗联合替莫唑胺剂量密集疗法治疗复发恶性脑胶质瘤的疗效. 方法 回顾性分析首都医科大学附属北京天坛医院神经外科自2008年6月到2012年6月收治的38例复发恶性脑胶质瘤患者资料,26例采用贝伐珠单抗单药治疗(单药组),12例采用替莫唑胺剂量密集疗法联合贝伐珠单抗化疗(联合治疗组),观察其无进展生存期及不良反应. 结果 单药组中位无进展生存时间为21.8周,6个月无进展生存率为37.8％;联合治疗组中位无进展生存时间为34.7周,6个月无进展生存率为52.7％,差异具有统计学意义(x2=8.161,辟0.023). 结论 贝伐珠单抗能提高复发恶性脑胶质瘤患者的无进展生存时间,联合治疗在延长复发恶性胶质瘤患者的无进展生存期方面优于单药组,可推荐为复发恶性脑胶质瘤的治疗方式.     

Primary central nervous system lymphoma treated with rituximab plus temozolomide in a second line schedule

We report a case of primary CNS lymphoma treated with high-dose methotrexate in the first line. After disease progression the patient received cranial radiotherapy with concomitant temozolomide, followed by rituximab plus temozolomide, with complete remission of the disease maintained for at least two years and without major toxicity.     

Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer.     

A phase II study of temozolomide in hormone-refractory prostate cancer

Introduction: Hormone-refractory disseminated prostate cancer is a major oncological problem. Preclinical studies with temozolomide, an oral alkylating agent, in prostate cancer have shown encouraging results. In phase I studies the safety of temozolomide in non-prostate cancer patients has been demonstrated. Based on these results, a phase II study of temozolomide in patients with metastatic disease who had developed progressive symptomatic disease while on antiandrogen therapy, was initiated. Methods: A group of 18 patients started a 5-day temozolomide regimen, with a 28-day treatment cycle. Response parameters (prostate-specific antigen, bone scan, quality of life questionnaire) and toxicity (common toxicity criteria for international studies) were recorded at regular intervals. Results: Of the 18 patients, 16 were evaluable by completing two or three cycles. All patients developed progressive disease within two cycles, except one who had progressive disease at the end of cycle 3. Of the 16 evaluable patients, 11 developed new bone metastases (bone scan), 1 developed lung metastases, 4 had progressive disease as reflected by a 25% increase in serum PSA together with subjective progression, and 7 and 5 had progressive disease as reflected by decreased quality of life and increased pain score, respectively. Toxicity was limited to nausea and vomiting, which was effectively treated with antiemetic medication, and anemia and thrombocytopenia, which returned to normal values within 1 week. Discussion: Treatment with temozolomide was generally well tolerated, with occasionally moderate toxicity. As all patients developed progressive disease the results are rather discouraging. Temozolomide is ineffective for the treatment of patients with symptomatic progressive hormone-refractory prostate cancer. Received: 25 October 1999 / Accepted: 11 January 2000     

Response to temozolomide in second-line treatment of recurrent nonsmall cell lung carcinoma: case report

Almost all patients with stage IV nonsmall cell lung cancer (NSCLC) who show an initial response to chemotherapy will eventually relapse. For patients with a good performance status at relapse, second-line chemotherapy is a standard treatment option. A case of recurrent NSCLC described herein profiles a patient previously treated with cisplatin, irinotecan, and radical thoracic radiation for stage IIIb NSCLC. The patient showed a complete response to first-line therapy that lasted for approximately 17 months. When new adenopathy was discovered, therapy with the oral chemotherapeutic agent temozolomide was initiated. After 2 treatment cycles,a near complete response was obtained and she remained free from disease progression during all subsequent treatment cycles with temozolomide. The patient remained free from disease progression for a total of 15 months when she was treated for dehydration and a computed tomography (CT) scan showed new small bilateral pleural effusions and enlarging subcarinal, right hilar, and left infrahilar lymph nodes. The patient died 21 months after her first treatment cycle with temozolomide, most likely because of progressive disease.     

Unusual and severe symptomatic impairment of neutrophil function after one cycle of temozolomide in patients with malignant glioma

Temozolomide, a recently approved cytotoxic agent for the treatment of malignant glioma, has shown promising results in the treatment studies published so far. However, cytopenia and related infectious complications have been reported in 2–8% of cases. Here we present three treatment-naive patients with malignant glioma experiencing cytopenia and/or infectious complications after the first cycle of temozolomide. Neutrophils obtained from each patient up to 6 weeks after the end of the temozolomide application showed normal phagocytic capacity but decreased oxygen radical production and thus impairment of microcidal activity. Our data suggest that a prolonged impairment of the immunological defense may occur in temozolomide-treated patients.