放射治疗合并替莫唑胺治疗多形性胶质母细胞瘤的研究

多形性胶质母细胞瘤（glioblastoma multiforme，GBM）是成人脑肿瘤中最常见的一种，恶性度极高。患者手术后容易复发，其中位生存期小于1年，大多数患者在确诊后2年内死亡。目前标准的治疗方法是手术加术后放疗，加或不加辅助化疗。最近的Ⅲ期临床研究结果显示，替莫唑胺与同期放疗加上辅助化疗的疗效要明显优于单纯放疗。中位生存期由单纯放疗组的12．1个月提高到了14．6个月；2年生存率也由单纯放疗的8％提高到26％。从而肯定了替莫唑胺对于新诊断的GBM患者的疗效。     

Combined Thalidomide and Temozolomide Treatment in Patients with Glioblastoma Multiforme

OBJECTIVES: Glioblastoma multiforme (GBM) may potentially be responsive to antiangiogenic therapies as these tumors are highly vascularized and overexpress angiogenic factors. Thalidomide exhibits antiangiogenic activity and may provide additive or synergistic antitumor effects when given concurrently with temozolomide, an alkylating agent. To further evaluate this new concept of combining an antiangiogenic with an alkylating agent, efficacy and tolerability of thalidomide alone and in combination with temozolomide were explored in a single-institution, nonrandomized open-label phase II study. PATIENTS AND METHODS: Forty-four patients with GBMs, who received thalidomide for a period of at least three months, were evaluated for survival, time to tumor progression (TTP), and side effects. Microsurgical tumor extirpation and radiotherapy preceded chemotherapy. Nineteen patients (43%) received thalidomide only (T), and 25 patients (57%) had a combined chemotherapy of thalidomide and temozolomide (TT). Median thalidomide dosage was 200 mg/day. Median temozolomide dosage was 200 mg/m2/day for five days, in monthly cycles. Neuroradiological outcomes were assessed by a semiquantitative grading system. RESULTS: Median survival was 103 weeks (95% CI, 65-141 weeks) for TT-patients and 63 weeks (95% CI, 49-77 weeks) for T-patients (p < 0.01). Median TTP for the TT-group was 36 weeks (95% CI, 20-52 weeks) and 17 weeks (95% CI, 13-21 weeks) for the T-group (p < 0.06). Neuroradiologically, 14 patients (56%) of the TT-group and six (32%) of the T-group had evidence of stable disease on at least two successive neuroradiological follow-ups. Progressive disease was found in nine patients (36%) of the TT-group and in 13 (68%) of the T-group. In two patients (8%) of the TT-group, a response with tumor regression was found. Thalidomide and concurrent temozolomide were safe and well tolerated with mild to moderate toxicities. CONCLUSIONS: The combination of thalidomide and temozolomide in the treatment of GBM appears to be more effective than that of thalidomide alone with respect to survival, TTP, and neuroradiological documentation of progression, stable disease or response. Further concurrent prospective studies of these agents in a larger group of patients with GBM will be required to establish the soundness of these intriguing observations.     

Bevacizumab in Combination With Radiotherapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme

Background.

Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM.

Methods.

After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m² and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150–200 mg/m² on days 1–5.

Results.

The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3–4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3–14.4 months). The median overall survival was 16 months (95% CI: 8.1–26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution.

Conclusion.

Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.     

复发难治多形性胶质母细胞瘤的综合治疗

恶性脑胶质瘤是成人最常见的原发脑肿瘤,治疗困难,预后差。以手术治疗为主,放疗、化疗联合应用的综合治疗策略对生存的改善有一定帮助,但即使初次治疗有效者大多最终又复发。我们报道一例复发难治多形性胶质母细胞瘤（glioblastoma multiforme,GBM）,患者经5次手术、放疗,以及包括替莫唑胺、伊立替康、替尼泊苷、顺铂、尼妥珠单抗、血管内皮抑素、干扰素β等在内的细胞毒药物及分子靶向药物等综合治疗,该患者随访至今,生存时间已超过33个月。本文结合此病例的治疗过程,对恶性胶质瘤的规范化治疗、复发恶性胶质瘤的挽救治疗以及恶性胶质瘤治疗新方法的探索进行讨论,并分析存在的不足和可以参考的经验。     

A Review of Modern Radiation Therapy Dose Escalation in Locally Advanced Head and Neck Cancer

The management of head and neck cancer is complex and often involves multimodality treatment. Certain groups of patients, such as those with inoperable or advanced disease, are at higher risk of treatment failure and may therefore benefit from radiation therapy dose escalation. This can be difficult to achieve without increasing toxicity. However, the combination of modern treatment techniques and increased research into the use of functional imaging modalities that assist with target delineation allows researchers to push this boundary further. This review aims to summarise modern dose escalation trials to identify the impact on disease outcomes and explore the growing role of functional imaging modalities. Studies experimenting with dose escalation above standard fractionated regimens as outlined in National Comprehensive Cancer Network guidelines using photon therapy were chosen for review. Seventeen papers were considered suitable for inclusion in the review. Eight studies investigated nasopharyngeal cancer, with the remainder treating a range of subsites. Six studies utilised functional imaging modalities for target delineation. Doses as high as 85.9 Gy in 2.6 Gy fractions (EQD2 90.2 Gy₁₀) were reportedly delivered with the aid of functional imaging modalities. Dose escalation in nasopharyngeal cancer resulted in 3-year locoregional control rates of 86.6–100% and overall survival of 82–95.2%. For other mucosal primary tumour sites, 3-year locoregional control reached 68.2–85.9% and 48.4–54% for overall survival. There were no clear trends in acute or late toxicity across studies, regardless of dose or addition of chemotherapy. However, small cohort sizes and short follow-up times may have resulted in under-reporting. This review highlights the future possibilities of radiation therapy dose escalation in head and neck cancer and the potential for improved target delineation with careful patient selection and the assistance of functional imaging modalities.     

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Clinical Studies in Sweden

A boron neutron capture therapy (BNCT) facility has been constructed at Studsvik, Sweden. It includes two filter/moderator configurations. One of the resulting neutron beams has been optimized for clinical irradiations with a filter/moderator system that allows easy variation of the neutron spectrum from the thermal to the epithermal energy range. The other beam has been designed to produce a large uniform field of thermal neutrons for radiobiological research. Scientific operations of the Studsvik BNCT project are overseen by the Scientific Advisory Board comprised of representatives of major universities in Sweden. Furthermore, special task groups for clinical and preclinical studies have been formed to facilitate collaboration with academia. The clinical Phase II trials for glioblastoma are sponsored by the Swedish National Neuro-Oncology Group and, presently, involve a protocol for BNCT treatment of glioblastoma patients who have not received any therapy other than surgery. In this protocol, p-boronophenylalanine (BPA), administered as a 6-h intravenous infusion, is used as the boron delivery agent. As of January 2002, 17 patients were treated. The 6-h infusion of 900mg BPA/kg body weight was shown to be safe and resulted in the average blood–boron concentration of 24g/g (range: 15–32g/g) at the time of irradiation (approximately 2–3h post-infusion). Peak and average weighted radiation doses to the brain were in the ranges of 8.0–15.5Gy(W) and 3.3–6.1Gy(W), respectively. So far, no severe BNCT-related acute toxicities have been observed. Due to the short follow-up time, it is too early to evaluate the efficacy of these studies.     

替莫唑胺联合放疗治疗胶质瘤患者的生存情况分析

目的 探讨分析替莫唑胺联合放疗治疗对胶质瘤患者生存情况的影响.方法 选取64例胶质瘤患者为研究对象,采用数字表法将其平均分成两组,对照组患者在术后行放疗,观察组患者在放疗基础上联合应替莫唑胺化疗,比较两组患者治疗后的生存情况及不良反应情况.结果 观察组临床疾病控制率(50.00％)明显高于对照组(25.00％),有统计学意义(P＜0.05);观察组患者无进展生存时间为(11.24±3.09)个月和生存时间为(15.64±3.87)个月,较对照组患者的无进展生存时间[(6.09±1.97)个月]和生存时间[(8.71±2.56)个月]明显要长,有统计学意义(P＜0.05);观察组患者白细胞下降、头皮溃疡、恶心呕吐、腹泻、血小板计数下降等不良反应发生率均低于对照组,均可自行缓解或对症用药后可控制.结论 胶质瘤患者术后采用替莫唑胺联合放疗治疗,与单纯的放疗相比较,能够有效控制肿瘤生长情况,延长患者无进展生存时间和总生存时间,治疗期间不良反应少,安全有效.