Adjuvant whole-brain radiation therapy after surgical resection of single brain metastases

Adjuvant whole-brain radiation therapy (WBRT) after resection of single brain metastases remains controversial. Despite a phase III trial to the contrary, clinicians often withhold WBRT after resection of single brain metastases based on the argument that available evidence does not inform regarding treatment of all patients, such as those with radioresistant tumors. However, there is limited information about whether subpopulations benefit equally from WBRT after resection. Therefore, we undertook a retrospective study to determine the clinical, radiographic, and histologic features that influenced the effectiveness of adjuvant WBRT. We reviewed 358 patients with newly diagnosed, single brain metastases, who underwent resection, of which 142 (40%) received adjuvant WBRT and 216 (60%) did not. Median follow-up was 60.1 months. There were multiple tumor histologies, including 197 (55%) "radiosensitive" and 161 (45%) "radioresistant" tumors. Compared with observation, WBRT significantly reduced recurrence both locally (HR = 0.58; 95% CI 0.35–0.98, P = .04) and at distant brain sites (HR = 0.43, 95% CI 0.30–0.61, P < .001). Multivariate analyses demonstrated that withholding WBRT was an independent predictor of local and distant recurrence. For local recurrence, tumors with a maximum diameter of ≥3 cm that did not receive adjuvant WBRT had an increased risk of recurring locally (HR = 3.14, 95% CI 1.02–9.69, P = .05). For distant recurrence, patients whose primary disease was progressing and who did not receive WBRT had an increased risk of distant recurrence (HR = 2.16, 95% CI 1.01–4.66, P = .05). There was no effect of WBRT based on tumor type. Adjuvant WBRT significantly reduces local and distant recurrences in subsets of patients, particularly those with metastases >3 cm or with active systemic disease.     

Stereotactic radiosurgery for multiple brain metastases

Stereotactic radiosurgery (SRS) alone has become one of the treatment options for patients with 1–4 metastases as the detrimental effects of whole brain radiation therapy on neurocognition and quality of life are becoming well known. Multiple randomized control trials also failed to show overall survival benefit of adding whole brain radiation therapy to SRS. However, the role of SRS in multiple brain metastases, especially those with ≥4 tumors, remains controversial. The literature is emerging, and the limited evidence suggests that the local control benefit is independent of the number of metastases, and that patients with more than four brain metastases have similar overall survival compared to those with 2–4 tumors. This review aims at summarizing the current evidence of SRS for multiple brain metastases, divided into limited (2–3) and multiple (≥4) lesions. It also reviews the technical aspects and cost–effectiveness of SRS.     

立体定向放疗与全脑放疗在多发脑转移瘤治疗中的作用分析

目的 总结立体定向放疗(SRT)加或不加全脑放疗(WBRT)治疗多发脑转移瘤的结果,探讨WBRT和SRT在多发脑转移瘤治疗中的作用。方法 1995—2010年收治的98例新诊断的多发(2~13个病灶)脑转移瘤患者。单纯SRT44例,WBRT加SRT54例。剂量分割模式依据转移瘤部位、体积及是否WBRT。用Kaplan-Meier法计算生存率,Cox回归模型进行各因素预后分析。中位生存期(MST)为从脑转移瘤放疗开始至各种原因所致死亡的时间的中位数。结果 全组患者中位随访时间12个月,随访率为100%。全组MST为13.5个月,其中SRT组、WBRT加SRT组的分别为13.0、13.5个月(χ²=0.31,P=0.578)。多因素分析显示仅卡氏评分(χ²=6.25,P=0.012)、原发灶诊断及脑转移瘤诊断间隔时间(χ²=7.34,P=0.025)和颅外病变情况(χ²=4.20,P=0.040)是预后因素。结论 SRT是多发脑转移瘤患者有效治疗手段,单纯SRT可取得与WBRT加SRT相似的生存期。首程SRT可能是多发脑转移瘤患者的另一治疗选择。     

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Efaproxiral (Efaproxyn, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O(2)) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction x 10 days), plus supplemental O(2) (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (> or =483 microg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.     

Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: an update

Brain metastases are unfortunately a common occurrence in patients with cancer. Whole-brain radiation therapy (WBRT) is still considered the standard of care in the treatment of brain metastases. Stereotactic radiosurgery (SRS) offers the additional ability to treat tumors with relative sparing of normal brain tissue in a single fraction. While the addition of SRS to WBRT has been shown to improve survival and local tumor control in selected patients, the idea of deferring WBRT in order to avoid its effects on normal tissues and using SRS alone continues to generate significant discussion and interest. Three recent randomized trials from Japan, Europe and the MD Anderson Cancer Center (TX, USA) have attempted to address this issue. In this article, we update a previous review by discussing these trials to compare the outcomes for SRS alone versus SRS plus WBRT for limited metastases. We also discuss recent nonrandomized evidence for the use of SRS alone for oligometastatic disease.     

脑转移瘤局部病灶加量容积旋转调强放疗海马体剂量学研究

目的 在脑转移瘤放射治疗中,对海马体的保护得到了越来越多的重视和研究.本研究探讨容积旋转调强放疗在脑转移瘤局部病灶加量对海马体保护的剂量学特点.方法 随机选取2013-12-01-2015-12-01在秦皇岛市第一医院放疗科治疗的15例脑转移患者,每例患者分别设计两种治疗计划,剂量体积约束条件相同,容积旋转调强放疗(volume-modulated arc therapy,VMAT)计划使用2个全弧,固定野调强放疗(fixed-field intensity modulated radiation theraPY,ff-IMRT)计划使用9个共面射野.在处方剂量要求相同情况下,比较两种计划的靶区和海马体的剂量学参数、机器跳数差异.结果 靶区剂量学参数中,VMAT计划的计划靶区体积(planning tumor volume,PTV)适形指数(0.82±0.07)好于ff-IMRT计划(0.78±0.08),t=2.457,P=0.028;对于海马体,左侧海马体最大值两计划差异无统计学意义,t=-1.175,P=0.260;VMAT计划的左侧海马体平均值为(1 186.43±1 358.29) cGy,右侧海马体最大值为(1 209.14±498.22) cGy,右侧海马体平均值为(738.16±422.70) cGy,双侧海马体最大值为(2 037.12±1 771.21) cGy,双侧海马体平均值为(940.68±765.00) cGy,低于ff-IMRT计划,差异有统计学意义,P＜0.05;对于正常组织(全身减计划靶体积,即B-P),VMAT计划的Vs(36.69±15.39)％,V15(18.61±9.87)％,V20(13.09±7.45)％小于ff-IMRT计划,差异有统计学意义,P＜0.05,其他正常组织指标无差异;VMAT计划的机器跳数(426±74)显著低于ff-IMRT计划(1 122±317),t=-8.446,P＜0.001.结论 VMAT在脑转移瘤局部病灶加量与ff-IMRT相比,明显的减少了海马体的受量和机器跳数,靶区适形度较好,并部分减少了周围正常组织的低剂量区受量,具有一定的剂量学优势.     

Whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases: a multicenter,open-label,randomized, controlled phase III trial

BackgroundErlotinib combined with whole-brain radiotherapy (WBRT) demonstrated a favorable objective response rate in a phase II single-arm trial of non–small cell lung cancer (NSCLC) patients with brain metastases. We assessed whether concurrent erlotinib with WBRT is safe and benefits patients in a phase III, randomized trial.MethodsNSCLC patients with two or more brain metastases were enrolled and randomly assigned (1:1) to WBRT (n = 115) or WBRT combined with erlotinib arms (n = 109). The primary endpoint was intracranial progression-free survival (iPFS) and cognitive function (CF) was assessed by the Mini-Mental State Examination (MMSE).ResultsA total of 224 patients from 10 centers across China were randomized to treatments. Median follow-up was 11.2 months. Median iPFS for WBRT concurrent erlotinib was 11.2 months vs 9.2 months for WBRT-alone (P = .601). Median PFS and overall survival (OS) of combination group were 5.3 vs 4.0 months (P = .825) and 12.9 vs 10.0 months (P = .545), respectively, compared with WBRT-alone. In EGFR-mutant patients, iPFS (14.6 vs 12.8 months; P = .164), PFS (8.8 vs 6.4 months; P = .702), and OS (17.5 vs 16.9 months; P = .221) were not significantly improved in combination group over WBRT-alone. Moreover, there were no significant differences in patients experiencing MMSE score change between the treatments.ConclusionConcurrent erlotinib with WBRT didn’t improve iPFS and excessive CF detriment either in the intent-to-treat (ITT) population or in EGFR-mutant patients compared with WBRT-alone, suggesting that while safe for patients already taking the drug, there is no justification for adding concurrent EGFR-TKI with WBRT for the treatment of brain metastases. Trial registration: Clinical trials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01887795","term_id":"NCT01887795"}}NCT01887795     

SRS、WBRT 及 WBRT ＋SRS 治疗1～4个脑转移瘤的 Meta 分析

目的：探讨立体定向放射外科（SRS）、全脑放疗（WBRT）及全脑放疗联合立体定向治疗1～4个脑转移瘤,并为进一步研究提供循证医学依据。方法：根据设定的纳入、排除标准,在 PubMed、Springer －link、Cancer list 数据库、中国生物医学文献数据库（CBM）、万方数据库、CNKI 知识网络服务平台及其他期刊进行相关随机对照试验检索。单变量计数资料的效应量用优势比（OR）和95％可信区间（95％CI）表示,用 Rev-man 5．2软件对数据进行异质性检验后采用固定效应模型或随机效应模型对数据进行分析。结果：共检索出1985－2014年间发表的126篇相关文献,最终得到8篇包含1213例脑转移瘤患者的随机对照试验符合所纳入的标准。SRS 与 WBRT ＋SRS 比较：WBRT ＋SRS 虽能提高脑转移瘤1年局部控制率及远处肿瘤控制率（OR ＝0．43,95％CI：0．29～0．63,P ＜0．0001;OR ＝0．42,95％CI：0．30～0．57,P ＜0．00001）;但不能提高1年生存率且不良反应及神经认知异常发生率高（OR ＝1．27,95％CI：0．93～1．73,P ＝0．14;OR ＝0．50,95％CI：0．28～0．89,P ＝0．02;OR ＝0．41,95％CI：0．21～0．78,P ＝0．006）。SRS 与 WBRT 比较：SRS 治疗脑转移瘤可明显提高患者1年生存率及1年局部肿瘤控制率,但远处肿瘤控制率与WBRT相当（OR＝2．78,95％CI：1．57～4．92,P ＝0．0004;OR ＝4．8,95％CI：2．69～8．57,P ＜0．00001;OR ＝0．52,95％CI：0．15～1．83,P ＝0．31）。WBRT ＋SRS 与单独 WRBT 比较：1年局部肿瘤控制率及1年生存率无明显差别（OR ＝1．23,95％CI：0．81～1．86,P ＝0．32;OR ＝1．21,95％CI：0．76～1．93,P ＝0．42）。结论：1～4个脑转移瘤患者,单独 SRS 是理想治疗方法。     

Distribution of metastatic disease in the brain in relation to the hippocampus: a retrospective single-center analysis of 6064 metastases in 632 patients

This study aimed to investigate the patterns of brain metastasis and to explore the risk factors affecting hippocampus metastasis (HM). We retrospectively analyzed the clinical information of patients with metastatic disease in the brain. The associations between clinicopathologic variables with HM and peri-hippocampal metastasis (PHM) were evaluated in univariate and multivariate regression analyses. A total of 632 patients with 6064 metastatic lesions were recruited into the present study. Of these, 4.1% (26/632) of patients developed HM, and 5.5% (35/632) of patients developed PHM. Only 0.5% (31/6064) of metastatic lesions were located in the hippocampus and 0.6% (37/6064) were in the PHM. Age ≤60 years was an independent risk factor for HM (odds ratio [OR]: 2.602, 95% confidence interval [CI]: 1.115–6.076, P = 0.027) and PHM (OR: 2.555, 95%CI: 1.229–5.310, P = 0.012) in univariate and multivariate analyses. The hippocampus is a rare site of brain metastasis. Younger patients (age ≤60 years) had increased risk of developing HM and PHM. The current study provides the opportunity to investigate the clinical feasibility of hippocampal sparing whole brain radiation therapy, especially in older patients.     

Comparative efficacy of whole-brain radiotherapy with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma

PurposeWe explored and compared the clinical effects of whole-brain radiotherapy (wbrt) with and without elemene liposomes in patients with multiple brain metastases from non-small-cell lung carcinoma (nsclc).MethodsWe retrospectively analyzed 62 patients with multiple brain metastases from nsclc who received wbrt (30 Gy in 10 fractions) at Shengjing Hospital of China Medical University from January 2012 to May 2013. In 30 patients, elemene liposomes (400 mg) were injected intravenously via a peripherally inserted central catheter for 21 consecutive days from the first day of radiotherapy. Overall survival (os) and nervous system progression-free survival (npfs) for the two groups were compared by Kaplan–Meier analysis. Factors influencing npfs were examined by Cox regression analysis. Chi-square or Fisher exact tests were used for group comparisons.ResultsThe median os was 9.0 months in the wbrt plus elemene group and 7.8 months in the wbrt-alone group (p = 0.581); the equivalent median npfs durations were 5.2 months and 3.7 months (p = 0.005). Patient treatment plan was an independent factor associated with npfs (p = 0.002). Tumour response and disease-control rates in the wbrt plus elemene group were 26.67% and 76.67% respectively; they were 18.75% and 62.5% in the wbrt group (p = 0.452). Compared with the patients in the wbrt-alone group, significantly fewer patients in the wbrt plus elemene group developed headaches (p = 0.04); quality of life was also significantly higher in the wbrt plus elemene group both at 1 month and at 2 months (p = 0.021 and p = 0.001 respectively).ConclusionsThe addition of elemene liposomes to wbrt might prolong npfs in patients with multiple brain metastases from nsclc, while also reducing the incidence of headache and improving patient quality of life.     

Pulsed radiation therapy for the treatment of newly diagnosed glioblastoma

BackgroundPulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM).MethodsThis is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation.ResultsTwenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)–mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID.ConclusionsTreatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration.     

Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from metastatic melanoma: a phase II Cytokine Working Group study

BACKGROUND.

The combination of temozolomide (TMZ) and thalidomide was reported to produce a high response rate, including shrinkage of brain metastases, in patients with metastatic melanoma. The authors tested the efficacy of a regimen including TMZ, thalidomide, and whole brain radiation therapy (WBRT) in patients with brain (CNS) metastases from melanoma.

METHODS.

Patients with melanoma, CNS metastases documented by magnetic resonance imaging, and no prior systemic chemotherapy received WBRT, 30 Gray in 10 fractions, Days 1 to 5 and 8 to 12; TMZ, 75 mg/m²/day, Weeks 1 to 6; and thalidomide, 100 mg/day, Weeks 1 to 4, then escalated by 100 mg/day at Weeks 5, 7, and 9 as tolerated to a maximum of 400 mg/day. CNS and systemic tumor response was assessed at Week 10. Patients without CNS or clinically significant systemic disease progression received additional cycles of TMZ at 10‐week intervals.

RESULTS.

Thirty‐nine patients received treatment, and 3 exhibited CNS response (1 complete response, 2 partial responses) (response rate, 7.6%; 95% confidence interval, 0.7%‐16.1%), all unconfirmed by repeat imaging. Seven patients had stable CNS disease at 10 weeks. No patient exhibited a systemic response. Only 4 patients received 2 cycles of therapy, and just 1 received 3. Median time to progression was 7 weeks, and median overall survival was 4 months. Grade 3‐4 side effects included deep venous thrombosis (3), pulmonary embolism (1), and CNS events (12). Eighteen (45%) patients required admission for side effects (7) and/or symptomatic disease progression (11).

CONCLUSIONS.

The efficacy of TMZ, thalidomide, and WBRT in the treatment of CNS metastatic melanoma is low. Other treatment approaches should be considered for this patient population. Cancer 2008. © 2008 American Cancer Society.     

脑转移瘤伽玛刀配合全脑放疗的临床研究

目的探讨脑转移瘤伽玛刀治疗配合全脑放疗的疗效。方法自2002年3月至2006年3月收治脑转移瘤患者79例。原发灶控制稳定,脑转移患者中,44例采用伽玛刀配合全脑放疗,35例单纯给予伽玛刀治疗。伽玛刀治疗处方等剂量线采用45%～75%等剂量包绕计划靶区,边缘剂量15～20 Gy,中心30～45 Gy;全脑放疗每次分割剂量为2～3 Gy,1次/d,每周照射5次,总剂量25～30 Gy。结果伽玛刀治疗开始后3个月,复查MRI,影像学结果显示总的有效率为83.5%（66/79）。伽玛刀配合全脑放疗组的1年生存率为29.5%,2年生存率9.1%;单纯伽玛刀组患者的1年生存率为17.1%,2年生存率2.9%。随访期内未见严重放射性并发症。结论对脑转移瘤采用伽玛刀配合全脑放疗是较有效的局部治疗方式,副反应轻,均能耐受治疗。