局限期小细胞肺癌脑预防照射研究进展

随着放化疗等综合治疗手段的应用,局限期小细胞肺癌的局控率和生存率均有了提高,然而脑转移成为影响有长期生存可能患者生存质量的重要因素。本文综述脑预防照射在局限期小细胞肺癌患者中应用的可行性、结果及可能引起的放疗后期毒性,及脑预防照射的开始时间、分割方式、放疗剂量等方面。     

Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer

IntroductionData on prophylactic cranial irradiation (PCI) after complete resection of SCLC are limited. The purpose of this study was to investigate the impact of PCI in this population.MethodsWe retrospectively identified completely resected SCLC at the Shanghai Chest Hospital between January 2006 and January 2014.ResultsA total of 349 patients (115 patients who received PCI [the PCI-treated cohort] and 234 patients who did not [the non–PCI-treated cohort]) were included in the study. The results demonstrated that the PCI-treated cohort had longer overall survival than the non–PCI-treated cohort among patients with pathologic stage (p-stage) II (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.30–0.99, p = 0.047) and p-stage III (HR = 0.54, 95% CI: 0.34–0.86, p = 0.009) disease. Among patients with p-stage III disease, there was a significantly higher risk for cerebral recurrence from the time of diagnosis in the non–PCI-treated cohort (p = 0.018). With regard to patients with p-stage I disease, neither overall survival benefit (HR = 1.61, 95% CI: 0.68–3.83, p = 0.282) nor risk for cerebral recurrence (p = 0.389) was significant between the PCI-treated and non–PCI-treated cohorts.ConclusionsThe data presented in the current study support using PCI in patients with p-stage II/III disease but not in patients with p-stage I disease. A relatively lower risk for brain metastases in p-stage I patients might explain the inferior efficacy of PCI in this population.     

Failure of a Short Course of Prophylactic Cranial Irradiation to Reduce the Incidence of Cerebral Relapse in Small Cell Lung Cancer

During 1981–1984, 17 patients achieving complete remission after chemotherapy for small cell lung cancer were treated with prophylactic cranial irradiation (PCI) 20 Gy in five fractions over five days. Seven patients (41%) developed CT-documented cerebral relapse within 14 to 43 weeks (median 38 weeks) from PCI. Since this result is similar to the rates of cerebral relapse reported for patients not receiving PCI, we conclude that this dose schedule is ineffective for cranial prophylaxis.     

小细胞肺癌术后化疗或放化疗后预防性脑照射的临床观察

目的:探讨小细胞肺癌术后化疗或放化疗后预防性脑照射(PCI)能否降低脑转移率,提高生存率。方法:1990年6月～1995年7月我院治疗小细胞肺癌术后化疗或放化疗后预防性脑照射30例(PCI组),男22例,女8例。临床分期分别为Ⅰ、Ⅱ和Ⅲa期各9、15和6例,化疗方案为CAE方案(C:环磷酰胺,A:阿霉素,E:依托铂甙)或EP方案(E:依托铂甙,P:顺铂),预防性脑照射剂量为30Gy/15次,1.8～2.0Gy/次;同期术后化疗或放化疗40例(对照组),男28例,女12例,Ⅰ、Ⅱ和Ⅲa期各10、20和10例。结果:脑转移率PCI组10.0%,对照组52.5%,两组间有显著的统计学意义(χ²=13.73,P<0.001)。PCI组1、3、5年生存率分别为83.3%、60.0%和20.0%,对照组1、3、5年生存率分别为80.0%、47.5%和15.0%,PCI组和对照组Ⅰ、Ⅱ和Ⅲa期5年生存率分别为60.0%和55.6%;、42.9%和38.5%;25.0%和10.0%,两组均无统计学差异。结论:小细胞肺癌术后化疗或放化疗后预防性脑照射可以降低脑转移率,是否能提高生存率,因例数较少难下确切的结论。     

Utility of Prophylactic Cranial Irradiation for Limited Stage Small Cell Lung Cancer in the Modern Era with Magnetic Resonance Imaging Surveillance

AimsTo retrospectively analyse the impact of prophylactic cranial irradiation (PCI) on survival and intracranial progression in patients with limited stage small cell lung cancer (LS-SCLC) in the modern era of widespread magnetic resonance imaging brain screening.Materials and methodsPatients with LS-SCLC treated within our network between 2009 and 2020 who responded to initial therapy were stratified by receipt of PCI and stage of disease. A propensity score match analysis was carried out for stage II–III patients. Overall and neurological survival were defined as time to death and presumed death due to uncontrolled intracranial disease, respectively. Brain metastasis-free survival and symptomatic brain metastasis-free survival were defined as freedom from intracranial progression and symptomatic intracranial progression, respectively. The effect of PCI on these outcomes was assessed using Kaplan–Meier and Cox proportional hazards models.ResultsIn total, 243 (69.6%) of 349 patients received PCI. On multivariate analysis in the propensity matched stage II–III cohort, PCI was a significant predictor of improved neurological survival (hazard ratio 0.23, 95% confidence interval 0.08–0.65; P = 0.01), brain metastasis-free survival (hazard ratio 0.25, 95% confidence interval 0.12–0.51; P < 0.01) and symptomatic brain metastasis-free survival (hazard ratio 0.21, 95% confidence interval 0.08–0.55; P < 0.01), but not improved overall survival. Two-year neurological survival estimates within the propensity matched cohort were 96.8% (95% confidence interval 87.6–99.2%) with PCI and 77.2% (95% confidence interval 63.0–86.4%) without PCI and 1- and 2-year estimates of incidence of brain metastases were 3.9% (95% confidence interval 1.3–11.7%) and 11.7% (95% confidence interval 5.6–23.5%) in the PCI group and 31.6% (95% confidence interval 22.1–43.9%) and 40.4% (95% confidence interval 29.2–54.0%) in the no PCI group, respectively.ConclusionsIn the modern era of magnetic resonance imaging screening, PCI was associated with reduced incidence of intracranial progression in patients with stage II–III LS-SCLC who respond to initial therapy. This, importantly, translated to a decreased risk of neurological death within our propensity matched cohort, without significant improvement in overall survival.     

Effect of Prophylactic Cranial Irradiation on Overall Survival in Metastatic Small-Cell Lung Cancer: A Propensity Score-Matched Analysis

Introduction

Patients with small-cell lung cancer (SCLC) have a high incidence of occult brain metastases and are often treated with prophylactic cranial irradiation (PCI). Despite a small survival advantage in some studies, the role of PCI in extensive stage SCLC remains controversial. We used the National Cancer Database to assess survival of patients with metastatic SCLC treated with PCI.

A Systematic Review of Risk Factors for Brain Metastases and Value of Prophylactic Cranial Irradiation in Non-Small Cell Lung Cancer

Background: The incidence of brain metastases (BM) varies in patients with non-small cell lung cancer(NSCLC), calls into question the value of prophylactic cranial irradiation (PCI). It is possible that clinicopathologiccharacteristics are associated with the development of BM, but these have yet to be identified in detail. Thus,we conducted the present meta-analysis on risk factors for BM and the value of PCI in patients with NSCLC.Methods: Eligible data were extracted and the risk factors for BM and the value of PCI in patients with NSCLCwere analyzed by calculating the pooled odds ratio (OR). Heterogeneity was detected using Q and I-squaredstatistics, and publication bias was tested by funnel plots and Egger’s test. Results: Six randomized controlledtrials with a focus on the value of PCI and 13 eligible studies with a focus on risk factors for BM were included.PCI significantly reduced the incidence of BM in patients with NSCLC (p=0.000, pooled OR=0.34, 95% confidenceinterval = 0.37-0.59). Compared with non-squamous cell carcinoma, squamous cell carcinoma was associatedwith a low incidence of BM in patients with NSCLC (p=0.000, pooled OR=0.47, 95% confidence interval =0.34-0.65). The funnel plot and Egger’s test suggested that there was no publication bias in the current meta-analysis.Conclusions: This meta-analysis provides statistical evidence that compared with non-squamous cell carcinoma,squamous cell carcinoma can be used as a predictor for BM in patients with NSCLC, and PCI might reduce theincidence of BM in patients with NSCLC, but does not provide a survival benefit.     

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937

IntroductionNRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1-year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive-disease SCLC.MethodsPatients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required.ResultsA total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2–74.7) for PCI and 50.8% (95% CI: 34.0–65.3) for PCI+cRT (p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32–0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT.ConclusionsOS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS.     

American Radium Society Appropriate Use Criteria on Radiation Therapy for Extensive-Stage SCLC

IntroductionThe standard-of-care therapy for extensive-stage SCLC has recently changed with the results of two large randomized trials revealing improved survival with the addition of immunotherapy to first-line platinum or etoposide chemotherapy. This has led to a lack of clarity around the role of consolidative thoracic radiation and prophylactic cranial irradiation in the setting of chemoimmunotherapy.MethodsThe American Radium Society Appropriate Use Criteria are evidence-based guidelines for specific clinical conditions that are reviewed by a multidisciplinary expert panel. The guidelines include a review and analysis of current evidence with the application of consensus methodology (modified Delphi) to rate the appropriateness of treatments recommended by the panel for extensive-stage SCLC.ResultsCurrent evidence supports either prophylactic cranial irradiation or surveillance with magnetic resonance imaging every 3 months for patients without evidence of brain metastases. Patients with brain metastases should receive whole-brain radiation with a recommended dose of 30 Gy in 10 fractions. Consolidative thoracic radiation can be considered in selected cases with the recommended dose ranging from 30 to 54 Gy; this recommendation was driven by expert opinion owing to the limited strength of evidence, as clinical trials addressing this question remain ongoing.ConclusionsRadiation therapy remains an integral component in the treatment paradigm for ES-SCLC.     

无锁骨上淋巴结转移的局限期小细胞肺癌颈部预防照射临床分析

目的：比较颈部预防照射对无锁骨上淋巴结转移的局限期小细胞肺癌预后的影响。方法：回顾性分析1998年2 月至2005年12月间天津医科大学附属肿瘤医院有完整记录的88例局限期小细胞肺癌临床资料,分为颈部预防照射组与无颈部预防照射组。比较两组患者生存率、复发率、远转率、颈部远转率。结果：颈部预防照射组与无颈部预防照射组1 年生存率分别为：82.00% 、84.20%（P=0.785）,3 年生存率42.86% 、52.63%（P=0.675）,5 年生存率26.67% 、31.42%（P=0.641）;1 年复发率9.09% 、12.50%（P=0.663）,3 年复发率39.39% 、32.00%（P=0.562）,5 年复发率61.54% 、47.62%（P=0.341）;1 年远转率27.08% 、25.71%（P=0.889）,3 年远转率68.18% 、57.14%（P=0.312）,5 年远转率75.00% 、70.00%（P=0.642）。 预防照射组与未预防照射组分别有3 例与5例患者2 年内发生颈部淋巴结转移,均伴有其他部位的远处转移灶,该8 例患者均死于别处转移。2 年颈部淋巴结转移率分别为8.33% 与18.52% ,无显著性区别（P=0.230）,平均生存期分别为25.67、27.40个月。结论：颈部预防照射未能显著提高患者生存率、降低复发率、远转率,特别是颈部远处转率。颈部预防照射在无锁骨上淋巴结转移的局限期小细胞肺癌治疗中不是必需的放疗靶区。     

Prophylactic Cranial Irradiation for Resectable Small-Cell Lung Cancer

After definitive chemoradiation for small-cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) has been established as standard of care in patients whose tumors respond to treatment. In the modern era, however, a subset of patients might receive upfront resection for SCLC, yet the role of PCI in these patients has not been elucidated. In this review, we examine the literature to better define the role of PCI in this subset of patients. For patients with ≥ T2 disease, incomplete resection, or those not receiving adjuvant chemotherapy, PCI is expected to offer a clinical benefit. For patients with T1 tumors treated with R0 resection, however, the rate of intracranial metastasis might be < 10%. In these patients, deferral of PCI might be appropriate because it would avoid known neurocognitive sequelae of cranial irradiation.     

The Role of Prophylactic Cranial Irradiation in Patients With Extensive Stage Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Introduction

The role of prophylactic cranial irradiation (PCI) is controversial in patients with extensive stage small cell lung cancer. The aim of this study was to determine the impact of PCI in these patients.

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27−32.91; 95% CI 3.64−6.22) and 14.70 (range, 0.27−32.91; 95% CI 0.27−43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p<0.05) and mOS (24.03 vs. 6.07 months, p<0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.     

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

IntruductionRadiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC.MethodsPatients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment.ResultsThirty-eight patients with ESCLC (median age 65 years, range: 37–79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1–13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1–8.1) and 8.4 months (95% confidence interval: 6.7-10.1).ConclusionsConcurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.