小细胞肺癌放射治疗进展

目的 放射治疗是小细胞肺癌治疗的主要方式,其实施过程涉及到小细胞肺癌的诸多环节,总结国内外关于小细胞肺癌放射治疗的研究现状,探讨胸部放射治疗和全脑预防性照射在小细胞肺癌治疗中的价值.方法 应用PubMed、西文生物医学期刊文献数据库、中国知网及万方期刊全文数据库检索系统,以"小细胞肺癌,放疗,全脑预防性照射"为中文关键词,以"small cell lung cancer,radiotherapy,prophylactic cranial irradiation"为英文关键词,联合检索1996-01-2016-12的相关文献.共检索到英文文献377篇,中文文献4篇.纳入标准:(1)小细胞肺癌;(2)放疗;(3)全脑预防性照射.排除标准:(1)非小细胞肺癌;(2)手术;(3)化疗.根据剔除标准剔除中文文献2条,英文文献326条,最后纳入分析37篇文献.结果局限期小细胞肺癌的胸部放疗的分割剂量和模式为45 Gy/30次,超分割放疗或60~70 Gy/30~35次,常规分割放疗.胸部放疗参与的最佳时间为于化疗第1个周期或第2个周期参与.胸部同步放化疗结束以后行全脑预防性照射,放疗期间可给予药物盐酸美金刚以保护神经认知功能或海马保护的调强放射治疗;广泛期小细胞肺癌的胸部放疗的分割剂量和模式为30 Gy/10次或45 Gy/15次.全脑预防性照射存在争议.结论胸部放射治疗和全脑预防性照射在小细胞肺癌治疗中起着非常重要的作用.     

A Herpes simplex virus-1 fatal encephalitis following chemo-radiotherapy, steroids and prophylactic cranial irradiation in a small cell lung cancer patient

Approximately 20-25% of patients with limited small cell lung cancer (SCLC) can be cured with an aggressive approach (chest radiation concomitant with chemotherapy) followed by prophylactic cranial irradiation (PCI) to a total dose of 30-36Gy with 3-2Gy per fraction, five fractions per week. Steroid prophylactic therapy with dexamethasone is usually prescribed during PCI to minimize acute radiation induced brain oedema. This approach may induce an immunosuppressive condition leading to a reactivation of an endogenous latent Herpes simplex virus and severe or fatal acute encephalitis may occur as our report will show. A 55-year-old man affected by locally advanced SCLC was referred to our institution after four cycles of chemotherapy with a good partial remission. Chest radiation started concomitantly with two cycles of chemotherapy followed by PCI 36Gy total dose and dexamethasone 8mg i.m. daily. Fifteen days after PCI completion the patient developed acute neurological symptoms of confusion, cognitive impairment, fever with shaking requiring severe sedation therapy. Twenty-five days later MRI T1 weighted images showed haemorrhagic streaked lines on cortical convolutions of the right cerebral hemisphere and diffuse oedema suggestive of herpetic encephalitis. The DNA consensus test on cerebrospinal fluid (CSF) was positive for Herpes simplex virus 1 infection (HSV-1). A diagnosis of herpetic encephalitis HSV-1 was made. Antiviral therapy with high doses of acyclovir was prescribed but symptoms did not ameliorate leading to a comatose state. The patient died 55 days after the end of PCI. In eligible SCLC patients, PCI is an important part of an aggressive therapeutic approach that improves overall and disease free survival decreasing the risk of relapse in the brain. A primary infection or a reactivation of an endogenous latent HSV in brain parenchyma under steroid therapy concomitant to brain irradiation may compromise these benefits.     

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.     

小细胞肺癌预防性脑照射的临床研究

目的 探讨性全脑照射（ＰＣＩ）对局限期小细胞肺癌（ＳＣＬＣ）脑转移率和生存率的影响。方法 １９９０年１月～１９９５年１２月间,５１例经化疗加放疗后完全缓解的局限期ＳＣＬＣ患者被承机分为脑照射组（２６例）和对照组（２５例）。脑照射组患者接受ＰＣＩ２５．２～３０．６Ｇｙ。结果 脑照射组患者的脑转移率为３．８％,明显你芋对照组的２８．０％（Ｐ〈０．０５）。脑照射组患者和,１,２,３年生存率分别为８４．６     

Prophylactic cranial irradiation in small-cell lung cancer

Prophylactic cranial irradiation is now known to improve survival to a significant degree in small-cell lung cancer (SCLC) patients; this is in addition to its established role in preventing the disabling symptoms of brain metastases. New information indicates that it confers a survival benefit for limited or extensive stage SCLC patients gaining a complete response in the chest. A review of causes of cerebral dysfunction as a complication indicates that such problems can be due to suboptimal radiation fractionation, chemotherapy, or an inappropriate combination of prophylactic brain irradiation with chemotherapy. Optimum treatment with prophylactic brain irradiation has been shown not to cause adverse effects with detailed psychometric testing. Several additional sources of information can be drawn together to suggest a dose-response pattern for prophylactic brain irradiation, leading to the recommendation that a dose of 25-36 Gy is optimal, delivered in 2-3 Gy daily fractions after the completion of chest irradiation and chemotherapy. This will be better defined in future clinical trials.     

Prophylactic cranial irradiation for small-cell lung cancer: how, when and for whom?

Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases and improves overall survival in both limited disease (LD) and extensive disease (ED) small-cell lung cancer (SCLC), in complete and good responders to initial chemo(radio)therapy. In LD-SCLC, a standard dose of 25 Gy given in ten fractions is recommended, whereas in ED-SCLC a shorter schedule of 20 Gy in five fractions could be used. The issues of acute neurotoxicity (NT) and the potential impact of PCI on quality of life are of particular concern in ED-SCLC patients, as their expected survival is short. In LD-SCLC late neurologic sequelae may worsen quality-adjusted life expectancy for long-term survivors, as the pronounced effect of NT becomes apparent after several years. Some novel potential approaches to reduce the PCI-related late NT have recently been investigated. Despite the growing incidence of lung cancer in elderly people, there are no established standards of treatment for this subset of the population.     

Accelerated hyperfractionated radiotherapy and concomitant chemotherapy in small cell lung cancer limited-disease. Dose response, feasibility and outcome for patients treated in western Sweden, 1998-2004

Addition of thoracic radiation therapy (TRT) to chemotherapy (CHT) can increase overall survival in patients with small cell lung cancer limited-disease (SCLC-LD). Accelerated fractionation and early concurrent platinum-based CHT, in combination with prophylactic cranial irradiation, represent up-front treatment for this group of patients. Optimised and tailored local and systemic treatment is important. These concepts were applied when a new regional treatment programme was designed at Sahlgrenska University Hospital in 1997. The planned treatment consisted of six courses of CHT (carboplatin/etoposide)+TRT±prophylactic cranial irradiation (PCI). Standard TRT was prescribed as 1.5 Gy BID to a total of 60 Gy during 4 weeks, starting concomitantly with the second or third course of CHT. However, patients with large tumour burdens, poor general condition and/or poor lung function received 45 Gy, 1.5 Gy BID, during 3 weeks. PCI in 15 fractions to a total dose of 30 Gy was administered to all patients with complete remission (CR) and “good” partial remission (PR) at response evaluation.

Eighty consecutive patients were treated between January 1998 and December 2004. Forty-six patients were given 60 Gy and 34 patients 45 Gy. Acute toxicity occurred as esophagitis grade III (RTOG/EORTC) in 16% and as pneumonitis grade I-II in10%. There were no differences in toxicity between the two groups. Three- and five-year overall survival was 25% and 16%, respectively. Median survival was 20.8 months with no significant difference between the two groups. In conclusion, TRT with a total dose of 60 or 45 Gy is feasible with comparable toxicity and no difference in local control or survival. Distant metastasis is the main cause of death in this disease; the future challenge is thus further improvement of the systemic therapy combined with optimised local TRT.     

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.     

Small-cell lung cancer: state of the art

Thirty years ago, there was a pervasive atmosphere of pessimism concerning the management of small-cell lung cancer (SCLC). Surgery or radiation therapy alone resulted in few cures since these techniques utilize a local therapy for a disseminated disease. Chemotherapy remains the backbone of treatment for all patients with SCLC, regardless of stage. For patients with limited-stage disease (LD), the addition of thoracic radiation to chemotherapy is standard. The optimal timing, dose, and schedule of radiation remains undefined. The majority of studies demonstrate equivalent or superior survival for early radiation when compared to delayed radiation. Approximately 50% of patients with LD will achieve a complete remission with chemoradiation and will be candidates for prophylactic cranial irradiation (PCI). While phase III trials have failed to demonstrate a statistically significant survival for PCI, brain relapse is clearly reduced, and a metaanalysis reports a small long-term survival advantage favoring patients receiving PCI. Unfortunately, unlike LD SCLC, advances in extensive-stage disease have been elusive, despite the testing of numerous strategies. Four courses of cisplatin (or carboplatin) plus etoposide remain standard first-line therapy. Promising results have been seen with irinotecan/cisplatin, but confirmatory trials are still needed. A plateau has been reached with chemotherapy regimens, and novel strategies are greatly needed to improve survival for patients with SCLC.     

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。     

Acute onset of brain atrophy and dementia in a patient with small cell lung cancer: a case report

A 59-year-old man who was diagnosed with small cell lung cancer (SCLC), achieved a complete response to the induction chemoradiotherapy and received prophylactic cranial irradiation (PCI) (25 Gy at 250 cGy per fraction) in October 2008. Three months later, he complained of anorexia, weight loss, fatigue, and short-term memory loss and developed dementia and systemic muscle weakness. Magnetic resonance imaging in April and July 2009 revealed the progression of the diffuse brain atrophy without evidence of the metastasis of SCLC. Paraneoplastic neurological syndrome was suspected because anti-Hu antibody was detected in his serum and cerebrospinal fluid, but the adverse effects of chemotherapy and/or radiotherapy were also suspected as the cause of his neurological disorder.     

Twice-daily prophylactic cranial irradiation for patients with limited disease small-cell lung cancer with complete response to chemotherapy and consolidative radiotherapy: report of a single institutional phase II trial

Prophylactic cranial irradiation (PCI) has been demonstrated to significantly reduce the incidence of brain relapse from limited disease small-cell lung cancer (LD SCLC), but concerns about neurologic toxicity remain. The purpose of this report was to update a phase II institutional trial that explored the impact of twice-daily PCI on neurologic toxicity as well as outcome for this group of patients. All eligible subjects had documented complete response to induction chemotherapy and consolidative chest irradiation. The whole brain was treated with twice-daily fractions of 1.5 Gy with megavoltage irradiation to an approximate total dose of 30.0-36.0 Gy. Although not devised as a randomized study, approximately half of the eligible patients declined the protocol enrollment of their own volition and were retrospectively evaluated as a "historical" control group regarding the incidence of brain metastases. Fifteen patients accepted twice-daily PCI, with 12 deferring treatment. Median follow-up was 20 months. Disease-free survival at 2 years was 54% with twice-daily PCI versus 0% without any PCI (p = 0.013). Overall survival at 2 years was 62% with twice-daily PCI versus 23% without PCI (p = 0.032). No statistically significant neurologic deterioration was detected in the PCI group posttreatment. Thus, twice-daily PCI should be considered for patients with LD SCLC who achieve a complete response to chemoirradiation. A multi-institutional randomized trial would be necessary before making definitive recommendations.     

先进诊疗技术下小细胞肺癌脑预防照射临床价值与研究进展

小细胞肺癌（SCLC）恶性程度高,侵袭性强,易发生颅脑转移。现有指南均推荐脑预防照射（PCI）作为初始系统性治疗后达到完全缓解的SCLC患者的标准治疗方案。但在MRI广泛应用于颅脑转移诊断的今天,放疗同时免疫治疗及分子靶向治疗的联合治疗方案广泛应用于肺癌,PCI在SCLC治疗中的价值受到质疑并面临挑战。而应用海马保护技术及相关药物减少PCI后神经认知功能损伤成为研究热点。本文将近期文献报道的PCI相关研究结果进行综述,为SCLC患者选择最适合的PCI个体化治疗方案提供参考。     

先进诊疗技术下小细胞肺癌脑预防照射临床价值与研究进展

小细胞肺癌（SCLC）恶性程度高,侵袭性强,易发生颅脑转移。现有指南均推荐脑预防照射（PCI）作为初始系统性治疗后达到完全缓解的SCLC患者的标准治疗方案。但在MRI广泛应用于颅脑转移诊断的今天,放疗同时免疫治疗及分子靶向治疗的联合治疗方案广泛应用于肺癌,PCI在SCLC治疗中的价值受到质疑并面临挑战。而应用海马保护技术及相关药物减少PCI后神经认知功能损伤成为研究热点。本文将近期文献报道的PCI相关研究结果进行综述,为SCLC患者选择最适合的PCI个体化治疗方案提供参考。     

Neurologic, neuropsychologic, and computed cranial tomography scan abnormalities in 2- to 10-year survivors of small-cell lung cancer

In order to evaluate the relationship between neurologic function and cranial irradiation, 20 patients treated on National Cancer Institute (NCI) small-cell lung cancer (SCLC) trials who were alive and free of cancer 2.4 to 10.6 years (median, 6.2) from the start of therapy were studied. All were tested with a neurologic history and examination, mental status examination, neuropsychologic testing, and review of serial computed cranial tomography (CCT) scans. Fifteen patients had been treated with prophylactic cranial irradiation (PCI), two patients with therapeutic cranial irradiation, and three received no cranial irradiation. All patients but one were ambulatory and none were institutionalized. Fifteen patients (75%) had neurologic complaints, 13 (65%) had abnormal neurologic examinations, 12 (60%) had abnormal mental status examinations, 13 (65%) had abnormal neuropsychologic testing, and 15 (75%) had abnormal CCT scans. Compared with those given low-dose maintenance chemotherapy during PCI using 200 to 300 rad per fraction, patients who were given high-dose induction chemotherapy during the time of cranial irradiation or large radiotherapy fractions (400 rad) were more likely to have abnormal mental status examinations (6/6 v 4/9) and abnormal neuropsychologic tests (6/6 v 4/9), but no major difference in CCT findings was present. CCT scans in the majority of cases (11/18) showed progressive ventricular dilatation or cerebral atrophy up to 8 years after stopping therapy. We conclude neurologic abnormalities are common in long-term survivors of SCLC, and may be more prominent in patients given high-dose chemotherapy during cranial irradiation or treated with large radiotherapy fractions. The CCT scan abnormalities are common and progressive years after prophylactic cranial irradiation and chemotherapy are stopped.     

Neurocognitive function in patients with small cell lung cancer : effect of prophylactic cranial irradiation

BACKGROUND: The use of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) has been tempered by fears of detrimental effects on cognitive function. Neuropsychologic testing was prospectively conducted before and after PCI to evaluate its effects on cognitive function in patients with SCLC. METHODS: Ninety-six patients who completely or partially responded to initial therapy underwent formal neurocognitive testing before PCI. Three patients who had central nervous system metastasis were excluded. Of the remaining patients, 69 received PCI (mean dose, 25 grays [Gy] in 10 fractions). Repeat testing was performed on 37 patients (median follow-up, 23 months; range, 6-120 months). RESULTS: Baseline impairment was defined as > or =1.5 standard deviations below the normative mean. Before undergoing PCI, 47% of patients had evidence of impaired cognitive function. After PCI, univariate analysis revealed significant transient declines in executive function (pre-PCI mean, 15.6 +/- 11.5; post-PCI, 27.1 +/- 17.6 [P = .008]) and language (pre-PCI mean, 33.8 +/- 9.9; post-PCI, 31.0 +/- 9.0 [P = .049]) at early timepoints. Controlling for noncentral nervous system disease progression the deficit in executive function was no longer significant. Moreover, these deficits were not sustained, and significant improvements in language and motor coordination were recorded. On multivariate analysis, no significant differences before and after PCI were found. CONCLUSIONS: Neurocognitive testing demonstrated that a substantial portion of patients with SCLC had impaired brain functioning at baseline. Persistent declines in cognitive function were not observed after cranial irradiation. These data do not favor the omission of PCI on the basis of fears of neurotoxic effects.     

Prophylactic cranial irradiation in lung cancer

As multi-modality treatments are now able to ensure better local control and a lower rate of extra cranial metastases, brain relapse has become a major concern in lung cancer. As survival is poor after development of brain metastases in spite of specific treatment, prophylactic cranial irradiation (PCI) has been introduced in the 70's. PCI has been evaluated in randomized trials in both small-cell (SCLC) and non-small-cell (NSCLC) lung cancers to reduce the incidence of brain metastases and possibly increase survival. PCI reduces significantly the BM rate in both limited disease (LD) and extensive disease (ED) SCLC and in non-metastatic NSCLC. Considering SCLC, PCI significantly improves overall survival in LD (from 15% to 20% at 3 years) and ED (from 13% to 27% at 1 year) in patients who respond to first-line treatment; it should thus be part of the standard treatment in all responders in ED and in good responders in LD. No dose-effect relationship for PCI was demonstrated in LD SCLC patients so that the recommended dose is 25Gy in 10 fractions. In NSCLC, even if the risk of brain dissemination is lower than in SCLC, it has become a challenging issue. Studies have identified subgroups at higher risk of brain failure. There are more local treatment possibilities for NSCLC patients with BM, but most of them will eventually recur so that PCI should be reconsidered. Few randomized trials have been performed and they were not able to show an effect on survival as they were underpowered. New trials are needed.     

Treatment of primary intraocular lymphoma with radiation therapy: a multi-institutional survey in Japan

This study evaluated the clinical features and treatment outcome of 15 patients with primary intraocular lymphoma. There were nine females, with a median age of 68 years. Thirteen patients presented with bilateral lesions and median time from the onset of symptoms to diagnosis was 12 months. All but one showed the B-cell phenotype. All patients received radiation therapy (RT) with a median of 41 Gy and 10 were administered chemotherapy as well. Three patients were treated with high-dose methotrexate and nine received prophylactic cranial irradiation (PCI) with a median of 30.6 Gy. Thirteen patients obtained a complete remission. The 2-year overall and disease free survival were 74% and 58%, respectively. Although only one patient experienced local recurrence, PCI did not prevent intracranial recurrence. One patient developed a grade 3 cognitive disturbance. It was concluded that ocular RT was effective to control primary lesions. However, some modifications are indispensable to improve outcomes.     

Zerebrale Metastasierung: Prophylaxe und Behandlung

Small cell lung cancer (SCLC) is characterized by a high prevalence of brain metastases, which affect more than half of the patients during the course of the disease. Since the meta-analysis of the late 1990s prophylactic cranial irradiation is a key element in multimodal therapy of limited disease SCLC with complete remission after chemotherapy. Recently, moreover, a multicenter phase III study in patients with advanced disease demonstrated a survival advantage following prophylactic radiotherapy to the brain. In the palliation of cerebral metastases whole brain radiotherapy remains the standard of treatment. The poor survival rates, however, strongly support the need for effective prophylaxis.     

The Case Against Prophylactic Cranial Irradiation in Limited Small Cell Lung Cancer

There have been significant advances in the treatment of small cell lung cancer during the past two decades. Systemic chemotherapy for extensive disease and combined modality therapy for limited small cell lung cancer has improved both quality and quantity of survival. In extensive disease, although the median survival time is improved with chemotherapy, only rarely is a patient cured. However, in limited disease, over 50% of the patients will achieve a complete remission and the 5-year survival is approximately 20%. There has been significant controversy concerning the role of prophylactic cranial irradiation, especially in patients with limited small cell lung cancer who achieve a complete remission. This article addresses the currently available data concerning benefit, toxicity, and results from randomized clinical trials using prophylactic cranial irradiation in patients with small cell lung cancer.