术后小细胞肺癌患者预防性脑照射研究进展

小细胞肺癌(SCLC)发病数较少,约占所有支气管肺癌的13%~20%,恶性程度较高,短时间内易复发转移。确诊时局限期小细胞肺癌约占SCLC的30%,符合手术患者仅占5%。放化疗后完全缓解者仍有一半以上患者发生脑转移。术后Ⅰ、Ⅱ、Ⅲ期SCLC患者脑转移发生率为6%~14%、13%~38%、11%~36%。预防性脑照射(PCI)可提高放化疗后完全缓解者总生存率,并降低脑转移发生率,是局限期SCLC综合治疗的重要组成部分。但是,PCI的临床应用仍存一些争议,手术完全切除的SCLC患者行PCI的疗效不一。本文对此问题进行文献综述,并介绍该领域的研究进展。     

SCLC脑预防照射——争议中的进展

SCLC是一种强侵袭性的恶性肿瘤,自然病程短,易发生脑转移,因此在放化疗基础上,应用脑预防照射对于减少脑转移的发生及提高患者生存具有重要意义。然而近年来关于脑预防照射的适应证及应用价值却争议不断。这些争议主要集中在广泛期SCLC中脑预防照射的价值,局限期SCLC中脑预防照射适应证以及是否另有替代方法等。本文旨在对现阶段脑预防照射临床应用的相关争议及进展进行相应探讨。     

National survey on prophylactic cranial irradiation: differences in practice patterns between medical and radiation oncologists

PURPOSE: Prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) patients remains controversial in the oncology community because of its potential for long-term toxicity and unproven survival benefit in randomized trials. A national survey of 9176 oncologists was conducted to characterize the use of PCI with regard to physician demographics, patient characteristics, and oncologists' beliefs. METHODS: Data was collected via a questionnaire letter survey. Biographical data, treatment patterns, and clinical impressions were analyzed by the generalized linear model and generalized estimating equations method. RESULTS: There were 1231 responders overall (13.4% of those surveyed), including 628 (51%) radiation oncologists (RO), 587 (48%) medical oncologists (MO), 8 (0.6%) surgical oncologists, and 8 (0.6%) from other oncology subspecialties. Of respondents, 74% overall recommend PCI in limited-stage patients, including 65% of MO and 82% RO (p = 0.001). Of responders who recommend PCI in limited-stage patients, 67% do so only after complete response to initial therapy. Only 30% of respondents recommend PCI for extensive-stage SCLC patients (p = 0.001), and 94% of these recommend PCI only when those patients have a complete response after initial therapy. Interestingly, 38% of responding MO feel that PCI improves survival of limited-stage patients, but only 11% believe PCI improves quality of life. Of the RO, 48% believe PCI improves survival in limited-stage SCLC, and 36% feel PCI improves quality of life (p < 0.05 and p < 0.01, respectively). MO responders believe PCI causes late neurological sequelae more often than do RO responders (95% vs. 84%, p < 0.05), with impaired memory (37%), chronic fatigue (19%), and loss of motivation (13%) as most commonly seen side effects. Only 1.5% overall, however, routinely obtain neuropsychiatric testing in PCI patients, and 42% overall never obtain them. CONCLUSION: Results confirm that oncologic subspecialists have statistically significant differences in opinion regarding the use of PCI. However, these differences may not translate into large differences in clinical practice. Most oncologists continue to recommend PCI in limited-stage SCLC patients, despite many believing PCI may not provide a survival advantage nor improve quality of life.     

局限期小细胞肺癌预防性脑照射后脑转移相关危险因素分析

小细胞肺癌具有易复发和转移的生物学特点,脑是小细胞肺癌肺外转移的好发部位。局限期小细胞肺癌患者行预防性脑照射(PCI)能够有效降低脑转移的发生率,延长总生存期。但是在PCI后仍有近1/3的患者发生脑转移。本文对PCI后脑转移的危险因素进行综述,目的在于判断何种局限期小细胞肺癌亚组患者能够从PCI中获益,从而为PCI的临...     

Patterns of recurrence and outcome in patients with surgically resected small cell lung cancer

Background

Although prophylactic cranial irradiation (PCI) in limited-stage (LS) small cell lung cancer (SCLC) patients who are surgically resected and treated with adjuvant chemotherapy is considered to be a reasonable treatment option, the efficacy of PCI for those patients remains unclear.

Methods

The records of 28 patients with SCLC undergoing curative surgery at the Aichi Cancer Center Hospital between 1995 and March 2008 were retrospectively reviewed to assess patterns of relapse and overall survival.

Results

The patients were 27 men and 1 woman. Eight patients underwent induction chemotherapy. Fourteen patients (50%) had pathologic stage (p-stage) I disease, 7 patients (25%) had p-stage II, and 7 patients (25%) had p-stage III. Nineteen patients underwent adjuvant chemotherapy and one patient received adjuvant chemoradiotherapy. There were a total of 13 deaths and 8 were disease-related. Most patients developed hematogenous distant metastases before their death. The 5-year overall probability of survival was 47%. Ten (36%) of the 28 patients had a relapse. Two had a local relapse alone, one patient had combined local and distant relapses, and seven patients had distant metastases alone as their first site of failure. Four patients with p-stage II/III disease developed brain metastases with a cumulative incidence at 1 and 2?years of 25 and 36%, respectively.

Conclusions

Our retrospective study suggested that PCI might have a role in surgically resected patients with p-stage II/III SCLC because of their relatively high frequency of brain metastasis.     

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.     

Limited-stage small-cell lung cancer: therapeutic options

Almost 40% of patients with newly diagnosed small-cell lung cancer (SCLC) have disease confined to the ipsilateral hemithorax and within a single radiation port, i.e., limited-stage disease. The median survival for this group of patients after treatment is approximately 15 months, with one in every four patients surviving 2 years. Current optimal treatment consists of chemotherapy with platinum/etoposide, given concurrently with thoracic radiation. Surgery may represent an option for very early-stage disease, but its added value is uncertain. Prophylactic cranial irradiation (PCI) is used for patients with limited-stage SCLC who have achieved a complete response following initial therapy, as it decreases the risk of brain metastases and provides an overall survival benefit. Newer targeted agents are currently being evaluated in this disease and hold the promise of improving current outcomes seen in patients with early-stage disease.     

小细胞肺癌治疗的新探索

与其他癌症相同,小细胞肺癌（ＳＣＬＣ）也秉承分期治疗的原则,手术只适用于早期患者,且能实施手术的患者仅占全部患者的５％,因此化疗、放疗仍是ＳＣＬＣ治疗的主要策略。近年来,胸部放疗提高局限期ＳＣＬＣ患者的３年生存率约５％,减少胸部复发风险约２５％,而预防性脑照射（ＰＣＩ）也进一步改善了ＳＣＬＣ的临床预后,新的治疗药物、靶点及策略不断涌现为ＳＣＬＣ的治疗带来了希望。     

Liver metastasis at the time of initial diagnosis of lung cancer

In order to evaluate clinicopathological features associated with liver metastases from lung cancer, we reviewed our experience of lung cancer patients seen in our division. Of the 1073 lung cancer patients diagnosed between October 1976 and May 2002, 62 (5.8%) patients had liver metastasis. The incidence of liver metastasis was 17.5% in small-cell lung cancer (SCLC) patients, whereas the incidence in non-small-cell lung cancer patients was 3.8%. Of the 62 patients, 17 had sole liver metastasis, and the remaining 45 had synchronous spread to the liver and one or more other organs. Six of 12 squamous cell carcinoma patients and 10 of 28 SCLC patients had sole liver metastasis. However, 19 of 20 adenocarcinoma patients showed liver metastasis with one or more other organs. In morphological liver metastasis, 26 of the 28 SCLC patients had multiple nodules, whereas 16 of the 34 non-small-cell lung cancer patients had a solitary liver nodule (p = 0.0006). Liver is a possible site of extrathoracic spread of disease for some patients with lung cancer, especially with SCLC. When the histological types are squamous cell carcinoma or SCLC, it would also be considered likely that an isolated liver mass represents a metastasis even though there is no metastatic disease elsewhere.     

The Role of Advanced Imaging in Assessing Response to Definitive Chemoradiation Before Prophylactic Cranial Irradiation in Limited-Stage Small-Cell Lung Cancer

Introduction

Prophylactic cranial irradiation (PCI) improves survival for small-cell lung cancer (SCLC). Evidence for PCI in limited-stage SCLC largely derives from studies requiring only chest x-ray (CXR) to determine remission status. We analyzed thoracic chemoradiation therapy (TCRT) outcomes according to imaging modality to determine which patients benefitted most from PCI.

Prophylactic Cranial Irradiation for Patients With Limited-Stage Small-Cell Lung Cancer With Response to Chemoradiation

BackgroundPrevious clinical studies have generally reported that prophylactic cranial irradiation (PCI) was given to patients with a complete response (CR) to chemotherapy and chest radiotherapy in limited-stage small-cell lung cancer (SCLC). It is not clear if those with incomplete response (IR) would benefit from PCI.Patients and MethodsThe Saskatchewan experience from 1981 through 2007 was reviewed. Patients were treated with chest radiotherapy and chemotherapy with or without PCI (typical doses: 2500 cGy in 10 fractions over 2 weeks, 3000 cGy in 15 fractions over 3 weeks, or 3000 cGy in 10 fractions over 2 weeks).ResultsThere were 289 patients treated for curative intent, 177/289 (61.2%) of whom received PCI. For the whole group of 289 patients, PCI resulted in significant overall survival (OS) and cause-specific survival (CSS) benefit (P = .0011 and 0.0005, respectively). The time to symptoms of first recurrence at any site with or without PCI was significantly different: 16.9 vs. 13.2 months (P = .0006). PCI significantly delayed the time to symptoms of first recurrence in the brain: 20.7 vs. 10.6 months (P < .0001). The first site of metastasis was the brain for 12.5% and 45.5% patients with CR with and without PCI, respectively (P = .02) and in 6.1% and 27.6% of patients with IR with and without PCI, respectively (P = .05). For the 93 patients with IR, PCI did not confer OS or CSS benefit (P = .32 and 0.39, respectively).ConclusionsPatients with IR benefited from PCI, with a reduced rate of and a delayed time for the development of brain metastases, although without significant OS or CSS benefit. PCI could be considered for all patients with limited-stage SCLC responding to chemoradiation.     

Place actuelle de l’irradiation prophylactique cérébrale

Prophylactic cranial irradiation (PCI) plays a role in the management of lung cancer patients, especially small cell lung cancer (SCLC) patients. As multimodality treatments are now able to ensure better local control and a lower rate of extracranial metastases, brain relapse has become a major concern in lung cancer. As survival is poor after development of brain metastases (BM) in spite of specific treatment, PCI has been introduced in the 1970's. PCI has been evaluated in randomized trials in both SCLC and non-small cell lung cancer (NSCLC) to reduce the incidence of BM 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 25 Gy 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 BM related to NSCLC, but most BM will eventually recur so that PCI should be reconsidered. Few randomized trials have been performed. Most of them could demonstrate a decreased incidence of BM in patients with PCI, but they were not able to show an effect on survival as they were underpowered. New trials are needed. Among long-term survivors, neuro-cognitive toxicity may be observed. Several approaches are being evaluated to reduce this possible toxicity. PCI has no place for other solid tumours at risk such as HER2+ breast cancer patients.     

Lambert-eaton myasthenic syndrome in a patient with small-cell lung cancer

Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune neuromuscular disorder, often has underlying small-cell lung cancer (SCLC). Thorough search for SCLC in patients with LEMS can result in early detection of limited-stage SCLC, one quarter of which can be successfully treated with chemotherapy and radiation therapy. To elucidate the pathogenesis, diagnosis, treatment, and prognosis of patients with SCLC and LEMS, we present a 51-year-old man who was diagnosed with LEMS and limited-stage SCLC after an 18-month history of weakness in the lower extremities. The patient exhibited a complete response in lung tumors and a resolution in LEMS symptoms after chemotherapy and radiation therapy.     

局限期小细胞肺癌序贯化放疗最佳放疗时机及预后因素分析

目的:探讨局限期小细胞肺癌序贯化放疗最佳放疗时机及影响预后的因素。方法:回顾性分析2012年10月至2015年8月中国医科大学肿瘤医院收治的133例局限期小细胞肺癌患者临床资料，根据放疗开始时机分为早放疗组（初治化疗≤2个周期开始放疗）和晚放疗组（初治化疗>2个周期开始放疗）,采用Kaplan-Meier法进行生存分析，Log-rank检验、Cox回归模型进行单因素及多因素分析。结果:中位随访时间为28个月。单因素分析结果，性别（P=0.015）、初治化疗疗效（P=0.021）、是否行全脑预防照射（P=0.012）对总生存期（overall survival, OS）有显著影响，性别（P=0.029）、放疗开始时机（P=0.005）对无进展生存期（progression-free survival, PFS）有显著影响，差异有统计学意义。多因素分析结果，性别、初治化疗是否有效、是否行全脑预防照射（prophylactic cranial irradiation, PCI）是影响OS的独立因素（P均<0.05），性别、放疗开始时机是影响PFS的独立因素（P均<0.05）。分组分析结果，早放疗组女性患者OS（P=0.013）及PFS（P=0.015）显著优于男性，差异有统计学意义；早放疗组中行PCI显著延长OS（P=0.015）但对PFS（P=0.474）的影响无统计学意义；初治化疗有效组早放疗较晚放疗显著延长PFS（P=0.008）但对OS（P=0.591）无显著影响。结论:性别、初治化疗疗效、胸部放疗时机及PCI是影响局限期小细胞肺癌预后的独立因素,早放疗组中女性及行PCI的患者预后较好，初治化疗有效患者应尽早开始放疗。     

Radiation Therapy for Small Cell Lung Cancer: An ASTRO Clinical Practice Guideline

PurposeSeveral sentinel phase III randomized trials have recently been published challenging traditional radiation therapy (RT) practices for small cell lung cancer (SCLC). This American Society for Radiation Oncology guideline reviews the evidence for thoracic RT and prophylactic cranial irradiation (PCI) for both limited-stage (LS) and extensive-stage (ES) SCLC.MethodsThe American Society for Radiation Oncology convened a task force to address 4 key questions focused on indications, dose fractionation, techniques and timing of thoracic RT for LS-SCLC, the role of stereotactic body radiation therapy (SBRT) compared with conventional RT in stage I or II node negative SCLC, PCI for LS-SCLC and ES-SCLC, and thoracic consolidation for ES-SCLC. Recommendations were based on a systematic literature review and created using a consensus-building methodology and system for grading evidence quality and recommendation strength.ResultsThe task force strongly recommends definitive thoracic RT administered once or twice daily early in the course of treatment for LS-SCLC. Adjuvant RT is conditionally recommended in surgically resected patients with positive margins or nodal metastases. Involved field RT delivered using conformal advanced treatment modalities to postchemotherapy volumes is also strongly recommended. For patients with stage I or II node negative disease, SBRT or conventional fractionation is strongly recommended, and chemotherapy should be delivered before or after SBRT. In LS-SCLC, PCI is strongly recommended for stage II or III patients who responded to chemoradiation, conditionally not recommended for stage I patients, and should be a shared decision for patients at higher risk of neurocognitive toxicities. In ES-SCLC, radiation oncologist consultation for consideration of PCI versus magnetic resonance surveillance is strongly recommended. Lastly, the use of thoracic RT is strongly recommended in select patients with ES-SCLC after chemotherapy treatment, including a conditional recommendation in those responding to chemotherapy and immunotherapy.ConclusionsRT plays a vital role in both LS-SCLC and ES-SCLC. These guidelines inform best clinical practices for local therapy in SCLC.     

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.     

Prophylactic cranial irradiation revisited: cost-effectiveness and quality of life in small-cell lung cancer.

PURPOSE: To investigate the therapeutic usefulness and cost-effectiveness of prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer (SCLC) who had achieved a complete remission. METHODS: A retrospective chart review was undertaken of all patients diagnosed in Saskatchewan with SCLC between 1987 and 1998 inclusive. Patients who achieved a complete remission were divided into two groups, depending on whether they underwent PCI (PCI+ and PCI-, respectively). The quality-of-life-adjusted survival was estimated by the Q-TWiST method (quality time without symptoms and toxicity). The mean incremental costs per month of incremental OS were calculated in a cost-effectiveness analysis. RESULTS: Among the 98 complete remission patients, the median OS for PCI+ and PCI- patients was 20.0 and 19.0 months, respectively (p > 0.05, nonsignificant). The median disease-free survival was 14.7 and 10.0 months, respectively (p < 0.05). The difference in the mean Q-TWiST survival was significant (p < 0.01). The mean marginal cost was $18,834/PCI+ patient and $17,885/PCI- patient (p > 0.05, nonsignificant). The cost-effectiveness ratio was $70/mo of incremental OS if u(tox) and u(rel) (the utility coefficients to reflect the value of time in health states of toxicity and relapse) were assumed to be 1.0. CONCLUSION: PCI is a cost-effective treatment that improves the quality-of-life-adjusted survival for patients with a complete remission of SCLC.     

Prognostic significance of serum p53 antibodies in patients with limited-stage small cell lung cancer

p53 tumour suppressor gene alterations are one of the most frequent genetic events in lung cancer. A subset of patients with p53 mutation and cancer exhibited circulating serum anti-p53 self-antibodies (p53-Ab). The prevalence of these antibodies in lung cancer is currently being analysed in a multicentric study. In a group of homogeneous SCLC patients, p53-Ab were detected in 20/97 (20.6%) individuals. In this group of patients, Cox's multivariate analysis identified disease extent (p = 0.022), WHO initial performance status greater than 0 (p = 0.005), and the absence of a complete response after 6 months of treatment (p < 0.0001) as independent prognostic variables, with p53-Ab being of borderline significance (p = 0.051). In the subset of limited-stage SCLC patients, Cox's multivariate analysis found p53-Ab (p = 0.033), WHO initial performance status greater than 0 (p = 0.028), and absence of a complete response (p < 0.001) to be independent prognostic variables. Thus, actuarial analysis showed that patients with limited-stage SCLC and p53-Ab had a median survival time of 10 months, whereas limited-stage SCLC patients without p53-Ab had a 17-month median survival time (p = 0.014).Therefore, serum assay of p53-Ab could help to identify a population of SCLC patients with an especially poor prognosis. This population could represent patients with tumours harboring aggressive p53 mutations.     

局限期小细胞肺癌放射治疗研究进展

小细胞肺癌（small cell lung cancer,SCLC）是高度恶性肿瘤,生物学特点是倍增时间短、增殖指数高和侵袭能力强。尽管对化放疗高度敏感,但极易耐药和复发,预后很差。确诊时约1/3属于局限期（limited-stage,LS）。LS-SCLC具有潜在治愈的可能,采用以铂类为基础的化疗联合胸部放疗,长期生存率达20%～25%。初治达完全或部分缓解的LS-SCLC患者行预防性脑照射(prophylactic cranial irradiation,PCI)可降低脑转移发生率,改善生活质量。随着SCLC患者生存期延长,局部治疗变得非常重要,如何最大程度地降低局部复发的危险性一直是临床研究热点。本文中我们分析了LS-SCLC放射治疗的研究现状,探索最佳放射剂量、次数、靶区、时机及PCI。     

Recent developments in radiotherapy for small-cell lung cancer: a review by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)

Small-cell lung cancer (SCLC) accounts for 13% of all lung tumours. The standard treatment in patients with limited-stage disease is radiotherapy combined with chemotherapy. In extensive SCLC, the importance of consolidation thoracic radiotherapy in patients with a good treatment response has become increasingly recognized. In both limited and extensive disease, prophylactic cranial irradiation is recommended in patients who respond to treatment. New therapeutic approaches such as immunotherapy are being increasingly incorporated into the treatment of SCLC, although more slowly than in non-small cell lung cancer (NSCLC). Diverse radiation dose and fractionation schemes, administered in varying combinations with these new drugs, are being investigated. In the present study we review and update the role of radiotherapy in the treatment of SCLC. We also discuss the main clinical trials currently underway in order to identify future trends.