小细胞肺癌NCCN指南2017第二版讨论（第三部分）

Small Cell Lung Cancer 小细胞肺癌

NCCN Guidelines Version 2.2017 NCCN指南2017第2版山东省肿瘤医院呼吸肿瘤内科张品良

Discussion
讨论

Radiotherapy
放射治疗

The Principles of Radiation Therapy in the algorithm describe the radiation doses, target volumes, and normal tissue dose volume constraints for mainly limited-stage SCLC, and include references to support the recommendations; prophylactic cranial irradiation (PCI) and treatment of brain metastases are also discussed (see the NCCN Guidelines for SCLC). The American College of Radiology (ACR) Appropriateness Criteria® are a useful resource. The Principles of Radiation Therapy in the NSCLC algorithm may also be useful (eg, general principles of radiotherapy, palliative radiotherapy) (see the NCCN Guidelines for NSCLC, available at NCCN.org). This section describes the studies supporting the NCCN recommendations for SCLC. A few reports have suggested that stereotactic ablative radiotherapy (SBRT) might be useful for select patients with limited-stage SCLC; however, there are insufficient data to make a recommendation.
工作步骤的放疗原则描述了放射剂量、靶区以及正常组织剂量体积限制，主要针对局限期小细胞肺癌患者，包括建议的支持参考；预防性脑照射（PCI）和脑转移瘤的治疗也进行了讨论（见小细胞肺癌NCCN指南）。非小细胞肺癌工作步骤中的放射治疗原则也可能是有用的（如，放射治疗的一般原则、姑息性放射治疗）（见非小细胞肺癌NCCN指南，可在NCCN.org获得）。本节描述了支持NCCN建议的小细胞肺癌研究。少量报告表明，对于选择性的局限期小细胞肺癌患者，立体定向消融放疗（SBRT）可能是有益的；然而，做出该推荐的数据不充分。

Thoracic Radiotherapy
胸部放疗

The addition of thoracic radiotherapy has improved survival for patients with limited-stage disease. Meta-analyses that included more than 2000 patients show that thoracic radiation for limited-stage disease yields a 25% to 30% reduction in local failure, and a corresponding 5% to 7% improvement in 2-year survival when compared with chemotherapy alone. However, achieving long-term local control using conventional chemoradiotherapy for patients with limited-stage SCLC remains a challenge.
对于局限期患者增加胸部放疗可改善生存。汇集2000多例患者的meta分析显示，与单纯化疗相比，局限期疾病胸部放疗局部失败率降低25%-30%，相应提高2年生存率5%-7%。然而，对于局限期小细胞肺癌患者，使用常规放化疗达到长期局部控制仍是一个挑战。

Timing of Radiation with Chemotherapy
放射联合化疗的时机

The administration of thoracic radiotherapy requires the assessment of several factors, including the timing of chemotherapy and radiotherapy (concurrent vs. sequential), timing of radiotherapy (early vs. late), volume of the radiation port (original tumor volume vs. shrinking field as the tumor responds), dose of radiation, and fractionation of radiotherapy. Early concurrent chemoradiotherapy is recommended for patients with limited-stage SCLC based on randomized trials. A randomized phase 3 trial by the Japanese Cooperative Oncology Group assessed sequential versus concurrent thoracic radiotherapy combined with EP for patients with limited-stage disease. They reported that patients treated with concurrent radiotherapy lived longer than those treated with sequential radiotherapy.
胸部放疗的管理需要评估一些因素，包括化疗联合放疗的时机（同步与序贯）、放射治疗的时机（早与晚）、放射入口体积（原始肿瘤体积与因肿瘤应答缩野）、放射剂量以及放疗分割。根据随机试验，对于局限期小细胞肺癌患者，推荐早期同步放化疗。日本肿瘤学协作组的一项随机3期试验评估了序贯与同步胸部放疗联合EP治疗局限期疾病患者。他们报道，接受同步放疗的患者比序贯放疗的患者寿命更长。

Another randomized phase 3 trial (by the National Cancer Institute of Canada)—comparing radiotherapy beginning with either cycle 2 or cycle 6 of chemotherapy—showed that early radiotherapy was associated with improved local and systemic control and with longer survival. Several systematic reviews and meta-analyses on the timing of thoracic radiotherapy in limited-stage SCLC have reported that early concurrent radiotherapy results in a small, but significant improvement in overall survival when compared with late concurrent or sequential radiotherapy. Another meta-analysis in patients with limited-stage SCLC showed that survival was improved with more rapid completion of the chemo/RT regimen (start of any chemotherapy until the end of radiotherapy [SER]). A recent meta-analysis of individual patient data from 12 trials (2,668 patients) reported that early concurrent chemo/RT increased 5-year overall survival (HR, 0.79; 95% CI, 0.69–0.91), although severe acute esophagitis was also increased, when compared with late concurrent therapy.
另一项随机3期试验（加拿大国家癌症研究所）比较在化疗的第2或第6周期开始放疗，结果显示，早期放疗改善局部和全身控制因而生存期更长。局限期小细胞肺癌胸部放疗时机的若干系统回顾和meta分析报告，与晚期同步或序贯放疗相比，早期同步放疗带来少许、却显著改善总生存。另一项局限期小细胞肺癌患者的meta分析表明，更快速完成化/放疗方案（化疗开始至放疗结束[SER]）改善生存。最近一项对12个试验（2668例）具体患者数据的meta分析报告，早期同时化/放疗改善5年总生存（HR，0.79；95% CI，0.69-0.91），虽然与晚同步治疗相比，严重的急性食管炎也增加。

Radiation Fractionation
放疗分割

The ECOG/Radiation Therapy Oncology Group compared once-daily to twice-daily radiotherapy with EP. In this trial, 412 patients with limited-stage SCLC were treated with concurrent chemoradiotherapy using a total dose of 45 Gy delivered either twice a day over 3 weeks or once a day over 5 weeks. The twice-daily schedule produced a survival advantage, but a higher incidence of grade 3 to 4 esophagitis was seen when compared with the once-daily regimen. Median survivals were 23 versus 19 months (P = .04), and 5-year survival rates were 26% versus 16% in the twice-daily and once-daily radiotherapy arms, respectively. A significant criticism of this trial is that the doses of radiation in the 2 arms were not biologically equivalent. In light of this, ongoing trials are evaluating biologically equivalent doses of 45 Gy delivered twice daily versus 60 to 70 Gy delivered once daily. Another concern regarding hyperfractionation is that twice-daily thoracic radiation is technically challenging for patients with bilateral mediastinal adenopathy.
ECOG/肿瘤放疗协作组比较了每日一次与每日两次放疗联合EP。在该试验中，412例局限期小细胞肺癌患者DT45Gy bid 3周以上或qd 5周以上同步放化疗。每日两次方案获得了生存优势，但与每日一次方案相比，3-4级食管炎的发病率较高。中位生存期每日两次和每日一次放疗组分别为23对19个月（P = 0.04），5年生存率分别为26%对16%。该试验一个值得注意的缺陷是，两组的放射剂量不是生物等效剂量。鉴于此，正在进行的试验评估45Gy的生物等效剂量每日两次对60-70Gy每日一次。超分割的另一个担心是，对于双侧纵隔淋巴结肿大的患者，每日两次胸部放疗在技术上面临挑战。

Another randomized phase 3 trial showed no survival difference between once-daily thoracic radiotherapy to 50.4 Gy with concurrent EP and a split course of twice-daily thoracic radiotherapy to 48 Gy with concurrent EP. However, split-course radiotherapy may be less efficacious because of interval tumor regrowth between courses. Overall, patients selected for combined modality treatment that incorporates twice-daily radiotherapy must have an excellent PS and good baseline pulmonary function.
另一项随机3期试验表明，每日一次胸部放疗50.4Gy联合EP与每日两次分割胸部放疗48Gy联合EP相比，无生存差异。然而，分割放疗可能不太有效，因为在放射间隔之间肿瘤再生长。总之，选择每日两次放疗的综合方式治疗的患者，必须具有很好的PS和良好的基线肺功能。

NCCN Guideline for Radiation in Limited-Stage SCLC
局限期小细胞肺癌放疗NCCN指南

For limited-stage disease in excess of T1-2, N0, the NCCN Guidelines recommend that radiotherapy should be used concurrently with chemotherapy and that radiotherapy should start with the first or second cycle (category 1). The optimal dose and schedule of radiotherapy have not been established. However, 45 Gy in 3 weeks (twice-daily regimen) is superior to 45 Gy once daily in 5 weeks. For twice-daily radiotherapy, the recommended schedule is 1.5 Gy twice daily to a total dose of 45 Gy in 3 weeks (category 1). For once-daily radiotherapy, the recommended schedule is 2.0 Gy once daily to a total dose of 60 to 70 Gy (see Principles of Radiation Therapy in the NCCN Guidelines for SCLC). The minimum standard for thoracic irradiation is CT-planned 3-D conformal radiotherapy. More advanced technologies may also be used when needed (eg, 4D-CT) (see Principles of Radiation Therapy in the NCCN Guidelines for SCLC). The radiation target volumes can be defined on the PET/CT scan obtained at the time of radiotherapy planning using definitions in reports 50 and 62 from the International Commission on Radiation Units & Measurement (ICRU). However, the pre-chemotherapy PET/CT scan should be reviewed to include the originally involved lymph node regions in the treatment fields.
对于超出T1-2N0的局限期患者，NCCN指南推荐放疗应该同步化疗，并且放疗应该在第一或第二周期开始（1类）。放疗的最佳剂量和方案尚未确定。然而，45Gy/3周（每日两次方案）优于45Gy/5周每日一次。对于每日两次放疗，推荐的计划是1.5Gy，BID，总剂量为45Gy/3周（1类）。对于每日一次放射治疗，推荐的计划是2.0Gy qd，总剂量为60-70Gy（见小细胞肺癌NCCN指南中的放射治疗原则）。胸部照射的最低标准是根据CT设计的三维适形放疗。当需要时也可以使用更先进的技术（如4D-CT）（见小细胞肺癌NCCN指南中的放射治疗原则）。在制定放疗计划时，放射靶体积可以使用国际辐射单位与测量委员会（ICRU）在50和62报告中的定义在获得的PET/CT扫描上确定。然而，为了将最初累及的淋巴结区包括在治疗野内，应复阅化疗前PET/CT扫描。

The normal tissue constraints used for NSCLC are appropriate for SCLC when using similar radiotherapy doses (see the NCCN Guidelines for NSCLC, available at NCCN.org). When using accelerated schedules (eg, 3–5 weeks), the spinal cord constraints from the CALCB 30610/RTOG 0538 protocol can be used as a guide (see Principles of Radiation Therapy in the NCCN Guidelines for SCLC). Intensity-modulated radiation therapy (IMRT) may be considered in select patients (see Principles of Radiation Therapy in the NCCN Guidelines for SCLC and the NCCN Guidelines for NSCLC).
当使用相似的放疗剂量时，用于非小细胞肺癌的正常组织限制适于小细胞肺癌（见非小细胞肺癌NCCN指南，可在NCCN.org获得）。当使用加速时间表时（如3–5周），可以使用CALCB 30610/RTOG 0538协议的脊髓限制作为指导（见小细胞肺癌NCCN指南中的放射治疗原则）。在选择性的病人中可以考虑调强放疗（IMRT）（见小细胞肺癌NCCN指南和非小细胞肺癌NCCN指南中的放射治疗原则）。

Thoracic Radiation in Extensive-Stage SCLC
广泛期小细胞肺癌的胸部放疗

Based on the results of a randomized trial by Jeremic et al, the addition of sequential thoracic radiotherapy may be considered in select patients with low-bulk metastatic extensive-stage disease who have a complete or near complete response after initial chemotherapy. In this trial, patients experiencing a complete response at distant metastatic sites after 3 cycles of EP were randomized to receive either 1) further EP; or 2) accelerated hyperfractionated radiotherapy (ie, 54 Gy in 36 fractions over 18 treatment days) in combination with carboplatin plus etoposide. The investigators found that the addition of radiotherapy resulted in improved median overall survival (17 vs. 11 months). In patients with extensive-stage SCLC who responded to chemotherapy, a phase 3 trial by Slotman et al (Dutch CREST trial) reported that the addition of sequential thoracic radiotherapy did not improve the primary endpoint of 1-year overall survival (33% vs. 28%, P = .066), but a secondary analysis did find improvement in 2-year overall survival (13% vs. 3%, P = .004) when compared with patients who did not receive sequential thoracic radiotherapy.
根据Jeremic等人的一项随机试验结果，在选择性的低负荷转移的广泛期疾病、初始化疗后完全或接近完全缓解的患者中可以考虑加入序贯胸部放疗。在该试验中，3周期EP后远处转移灶完全缓解的患者随机接受1）继续EP；或2）加速超分割放疗（即54Gy/36f，18天以上）联合卡铂加依托泊苷。研究者发现，放疗的加入延长了中位总生存期（17对11个月）。在化疗有效的广泛期小细胞肺癌患者中，Slotman等人的一项3期试验（荷兰CREST研究）报道，与未接受序贯胸部放疗的患者相比，序贯胸部放疗的加入并不能改善主要终点1年总生存率（33%对28%，P = 0.066），但二次分析确实发现改善2年总生存率（13%对3%，P = 0.004）。

Prophylactic Cranial Irradiation
预防性脑照射

Intracranial metastases occur in more than 50% of patients with SCLC. Randomized studies have shown that PCI is effective in decreasing the incidence of cerebral metastases, but most individual studies did not have sufficient power to show a meaningful survival advantage. A meta-analysis of all randomized PCI trials (using data from individual patients) reported a 25% decrease in the 3-year incidence of brain metastases, from 58.6% in the control group to 33.3% in the PCI-treated group. Thus, PCI seems to prevent (and not simply delay) the emergence of brain metastases. This meta-analysis also reported a 5.4% increase in 3-year survival in patients treated with PCI, from 15.3% in the control group to 20.7% in the PCI group. Although the number of patients with extensive-stage disease was small in this meta-analysis, the observed benefit was similar in patients with both limited- and extensive-stage disease.
超过50%的小细胞肺癌患者发生颅内转移。随机研究表明，预防性脑照射（PCI）可有效降低脑转移瘤的发病率，但大多数独立研究并没有充分的能力证明有意义的生存优势。对目前全部随机PCI试验（使用具体患者的数据）的一项meta分析报告，3年脑转移发病率从对照组的58.6%降低PCI治疗组的33.3%，下降了25%。因此，PCI似乎预防（而不是仅仅延迟）脑转移的发生。该meta分析还报告，PCI治疗的患者3年生存率从对照组的15.3%增加到PCI组的20.7%，增加了5.4%。虽然在这项meta分析中广泛期患者数量少，但是在局限期和广泛期患者中观察到的获益均相似。

A retrospective study of patients with limited-stage disease also found that PCI increased survival at 2, 5, and 10 years compared with those who did not receive PCI. A randomized trial from the EORTC assessed PCI versus no PCI in 286 patients with extensive-stage SCLC whose disease had responded to initial chemotherapy; PCI decreased symptomatic brain metastases (14.6% vs. 40.4%) and increased the 1-year survival rate (27.1% vs. 13.3%) compared with controls. Preliminary data from a Japanese phase 3 trial suggest that PCI did not improve survival in patients with extensive-stage disease who had MRI to confirm that they did not have brain metastases.
对局限期患者的一项回顾性研究也发现，与那些未接受PCI的患者相比，PCI增加2年、5年和10年生存率。EORTC的一项随机试验评估了286例初次化疗有效的广泛期小细胞肺癌患者PCI与没有PCI；与对照组相比，PCI减少了症状性脑转移（14.6%对40.4%），并提高了1年生存率（27.1%对13.3%）。日本一项3期试验的初步数据表明，PCI未改善磁共振成像确认无脑转移瘤的广泛期患者的生存。

Late neurologic sequelae have been attributed to PCI, particularly in studies using fractions greater than 3 Gy and/or administering PCI concurrently with chemotherapy. Thus, PCI is not recommended for patients with poor PS (3–4) or impaired neurocognitive function. Older age (>60 years) has also been associated with chronic neurotoxicity. When given after the completion of chemotherapy and at a low dose per fraction, PCI may cause less neurologic toxicity.
迟发性神经系统后遗症被认为是PCI造成的，特别是在使用分割大于3Gy和/或PCI同步化疗的研究中。因此，对于PS差（3–4）或神经认知功能受损的患者不建议PCI。老年（>60岁）也与慢性神经毒性相关。在化疗结束后给予且每次分割剂量低时，PCI导致的神经毒性可能会较轻。

Before the decision is made to administer PCI, a balanced discussion between the patient and physician is necessary. PCI is a category 1 recommendation for patients with limited-stage disease who attain a complete or partial response; PCI is a category 2A recommendation for patients with extensive-stage disease. PCI is also recommended for all patients who have had a complete resection (see Principles of Surgical Resection in the NCCN Guidelines for SCLC). The preferred dose for PCI to the whole brain is 25 Gy in 10 daily fractions (2.5 Gy/fraction), (see Principles of Radiation Therapy in the NCCN Guidelines for SCLC). The NCCN Panel feels that a shorter course of PCI may be appropriate (eg, 20 Gy in 5 fractions) for selected patients with extensive-stage disease. Higher doses (eg, 36 Gy) increased mortality and toxicity when compared with standard doses (25 Gy). PCI should not be given concurrently with systemic therapy, and high total radiotherapy dose (>30 Gy) should be avoided because of the increased risk of neurotoxicity. Fatigue, headache, and nausea/vomiting are the most common acute toxic effects after PCI. After the acute toxicities of initial therapy have resolved, PCI can be administered. For patients not receiving PCI, surveillance for metastases with brain imaging should be considered.
在决定实施PCI之前，病人和医生之间的权衡讨论是必要的。对于获得完全或部分缓解的局限期患者，PCI是一个1类推荐；对于广泛期患者，PCI是一个2A类推荐。对于所有完全切除的患者也建议PCI（见小细胞肺癌NCCN指南中的手术切除原则）。PCI的首选剂量为25Gy/10f，2.5Gy/f，qd（见小细胞肺癌NCCN指南中的放射治疗原则）。NCCN小组认为，对于选择性的广泛期患者，更短疗程PCI可能是合理的（如20Gy/5f）。与标准剂量（25Gy）相比，更高剂量（如36Gy）增加死亡率和毒性。PCI不应与全身治疗同时给予，并且应避免放疗总量高（>30 Gy），因为增加神经毒性风险。PCI后，疲劳、头痛和恶心/呕吐是最常见的急性毒性。在初始治疗的急性毒性消除后，可以给予PCI。对于未接受PCI的患者，应考虑脑影像学监测转移。

Palliative Radiotherapy
姑息性放疗

For patients with localized symptomatic sites of disease (ie, painful bony lesions, spinal cord compression, obstructive atelectasis) or with brain metastases, radiotherapy can provide excellent palliation (see Initial Treatment in the NCCN Guidelines for SCLC and the NCCN Guidelines for NSCLC, available at NCCN.org). Orthopedic stabilization may be useful in patients at high risk for fracture because of osseous structural impairment. Because patients with SCLC often have a short life span, surgery is not usually recommended for spinal cord compression. Whole-brain radiotherapy is recommended for brain metastases in patients with SCLC due to the frequent occurrence of multiple metastases (see Principles of Radiation Therapy in the NCCN Guidelines for SCLC and the NCCN Guidelines for Central Nervous System Cancers, available at NCCN.org). Although late complications, such as neurocognitive impairment, may occur with whole-brain radiotherapy this is less of an issue in patients with SCLC because long-term survival is rare. The recommended dose for whole-brain radiotherapy is 30 Gy in 10 daily fractions. In patients who develop brain metastases after PCI, stereotactic radiosurgery may be considered.
对于有症状的病变局部（即痛性骨损害、脊髓压迫、阻塞性肺不张）或脑转移患者，放疗可完美缓解（见小细胞肺癌NCCN指南和非小细胞肺癌NCCN指南中的初始治疗，可在NCCN.org获得）。在因骨结构损伤的骨折高危患者中，矫形稳定可能是有益的。因为小细胞肺癌患者往往寿命短，所以，通常不推荐手术治疗脊髓压迫。对于小细胞肺癌患者中的脑转移，由于经常出现多发转移，因此推荐全脑放疗（见小细胞肺癌NCCN指南和中枢神经系统肿瘤NCCN指南中的放射治疗原则，可在NCCN.org获得）。虽然全脑放疗可能发生晚期并发症，如神经认知障碍，但是在小细胞肺癌患者中这不是一个大问题，因为长期生存罕见。推荐的全脑放疗剂量为30Gy/10f，qd。在PCI后发生脑转移的患者中，可以考虑立体定向放射外科。