晚期非小细胞肺癌一线化疗.doc

灵**哥

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　Case 病例
　　A 59-year-old bus driver develops a cough with occasional hemoptysis. Chest x-ray reveals a 4 cm mass in the left upper lobe. CT scan of the lung reveals mediastinal adenopathy. He is seen by a pulmonologist who undertakes bronchoscopy. A biopsy of the left upper lobe lesion reveals poorly differentiated adenocarcinoma. CT scan of the abdomen reveals multiple hepatic defects and a 2 cm left adrenal mass. Biopsy of one of the hepatic lesions reveals adenocarcinoma. His laboratory profile including blood counts and renal and hepatic function tests is normal. His ECOG performance status is 1.
　　一位59岁的汽车司机出现咳嗽并偶尔咳血。胸部X光显示肺左上叶有一4厘米肿块。肺CT扫描显示纵隔淋巴结肿大。支气管镜检查取左上叶病灶活检显示为低分化腺癌。腹部CT扫描显示多处肝损害和一个2厘米的肾上腺肿块。对其中一个肝脏病灶的活检显示为腺癌。他的实验室检测结果包括血细胞计数及肝肾功能为正常。ECOG一般状况评分为1。




专家评论
储大同教授 / Dr. Frank Fossella / Dr. Thomas Lynch
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储大同教授
医科院肿瘤医院内科主任
中国抗癌协会临床肿瘤学协作中心主任委员

目前国际上有几个大型Ⅲ期随机研究，其中在评价ⅢB和Ⅳ期NSCLC治疗的各方案中，ECOG1594最后推荐了卡铂+泰素（TCb）方案，理由是：虽然生存期、有效率与其他三组无统计学上的差异，但相对来说生存质量较好。ECOG1594也包含了泰索帝+顺铂方案（DC），但未被推荐。值得注意的是，TCb方案在先前的SWOG9509研究中，对比第二代标准方案诺维本+顺铂（NC）时，无论是生存期、还是有效率均未占优势，仅仅表现出毒副作用较轻、生活质量较好的优势。而DC方案在TAX326中，无论在有效率、还是生存期（超出1.2个月），在统计学上均优于NC方案。在这种状况下，年龄和行为状态评分以及肾功能状态等，就成为个体化方案选择的考虑因素了。所以，对本例59岁，ECOG 1、肝肾功能及血相正常的患者，可能DC方案更为合适。如果是高龄，胃肠功能较弱的患者，可能TCb方案更好。

另一个未知因素是：如何评价健择+卡铂（GCb）方案与ECOG1594以及TAX326中的其他方案的优劣。GCb与健择+顺铂（GC）在捷克肺癌研究组Ⅲ期、随机研究中证实：有更好的一年生存率：40%比30%（统计学未通过），并有更好的生活质量。GCb方案在伦敦肺癌研究组中，对比另一个欧洲通用的、很强的第二代方案：丝裂霉素+异环磷酰胺+顺铂（MIC）时，虽然有效率一样均为41%，但中位生存期远远超过后者（10.2个月比6.9个月，P=0.028），在生存质量的多项指标评估中，均具统计学的明显差异。同时研究人员发现：GCb方案组血小板下降较明显，但并不造成临床上的出血现象。

因此，迄今为止，从循证医学的角度分析，在大型研究中能够在生存期上，超过第2代代表性标准方案（NC和MIC）的只有DC方案和GCb方案。遗憾的是：这二者之间未进行过直接的对比研究。此例患者，GCb方案也是可选的。

该患者的病理类型是腺癌，Ⅱ期临床研究显示：健择+泰索帝比含铂的方案，具有更高的有效率。可能由于Ras基因、ERCC1基因的表达与在磷癌中的不一样有关，但作为推荐的使用方案，有待于严格的Ⅲ期随机临床研究，来进一步证实。
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Dr. Frank Fossella
Medical Director
Thoracic Oncology Multidisciplinary Care Center
MD Anderson Cancer Center
Houston, Texas

Given this patient’s relatively young age and good performance status, it is certainly appropriate to offer him a trial of systemic chemotherapy, given the evidence showing a modest survival advantage with platinum-based chemotherapy versus supportive care alone. In a non-protocol setting, we now have several active agents which may be useful in the treatment of advanced NSCLC. There are several phase III trials comparing several of these regimens that may offer some insight into which regimens might be preferable in this setting.

考虑到此患者年龄相对较轻，一般状况较好，且临床研究表明以铂类为基础的化疗一线治疗晚期NSCLC较支持治疗产生了适度的生存优势，故对其试用全身化疗肯定是适当的。在临床实践中，我们现有几个药物可以用于晚期NSCLC的治疗。目前有几个对这些药物进行比较的III 期临床研究，应该能对此类患者最佳治疗方案的选择产生提示。

ECOG 1594 was a large randomized trial in which 1105 patients with stage IIIB or IV NSCLC were randomized to receive 1 of 4 platinum-based regimens: paclitaxel plus cisplatin, gemcitabine plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin. There was no significant difference in the 4 groups with respect to response rate (15% - 21%), median survival (7.4 – 8.2 months), and 1-year survival (31% - 36%). However, there was no accounting in this trial for the possible impact of second-line therapy patients may have received after removal from this study. There was a slight increase in time-to-progression for the gemcitabine/cisplatin arm; however, this modest difference may be explained by the fact that this arm was the only one that used an every-4-week cycle. The incidence of thrombocytopenia and anemia were higher in the gemcitabine/cisplatin arm. With regard to non-hematologic toxicities, nausea and vomiting occurred with least frequency in the paclitaxel/carboplatin arm, and there was a slightly higher incidence of renal toxicity in the gemcitabine/cisplatin arm. However, the incidence of other toxicities was equivalent across the four treatment groups. The investigators concluded from ECOG 1594 that the four regimens studied in this trial showed no significant differences in survival or response rate, and relatively minor differences in toxicities, so that any of these regimens would be equally acceptable treatment options for advanced NSCLC. One caveat with this trial, as with any study of this kind, is that it does not take into account the possible impact of second-line therapy.

ECOG1594是一个大型的随机研究，1105位IIIB期或IV期的NSCLC病人被随机分组到4个含铂方案中：紫杉醇+顺铂，健择＋顺铂，泰索帝＋顺铂，紫杉醇＋卡铂。从缓解率(15% - 21%), 中位生存期（7.4 – 8.2 个月）和一年生存率(31% - 36%)来看，4组间无显著差异。但此研究未考虑患者出组后接受二线治疗可能带来的影响。健择/顺铂组TTP稍有延长，但此不大的差异可能是由于这组是唯一采用4周方案而造成的。血小板减少和贫血的发生率在健择/顺铂组较高。从非血液学毒性看，紫杉醇/卡铂组恶心和呕吐的发生率最低，而健择/顺铂组肾毒性发生率稍高。而其它毒性在4组间有相似的发生率。ECOG1594的研究者最后的结论是：此研究中的4种方案在生存或缓解率上无显著差异，在毒性上有相对很小的差异，因此对于晚期NSCLC，其中的任何一个方案均为同样可以接受的治疗选择。需要提醒的是，与任何一个同类的研究一样，此试验未考虑二线治疗的可能影响。

TAX 326 was another large randomized trial in which 1218 patients with stage IIIB or IV NSCLC were randomized to receive either docetaxel + cisplatin (DC) or docetaxel + carboplatin (DCb) versus a reference regimen of vinorelbine + cisplatin (VC). In the first comparison of DC versus VC, the overall survival in the DC arm was greater than the VC control (p = 0.044). The survival curves separate at about 4 months, and then remain non-overlapping throughout the follow-up period. Median survival was 11.3 months, 1-year survival was 46%, and 2-year survival was 21%, compared with 10.1 months, 41%, and 14% in the control group. In support of the survival benefit is the fact that the response rate was also in favor of the DC arm: 32% versus 25% in the VC control (p = 0.029). In the second comparison of DCb versus VC, the overall, median, and 1-year survivals between these 2 groups were equivalent, as were the response rates of 24%-25%.

TAX326是另一个大型随机研究，1218位IIIB期或IV期的NSCLC病人被随机分组到泰索帝＋顺铂组（DC）或泰索帝＋卡铂组(DCb)及诺维本＋顺铂（VC）对照组。在DC对VC的比较中，DC组的总生存>VC组（p=0.044）。生存曲线在4个月时分开并在整个随访期一直未发生交叉。中位生存期为11.3个月，1年生存率为46％，2年生存率为21％，相应的对照组为10.1个月，41％，14％。缓解率亦支持DC组产生的生存益处：32％对VC组的25％(p=0.029)。在DCb对VC的比较中，2组的总生存、中位生存期和1年生存率相当，缓解率也差不多（24％－25％）。

One unique aspect of this trial was the demonstrated impact on quality of life (QoL) for patients treated in the docetaxel arms. QoL was evaluated prospectively using the LCSS and EuroQoL instruments. In the first comparison of DC versus VC, the changes in global QoL were consistently positive in the DC group, while the changes in the VC group were consistently negative (p = 0.016). Similar improvements were seen in other clinical benefit parameters. For example, there was a greater improvement in the pain score and in weight loss for the patients in the DC group compared to VC (p = 0.033 for pain; p < 0.001 for weight loss), and a consistent trend favoring DC compared with VC was also noted for improvement in performance status. Similar improvements in QoL parameters were also noted in the second comparison of DCb versus VC. Changes in global QoL, pain, weight loss, and performance status consistently favored the patients in the DCb arm.

此研究独特的一面是显示出泰索帝组对患者生活质量（QoL）的改善。QoL采用LCSS和欧洲QoL量表进行前瞻性评估。在DC对VC的比较中，总体QoL的变化在DC组一直保持在基线上方，而VC组的变化一直在基线下方(p = 0.016)。其它的临床效益参数也显示出类似的改善。例如，DC组患者的疼痛评分及体重减轻较VC组有很大改善（疼痛评分p = 0.033，体重减轻p < 0.001），一般状况改善的一致倾向也是DC组好于VC组。类似的QoL参数的改善同样表现在DCb对VC的比较中。总体QoL、疼痛、体重减轻及一般状况的改善均对DCb 组的患者更加有利。

The incidence of severe anemia and severe nausea/vomiting was significantly higher with VC than either of the docetaxel arms. However, other toxicity was comparable between the 3 groups.

严重的贫血和严重的恶心/呕吐的发生率是VC组显著高于泰索帝2个组。但其它毒性的发生率在3组相似。

In conclusion, the response rate and overall survival with docetaxel + cisplatin were greater than that seen with VC. And the response rate and survival with docetaxel + carboplatin were equivalent to the control regimen. Patients in the control group had a higher incidence of anemia, nausea, and vomiting. And, finally, significant improvement in several quality of life parameters were noted to both docetaxel groups as compared with the control regimen.

总之，缓解率及总生存在泰索帝＋顺铂组比VC组好，在泰索帝＋卡铂组与对照组相当。对照组的患者贫血、恶心和呕吐的发生率较高。并且，泰索帝2组的生活质量参数与对照组相比有显著改善。

In support of TAX 326 is a phase III Japanese trial reported by Kunitoh. In this trial, 302 patients with stage IV NSCLC were randomized to receive docetaxel + cisplatin (DC) versus their reference regimen of vindesine + cisplatin (VdC). There was a significantly higher response rate in the patients who received DC: 37% versus 21% with VdC, as well as an improvement in overall and median survival favoring the DC arm.

支持TAX326的另一个III 期临床研究是日本的Kunitoh报道的。在此研究中，302位IV期NSCLC患者随机分入泰索帝＋顺铂组(DC)或长春地辛＋顺铂对照组(VdC)。DC组患者的缓解率显著高于VdC组：37％对21％。总生存及中位生存期也是DC组较好。

In summary, the ECOG 1594 trial showed comparable activity and toxicity between four commonly used platinum-based chemotherapy regimens. And two additional phase III trials comparing docetaxel + platinum combinations versus another platinum-containing reference regimen have shown improvement in response rate and survival with cisplatin plus docetaxel. Furthermore, one of those trials (TAX 326) showed significant improvement in several quality of life parameters for patients who received docetaxel plus either cisplatin or carboplatin compared with the control regimen. These studies support the emerging role for docetaxel plus platinum combinations (Option # 4) in the first-line treatment of advanced NSCLC

总而言之，ECOG1594研究表明，4种常用的以铂类为基础的化疗方案有相似的活性和毒性。另外2个比较泰索帝联合铂类与常规含铂方案一线治疗晚期NSCLC的III 期研究显示，顺铂＋泰索帝产生了较对照方案(VC或VdC)明显更高的缓解率和更佳的远期生存。此外，TAX326研究显示，与诺维本/顺铂比较，泰索帝联合顺铂或卡铂组的多项生活质量参数均有明显改善。这些研究支持泰索帝与铂类联合用于晚期NSCLC一线治疗的新兴地位（选项4）。
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Dr. Thomas Lynch
Assistant Professor of Medicine
Massachusetts General Hospital
Boston, Massachusetts

This patient is a 59-year-old man who presents with stage IV adenocarcinoma of the lung with pulmonary, mediastinal, adrenal and liver involvement. We are told that his PS is 1 and that his laboratory profile is normal. We are then asked to choose optimal chemotherapy for this patient.

这是一位59岁的男性病人，患IV期肺腺癌，肺、纵隔、肾上腺和肝受累。我们被告知他的PS＝1，实验室检查结果正常。要求我们为这位患者选一个最佳的化疗方案。

It is important to emphasize that we now have ample evidence that chemotherapy prolongs survival in patients with advanced NSCLC. Multiple randomized trials, as well as a meta-**ysis support the ability of platinum-based chemotherapy to prolong survival compared to best supportive care in advanced disease patients. The survival benefit is most evident for those patients with a good performance status. This patient is thus an excellent candidate for a platinum-based regimen for his NSCLC.

首先需强调的是，我们目前有充分的证据表明化疗可以延长晚期NSCLC患者的生存期。多个随机研究及meta-分析证明以铂类为基础的化疗与最佳支持治疗相比可延长晚期患者的生存期。一般状况好的病人生存益处更明显。因此这位NSCLC患者是采用含铂方案治疗的极佳人选。

Of the 7 choices provided I would choose either a taxane or gemcitabine with a platinum compound as optimal therapy at this point in time (Choice 1, 2 or 4). Data presented at this year’s ECCO meeting show that docetaxel/cisplatin (choice 4) is superior to vinorelbine/cisplatin (choice 3) in advanced NSCLC in terms of response median and overall survival1. Data from ECOG 1594 showed that cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel and carboplatin/paclitaxel produced equivalent survival rates. At this point these are all reasonable choices for patients with advanced disease. Choices between them are based on toxicity profile in a given patient.

在这7个选项中，我选择紫杉类或健择与铂类联合作为最佳治疗（选项1，2或4）。今年ECCO会议报道在晚期NSCLC治疗中泰索帝/顺铂（选项4）从有效率、中位和总生存期上优于诺维本/顺铂（选项3）1。ECOG1594研究的数据显示顺铂/紫杉醇、顺铂/健择、顺铂/泰索帝和卡铂/紫杉醇可达到相同的生存率。从这一点上看，对晚期患者，这些方案均为合理选择。对特定病人应针对毒性反应进行选择。

A key question raised by this patient is whether to use cisplatin or carboplatin. This remains an unanswered question and the ultimate choice between them is often decided by custom. In North America, this would usually be carboplatin and in Europe it would be cisplatin. 这一患者带来的关键问题是用顺铂还是用卡铂。而这一问题目前还没有答案，最终的选择往往是由用药习惯决定的。在北美常用卡铂，在欧洲则是顺铂。

I would not choose a non-platinum-containing regimen such as choice 5 or 6. Data from the Spanish trial presented at ECCO this year showed that a non-platinum regimen had an inferior survival compared with platinum-based regimens2. While both gemcitabine-docetaxel and gemcitabine-vinorelbine are regimens with significant activity and acceptable toxicity they require larger randomized trials before they can be said to be standard of care.

我不会选择非铂类联合方案，如选项5或6。今年ECCO会议发布的西班牙研究资料表明非铂方案与含铂方案相比生存期要差2。虽然健择－泰索帝和健择－诺维本均为具有显著活性和可接受毒性的方案，在它们可被称为标准治疗方案之前还需要进行更大规模的随机临床研究以评估其疗效和不良反应。

Choice 7 (other) in this case would be single-agent therapy. I would not choose this for this patient given his age and performance status. However, for older patients, this is a very reasonable choice. In the MILES study presented at ASCO this year Dr. Gridelli showed that single-agent vinorelbine or single-agent gemcitabine provided the same survival with less toxicity than the combined regimen3.

选项7（其它）在此病例应为单药治疗。考虑到此患者的年龄和一般状况，我不会选此项。但对于年龄更大的病人，这却是一个非常合理的选择。在今年ASCO会议上Dr. Gridelli报道的MILES研究显示，诺维本单药或健择单药与联合用药相比，生存期相似、毒性较低。

一**人

:lol:

一**人

:D :D

j****6

感谢，受益非浅啊！:victory: :victory:

5****3

:victory: :handshake