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迄今为止最大宗的一项术前化疗、也是人们一直在关注的由SWOG牵头，有ACOSOG、ECOG、NCCTG、NCIC和RTOG等协作组织一起参加的S9900研究[2]。该研究的入组对象为ⅠB~ⅢA(T3N0-1非N2)期的病人，原预计入组600例，因辅助化疗已有阳性结果，再用单独手术做对照不符合伦理学原则，因此尽管尚未达到入组例数，该临床研究提前于2004年7月结束入组。总共有354例病人入组，180例入组术前化疗，174例入组单独手术，最后确定的例数为335例。术前化疗方案为泰素225mg/m2/3h，卡铂AUC=6，3周重复共3周期。手术至少为肺叶+纵隔淋巴结采样术。全组按ⅠB/ⅡA∶ⅡB/ⅢA分层。中位年龄64岁，63%为T2N0M0，5%为T1N1M0，19%为T2N1M0，10%为T3N0M0，3%为T3N1M0。31%是腺癌。主要的终点指标是术前化疗组2.7年的中位生存时间增加33%。
77%患者完成术前3周期的化疗，其影像学有效率为40%，治疗相关死亡化疗组3例，手术30天死亡率化疗组6例，单手术组4例。结果见表1。
表3 S9900术前化疗与单手术比较临床研究结果 | | PC化疗组 | 单手术组 | | | 例数 | 168 | 167 | | 无进展生存时间
中位生存时间（月）
1年生存率（%）
2年生存率（%） | 29
68
54 | 20
68
47 | HR=0.85(0.63~1.14)
P=0.26 | 总生存时间
中位生存时间（月）
1年生存率（%）
2年生存率（%） | 42
82%
68% | 37
79%
64% | HR=0.88(0.63~1.23)
P=0.47 |
虽然是提前终止研究，但它仍然是早期非小细胞肺癌术前化疗最大的随机对照研究，目前报道虽然是一个初步结果，但它充分肯定了术前化疗这一方法的可操作性，无复发生存率和总生存率虽然没有统计学意义，但显示了有利于术前化疗的趋向。
术前化疗的研究还有Scagliotti 牵头的Chest Ⅲ期临床试验[3]，该研究比较术前3周期健择/顺铂然后手术和单独手术的疗效差别，原计划入组700例，因被认为不符伦理学而提前终止。2000年9月~2004年12月，来自欧洲44个中心共267例患者被随机，141入组单手术组，126例入组术前化疗组。术前化疗的反应率为32.5%（21.1%不能评价），完成术前3周期化疗的79.4%，6个月的无复发生存率是89.1%对79.6%。
总体上讲，术前化疗的地位目前没有术后化疗那么明确，而且可能也难于明确了，因为大部分研究因伦理问题而停止。未来的方向应是术前化疗对术后化疗的随机对照研究。
手术（术前予或不予紫杉醇和卡铂）治疗早期非小细胞肺癌：西南肿瘤协作组试验 S9900，一项组间、随机、3期试验
Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.
出处：J Clin Oncol 2010 Apr 28(11) :1843-9
作者：Pisters KM;Vallieres E; Crowley JJ;Franklin WA;Bunn PA Jr;Ginsberg RJ;Putnam JB Jr;Chansky K;Gandara D
目的：早期非小细胞肺癌(NSCLC)患者进行完全切除术后预后依然很差。之前关于可切除的NSCLC进行术前（诱导）化疗的研究证明了其可行性，存活数据也是鼓舞人心的。本随机、3期试验对术前用紫杉醇和卡铂化疗与只进行手术的早期NSCLC患者的总体存活率(OS)进行了比较。
患者和方法：临床1B-3A期的NSCLC患者（排除肺上沟瘤和N2期病情的患者）符合入选条件。患者被随机分配入仅手术组或进行3个周期的紫杉醇（225 mg/m2）和卡铂（曲线下面积为6）化疗后手术切除组。主要终点是OS；次要终点是无进展存活率 (PFS)、化疗反应以及毒性。
结果：在其他研究报告了术前化疗对存活率有益处后，这项涉及354名患者的试验在早期就结束了。仅手术组的中位OS为41个月，而术前化疗组为62个月（风险比为0.79；95% 可信区间CI为0.60-1.06；P = 0.11）。仅手术组的中位PFS为20个月，术前化疗组为33个月（风险比为0.80；95% CI为0.61-1.04；P = 0.10）。41%的患者可见对化疗有显著反应；未观察到意外毒性。
结论：这项试验在出现支持术前化疗的强有力证据后即提前结束了。虽然术前化疗的OS和PFS较高，但差异并无统计学意义。目前，有较强的证据支持对早期NSCLS进行术前化疗。
美国西南肿瘤组(SWOG)牵头启动了S9900研究,以评价NSCLC新辅助化疗后手术能否改善生存。该研究以ⅠB~ⅢA(T3N0-1非N2)期患者为研究对象,原计划入组600例,但因术后辅助化疗已有阳性结果,再用单独手术作对照不符合伦理学原则,故于2004年7月提前结束入组,最终共入组354例患者,包括术前化疗组180例和单独手术组174例。全组按ⅠB /ⅡA和ⅡB /ⅢA期分层,70%为ⅠB /ⅡA期,30%为ⅡB /ⅢA期。术前化疗方案为紫杉醇+卡铂(PC方案),重复使用3个周期,有效率为41%。S9900研究中位随访46个月的患者生存结果见表1,提示作为第三代含铂方案的代表之一,PC方案术前化疗与单独手术相比,有改善生存的趋势。
共纳入354例病人，2007年ASCO年会报道的一项由美国西南肿瘤组(Southwest Oncology GroupSWOG启动的S9900试验[3]未取得阳性结果。该试验同样针对ⅠB-ⅢAT3N0-1非N2期患者。其中术前化疗组180例，单独手术组174例。术前化疗方案为紫杉醇225mg/m2+卡铂AUC=6PC重复使用三个周期，有效率41%治疗相关死亡3例。2007年报道的S9900试验中位随访期达46个月的生存结果，其中术前化疗组与单手术组的5年无疾病进展生存率分别为33% vs 21%P=0.0985年生存率分别为33% vs 21%P=0.24这提示紫杉醇+卡铂术前化疗与单独手术相比，生存期无显著性优势。
S9900: Surgery alone or surgery plus induction (ind) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Follow-up on a phase III trial.
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 7520
K. Pisters, E. Vallieres, P. A. Bunn, J. Crowley, K. Chansky, R. Ginsberg, D. R. Gandara, Southwest Oncology Group
Background: Small randomized and non-randomized studies suggest induction chemotherapy may improve survival in early stage NSCLC. The primary objective of this study was to determine if induction PC could improve survival over surgery alone. Preliminary results of this trial were reported at ASCO 2005 (J Clin Oncol, ASCO Proc 23(16S) 2005:7012). Median time for patients alive at last contact is now 46 months (mos). Methods: Consenting patients with clinical stage T2N0, T1-2N1 and T3N0-1 NSCLC (excluding superior sulcus tumors) were stratified by clinical stage (IB/IIA vs. IIB/IIIA) and randomized to induction PC (P:225 mg/m2 over 3 hours, C:AUC=6) on day 1, every 3 weeks × 3 or surgery alone. Eligible patients had a performance status 0-1, age =18 years (yrs), predicted post- resection FEV1 =1.0L. Surgery was at least a lobectomy and mediastinal nodal sampling. The primary endpoint was a 33% increase in overall survival over expected 2.7 yrs median for surgery. Planned sample size was 600 patients, 81% power, 1-sided test, 0.025 significance. Results: S9900 closed 07/04 when adjuvant chemotherapy became standard. 354 patients had accrued; 174-surgery alone, 180- induction PC; 19 were ineligible. Median age 65 yrs, 66% male, 70% IB/IIA, 30% IIB/IIIA. Major radiographic response to induction PC was 41%. Treatment-related deaths: 3 during induction PC, 11 within 30 days of surgery (7-induction PC arm, 4-control). Progression-free survival (PFS), overall (OS) survival rates and hazard ratios (HR) are shown. Conclusions: PFS and OS continue to trend in favor of induction PC with HR similar to those observed in adjuvant trials, supporting the role of chemotherapy in operable NSCLC. Randomized trials comparing induction to adjuvant chemotherapy are warranted. Supported by SWOG CA30102.
| PFS, HR=0.79 (.60-1.04), p=0.098 | OS, HR=0.83 (.61-1.14), p=0.24 |
| Median | 1 yr | 3 yr | 5 yr | Median | 1 yr | 3 yr | 5 yr | Ind PC | 33 mos | 68% | 48% | 41% | 50 mos | 82% | 61% | 48% | Surgery | 21 mos | 68% | 39% | 32% | 47 mos | 79% | 57% | 42% |
S9900: A phase III trial of surgery alone or surgery plus preoperative (preop) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): Preliminary results.
Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 7012
K. Pisters, E. Vallieres, P. Bunn, J. Crowley, R. Ginsberg, P. Ellis, B. Meyers, R. Marks, J. Treat, D. Gandara, Southwest Oncology Group
Background: At the time of study design, phase III trials in stage IIIA NSCLC patients (pts) found improved survival with preop but not adjuvant chemotherapy. A large phase II trial in early stage (ES) NSCLC found preop PC feasible with encouraging survival. S9900 was undertaken to determine whether preop PC could improve survival compared to surgery alone. ACOSOG, ECOG, NCCTG, NCIC and RTOG also participated. Methods: Consenting pts with clinical stage T2N0, T1-2N1, and T3N0-1 NSCLC (excluding superior sulcus tumors) were stratified by clinical stage (IB/IIA vs. IIB/IIIA) and randomized to preop PC (P:225 mg/m2 over 3 hours, C:AUC=6) on day 1, every 3 weeks x 3 or surgery alone. Eligible pts had performance status 0-1, age ≥ 18 years (yrs), predicted post-resection FEV1 ≥ 1.0L. Surgery was at least a lobectomy and mediastinal nodal sampling. The primary endpoint was 33% increase over expected 2.7 yrs median for surgery. Planned sample size of this prospective, randomized trial was 600 pts, 81% power, 1-sided test, 0.025 significance. Current median followup 28 months (mo). Results: S9900 closed to new pt entry in 07/04 following the positive adjuvant data. 354 pts were accrued; 174-surgery alone, 180-preop PC; 16 pts ineligible. Median age 65 yrs, 66% male, 70% IB/IIA, 30% IIB/IIIA. Major radiographic response to PC was 40%. Treatment-related deaths during PC-3, within 30 days of surgery-6 on preop PC arm, 4 on control. Progression free survival (PFS): median, 1 & 2 yr - 29 mo, 68%, 54% preop PC; 20 mo, 68%, 47% control; hazard rate 0.85 (0.63-1.14), p=0.26. Overall survival (OS): median, 1 & 2 yr - 42 mo, 82%, 68% preop PC; 37 mo, 79%, 64% surgery arm; hazard rate 0.88 (0.63-1.23), p=0.47. Conclusions: Although closed early because of adjuvant data, this study is one of the largest randomized trials examining preop chemotherapy in ES NSCLC. As such, it represents a landmark regarding feasibility of this approach. PFS and OS trends favor preop PC, supporting role of chemotherapy in ES NSCLC. Meta-analysis of randomized ES preop trials is planned. Randomized trials comparing preop to adjuvant chemotherapy are warranted. Supported by SWOG CA30102.
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