晚期非小细胞肺癌化疗后初始评效为PR和SD患者无疾病进展生存的比较
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摘要
目的
通常以肿瘤的大小变化作为评价任何抗实体肿瘤治疗疗效的客观指标。在2000年制定了新的实体瘤治疗疗效评价标准(Response Evaluation Criteria in Solid Tumours, RECIST),是目前临床上最常用的抗肿瘤治疗的疗效评价标准。应用RECIST测量标准,疗效反应分为四种,即完全缓解(complete response, CR)、部分缓解(partial response, PR)、疾病稳定(stable disease, SD)和疾病进展(progressive disease, PD)。
临床医生根据肿瘤治疗后的疗效反应来选择最佳的治疗方法。根据RECIST标准,CR和PR均为肿瘤明显缩小,PD为肿瘤增大或出现新发病灶,而SD是相对复杂的分类,即可表现为完全不变,也可表现为轻度的缩小或轻度增大。通常情况下,肿瘤缩小意味着对已接受的治疗方法有效,而增大意味着无效。但在改变治疗策略时,目前的原则是,只有达到PD的患者才停止原治疗,改为另外的治疗方案。对于评效为SD的患者,虽然临床上仍采用原有治疗方案进行治疗,但因疗效评价标准对反应类型的界定并没有基于临床数据,加上定义SD的肿瘤变化的复杂性,SD一直被看作为有争议的分类,因此其临床意义不是非常明确。
化疗仍是晚期非小细胞肺癌患者治疗的主要手段,然而仅有很少的晚期非小细胞肺癌经标准一线铂类为基础化疗后表现为肿瘤缩小,更多的患者表现为SD。在临床治疗中,通常每两周期化疗后进行一次疗效评价,这样对晚期非小细胞肺癌患者给于两周期一线铂类为基础化疗后首次评效为SD的患者,在尽早决定后续治疗策略上则显得更为重要。
无疾病进展时间(progression-free survival, PFS)能更快速、准确的反映一线治疗(初始治疗)是否带来生存益处,因此PFS可以作为是否改变一线治疗方案的依据。那么,是否不同水平的初始评效为SD,即肿瘤缩小或增大程度不同,其PFS是有差异的?是否所有的初始SD的患者都能从原有化疗方案中获益?明确这些将有利于临床医生更早的决定治疗方案的调整,从而达到个体化治疗。
本研究的目的：(1)应用RECIST,针对晚期非小细胞肺癌给于两周期一线铂类为基础化疗后首次评效为PR和SD的患者,通过比较他们的PFS有无差异,来明确SD的临床意义；(2)在初始评效为SD患者中,探讨肿瘤大小变化的百分比与他们的PFS之间关系。从而,指导临床医生尽早决定是否需要继续或改变现有治疗策略。
材料与：方法
(一)患者选择
1、入组标准
(1)年龄在18-75岁之间,性别不限；
(2)经病理组织学或细胞学确诊的不能切除、非根治性切除或术后复发转移的晚期非小细胞肺癌的患者；
(3)以前从未接受过化疗或术后辅助化疗结束后复发或转移,距末次化疗超过6个月；
(4)根据RECIST,至少有一个可测量的肿瘤客观病灶；
(5)位于接受过放射治疗的区域的病灶不能作为可测量病灶；
(6)如果肝转移病灶接受过介入治疗不能作为可测量病灶；
(7)空腔脏器不作为靶病灶；
(8)预计生存≥3个月；
(9) ECOG评分0或1；
(10)血液学、心脏、肝功能、肾功能基本正常。
2、排除标准
(1)仅有不可测量病灶如骨转移或胸腹腔积液为唯一观察指标者；
(2)试验期间对唯一的目标病灶进行放疗；
(3)脑转移者；脑膜转移者；
(4)严重肝肾功能不全者；心功能不全Ⅲ／Ⅳ级或6个月内发生过心肌梗塞；
(5)有严重未控制的内科疾病或急性感染者；
(6)已知既往多种药物过敏者。
(二)治疗
1、方案
所有入组非小细胞肺癌患者均给于给予铂类为基础的标准的联合化疗方案,即NP、GP、PP、TP,均21天为1周期。根据病人的身体状况及意愿选择上述化疗方案。每个患者至少进行2周期的化疗,2周期后进行疗效评定。PD患者出组,CR、PR、SD患者继续原方案。共4-6周期。
2、剂量调整方案
(1)按照NCI-CTC毒性评价标准,出现骨髓毒性Ⅲ度或以上,下一周期剂量减少15%-25%或推迟1-2周化疗。如果减量后仍出现Ⅲ-Ⅳ度毒性,则停止治疗；如出现Ⅳ度粒细胞减少合并严重感染性发热则终止治疗。
(2)按照NCI-CTC毒性评价标准,非血液学毒性(脱发除外)出现Ⅲ度或Ⅲ度以上时,下一周期剂量减少15%-25%
(3)心脏毒性：2-4级,停止治疗。
3、辅助治疗方案
止吐药物、集落刺激因子、双磷酸盐类药物
(三)影像资料收集及研究
按RECIST测量方法,每个患者都在化疗前1个月内给于基线检查,可测靶病灶行薄层螺旋CT检查。所有的影像扫描由有资格的放射科医师进行,以确保检查结果的可靠性。初始2周期化疗结束后,每个病人都由同一放射科医师对靶病灶进行测量。按照RECIST,计算所有靶病灶的最长径之和,并与基线状态的最长经之和相比,得出靶病灶化疗前后大小变化的百分比。如果病灶增加超过20%,或出现新病灶,提示PD,退出研究组；缩小30%或以上,提示PR；介于PR和PD之间为SD；全部肿瘤病灶消失,提示CR。SD患者计算出具体靶病灶变化的百分比,用于进一步研究。
(四)随访
1、随访对象
除化疗2周期后评效PD患者,所有病人都应当进行随访。
2、随访时间
化疗期间,CR、PR、SD患者每2周期评效一次,出现PD或死亡者观察终止；化疗周期全部结束后(除有病情变化需随时复查外),每2个月复查评效一次,直到PD或死亡。
3、随访内容
(1)靶病灶的大小变化百分比：依据RECIST,计算所有靶病灶的最长径之和减去基线状态的最长经之和,并与基线状态的最长经之和相比。
(2)PFS：治疗开始到疾病进展或死亡
(五)统计分析
1、根据RECIST测量方法,将化疗两周期前后靶病灶缩小百分比,即化疗反应分类,定义为≥30%[PR],≥25%,≥20%,≥15%,≥10%,≥5%,和≥0%。分别以缩小30%、25%、20%、15%、10%、5%、0%为分界点,比较两组PFS差异。
2、PFS采用Kaplan-meier曲线法进行描述。
3、用log-rank检验比较两组PFS。
4、基线状态的均衡性分析：如为定性资料采用X2检验；定量资料采用Kruskal-Wallis检验或方差分析。
5.采用COX回归模型方法进行多因素分析。
以上采用SPSS13.0统计软件进行统计分析。P<0.05有统计学意义。
结果
1、化疗两周期后疗效反应类型分布及患者特征
在2007年8月到2009年11月间,来自中国医科大学附属第一医院和辽宁省肿瘤医院的188名患者入组临床研究,其中9人化疗1周期后脱落。179人进行了2周期铂类为基础一线化疗后的首次评效,根据RECIST,37人为PR,117人为SD,25人为PD,没有CR病人。共有154人(PR+SD)进入最终分析,他们的中位年龄57岁,38%的病人为60岁以上,60%为男性,63%为ⅣV期,42%病人体重下降≥5%,ECOG为0或1分。
2、两周期化疗后初始评效为SD患者的靶病灶大小变化的分布
肿瘤缩小在25%和30%之间17人,20%和25%之间18人,15%和20%之间16人,10%和15%之间12人,5%和10%之间8人,0%和5%之间29人,其他为肿瘤增大不超过20%。
3、两周期化疗后初始评效为PR和SD患者PFS的比较
经统计分析这两组病人的基本特征无统计学差异,即基线状态下两组病人特征是均衡的。37人评效为PR的病人中位PFS为249天(95%可信区间为187-310天)；117人评效为SD的病人中位PFS为220天(95%可信区间为191-248天)。经log-rank检验两组无统计学差异(P=0.991)
4、初始评效为SD的患者中,靶病灶大小变化率与PFS之间的关系
肿瘤缩小为≥25%,≥20%,≥15%,≥10%,≥5%,≥0%时,中位PFS分别为289天、270天、242天、225天、221天、221天。并分别以这五个百分比为分界点,采用log-rank检验比较两组的PFS,均无统计学差异(P>0.05)。表明在SD患者中没有找到一个最佳的肿瘤缩小百分比能更好的预测PFS。
5.将影响晚期非小细胞肺癌的其他预后因素,性别、年龄、体重丢失、ECOG评分状态及疾病分期,进行多因素分析,发现体重丢失≥5%、ECOG评分状态≥1预后差(P<0.05)。COX回归模型方法显示性别、年龄、疾病分期、2周期化疗后初始评效为SD患者中靶病灶大小变化的百分比同PFS之间均没有明显联系(P>0.05)。
结论
1.晚期非小细胞肺癌经两周期一线铂类为基础的化疗后初始评效为PR和SD的患者表现为相似的PFS。
2.对于化疗后首次评效为SD的患者,其不同水平的SD,即肿瘤缩小或增大的百分比不同,均有相似的PFS。
3.在功能性评估没有被纳入评效标准前,RECIST仍然是目前晚期非小细胞肺癌化疗后疗效评价的标准,是指导临床治疗决策调整的依据。
Objective
The change of tumour size is regarded as an objective indicator in assessing the efficiency of any anticancer therapy. Currently, the Response Evaluation Criteria in Solid Tumours (RECIST) based on morphologic evaluation, is widely used in evaluating the response to anticancer treatment. Using RECIST measurement criteria, patients in clinical treatments are stratified into one of four groups; i.e. complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) on the basis of change in lesion size.
The purpose of stratification of patients into response categories is to acquire optimal treatment schemes. CR and PR indicate apparent decrease in tumour size. PD means a significant increase in tumour size or with the appearance of new lesions SD is a relatively more complex category, and ranges from a minor decrease to a minor increase. It is generally accepted that a decrease in tumour size suggests effectiveness of the current therapy and an increase in tumour size indicates ineffectiveness. But when it comes to replacement of the current medical decision, only PD patients accept an alternative therapy in clinical practice. The maintenance of SD patients on their original treatment schemes is accepted as the norm in routine practice, although RECIST does not provide any reliable suggestion for clinicians to follow. The definition of response categories in RECIST is an arbitrary convention that is not based on any clinical data, for it has been adapted from the earlier WHO criteria on the assumption that the tumour is spherical model. SD, with its complex components, has long been viewed as a controversial category with an equivocal result and its clinical significance is unclear.
Chemotherapy is still the dominant treatment for advanced non-small cell lung cancer (NSCLC). However, the reality is that only a few patients with advanced NSCLC experience tumor decrease after standard first-line platinum-based chemotherapy and many more patients experience SD. So, it is very important to choose a suitable treatment regimen for advanced NSCLC patients who get SD in their initial assessment after the first two courses of first-line platinum-based chemotherapy. However, whether the different level of SD undergoes different PFS, whether all SD patients benefit from the original treatments is of great importance in current clinical practice. PFS is believed to be a rapid and accurate indicator for assessing the effectiveness of first-line treatment and predicting survival benefits. It can be used as a scale for retaining/replacing first-line treatments.
The objectives of this study were:(1) to clarify the clinical significance of SD by comparing the PFS of PR and SD patients after the first two courses of chemotherapy; and (2) to explore the relationship between the change of tumour size, which ranges from minor decrease to minor increase, and their PFS among the achieved SD patients with advanced NSCLC according to RECIST standard in their initial assessment after the first two cycles of first-line platinum-based chemotherapy, to provide some guidance for clinical practice at a relatively early time.
Materials and Methods
1. Patient Selection
Male and female patients in the age range 18-80 years were eligible for the research if they met the following criteria; histologically or cytologically confirmed with non-small cell lung cancer (NSCLC) that is unresectable, recurrent or metastatic; no previous adjuvant chemotherapy or recurrent metastatic NSCLC patients who have not received adjuvant chemotherapy for at least 6 months before the trial; at least one measurable tumour lesion not located in the locus that has received radiotherapy according to RECIST. Liver metastatic lesions that had received interventional therapy were not regarded as measurable lesions and hollow viscous lesions were not regarded as target lesions.. The other requisites were: anticipated time of survival of at least three months; a desirable life exponent, i.e.0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) performance status; adequate renal, hepatic, cardiac and hematologic function.
Patients were not enrolled in the study if they had only immeasurable lesions, such as malignant pleural effusion, ill-defined pulmonary densities and osseous metastasis, or if their only measurable lesion had received radiotherapy during the research; or they had brain metastases or meningeal metastases.
2. Treatments
All patients with advanced NSCLC were assigned to a combination of platinum-based chemotherapy, i.e. NP, GP, TP or DP treatment schemes according to their own conditions. Each patient received 4-6 courses of chemotherapy, and each course lasted 3 weeks. An assessment was made after every 2 courses of chemotherapy. Patients with PD were excluded from this group and received a different treatment regimen.
3. Dosage Adjustment Scheme
Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) toxicity scale. If hematologic toxicityⅢor greater occurred, the dosage for the next cycle was decreased to 75-85% of the original dosage or the next course of treatment was postponed by 1 or 2 weeks. If hematologic toxicityⅢor greater remained, or a fever from combined severe infection and granulocytopenia IV occurred, the planned treatment was terminated. If non-hematologic toxicity (except trichomadesis)Ⅲor greater occurs, the dosage for the next course was adjusted to 75-85% of the original dosage. If cardiotoxicityⅡ-Ⅳ occurred, treatment was discontinued.
Throughout chemotherapy, adjuvant medicine such as antanacathartic, colony-stimulating factor and diphosphonate were given to reduce adverse events when necessary.
4. Image Data Collection and Study
Each patient had a base-line check within one month before their first-line chemotherapeutic treatment started. To ensure the credibility of the study, images of measurable lesions were obtained by the qualified radiologists through Spiro-CT or MRI scans. Subsequent images were obtained by the same radiologist after the first 2 courses of chemotherapy for each patient. To minimize variation between operators, all measurements of the images were done at the same anatomic level and orientation by an independent qualified radiologist. In contrast with the base-line images, any change in the size of target lesions was calculated according to RECIST. Patients with an increase of 20% or more in lesion size or those with new lesions were regarded as having PD and were excluded from the study. Patients with a change of lesion size ranging from an increase of< 20% to a decrease of< 30% and with no new lesion were stratified as having SD. Patients with a 30% or greater decrease in the target lesion were regarded as achieving PR. Patients with disappearance of the lesion were stratified as achieving CR. For those with SD, the percentage of change in tumour size has been recorded for further study.
5. Follow-up Visit
A follow-up visit was given to each patient who achieved CR, PR and SD. The assessment process was repeated every 2 courses until the end of the chemotherapy, or the aggravation of the disease, and after that, every 2 months until the progression of the disease or death occurred. This kind of service could be provided to meet a patient's need at any time. The percentage of change in size of target tumours and the PFS were the main contents for a follow-up visit.
6. Statistical Analysis
SPSS13.0 software was used for all statistical analysis. The correlation between the change in size of target lesions before and after the first two courses of chemotherapy and their PFS was calculated. According to the RECIST standard, the sum of the longest dimension of all the target lesions was calculated for each patient to provide the baseline before treatment. The same measurements and calculation were done after the first two courses of chemotherapy to obtain the initial assessment sum. The change ratio of target lesions was calculated as: (Assessment sum-Baseline sum)/Baseline sum PFS was calculated from the date of first treatment to disease progression or death. The Kaplan-Meier curve was used to describe PFS, and a log-rank test was used to compare the PFS of each category defined according to the percentage reduction in tumour size i.e.≥30%[PR],≥25%,≥20%,≥15%,≥10%,≥5%, and> 0%.Theχ2 test was used for qualitative data analysis, and the Kruskal-Wallis test or variance analysis was used to analyse the quantitative data. P<0.05 was set as the level of statistical significance.
Results
1. Distribution of Response Categories and Patient Characteristics
Altogether,188 patients were enrolled in the trial but 9 withdrew after completing their first cycle of chemotherapy. The remaining 179 patients with inoperative NSCLC had the initial assessment after the first two courses of first-line platinum-based chemotherapy:37 achieved PR and 117 were regarded as SD and these 154 patients (PR+SD) were eligible for the final analysis. The remaining 25 had PD and no CR according to RECIST. The characteristics of the patients included in this analysis:the median age of the patients when enrolled into the study was 57 years (range 26-77 years), with 38%>60 years. A total of 92 males (60%) were eligible for the analysis. The vast majority of patients (63%) had stage IV disease,64 patients (42%) reported a weight loss of≥5%, and the majority of patients had an ECOG performance status of 0 or 1.
2. Distribution of Change in Tumour Size of Initial SD Patients
There was a decrease of tumour size of 25-30% for 17,20-25% for 18,15-20% for 16,10-15% for 12 and 5-10% for 8 and 0-5% for 29. The increase of tumour size in the other patients was<20%.
3. Comparison of PFS of Patients with Initial PR and SD
Careful examination found no statistically significant difference of patient characteristics between the two groups, i.e. baseline characteristics were well balanced between PR and SD. The median PFS was 249 days (95% confidence interval,187-310 days) for the 37 patients with PR and 220 days (95% confidence interval,191-248 days) for the 117 patients with SD. The log-rank test found no significant difference (P= 0.991) of PFS between the PR and SD subgroups.
4. Relationship between Change in Target Lesion Size and PFS among Initial SD Patients
The median PFS of patients with≥25%,>20%,≥15%,≥10%,≥5%or≥0% decrease in tumour size was 289 days,270 days,242 days,225 days,221 days or 221 days, respectively. The P value associated with the log-rank test comparing the PFS of responding patients with that of non-responding patients using different definitions of response. No significantly better cut-off point, i.e. optimal percentage of decrease in tumour size, was found in predicting the PFS of the patients with SD.
In addition, among SD patients, those with an initial decrease of 30-20% in tumour size were not significantly distinguishable (P>0.05) from those with an initial increase.
5. Multivariate analysis included factors such as sex, age, weight loss, ECOG performance status, and stage of disease, which might have a potential effect on prognosis of NSCLC patients. ECOG 1 and weight loss of≥5% was relatively worse for predicting PFS(P<0.05). Cox regression analysis showed that other prognostic factors like age, sex, stage of disease, the percentage of change in target lesion size of patients with SD derived from the initial assessment after the first two courses of chemotherapy are not associated with PFS (P>0.05)
Conclusions
1. Initial PR and SD enjoy similar PFS for patients with advanced NSCLC.
2. Within the initial SD subgroup, different percentages of tumour shrinkage or increase undergo similar PFS.
3. RECIST remains a reliable norm in assessing the effectiveness of chemotherapy for patients with advanced NSCLC before functional assessment has been integrated into the criteria.
通常以肿瘤的大小变化作为评价任何抗实体肿瘤治疗疗效的客观指标。在2000年制定了新的实体瘤治疗疗效评价标准(Response Evaluation Criteria in Solid Tumours, RECIST),是目前临床上最常用的抗肿瘤治疗的疗效评价标准。应用RECIST测量标准,疗效反应分为四种,即完全缓解(complete response, CR)、部分缓解(partial response, PR)、疾病稳定(stable disease, SD)和疾病进展(progressive disease, PD)。
临床医生根据肿瘤治疗后的疗效反应来选择最佳的治疗方法。根据RECIST标准,CR和PR均为肿瘤明显缩小,PD为肿瘤增大或出现新发病灶,而SD是相对复杂的分类,即可表现为完全不变,也可表现为轻度的缩小或轻度增大。通常情况下,肿瘤缩小意味着对已接受的治疗方法有效,而增大意味着无效。但在改变治疗策略时,目前的原则是,只有达到PD的患者才停止原治疗,改为另外的治疗方案。对于评效为SD的患者,虽然临床上仍采用原有治疗方案进行治疗,但因疗效评价标准对反应类型的界定并没有基于临床数据,加上定义SD的肿瘤变化的复杂性,SD一直被看作为有争议的分类,因此其临床意义不是非常明确。
化疗仍是晚期非小细胞肺癌患者治疗的主要手段,然而仅有很少的晚期非小细胞肺癌经标准一线铂类为基础化疗后表现为肿瘤缩小,更多的患者表现为SD。在临床治疗中,通常每两周期化疗后进行一次疗效评价,这样对晚期非小细胞肺癌患者给于两周期一线铂类为基础化疗后首次评效为SD的患者,在尽早决定后续治疗策略上则显得更为重要。
无疾病进展时间(progression-free survival, PFS)能更快速、准确的反映一线治疗(初始治疗)是否带来生存益处,因此PFS可以作为是否改变一线治疗方案的依据。那么,是否不同水平的初始评效为SD,即肿瘤缩小或增大程度不同,其PFS是有差异的?是否所有的初始SD的患者都能从原有化疗方案中获益?明确这些将有利于临床医生更早的决定治疗方案的调整,从而达到个体化治疗。
本研究的目的：(1)应用RECIST,针对晚期非小细胞肺癌给于两周期一线铂类为基础化疗后首次评效为PR和SD的患者,通过比较他们的PFS有无差异,来明确SD的临床意义；(2)在初始评效为SD患者中,探讨肿瘤大小变化的百分比与他们的PFS之间关系。从而,指导临床医生尽早决定是否需要继续或改变现有治疗策略。
材料与：方法
(一)患者选择
1、入组标准
(1)年龄在18-75岁之间,性别不限；
(2)经病理组织学或细胞学确诊的不能切除、非根治性切除或术后复发转移的晚期非小细胞肺癌的患者；
(3)以前从未接受过化疗或术后辅助化疗结束后复发或转移,距末次化疗超过6个月；
(4)根据RECIST,至少有一个可测量的肿瘤客观病灶；
(5)位于接受过放射治疗的区域的病灶不能作为可测量病灶；
(6)如果肝转移病灶接受过介入治疗不能作为可测量病灶；
(7)空腔脏器不作为靶病灶；
(8)预计生存≥3个月；
(9) ECOG评分0或1；
(10)血液学、心脏、肝功能、肾功能基本正常。
2、排除标准
(1)仅有不可测量病灶如骨转移或胸腹腔积液为唯一观察指标者；
(2)试验期间对唯一的目标病灶进行放疗；
(3)脑转移者；脑膜转移者；
(4)严重肝肾功能不全者；心功能不全Ⅲ／Ⅳ级或6个月内发生过心肌梗塞；
(5)有严重未控制的内科疾病或急性感染者；
(6)已知既往多种药物过敏者。
(二)治疗
1、方案
所有入组非小细胞肺癌患者均给于给予铂类为基础的标准的联合化疗方案,即NP、GP、PP、TP,均21天为1周期。根据病人的身体状况及意愿选择上述化疗方案。每个患者至少进行2周期的化疗,2周期后进行疗效评定。PD患者出组,CR、PR、SD患者继续原方案。共4-6周期。
2、剂量调整方案
(1)按照NCI-CTC毒性评价标准,出现骨髓毒性Ⅲ度或以上,下一周期剂量减少15%-25%或推迟1-2周化疗。如果减量后仍出现Ⅲ-Ⅳ度毒性,则停止治疗；如出现Ⅳ度粒细胞减少合并严重感染性发热则终止治疗。
(2)按照NCI-CTC毒性评价标准,非血液学毒性(脱发除外)出现Ⅲ度或Ⅲ度以上时,下一周期剂量减少15%-25%
(3)心脏毒性：2-4级,停止治疗。
3、辅助治疗方案
止吐药物、集落刺激因子、双磷酸盐类药物
(三)影像资料收集及研究
按RECIST测量方法,每个患者都在化疗前1个月内给于基线检查,可测靶病灶行薄层螺旋CT检查。所有的影像扫描由有资格的放射科医师进行,以确保检查结果的可靠性。初始2周期化疗结束后,每个病人都由同一放射科医师对靶病灶进行测量。按照RECIST,计算所有靶病灶的最长径之和,并与基线状态的最长经之和相比,得出靶病灶化疗前后大小变化的百分比。如果病灶增加超过20%,或出现新病灶,提示PD,退出研究组；缩小30%或以上,提示PR；介于PR和PD之间为SD；全部肿瘤病灶消失,提示CR。SD患者计算出具体靶病灶变化的百分比,用于进一步研究。
(四)随访
1、随访对象
除化疗2周期后评效PD患者,所有病人都应当进行随访。
2、随访时间
化疗期间,CR、PR、SD患者每2周期评效一次,出现PD或死亡者观察终止；化疗周期全部结束后(除有病情变化需随时复查外),每2个月复查评效一次,直到PD或死亡。
3、随访内容
(1)靶病灶的大小变化百分比：依据RECIST,计算所有靶病灶的最长径之和减去基线状态的最长经之和,并与基线状态的最长经之和相比。
(2)PFS：治疗开始到疾病进展或死亡
(五)统计分析
1、根据RECIST测量方法,将化疗两周期前后靶病灶缩小百分比,即化疗反应分类,定义为≥30%[PR],≥25%,≥20%,≥15%,≥10%,≥5%,和≥0%。分别以缩小30%、25%、20%、15%、10%、5%、0%为分界点,比较两组PFS差异。
2、PFS采用Kaplan-meier曲线法进行描述。
3、用log-rank检验比较两组PFS。
4、基线状态的均衡性分析：如为定性资料采用X2检验；定量资料采用Kruskal-Wallis检验或方差分析。
5.采用COX回归模型方法进行多因素分析。
以上采用SPSS13.0统计软件进行统计分析。P<0.05有统计学意义。
结果
1、化疗两周期后疗效反应类型分布及患者特征
在2007年8月到2009年11月间,来自中国医科大学附属第一医院和辽宁省肿瘤医院的188名患者入组临床研究,其中9人化疗1周期后脱落。179人进行了2周期铂类为基础一线化疗后的首次评效,根据RECIST,37人为PR,117人为SD,25人为PD,没有CR病人。共有154人(PR+SD)进入最终分析,他们的中位年龄57岁,38%的病人为60岁以上,60%为男性,63%为ⅣV期,42%病人体重下降≥5%,ECOG为0或1分。
2、两周期化疗后初始评效为SD患者的靶病灶大小变化的分布
肿瘤缩小在25%和30%之间17人,20%和25%之间18人,15%和20%之间16人,10%和15%之间12人,5%和10%之间8人,0%和5%之间29人,其他为肿瘤增大不超过20%。
3、两周期化疗后初始评效为PR和SD患者PFS的比较
经统计分析这两组病人的基本特征无统计学差异,即基线状态下两组病人特征是均衡的。37人评效为PR的病人中位PFS为249天(95%可信区间为187-310天)；117人评效为SD的病人中位PFS为220天(95%可信区间为191-248天)。经log-rank检验两组无统计学差异(P=0.991)
4、初始评效为SD的患者中,靶病灶大小变化率与PFS之间的关系
肿瘤缩小为≥25%,≥20%,≥15%,≥10%,≥5%,≥0%时,中位PFS分别为289天、270天、242天、225天、221天、221天。并分别以这五个百分比为分界点,采用log-rank检验比较两组的PFS,均无统计学差异(P>0.05)。表明在SD患者中没有找到一个最佳的肿瘤缩小百分比能更好的预测PFS。
5.将影响晚期非小细胞肺癌的其他预后因素,性别、年龄、体重丢失、ECOG评分状态及疾病分期,进行多因素分析,发现体重丢失≥5%、ECOG评分状态≥1预后差(P<0.05)。COX回归模型方法显示性别、年龄、疾病分期、2周期化疗后初始评效为SD患者中靶病灶大小变化的百分比同PFS之间均没有明显联系(P>0.05)。
结论
1.晚期非小细胞肺癌经两周期一线铂类为基础的化疗后初始评效为PR和SD的患者表现为相似的PFS。
2.对于化疗后首次评效为SD的患者,其不同水平的SD,即肿瘤缩小或增大的百分比不同,均有相似的PFS。
3.在功能性评估没有被纳入评效标准前,RECIST仍然是目前晚期非小细胞肺癌化疗后疗效评价的标准,是指导临床治疗决策调整的依据。
Objective
The change of tumour size is regarded as an objective indicator in assessing the efficiency of any anticancer therapy. Currently, the Response Evaluation Criteria in Solid Tumours (RECIST) based on morphologic evaluation, is widely used in evaluating the response to anticancer treatment. Using RECIST measurement criteria, patients in clinical treatments are stratified into one of four groups; i.e. complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) on the basis of change in lesion size.
The purpose of stratification of patients into response categories is to acquire optimal treatment schemes. CR and PR indicate apparent decrease in tumour size. PD means a significant increase in tumour size or with the appearance of new lesions SD is a relatively more complex category, and ranges from a minor decrease to a minor increase. It is generally accepted that a decrease in tumour size suggests effectiveness of the current therapy and an increase in tumour size indicates ineffectiveness. But when it comes to replacement of the current medical decision, only PD patients accept an alternative therapy in clinical practice. The maintenance of SD patients on their original treatment schemes is accepted as the norm in routine practice, although RECIST does not provide any reliable suggestion for clinicians to follow. The definition of response categories in RECIST is an arbitrary convention that is not based on any clinical data, for it has been adapted from the earlier WHO criteria on the assumption that the tumour is spherical model. SD, with its complex components, has long been viewed as a controversial category with an equivocal result and its clinical significance is unclear.
Chemotherapy is still the dominant treatment for advanced non-small cell lung cancer (NSCLC). However, the reality is that only a few patients with advanced NSCLC experience tumor decrease after standard first-line platinum-based chemotherapy and many more patients experience SD. So, it is very important to choose a suitable treatment regimen for advanced NSCLC patients who get SD in their initial assessment after the first two courses of first-line platinum-based chemotherapy. However, whether the different level of SD undergoes different PFS, whether all SD patients benefit from the original treatments is of great importance in current clinical practice. PFS is believed to be a rapid and accurate indicator for assessing the effectiveness of first-line treatment and predicting survival benefits. It can be used as a scale for retaining/replacing first-line treatments.
The objectives of this study were:(1) to clarify the clinical significance of SD by comparing the PFS of PR and SD patients after the first two courses of chemotherapy; and (2) to explore the relationship between the change of tumour size, which ranges from minor decrease to minor increase, and their PFS among the achieved SD patients with advanced NSCLC according to RECIST standard in their initial assessment after the first two cycles of first-line platinum-based chemotherapy, to provide some guidance for clinical practice at a relatively early time.
Materials and Methods
1. Patient Selection
Male and female patients in the age range 18-80 years were eligible for the research if they met the following criteria; histologically or cytologically confirmed with non-small cell lung cancer (NSCLC) that is unresectable, recurrent or metastatic; no previous adjuvant chemotherapy or recurrent metastatic NSCLC patients who have not received adjuvant chemotherapy for at least 6 months before the trial; at least one measurable tumour lesion not located in the locus that has received radiotherapy according to RECIST. Liver metastatic lesions that had received interventional therapy were not regarded as measurable lesions and hollow viscous lesions were not regarded as target lesions.. The other requisites were: anticipated time of survival of at least three months; a desirable life exponent, i.e.0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) performance status; adequate renal, hepatic, cardiac and hematologic function.
Patients were not enrolled in the study if they had only immeasurable lesions, such as malignant pleural effusion, ill-defined pulmonary densities and osseous metastasis, or if their only measurable lesion had received radiotherapy during the research; or they had brain metastases or meningeal metastases.
2. Treatments
All patients with advanced NSCLC were assigned to a combination of platinum-based chemotherapy, i.e. NP, GP, TP or DP treatment schemes according to their own conditions. Each patient received 4-6 courses of chemotherapy, and each course lasted 3 weeks. An assessment was made after every 2 courses of chemotherapy. Patients with PD were excluded from this group and received a different treatment regimen.
3. Dosage Adjustment Scheme
Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) toxicity scale. If hematologic toxicityⅢor greater occurred, the dosage for the next cycle was decreased to 75-85% of the original dosage or the next course of treatment was postponed by 1 or 2 weeks. If hematologic toxicityⅢor greater remained, or a fever from combined severe infection and granulocytopenia IV occurred, the planned treatment was terminated. If non-hematologic toxicity (except trichomadesis)Ⅲor greater occurs, the dosage for the next course was adjusted to 75-85% of the original dosage. If cardiotoxicityⅡ-Ⅳ occurred, treatment was discontinued.
Throughout chemotherapy, adjuvant medicine such as antanacathartic, colony-stimulating factor and diphosphonate were given to reduce adverse events when necessary.
4. Image Data Collection and Study
Each patient had a base-line check within one month before their first-line chemotherapeutic treatment started. To ensure the credibility of the study, images of measurable lesions were obtained by the qualified radiologists through Spiro-CT or MRI scans. Subsequent images were obtained by the same radiologist after the first 2 courses of chemotherapy for each patient. To minimize variation between operators, all measurements of the images were done at the same anatomic level and orientation by an independent qualified radiologist. In contrast with the base-line images, any change in the size of target lesions was calculated according to RECIST. Patients with an increase of 20% or more in lesion size or those with new lesions were regarded as having PD and were excluded from the study. Patients with a change of lesion size ranging from an increase of< 20% to a decrease of< 30% and with no new lesion were stratified as having SD. Patients with a 30% or greater decrease in the target lesion were regarded as achieving PR. Patients with disappearance of the lesion were stratified as achieving CR. For those with SD, the percentage of change in tumour size has been recorded for further study.
5. Follow-up Visit
A follow-up visit was given to each patient who achieved CR, PR and SD. The assessment process was repeated every 2 courses until the end of the chemotherapy, or the aggravation of the disease, and after that, every 2 months until the progression of the disease or death occurred. This kind of service could be provided to meet a patient's need at any time. The percentage of change in size of target tumours and the PFS were the main contents for a follow-up visit.
6. Statistical Analysis
SPSS13.0 software was used for all statistical analysis. The correlation between the change in size of target lesions before and after the first two courses of chemotherapy and their PFS was calculated. According to the RECIST standard, the sum of the longest dimension of all the target lesions was calculated for each patient to provide the baseline before treatment. The same measurements and calculation were done after the first two courses of chemotherapy to obtain the initial assessment sum. The change ratio of target lesions was calculated as: (Assessment sum-Baseline sum)/Baseline sum PFS was calculated from the date of first treatment to disease progression or death. The Kaplan-Meier curve was used to describe PFS, and a log-rank test was used to compare the PFS of each category defined according to the percentage reduction in tumour size i.e.≥30%[PR],≥25%,≥20%,≥15%,≥10%,≥5%, and> 0%.Theχ2 test was used for qualitative data analysis, and the Kruskal-Wallis test or variance analysis was used to analyse the quantitative data. P<0.05 was set as the level of statistical significance.
Results
1. Distribution of Response Categories and Patient Characteristics
Altogether,188 patients were enrolled in the trial but 9 withdrew after completing their first cycle of chemotherapy. The remaining 179 patients with inoperative NSCLC had the initial assessment after the first two courses of first-line platinum-based chemotherapy:37 achieved PR and 117 were regarded as SD and these 154 patients (PR+SD) were eligible for the final analysis. The remaining 25 had PD and no CR according to RECIST. The characteristics of the patients included in this analysis:the median age of the patients when enrolled into the study was 57 years (range 26-77 years), with 38%>60 years. A total of 92 males (60%) were eligible for the analysis. The vast majority of patients (63%) had stage IV disease,64 patients (42%) reported a weight loss of≥5%, and the majority of patients had an ECOG performance status of 0 or 1.
2. Distribution of Change in Tumour Size of Initial SD Patients
There was a decrease of tumour size of 25-30% for 17,20-25% for 18,15-20% for 16,10-15% for 12 and 5-10% for 8 and 0-5% for 29. The increase of tumour size in the other patients was<20%.
3. Comparison of PFS of Patients with Initial PR and SD
Careful examination found no statistically significant difference of patient characteristics between the two groups, i.e. baseline characteristics were well balanced between PR and SD. The median PFS was 249 days (95% confidence interval,187-310 days) for the 37 patients with PR and 220 days (95% confidence interval,191-248 days) for the 117 patients with SD. The log-rank test found no significant difference (P= 0.991) of PFS between the PR and SD subgroups.
4. Relationship between Change in Target Lesion Size and PFS among Initial SD Patients
The median PFS of patients with≥25%,>20%,≥15%,≥10%,≥5%or≥0% decrease in tumour size was 289 days,270 days,242 days,225 days,221 days or 221 days, respectively. The P value associated with the log-rank test comparing the PFS of responding patients with that of non-responding patients using different definitions of response. No significantly better cut-off point, i.e. optimal percentage of decrease in tumour size, was found in predicting the PFS of the patients with SD.
In addition, among SD patients, those with an initial decrease of 30-20% in tumour size were not significantly distinguishable (P>0.05) from those with an initial increase.
5. Multivariate analysis included factors such as sex, age, weight loss, ECOG performance status, and stage of disease, which might have a potential effect on prognosis of NSCLC patients. ECOG 1 and weight loss of≥5% was relatively worse for predicting PFS(P<0.05). Cox regression analysis showed that other prognostic factors like age, sex, stage of disease, the percentage of change in target lesion size of patients with SD derived from the initial assessment after the first two courses of chemotherapy are not associated with PFS (P>0.05)
Conclusions
1. Initial PR and SD enjoy similar PFS for patients with advanced NSCLC.
2. Within the initial SD subgroup, different percentages of tumour shrinkage or increase undergo similar PFS.
3. RECIST remains a reliable norm in assessing the effectiveness of chemotherapy for patients with advanced NSCLC before functional assessment has been integrated into the criteria.
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34 Ollivier L, Leclere.J, Thiesse P, Di Stefano D, Vincent C. Measurement of tumour response to cancer treatment: morphologic imaging role. Bull Cancer.2007,94:171-177.
35 Schuetze SM, Baker LH, Benjamin RS, Canetta R. Selection of response criteria for clinical trials of sarcoma treatment. The Oncologist.2008,13 (Suppl 2):32-40.
36 Delbeke D. Oncological applications of FDG PETimaging. J Nucl Med.1999; 40(10): 1706-1715.
37 Weber WA, Figlin R. Monitoring cancer treatment with PET/CT: does it make a difference? J Nucl Med.2007;48(suppl 1):36-44.
38 Husband JE, Hawkes DJ, Peckham MJ. CT estimations of mean attenuation values and volume in testicular tumors:a comparison with surgical and histologic findings. Radiology.1982; 144(3):553-558.
39 Shankar S, vanSonnenberg E, Desai J, Dipiro PJ, Van Den Abbeele A, Demetri GD. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology.2005; 235(3):892-898.
40 Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res.2005; 11(16):5928-5934.
41 Ratain MJ. Phase Ⅱ oncology trials:let's be positive. Clin Cancer Res.2005; 11(16): 5661-5662.
42 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med.2005; 353(2):123-132.
43 Choi H. Critical issues in response evaluation on computed tomography:lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep.2005; 7(4):307-311.
44 de Geus-Oei LF, van der Heijden HF, Visser EP, et al. Chemotherapy response evaluation with 18F-FDG PET in patients with non-small cell lung cancer. J Nucl Med.2007,48:1592-1598.
45 Corneline J. Hoekstra, Sigrid G. Stroobants, Egbert F. Smit, et al. Prognostic relevance of response evaluation using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer. J Clin Oncol.2005,23:8362-8370.
46 Oremek GM, Sauer-Eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lung cancer. Anticancer Res.2007,27:1911-1915.
47 Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer.2006,107: 2866-2872.
1 WHO handbook for reporting results of cancer treatment [M]. Offset Publication No.48.Geneva(Switzerland):World Health Organization.1979.
2 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst.2000; 92(3):205-216.
3 Zubrod CG, Schneiderman SM, Frei E, et al. Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard andthiophosphamide [J]. J Chronic Dis.1960; 11:7-33.
4 Moertel CG, Hanley JA. The effect of measuring error on the results of therapeutic trials in advanced cancer [J]. Cancer.1976; 38:388-394.
5 James K, Eisenhauer E, Christian M, et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst.1999; 91(6):523-528.
6 Padhani AR, Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol.2001; 74(887):983-986.
7 Warr D, McKinney S, Tannock L. Influence of measurement error on response rates [J]. Cancer Treat Reg.1985; 69:1127-1130.
88易俊林,王绿化.评价实体瘤疗效的指导原则简介[J].国外医学临床放射学分册.2003；J26(5)：330-332.
9 Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline. J Clin Epidemiol.2004;57(4):358-365.
10 Therasse P. Measuring the clinical response. What does it mean? Eur J Cancer.2002; 38(14): 1817-23.
11 Padhani AR, Husband JE. Are current tumour response criteria relevant for the 21st century? Br J Radiol.2000; 73(874):1031-3.
12 Duffaud F, Therasse P. New guidelines to evaluate the response to treatment in solid tumors[J]. Bull Cancer.2000; 87(12):869-870.
13 Chikako Suzuki, Hans Facobsson, Thomas Hatschek, et al. Radiologic measurements of tumor response to treatment: practical approaches and limitations. RadioGraphics.2008; 28:329-344.
14 James K, Eisenhauer E, Christian M, et al. Measuring response in solid tumois: Unidimensional versus bidimensional measurement [J]. JNCI.1999; 91(6):523-528.
15 Lavin PT, Flowerdew G. Studies in variation associated with the measurement of solid tumors[J]. Cancer.1980; 46(5):1286-1290.
16 Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline[J]. J Clin Epidemiol.2004; 57(4):358-365.
17 James K, Eisenhauer E, Therasse P. Re:Measure once or twice:does it really matter? J Natl Cancer Inst.1999; 91(20):1780-1781.
18 Prasad SR, Jhaveri KS, Saini S, Hahn PF, Halpern EF, Sumner JE. CT tumor measurement for therapeutic response assessment:comparison of unidimensional, bidimensional, and volumetric techniques-initial observations.Radiology.2002; 225(2):416-419.
19陈智伟,廖美琳,陈玉蓉等.WHO标准和RECIST标准评价肺癌化疗疗效的比较(J].循证医学.2004；4(2)：83-84.
20 Tran LN, Brown MS, Goldin JG, et al. Comparison of treatment response classifications between unidimensional, bidimensional, and volumetric measurements of metastatic lung lesions on chest computed tomography. Acad Radiol.2004; 11(12):1355-1360.
21 Warren KE, Patronas N, Aikin AA, Albert PS, Balis FM. Comparison of one-, two-, and threedimensional measurements of childhood brain tumors. J Natl Cancer Inst.2001; 93(18): 1401-1405.
22 Husband JE, Schwartz LH, Spencer J, et al. Evaluation of the response to treatment of solid tumours:a consensus statement of the International Cancer Imaging Society. Br J Cancer.2004; 90(12):2256-2260.
23 Karnofsky DA. Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin Pharmacol Ther.1961; 2:709-712.
24 Padhani AR, Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol.2001; 74:983-986.
25 Sirohi B, Ashley S, Norton A, et al. Early response to platinum-based first-Line chemotherapy in non-small cell lung cancer may predict survival. J Thorac Oncol.2007; 2:735-740.
26 Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol. 2000; 18:2981-2989.
27 Fidias P, Dakhil SR, Lyss AP, et al. Updated report of a phase III study of induction therapy with gemcitabine + carboplatin (GC) followed by either delayed vs immediate second line therapy with docetaxel (D) in advanced non small cell lung cancer (NSCLC) [Abstract]. J Clin Oncol.2006; 24:s18.
28 Victorson D, Soni M, Cella D. Metaanalysis of the correlation between radiographic tumor response and patient-reported outcomes. Cancer.2006; 106:494-504.
29 De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Annals of Oncology.2008; 19:508-515.
30 Piessevaux H, Buyse M, De Roock W, et al. Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial). Annals of Oncology.2009; 20:1375-1382
31 Piessevaux H, De Roock W, Van Cutsem E, et al. Use of tumor size decrease at 6 weeks (w) to predict response (OR), time to progression (TTP), and survival (OS) in chemorefractory metastatic colorectal cancer (cmCRC) treated with cetuximab (CTX) (BOND trial) [abstract]. J Clin Oncol.2008; 26:s15.
32 Husband JE, Hawkes DJ, Peckham MJ. CT estimations of mean attenuation values and volume in testicular tumors:a comparison with surgical and histologic findings. Radiology.1982; 144(3):553-558.
33 Shankar S, vanSonnenberg E, Desai J, Dipiro PJ, Van Den Abbeele A, Demetri GD. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology.2005; 235(3):892-898.
34 Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res.2005; 11(16):5928-5934.
35 Ratain MJ. Phase Ⅱoncology trials:let's be positive. Clin Cancer Res.2005; 11(16): 5661-5662.
36 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med.2005; 353(2):123-132.
37 Choi H. Critical issues in response evaluation on computed tomography:lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep.2005; 7(4):307-311.
38 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate:proposal of new computed tomography response criteria. J Clin Oncol.2007; 25:1753-1759.
2 Primo N. Lara Jr, Mary W. Redman, Karen Kelly, et al. Disease Control Rate at 8 Weeks Predicts Clinical Benefit in Advanced Non-Small-Cell Lung Cancer: Results From Southwest Oncology Group Randomized Trials. J Clin Oncol.2008,26:463-467.
3 Chikako Suzuki, Hans Jacobsson, Thomas Hatschek, et al. Radiologic Measurements of Tumor Response to Treatment: Practical Approaches and Limitations. Radiographics.2008,28: 329-344.
4 Karnofsky DA. Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin Pharmacol Ther.1961,2:709-712.
5 Moertel CG, Hanley JA:The effect of measuring error on the results of therapeutic trials in advanced cancer. Cancer.1976,38:388-394.
6 James K, Eisenhauer E, Christian M, et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst.1999,91:523-528.
7 Padhani AR, Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol.2001,74:983-986.
8 Sirohi B, Ashley S, Norton A, et al. Early response to platinum-based first-Line chemotherapy in non-small cell lung cancer may predict survival. J Thorac Oncol.2007,2:735-740.
9 Therasse P:Measuring the clinical response. What does it mean? Eur J Cancer.2002,38: 1817-1823.
10 Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol.2000,18: 2981-2989.
11 Fidias P, Dakhil SR, Lyss AP, et al. Updated report of a phase III study of induction therapy with gemcitabine + carboplatin (GC) followed by either delayed vs immediate second line therapy with docetaxel (D) in advanced non small cell lung cancer (NSCLC) [Abstract]. J Clin Oncol.2006,24:s18.
12 Victorson D, Soni M, Cella D. Metaanalysis of the correlation between radiographic tumor response and patient-reported outcomes. Cancer.2006,106:494-504.
13 De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Annals of Oncology.2008,19:508-515.
14 Piessevaux H, Buyse M, De Roock W, et al. Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial). Annals of Oncology.2009,20:1375-1382.
15 Piessevaux H, De Roock W, Van Cutsem E, et al. Use of tumor size decrease at 6 weeks (w) to predict response (OR), time to progression (TTP), and survival (OS) in chemorefractory metastatic colorectal cancer (cmCRC) treated with cetuximab (CTX) (BOND trial) [abstract]. J Clin Oncol.2008,26:s15.
16 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate:proposal of new computed tomography response criteria. J Clin Oncol.2007,25:1753-1759.
17 Marc Buyse, Tomasz Burzykowski, Kevin Carroll, et al. Progression-free survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol.2007,25:5218-5224.
18 Tang PA, Bentzen SM, Chen EX, Siu LL. Surrogate end points for median overall survival in metastatic colorectal cancer: literature-based analysis from 39 randomized controlled trials of first-line chemotherapy. J Clin Oncol.2007,25:4562-4568.
19 Carroll KJ. Analysis of progression-free survival in oncology trials:some common statistical issues. Pharm Stat.2007,6:99-113.
20 Shi Q, Sargent DJ. Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials. Int J Clin Oncol 2009,14:102-111.
21 Victor A Levin, Sandra Ictech and Kenneth R Hess. Impact of phase II trials with progression-free survival as end-points on survival-based phase III studies in patients with anaplastic gliomas. BMC Cancer.2007,7:106.
22 Methy N, Bedenne L, Bonnetain F. Validation of surrogate endpoints in digestive oncology. Bull Cancer.2009,96:591-595.
23 Lynch TJ, Bonomi PD, Butts C, et al. Novel agents in the treatment of lung cancer: Fourth Cambridge Conference. Clin Cancer Res.2007,13:4583-4588.
24 Buyse M, Thirion P, Carlson RW, et al. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet.2000,356:373-378.
25 Birchard KR, Hoang JK, Herndon JE Jr, Patz EF Jr. Early changes in tumor size in patients treated for advanced stage nonsmall cell lung cancer do not correlate with survival. Cancer. 2009,115:581-586.
26 Cesano A, Lane SR, Poulin R, Ross G, Fields SZ. Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small cell lung cancer and ovarian cancer patients. Int J Oncol 1999,15:1233-1238.
27 Cesano A, Lane SR, Ross GA, Fields SZ. Stabilization of disease as an indicator of clinical benefit associated with chemotherapy in non-small cell lung cancer patients. Int J Oncol.2000, 17:587-590.
28 Liu-Jarin X, Stoopler MB, Raftopoulos H, Ginsburg M,Gorenstein L, Borczuk AC. Histologic assessment of non-small cell lung carcinoma after neoadjuvant therapy. Mod Pathol.2003,16: 1102-1108.
29 Esendagli G, Bruderek K, Goldmann T, et al. Malignant and non-malignant lung tissue areas are differentially populated by natural killer cells and regulatory T cells in non-small cell lung cancer. Lung Cancer.2008,59:32-40.
30 Van den Abbeele AD, Badawi RD. Use of positron emission tomography in oncology and its potential role to assess response to imatinib mesylate therapy in gastrointestinal stromal tumors (GISTs). Eur J Cancer.2002,38 (suppl 5):60-65.
31 Junker K, Langner K, Klinke F, Bosse U, Thomas M. Grading of tumor regression in non-small cell lung cancer: morphology and prognosis. Chest.2001,120:1584-1591.
32 Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Mueller KM. Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol.1997,123:469-477.
33 Weber WA. Assessing tumor response to therapy. J Nucl Med.2009,50 (Suppl 1):1-10.
34 Ollivier L, Leclere.J, Thiesse P, Di Stefano D, Vincent C. Measurement of tumour response to cancer treatment: morphologic imaging role. Bull Cancer.2007,94:171-177.
35 Schuetze SM, Baker LH, Benjamin RS, Canetta R. Selection of response criteria for clinical trials of sarcoma treatment. The Oncologist.2008,13 (Suppl 2):32-40.
36 Delbeke D. Oncological applications of FDG PETimaging. J Nucl Med.1999; 40(10): 1706-1715.
37 Weber WA, Figlin R. Monitoring cancer treatment with PET/CT: does it make a difference? J Nucl Med.2007;48(suppl 1):36-44.
38 Husband JE, Hawkes DJ, Peckham MJ. CT estimations of mean attenuation values and volume in testicular tumors:a comparison with surgical and histologic findings. Radiology.1982; 144(3):553-558.
39 Shankar S, vanSonnenberg E, Desai J, Dipiro PJ, Van Den Abbeele A, Demetri GD. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology.2005; 235(3):892-898.
40 Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res.2005; 11(16):5928-5934.
41 Ratain MJ. Phase Ⅱ oncology trials:let's be positive. Clin Cancer Res.2005; 11(16): 5661-5662.
42 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med.2005; 353(2):123-132.
43 Choi H. Critical issues in response evaluation on computed tomography:lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep.2005; 7(4):307-311.
44 de Geus-Oei LF, van der Heijden HF, Visser EP, et al. Chemotherapy response evaluation with 18F-FDG PET in patients with non-small cell lung cancer. J Nucl Med.2007,48:1592-1598.
45 Corneline J. Hoekstra, Sigrid G. Stroobants, Egbert F. Smit, et al. Prognostic relevance of response evaluation using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer. J Clin Oncol.2005,23:8362-8370.
46 Oremek GM, Sauer-Eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lung cancer. Anticancer Res.2007,27:1911-1915.
47 Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer.2006,107: 2866-2872.
1 WHO handbook for reporting results of cancer treatment [M]. Offset Publication No.48.Geneva(Switzerland):World Health Organization.1979.
2 Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst.2000; 92(3):205-216.
3 Zubrod CG, Schneiderman SM, Frei E, et al. Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard andthiophosphamide [J]. J Chronic Dis.1960; 11:7-33.
4 Moertel CG, Hanley JA. The effect of measuring error on the results of therapeutic trials in advanced cancer [J]. Cancer.1976; 38:388-394.
5 James K, Eisenhauer E, Christian M, et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst.1999; 91(6):523-528.
6 Padhani AR, Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol.2001; 74(887):983-986.
7 Warr D, McKinney S, Tannock L. Influence of measurement error on response rates [J]. Cancer Treat Reg.1985; 69:1127-1130.
88易俊林,王绿化.评价实体瘤疗效的指导原则简介[J].国外医学临床放射学分册.2003；J26(5)：330-332.
9 Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline. J Clin Epidemiol.2004;57(4):358-365.
10 Therasse P. Measuring the clinical response. What does it mean? Eur J Cancer.2002; 38(14): 1817-23.
11 Padhani AR, Husband JE. Are current tumour response criteria relevant for the 21st century? Br J Radiol.2000; 73(874):1031-3.
12 Duffaud F, Therasse P. New guidelines to evaluate the response to treatment in solid tumors[J]. Bull Cancer.2000; 87(12):869-870.
13 Chikako Suzuki, Hans Facobsson, Thomas Hatschek, et al. Radiologic measurements of tumor response to treatment: practical approaches and limitations. RadioGraphics.2008; 28:329-344.
14 James K, Eisenhauer E, Christian M, et al. Measuring response in solid tumois: Unidimensional versus bidimensional measurement [J]. JNCI.1999; 91(6):523-528.
15 Lavin PT, Flowerdew G. Studies in variation associated with the measurement of solid tumors[J]. Cancer.1980; 46(5):1286-1290.
16 Mazumdar M, Smith A, Schwartz LH. A statistical simulation study finds discordance between WHO criteria and RECIST guideline[J]. J Clin Epidemiol.2004; 57(4):358-365.
17 James K, Eisenhauer E, Therasse P. Re:Measure once or twice:does it really matter? J Natl Cancer Inst.1999; 91(20):1780-1781.
18 Prasad SR, Jhaveri KS, Saini S, Hahn PF, Halpern EF, Sumner JE. CT tumor measurement for therapeutic response assessment:comparison of unidimensional, bidimensional, and volumetric techniques-initial observations.Radiology.2002; 225(2):416-419.
19陈智伟,廖美琳,陈玉蓉等.WHO标准和RECIST标准评价肺癌化疗疗效的比较(J].循证医学.2004；4(2)：83-84.
20 Tran LN, Brown MS, Goldin JG, et al. Comparison of treatment response classifications between unidimensional, bidimensional, and volumetric measurements of metastatic lung lesions on chest computed tomography. Acad Radiol.2004; 11(12):1355-1360.
21 Warren KE, Patronas N, Aikin AA, Albert PS, Balis FM. Comparison of one-, two-, and threedimensional measurements of childhood brain tumors. J Natl Cancer Inst.2001; 93(18): 1401-1405.
22 Husband JE, Schwartz LH, Spencer J, et al. Evaluation of the response to treatment of solid tumours:a consensus statement of the International Cancer Imaging Society. Br J Cancer.2004; 90(12):2256-2260.
23 Karnofsky DA. Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin Pharmacol Ther.1961; 2:709-712.
24 Padhani AR, Ollivier L. The RECIST (Response Evaluation Criteria in Solid Tumors) criteria: implications for diagnostic radiologists. Br J Radiol.2001; 74:983-986.
25 Sirohi B, Ashley S, Norton A, et al. Early response to platinum-based first-Line chemotherapy in non-small cell lung cancer may predict survival. J Thorac Oncol.2007; 2:735-740.
26 Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol. 2000; 18:2981-2989.
27 Fidias P, Dakhil SR, Lyss AP, et al. Updated report of a phase III study of induction therapy with gemcitabine + carboplatin (GC) followed by either delayed vs immediate second line therapy with docetaxel (D) in advanced non small cell lung cancer (NSCLC) [Abstract]. J Clin Oncol.2006; 24:s18.
28 Victorson D, Soni M, Cella D. Metaanalysis of the correlation between radiographic tumor response and patient-reported outcomes. Cancer.2006; 106:494-504.
29 De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Annals of Oncology.2008; 19:508-515.
30 Piessevaux H, Buyse M, De Roock W, et al. Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial). Annals of Oncology.2009; 20:1375-1382
31 Piessevaux H, De Roock W, Van Cutsem E, et al. Use of tumor size decrease at 6 weeks (w) to predict response (OR), time to progression (TTP), and survival (OS) in chemorefractory metastatic colorectal cancer (cmCRC) treated with cetuximab (CTX) (BOND trial) [abstract]. J Clin Oncol.2008; 26:s15.
32 Husband JE, Hawkes DJ, Peckham MJ. CT estimations of mean attenuation values and volume in testicular tumors:a comparison with surgical and histologic findings. Radiology.1982; 144(3):553-558.
33 Shankar S, vanSonnenberg E, Desai J, Dipiro PJ, Van Den Abbeele A, Demetri GD. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology.2005; 235(3):892-898.
34 Goffin J, Baral S, Tu D, Nomikos D, Seymour L. Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval. Clin Cancer Res.2005; 11(16):5928-5934.
35 Ratain MJ. Phase Ⅱoncology trials:let's be positive. Clin Cancer Res.2005; 11(16): 5661-5662.
36 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med.2005; 353(2):123-132.
37 Choi H. Critical issues in response evaluation on computed tomography:lessons from the gastrointestinal stromal tumor model. Curr Oncol Rep.2005; 7(4):307-311.
38 Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate:proposal of new computed tomography response criteria. J Clin Oncol.2007; 25:1753-1759.