CA125水平变化在卵巢癌患者管理中的重要意义

PURPOSE: A previous report suggested the nadir serum CA-125 level within the group of patients with ovarian cancer who achieved normalization of CA-125 accurately defined the risk of relapse. Using similar CA-125 subgroups, we sought to determine if the baseline CA-125 level before initiation of maintenance chemotherapy in women achieving a clinically-defined complete response to primary chemotherapy would be of prognostic value.目的: 研究报告表明，在卵巢癌患者中达到CA-125正常化的最低血清CA-125水平准确地定义了复发的风险。使用类似的CA-125亚组，我们试图确定维持化疗开始前的基线CA-125水平是否具有临床定义的对初次化疗完全缓解的妇女的预后价值。

PATIENTS AND METHODS: Patients included in this retrospective analysis had been treated on one of two previously reported trials of maintenance chemotherapy (three v 12-monthly cycles of paclitaxel; oral altretamine), with a baseline CA-125 level of < or = 35 u/mL. Progression-free survival (PFS) from study entry was analyzed by the Cox regression model.本次回顾性分析中纳入的患者接受过两项先前报道的维持化疗试验之一（紫杉醇 12 个月周期，3 次或 12 个月周期；口服六甲蜜胺），基线 CA-125 水平≤35 u/mL。通过 Cox 回归模型分析了从研究开始的无进展生存期 (PFS)。

RESULTS: The distribution of premaintenance baseline CA-125 levels for the 384 patients was 58%, 34%, and 8% for values of (A) < or = 10 u/mL, (B) 11 to 20 u/mL, and (C) 21 to 35 u/mL, respectively. The baseline CA-125 was highly statistically significant, either as a categoric variable (P < .001) or as a continuous variable (P < .0001). Median PFS was 24 months, 17 months, and 7 months for groups (A), (B), and (C), respectively. There was no evidence the CA-125 effect differed by trial or treatment in an interaction analysis (P = .70).结果:384 名患者的维持治疗前基线 CA-125 水平分布分别为 (A) < 或 = 10 u/mL、(B) 11 至 20 u/mL 和 (C) 21 至 35 u/mL，分别为 58%、34% 和 8%。基线 CA-125 具有高度统计学意义，无论是作为分类变量 (P < .001) 还是作为连续变量 (P < .0001)。组 (A)、(B) 和 (C) 的中位 PFS 分别为 24 个月、17 个月和 7 个月。在相互作用分析中，没有证据表明 CA-125 效应因试验或治疗而异 (P = .70)。

CONCLUSION: The baseline CA-125 level before initiation of maintenance chemotherapy strongly predicts the risk of subsequent relapse. Patients with premaintenance baseline CA-125 values < or = 10 u/mL have a superior PFS compared with higher levels in the normal CA-125 range.

结论: 开始维持化疗前的基线 CA-125 水平强烈预测后续复发的风险。维持化疗前基线 CA-125 值 ≤ 10 u/mL 的患者与正常 CA-125 范围内的较高水平患者相比，PFS 更长。

DISCUSSION： Crawford et al observed that survival for one series of ovarian cancer patients receiving chemotherapy varied between groups that attained nadir CA-125 ≤10 u/mL (best) v 11 to 20 u/mL v 21 to 30 u/mL

(worst). In their subsequent examination of patients (n556) treated

with front-line chemotherapy consisting of either carboplatin/paclitaxel or carboplatin/docetaxel (SCOTROC trial), the authors validated this observation and found that women responding to treatment and whose nadir serum CA-125 antigen level was ≤10 u/mL experienced a median PFS of 17 months compared with 13 months if the nadir CA-125 was 11 to 20 u/mL and only 8 months with a nadir CA-125 of  20 u/mL. Crawford 等人 观察到，一组接受化疗的卵巢癌患者的生存率在 CA-125 最低值 10 u/mL（最好）vs 11 至 20 u/mL v 21 至 30 u/mL （最差）的组之间有所不同。在随后对接受卡铂/紫杉醇或卡铂/多西他赛一线化疗（SCOTROC 试验）的患者（n556）进行的检查中，作者验证了这一观察结果，并发现对治疗有反应且血清 CA-125 抗原水平最低值为 10 u/mL 的女性的中位 PFS 为 17 个月，而如果 CA-125 最低值为 11 至 20 u/mL，则中位 PFS 为 13 个月，如果 CA-125 最低值为 20 u/mL，则中位 PFS 仅为 8 个月。

In the current analysis, using similar serum CA-125 groups as employed in the Crawford study, we have shown that the baseline antigen level obtained at the time of initiation of maintenance chemotherapy in women with advanced ovarian cancer, who attained a clinically-defined complete response (which included a CA-125 level ≤ 35 u/mL) to primary chemotherapy, is a significant prognostic factor for subsequent disease relapse. Further, the overall impact of this clinical feature was not affected by the specific maintenance regimen administered. (It is likely the one exception to this finding, the prolonged median PFS observed in women with baseline CA-125 antigen levels of 21 to 35 u/mL who received maintenance altretamine,was because of small patient numbers [n＝8] in this sub-group.) 在当前分析中，我们使用与 Crawford 研究中类似的血清 CA-125 组，结果表明，在晚期卵巢癌女性中，在对主要化疗达到临床定义的完全缓解（包括 CA-125 水平为 35 u/mL）时，开始维持化疗时获得的基线抗原水平是随后疾病复发的重要预后因素。此外，该临床特征的总体影响不受所施用的特定维持方案的影响。（这一发现的唯一例外可能是，在接受维持治疗的基线 CA-125 抗原水平为 21 至 35 u/mL 的女性中观察到的中位 PFS 延长，这是因为该亚组中的患者人数较少 [n＝8]。）

What are the potential clinical implications of these findings?

First, the similar results found in patients treated with three different

maintenance chemotherapy programs (3-monthly and 12-monthly

cycles of single-agent paclitaxel; six cycles of altretamine) and after the

attainment of a major clinical response to carboplatin plus either

paclitaxel or docetaxel (with normalization of the serum CA-125

level) suggest that the observation is not unique to a particular

treatment program. However, a definitive statement regarding this

point is not possible because of relatively small numbers in each

individual patient subgroup. 这些发现的潜在临床意义是什么？首先，在接受三种不同维持化疗方案（每 3 个月和每 12 个月单药紫杉醇治疗；每 6 个周期的六甲蜜胺）的患者中以及在对卡铂加紫杉醇或多西他赛产生重大临床反应（血清 CA-125 水平正常化）后的患者中发现的类似结果表明，这种观察结果并非特定治疗方案所独有。然而，由于每个患者亚组的数量相对较少，因此无法就这一点做出明确的陈述。

Second, the data suggest that future trials of maintenance therapy

in this clinical setting should consider this factor to be certain that

randomized treatment assignments are balanced within each subgroup (as was the case in S9701/GOG178). 其次，数据表明，未来在这种临床环境下进行的维持治疗试验应考虑这一因素，以确保每个亚组内的随机治疗分配是平衡的（就像 S9701/GOG178 的情况一样）

Third, while the total number of patients in each premaintenance

therapy baseline serum CA-125 antigen subgroup in the randomized

trial comparing three v 12 cycles of monthly paclitaxel is limited and

do not permit a definitive statement regarding the impact of this

clinical factor on the outcome of maintenance therapy, it is of potential interest that the subgroup with the greatest difference in median

PFS (9 months) was the group with patients with the lowest baseline

CA-125 antigen levels (≤ 10 u/mL). Again, while it is possible this

finding is solely because of the problem of small numbers, it is

reasonable to speculate this provocative outcome may result from

the extended paclitaxel treatment being most effective in patients

with: (A) the smallest volume of residual cancer; or (B) the most

chemo-sensitive tumors; or (C) a combination of these two factors.

Hopefully, future clinical trials will be able to either confirm or

refute this hypothesis. 第三，虽然在比较 3 个周期和 12 个周期每月紫杉醇治疗的随机试验中，每个维持治疗前基线血清 CA-125 抗原亚组的患者总数有限，无法就这一临床因素对维持治疗结果的影响做出明确的陈述，但潜在的兴趣在于，中位 PFS（9 个月）差异最大的亚组是基线 CA-125 抗原水平最低的患者组（ 10 u/mL）。同样，虽然这一发现可能完全是因为样本量小，但可以合理地推测，这一令人振奋的结果可能是由于延长紫杉醇治疗对以下患者最有效：(A) 残留癌症体积最小；或 (B) 对化疗最敏感的肿瘤；或 (C) 这两个因素的组合。希望未来的临床试验能够证实或反驳这一假设。

Finally, perhaps the major difficulty faced by clinicians considering maintenance chemotherapy in patients with ovarian cancer, who

have achieved a clinically-defined complete response to primary chemotherapy, is the determination of the therapeutic ratio of possible

harm versus potential benefit for an individual patient. It will be

important for future trials of maintenance treatment in ovarian cancer

to carefully assess a role for the premaintenance therapy baseline

CA-125 level as one method to help clinicians advise patients in this

difficult clinical setting.最后，对于已经实现临床定义的对主要化疗完全缓解的卵巢癌患者，临床医生考虑维持化疗时面临的主要困难可能是确定对个体患者可能造成的危害与潜在益处的治疗比率。对于卵巢癌维持治疗的未来试验来说，重要的是仔细评估维持治疗前基线 CA-125 水平的作用，作为一种帮助临床医生在这种困难的临床环境中为患者提供建议的方法。

延展阅读：

第一，CA125单独用于卵巢癌的筛查是缺乏敏感性和特异性的。对于拒绝手术或需要等待降低风险手术的这些患者，SGO和NCCN指南都推荐进行筛查，但是没有证明可以降低卵巢癌患者死亡风险。在缺乏足够证据的情况下，FDA和NCCN均不推荐CA125和HE4联合筛查卵巢癌；频繁的筛查，尤其对一些假阳性人群，它可能会增加一些心理负担甚至精神创伤。

第二，CA125升高或降低对卵巢癌患者的治疗疗效有一定的评估作用。术前CA125水平并非患者的独立预后因素，但术后CA125与预后存在一定的相关性。化疗后2个周期，CA125降至35 U/ml以下，或者下降超过50%的这些患者，可能会有更好的生存获益。初治完全缓解后患者CR患者CA125的水平最低值≤5 U/ml，会有更好的PFS和OS。

第三，CA125在卵巢癌患者的监测当中目前还存在争议，不同协会的推荐有所不同。2016年欧洲肿瘤标记物小组（EGTM）认为，尽管存在争议，但是以下4种情况仍然建议监测CA125。1、患者初治治疗后达到了CR，已经或正在作为临床试验的一部分，应该监测CA125；2、患者有资格参加后续的一些临床试验；3、患者不会进行常规即每3个月的一些影像学随访；4、有条件进行二次手术的一些患者。

2020年NCCN指南小组认为，初始CA125升高的这些患者，可以监测CA125。

CA125监测的随访频率，还存在争议，患者应该与医生讨论监测的利和弊。

还有一种情况，仅仅CA125升高，即所谓的生化复发。生化复发到影像学进展的中位时间统计是2~6个月。目前我国和NCCN指南推荐，对生化复发的患者推荐（1）推荐参加临床试验；（2）随诊观察直到临床复发再开始挽救治疗，或者立即开始以铂类为基础的化疗和/或最佳的支持治疗。而CA125与RECIST1.1标准相结合的肿瘤评估方法，目前被GCIG推荐用于临床研究，并且在研究中广泛应用。

Markman M, Liu PY, Rothenberg ML, Monk BJ, Brady M, Alberts DS. Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. J Clin Oncol. 2006 Mar 20;24(9):1454-8. doi: 10.1200/JCO.2005.04.7373. PMID: 16549840.