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: 研究報告表明，在卵巢癌患者中達到CA-125正常化的最低血清CA-125水平準確地定義了復發的風險。使用類似的CA-125亞組，我們試圖確定維持化療開始前的基線CA-125水平是否具有臨床定義的對初次化療完全緩解的婦女的預后價值。

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.本次回顧性分析中納入的患者接受過兩項先前報道的維持化療試驗之一（紫杉醇 12 個月周期，3 次或 12 個月周期；口服六甲蜜胺），基線 CA-125 水平≤35 u/mL。通過 Cox 回歸模型分析了從研究開始的無進展生存期 (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).結果:384 名患者的維持治療前基線 CA-125 水平分布分別為 (A) < 或 = 10 u/mL、(B) 11 至 20 u/mL 和 (C) 21 至 35 u/mL，分別為 58%、34% 和 8%。基線 CA-125 具有高度統計學意義，無論是作為分類變量 (P < .001) 還是作為連續變量 (P < .0001)。組 (A)、(B) 和 (C) 的中位 PFS 分別為 24 個月、17 個月和 7 個月。在相互作用分析中，沒有證據表明 CA-125 效應因試驗或治療而異 (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.

結論: 開始維持化療前的基線 CA-125 水平強烈預測后續復發的風險。維持化療前基線 CA-125 值 ≤ 10 u/mL 的患者與正常 CA-125 范圍內的較高水平患者相比，PFS 更長。

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 觀察到，一組接受化療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）的組之間有所不同。在隨后對接受卡鉑/紫杉醇或卡鉑/多西他賽一線化療（SCOTROC 試驗）的患者（n556）進行的檢查中，作者驗證了這一觀察結果，并發現對治療有反應且血清 CA-125 抗原水平最低值為 10 u/mL 的女性的中位 PFS 為 17 個月，而如果 CA-125 最低值為 11 至 20 u/mL，則中位 PFS 為 13 個月，如果 CA-125 最低值為 20 u/mL，則中位 PFS 僅為 8 個月。

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.) 在當前分析中，我們使用與 Crawford 研究中類似的血清 CA-125 組，結果表明，在晚期卵巢癌女性中，在對主要化療達到臨床定義的完全緩解（包括 CA-125 水平為 35 u/mL）時，開始維持化療時獲得的基線抗原水平是隨后疾病復發的重要預后因素。此外，該臨床特征的總體影響不受所施用的特定維持方案的影響。（這一發現的唯一例外可能是，在接受維持治療的基線 CA-125 抗原水平為 21 至 35 u/mL 的女性中觀察到的中位 PFS 延長，這是因為該亞組中的患者人數較少 [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. 這些發現的潛在臨床意義是什么？首先，在接受三種不同維持化療方案（每 3 個月和每 12 個月單藥紫杉醇治療；每 6 個周期的六甲蜜胺）的患者中以及在對卡鉑加紫杉醇或多西他賽產生重大臨床反應（血清 CA-125 水平正常化）后的患者中發現的類似結果表明，這種觀察結果并非特定治療方案所獨有。然而，由于每個患者亞組的數量相對較少，因此無法就這一點做出明確的陳述。

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，數據表明，未來在這種臨床環境下進行的維持治療試驗應考慮這一因素，以確保每個亞組內的隨機治療分配是平衡的（就像 S9701/GOG178 的情況一樣）

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，雖然在比較 3 個周期和 12 個周期每月紫杉醇治療的隨機試驗中，每個維持治療前基線血清 CA-125 抗原亞組的患者總數有限，無法就這一臨床因素對維持治療結果的影響做出明確的陳述，但潛在的興趣在于，中位 PFS（9 個月）差異最大的亞組是基線 CA-125 抗原水平最低的患者組（ 10 u/mL）。同樣，雖然這一發現可能完全是因為樣本量小，但可以合理地推測，這一令人振奮的結果可能是由于延長紫杉醇治療對以下患者最有效：(A) 殘留癌癥體積最小；或 (B) 對化療最敏感的腫瘤；或 (C) 這兩個因素的組合。希望未來的臨床試驗能夠證實或反駁這一假設。

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，對于已經實現臨床定義的對主要化療完全緩解的卵巢癌患者，臨床醫生考慮維持化療時面臨的主要困難可能是確定對個體患者可能造成的危害與潛在益處的治療比率。對于卵巢癌維持治療的未來試驗來說，重要的是仔細評估維持治療前基線 CA-125 水平的作用，作為一種幫助臨床醫生在這種困難的臨床環境中為患者提供建議的方法。

延展閱讀：

第一，CA125單獨用于卵巢癌的篩查是缺乏敏感性和特異性的。對于拒絕手術或需要等待降低風險手術的這些患者，SGO和NCCN指南都推薦進行篩查，但是沒有證明可以降低卵巢癌患者死亡風險。在缺乏足夠證據的情況下，FDA和NCCN均不推薦CA125和HE4聯合篩查卵巢癌；頻繁的篩查，尤其對一些假陽性人群，它可能會增加一些心理負擔甚至精神創傷。

第二，CA125升高或降低對卵巢癌患者的治療療效有一定的評估作用。術前CA125水平并非患者的獨立預后因素，但術后CA125與預后存在一定的相關性。化療后2個周期，CA125降至35 U/ml以下，或者下降超過50%的這些患者，可能會有更好的生存獲益。初治完全緩解后患者CR患者CA125的水平最低值≤5 U/ml，會有更好的PFS和OS。

第三，CA125在卵巢癌患者的監測當中目前還存在爭議，不同協會的推薦有所不同。2016年歐洲腫瘤標記物小組（EGTM）認為，盡管存在爭議，但是以下4種情況仍然建議監測CA125。1、患者初治治療后達到了CR，已經或正在作為臨床試驗的一部分，應該監測CA125；2、患者有資格參加后續的一些臨床試驗；3、患者不會進行常規即每3個月的一些影像學隨訪；4、有條件進行二次手術的一些患者。

2020年NCCN指南小組認為，初始CA125升高的這些患者，可以監測CA125。

CA125監測的隨訪頻率，還存在爭議，患者應該與醫生討論監測的利和弊。

還有一種情況，僅僅CA125升高，即所謂的生化復發。生化復發到影像學進展的中位時間統計是2~6個月。目前我國和NCCN指南推薦，對生化復發的患者推薦（1）推薦參加臨床試驗；（2）隨診觀察直到臨床復發再開始挽救治療，或者立即開始以鉑類為基礎的化療和/或最佳的支持治療。而CA125與RECIST1.1標準相結合的腫瘤評估方法，目前被GCIG推薦用于臨床研究，并且在研究中廣泛應用。

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.