轉自《腫瘤瞭望》

隨著PARP抑制劑（PARPi）在卵巢癌中的循證醫學證據積累及獲批藥品和適應癥增加，卵巢癌的全程管理策略發生了巨大變化。ASCO召集專家小組，首次編寫了卵巢癌PARPi治療策略的ASCO指南。該指南全文于近日以快速交流形式刊載于JCO雜志，在5大主要臨床問題的框架下提出了15條建議。

重復使用PARPi

問題1：在治療過程中，EOC（上皮性卵巢癌）是否可以重復使用PARPi治療？

Recommendation 1.0：Repeating PARPi therapy in the treatment of EOC is not recommended at this time. Consideration should be made as to the best time in the life cycle of an individual patient’s EOC in which to use PARPi; clinical trial participation is encouraged (Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: strong).

推薦1.0：目前不建議在EOC治療中重復使用PARPi。應考慮在個體患者的EOC生命周期中使用PARPi的最佳時間；鼓勵參加臨床試驗（類型：非正式共識，利大于弊；證據質量：不足；推薦程度：強）。

新診斷卵巢癌

問題2：哪些新診斷的EOC患者可以使用PARPi？

a. 哪些EOC組織學類型的患者可推薦使用PARPi？

b. 哪些生物標志亞型可用于推薦使用PARPi？

Recommendation 2.0：PARPis are not recommended for use in initial treatment of early-stage (ie, stage I-II) EOC, because there is insufficient evidence to support use in this population. (Type: informal consensus; benefits outweigh harms; Evidence quality:insufficient; Strength of recommendation: strong)

推薦2.0：不建議在早期（Ⅰ-Ⅱ期）EOC初始治療時使用PARPi，因為沒有足夠證據支持在此類人群中應用（類型：非正式共識，利大于弊；證據質量：不足；建議程度：強）。

Recommendation 2.1：Women with newly diagnosed stage III-IV EOC whose disease is in CR/PR to first-line, platinum-based chemotherapy should be offered PARPi maintenance therapy with olaparib (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 and BRCA2 genes) or niraparib (all women) for treatment of high-grade serous or endometrioid ovarian cancer.

• PARPi maintenance therapy should consist of olaparib (300 mg orally every 12 hours for 2 years) or niraparib (200-300 mg orally daily for 3 years). Longer duration could be considered in selected individuals.

(Type: evidence based, benefits outweigh harms; Evidencequality: high; Strength of recommendation: strong).

推薦2.1：新診斷的Ⅲ-Ⅳ期EOC，一線基于鉑類化療獲得完全緩解（CR）或部分緩解（PR）的患者，應給予PARPi維持治療，在高級別漿液性（HGS）或子宮內膜樣卵巢癌中使用奧拉帕利（攜帶BRCA1或BRCA2基因胚系或體系致病或可能致病突變的患者）或尼拉帕利（所有患者）。

• PARPi維持療法應包括奧拉帕利（每12小時300毫克口服，共兩年）或尼拉帕利（每天200-300毫克口服，共3年）。經選擇的患者可考慮延長療程。

（類型：基于證據，利大于弊；證據質量：高；推薦強度：強）。

Recommendation 2.2：The addition of olaparib to bevacizumab maintenance may be offered to patients who have stage III-IV, high-grade serous or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have a CR/PR to chemotherapy plus bevacizumab combination (Type: evidence based, benefits outweigh harms; Evidence quality: strong; Strength of recommendation: strong).

推薦2.2：Ⅲ-Ⅳ期HGS或子宮內膜樣癌，并且使用Myriad myChoice CDx檢測確定存在胚系或體系或可能致病性的BRCA1或BRCA2基因和/或基因組不穩定，以及對化療聯合貝伐單抗治療達到CR/PR的患者，可在貝伐珠單抗維持治療中增加奧拉帕利（類型：基于證據，利大于弊；證據質量：強；推薦強度：強）。

Recommendation 2.3：Inclusion of the PARPi veliparib with combination chemotherapy followed by veliparib maintenance therapy cannot be recommended at this time. There are no data that this approach is superior, equal, or less toxic than a switch maintenance (Type: evidence based; benefits/harms ratio unknown; Evidence quality: intermediate;Strength of recommendation: strong).

推薦2.3：目前不能推薦含PARPi維拉帕利聯合化療序貫維利帕利維持的治療。沒有數據表明這種方法比換藥維持療效更好、相當或者毒性較小（類型：基于證據；獲益/傷害比未知；證據質量：中度；推薦強度：強）。

復發性卵巢癌：二線或更多維持

問題:3：復發性EOC是否推薦PARPi單藥治療？

a. 在哪些情況下可以單藥治療（如二線維持或復發性疾病治療）？

b. 單藥治療的劑量和療程如何？

Recommendation 3.0：PARPi monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARPi and who have responded to platinumbased therapy regardless of BRCA mutation status; treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care.

• Options include: olaparib 300 mg every 12 hours; rucaparib 600 mg every 12 hours; niraparib 200-300 mg once daily.

(Type: evidence based, benefits outweigh harms; Evidencequality: high; Strength of recommendation: strong)

推薦3.0：既往未接受過PARPi治療，并且對以鉑為基礎的療法有反應的EOC患者，無論其BRCA突變狀態如何，可以給予PARPi單藥維持（二線或更多線）治療，直至疾病進展或者盡管減少劑量和給予最佳支持治療仍不能耐受毒性。

• 選擇包括：奧拉帕利每12小時300毫克；盧卡帕利每12小時600毫克；尼拉帕利每天200-300毫克。

（類型：基于證據，利大于弊；證據質量：高；推薦強度：強）。

Recommendation 3.1：Treatment with a PARPi should be offered to patients with recurrent EOC who have not already received a PARPi and have a germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes.

• Options include: olaparib 300 mg every 12 hours; rucaparib 600 mg every 12 hours; niraparib 200-300 mg once daily.

(Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong)

推薦3.1：尚未接受PARPi治療，且存在BRCA1或BRCA2基因胚系或體系致病性或可能致病性突變的復發性EOC患者，應給予PARPi治療。

• 選擇包括：奧拉帕利每12小時300毫克；盧卡帕利每12小時600毫克；尼拉帕利每天200-300毫克。

（類型：基于證據，利大于弊；證據質量：高；推薦強度：強）。

Recommendation 3.2：Treatment with a PARPi monotherapy should be offered to patients with recurrent EOC who have not already received a PARPi and whose tumor demonstrates genomic instability, as determined by Myriad myChoice CDx, and has not recurred within 6 months of platinum-based therapy (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

推薦3.2：尚未接受過PARPi治療，其腫瘤由Myriad myChoice CDx確定存在基因組不穩定性，且既往基于鉑類化療6個月內未復發的復發性EOC患者，應給予PARPi單藥治療（類型：基于證據，利大于弊；證據質量：高；推薦強度：強）。

Recommendation 3.3：PARPis are not recommended for treatment of BRCAwt or platinum-resistant, recurrent EOC (Type: evidence based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).

推薦3.3：不建議PARPi用于治療BRCA野生型或鉑耐藥的復發性EOC（類型：基于證據，利大于弊；證據質量：高；推薦強度：強）。

PARPi聯合治療

問題4：是否推薦PARPis聯合化療或其他靶向治療？

Recommendation 4.0：PARPis are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents outside the context of a clinical trial. Clinical trial participation is encouraged (Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: moderate).

推薦4.0：在臨床試驗以外，不建議PARPi與化療、其他靶向藥物或免疫腫瘤藥物聯合使用。鼓勵參與臨床試驗（類型：非正式共識，利大于弊；證據質量：不足；推薦強度：強）。

不良事件

問題5：臨床醫生應如何管理不同的PARPi毒性反應？

Recommendation 5.0 Anemia:

a. Patients requiring a blood transfusion for symptom relief and/or hemoglobin level＜8 g/dL should be monitored. PARPi dose should be reduced with evidence of repeated anemia to avoid multiple transfusions.

b. Patients with progressive anemia may be offered growth factor per ASCO guidelines and physician and patient comfort.

(Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation:moderate).

推薦5.0（貧血）：

a. 需要輸血以緩解癥狀和/或血紅蛋白水平＜8g/dL的患者，應監測貧血情況。有反復貧血證據的患者應減少PARPi劑量，以避免多次輸血。

b. 根據ASCO指南、醫生以及患者舒適度等情況，對于進行性貧血患者可給予生長因子治療。

（類型：非正式共識，利大于弊；證據質量：不足；推薦力度：中等）。

Recommendation 5.1 Neutropenia:

a. Growth factor is not indicated for use in patients receiving daily PARPi.

b. Neutropenia (grade 4 lasting $ 5-7 days or associated with fever) should result in dose hold until recovery of infection and granulocyte count, then dose may be reduced. Growth factor support may be used in this setting to support patient safety during the drug hold.

(Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation:moderate),

推薦5.1（中性粒細胞減少）：

a. 患者每日接受PARPi治療，并非生長因子治療的適應癥。

b. 中性粒細胞減少癥（4度持續至少5-7天或伴有發燒）應暫停用藥，直到感染消失和粒細胞計數恢復，然后減少劑量。這種情況下可以用生長因子支持療法，以確保患者在停藥期間的安全。

（類型：非正式共識，利益大于壞;證據質量：不足;推薦力度：中等）。

Recommendation 5.2 Platelets:

a. Thrombocytopenia is most common with niraparib. Niraparib dosing guidelines should be used tolower starting dose (200 mg) based on weight and platelet count.

b. Discontinue PARPi for persistent thrombocytopenia or significant bleeding despite dose reduction.

(Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: moderate).

推薦5.2（血小板）：

a. 血小板減少癥在使用尼拉帕利時最為常見。參考尼拉帕利劑量調整指南，根據體重和血小板計數，起始劑量減量（200毫克）。

b. 盡管降低了劑量，但持續性血小板減少癥或明顯出血患者需停用PARPi。

（類型：非正式共識，利大于弊；證據質量：不足；推薦力度：中等）

Recommendation 5.3 Persistent cytopenia：

Evaluation for treatment-related MDS/AML should be initiated in patients with persistent cytopenia that occurs despite drug hold.(Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: moderate).

推薦5.3（持續性血細胞減少）：

盡管停藥后仍發生持續性血細胞減少的患者，應著手評估有無與治療相關的骨髓增生綜合征/急性骨髓性白血病。（類型：非正式共識，利大于弊；證據質量：不足；推薦力度：中等）。

Recommendation 5.4 Nausea：

a. Many patients will have tachyphylaxis of nausea symptoms over the first cycle of therapy.

b. Persistent nausea requiring daily antiemetic intervention, causing a reduction in performance status, and/or resulting in . 5% weight loss should result in dose reduction.

(Type: informal consensus, benefits outweigh harms; Evidence quality: insufficient; Strength of recommendation: moderate).

推薦5.4（惡心）：

a. 許多患者在治療的第一個周期會發生可以快速耐受的惡心癥狀。

b. 持續惡心需要每日止吐干預、導致身體狀態下降和/或體重下降＞5%的患者，應降低用藥劑量。

（類型：非正式共識，利大于弊；證據質量：不足；推薦力度：中等）。

參考資料：

Tew WP, Lacchetti C, Ellis A, et al. PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline [published online ahead of print, 2020 Aug 13]. J Clin Oncol. 2020;JCO2001924. doi:10.1200/JCO.20.01924

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