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ASCO指南:卵巢癌的PARP抑制剂治疗策略

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转自《肿瘤瞭望》

随着PARP抑制剂(PARPi)在卵巢癌中的循证医学证据积累及获批药品和适应症增加,卵巢癌的全程管理策略发生了巨大变化。ASCO召集专家小组,首次编写了卵巢癌PARPi治疗策略的ASCO指南。该指南全文于近日以快速交流形式刊载于JCO杂志,在5大主要临床问题的框架下提出了15条建议。

重复使用PARPi

问题1:在治疗过程中,EOC(上皮性卵巢癌)是否可以重复使用PARPi治疗?

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).

推荐1.0:目前不建议在EOC治疗中重复使用PARPi。应考虑在个体患者的EOC生命周期中使用PARPi的最佳时间;鼓励参加临床试验(类型:非正式共识,利大于弊;证据质量:不足;推荐程度:强)。

新诊断卵巢癌

问题2:哪些新诊断的EOC患者可以使用PARPi?


a. 哪些EOC组织学类型的患者可推荐使用PARPi?

b. 哪些生物标志亚型可用于推荐使用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)

推荐2.0:不建议在早期(Ⅰ-Ⅱ期)EOC初始治疗时使用PARPi,因为没有足够证据支持在此类人群中应用(类型:非正式共识,利大于弊;证据质量:不足;建议程度:强)。

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).

推荐2.1:新诊断的Ⅲ-Ⅳ期EOC,一线基于铂类化疗获得完全缓解(CR)或部分缓解(PR)的患者,应给予PARPi维持治疗,在高级别浆液性(HGS)或子宫内膜样卵巢癌中使用奥拉帕利(携带BRCA1或BRCA2基因胚系或体系致病或可能致病突变的患者)或尼拉帕利(所有患者)。

  • PARPi维持疗法应包括奥拉帕利(每12小时300毫克口服,共两年)或尼拉帕利(每天200-300毫克口服,共3年)。经选择的患者可考虑延长疗程。

(类型:基于证据,利大于弊;证据质量:高;推荐强度:强)。

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).

推荐2.2:Ⅲ-Ⅳ期HGS或子宫内膜样癌,并且使用Myriad myChoice CDx检测确定存在胚系或体系或可能致病性的BRCA1或BRCA2基因和/或基因组不稳定,以及对化疗联合贝伐单抗治疗达到CR/PR的患者,可在贝伐珠单抗维持治疗中增加奥拉帕利(类型:基于证据,利大于弊;证据质量:强;推荐强度:强)。

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).

推荐2.3:目前不能推荐含PARPi维拉帕利联合化疗序贯维利帕利维持的治疗。没有数据表明这种方法比换药维持疗效更好、相当或者毒性较小(类型:基于证据;获益/伤害比未知;证据质量:中度;推荐强度:强)。

复发性卵巢癌:二线或更多维持

问题:3:复发性EOC是否推荐PARPi单药治疗?


a. 在哪些情况下可以单药治疗(如二线维持或复发性疾病治疗)?

b. 单药治疗的剂量和疗程如何?

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)

推荐3.0:既往未接受过PARPi治疗,并且对以铂为基础的疗法有反应的EOC患者,无论其BRCA突变状态如何,可以给予PARPi单药维持(二线或更多线)治疗,直至疾病进展或者尽管减少剂量和给予最佳支持治疗仍不能耐受毒性。

  • 选择包括:奥拉帕利每12小时300毫克;卢卡帕利每12小时600毫克;尼拉帕利每天200-300毫克。

(类型:基于证据,利大于弊;证据质量:高;推荐强度:强)。

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)

推荐3.1:尚未接受PARPi治疗,且存在BRCA1或BRCA2基因胚系或体系致病性或可能致病性突变的复发性EOC患者,应给予PARPi治疗。

  • 选择包括:奥拉帕利每12小时300毫克;卢卡帕利每12小时600毫克;尼拉帕利每天200-300毫克。

(类型:基于证据,利大于弊;证据质量:高;推荐强度:强)。

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).

推荐3.2:尚未接受过PARPi治疗,其肿瘤由Myriad myChoice CDx确定存在基因组不稳定性,且既往基于铂类化疗6个月内未复发的复发性EOC患者,应给予PARPi单药治疗(类型:基于证据,利大于弊;证据质量:高;推荐强度:强)。

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).

推荐3.3:不建议PARPi用于治疗BRCA野生型或铂耐药的复发性EOC(类型:基于证据,利大于弊;证据质量:高;推荐强度:强)。

PARPi联合治疗

问题4:是否推荐PARPis联合化疗或其他靶向治疗?

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).

推荐4.0:在临床试验以外,不建议PARPi与化疗、其他靶向药物或免疫肿瘤药物联合使用。鼓励参与临床试验(类型:非正式共识,利大于弊;证据质量:不足;推荐强度:强)。

不良事件

问题5:临床医生应如何管理不同的PARPi毒性反应?

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).

推荐5.0(贫血):

a. 需要输血以缓解症状和/或血红蛋白水平<8g/dL的患者,应监测贫血情况。有反复贫血证据的患者应减少PARPi剂量,以避免多次输血。

b. 根据ASCO指南、医生以及患者舒适度等情况,对于进行性贫血患者可给予生长因子治疗。

(类型:非正式共识,利大于弊;证据质量:不足;推荐力度: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),

推荐5.1(中性粒细胞减少):

a. 患者每日接受PARPi治疗,并非生长因子治疗的适应症。

b. 中性粒细胞减少症(4度持续至少5-7天或伴有发烧)应暂停用药,直到感染消失和粒细胞计数恢复,然后减少剂量。这种情况下可以用生长因子支持疗法,以确保患者在停药期间的安全。

(类型:非正式共识,利益大于坏;证据质量:不足;推荐力度: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).

推荐5.2(血小板):

a. 血小板减少症在使用尼拉帕利时最为常见。参考尼拉帕利剂量调整指南,根据体重和血小板计数,起始剂量减量(200毫克)。

b. 尽管降低了剂量,但持续性血小板减少症或明显出血患者需停用PARPi。

(类型:非正式共识,利大于弊;证据质量:不足;推荐力度: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).

推荐5.3(持续性血细胞减少):

尽管停药后仍发生持续性血细胞减少的患者,应着手评估有无与治疗相关的骨髓增生综合征/急性骨髓性白血病。(类型:非正式共识,利大于弊;证据质量:不足;推荐力度: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).

推荐5.4(恶心):

a. 许多患者在治疗的第一个周期会发生可以快速耐受的恶心症状。

b. 持续恶心需要每日止吐干预、导致身体状态下降和/或体重下降>5%的患者,应降低用药剂量。

(类型:非正式共识,利大于弊;证据质量:不足;推荐力度:中等)。

参考资料:

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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