Rio de Janeiro Trophoblastic Disease Centre, Maternity School of Rio de Janeiro Federal University, Antonio Pedro University Hospital of Fluminense Federal University, Niterói, Rio de Janeiro, Brazil; Postgraduate Programme in Perinatal Health, Faculty of Medicine, Maternity School of Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Postgraduate Programme in Medical Sciences, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil; Young Leadership Physicians Programme, National Academy of Medicine, Rio de Janeiro, Brazil.
Rio de Janeiro Trophoblastic Disease Centre, Maternity School of Rio de Janeiro Federal University, Antonio Pedro University Hospital of Fluminense Federal University, Niterói, Rio de Janeiro, Brazil; Postgraduate Programme in Perinatal Health, Faculty of Medicine, Maternity School of Rio de Janeiro Federal University, Rio de Janeiro, Brazil.
Lancet Oncol. 2021 Aug;22(8):1188-1198. doi: 10.1016/S1470-2045(21)00262-X. Epub 2021 Jun 25.
Patients with gestational trophoblastic neoplasia who have an International Federation of Gynaecology and Obstetrics (FIGO) risk score of 5 or 6 usually receive non-toxic single-agent chemotherapy as a first-line treatment. Previous studies suggest that only a third of patients have complete remission, with the remaining patients requiring toxic multiagent chemotherapy to attain remission. As stratification factors are unknown, some centres offer multiagent therapy upfront, resulting in overtreatment of many patients. We aimed to identify predictive factors for resistance to single-agent therapy to inform clinicians on which patients presenting with a FIGO score of 5 or 6 are likely to benefit from upfront multiagent chemotherapy.
We did a multicentre, retrospective, cohort study of patients with gestational trophoblastic neoplasia presenting with a FIGO score of 5 or 6, who received treatment at three gestational trophoblastic neoplasia reference centres in the UK, Brazil, and the USA between Jan 1, 1964, and Dec 31, 2018. All patients who had been followed up for at least 12 months after remission were included. Patients were excluded if they had received a non-standard single-agent treatment (eg, etoposide); had been given a previously established first-line multiagent chemotherapy regimen; or had incomplete data for our analyses. Patient data were retrieved from medical records. The primary outcome was the incidence of chemoresistance after first-line or second-line single-agent chemotherapy. Variables associated with chemoresistance to single-agent therapies were identified by logistic regression analysis. In patient subgroups defined by choriocarcinoma histology and metastatic disease status, we did bootstrap modelling to define thresholds of pretreatment human chorionic gonadotropin concentrations and identify groups of patients with a greater than 80% risk (ie, a positive predictive value [PPV] of 0·8) of resistance to single-agent chemotherapy.
Of 5025 patients with low-risk gestational trophoblastic neoplasia, we identified 431 patients with gestational trophoblastic neoplasia presenting with a FIGO risk score of 5 or 6. All patients were followed up for a minimum of 2 years. 141 (40%) of 351 patients developed resistance to single-agent treatments and required multiagent chemotherapy to achieve remission. Univariable and multivariable logistic regression revealed metastatic disease status (multivariable logistic regression analysis, odds ratio [OR] 1·9 [95% CI 1·1-3·2], p=0·018), choriocarcinoma histology (3·7 [1·9-7·4], p=0·0002), and pretreatment human chorionic gonadotropin concentration (2·8 [1·9-4·1], p<0·0001) as significant predictors of resistance to single-agent therapies. In patients with no metastatic disease and without choriocarcinoma, a pretreatment human chorionic gonadotropin concentration of 411 000 IU/L or higher yielded a PPV of 0·8, whereas in patients with either metastases or choriocarcinoma, a pretreatment human chorionic gonadotropin concentration of 149 000 IU/L or higher yielded the same PPV for resistance to single-agent therapy.
Approximately 60% of women with gestational trophoblastic neoplasia presenting with a FIGO risk score of 5 or 6 achieve remission with single-agent therapy; almost all remaining patients have complete remission with subsequent multiagent chemotherapy. Primary multiagent chemotherapy should only be given to patients with metastatic disease and choriocarcinoma, regardless of pretreatment human chorionic gonadotropin concentration, or to those defined by our new predictors.
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For the Portuguese translation of the abstract see Supplementary Materials section.
国际妇产科联合会（FIGO）风险评分 5 或 6 的妊娠滋养细胞肿瘤患者通常接受非毒性单药化疗作为一线治疗。先前的研究表明，只有三分之一的患者完全缓解，其余患者需要毒性更大的联合化疗才能缓解。由于分层因素未知，一些中心提供了联合化疗，导致许多患者过度治疗。我们旨在确定对单药治疗耐药的预测因素，以便告知临床医生哪些具有 FIGO 评分 5 或 6 的患者可能从初始联合化疗中受益。
我们对英国、巴西和美国的三个妊娠滋养细胞肿瘤参考中心在 1964 年 1 月 1 日至 2018 年 12 月 31 日期间就诊的 FIGO 评分 5 或 6 的妊娠滋养细胞肿瘤患者进行了多中心、回顾性、队列研究。所有接受过至少 12 个月缓解后随访的患者均被纳入。如果患者接受了非标准的单药治疗（如依托泊苷）、已接受既定的一线联合化疗方案或我们的分析存在不完整的数据，则将其排除在外。患者数据从病历中检索。主要结局是一线或二线单药化疗后耐药的发生率。通过逻辑回归分析确定与单药治疗耐药相关的变量。在绒毛膜癌组织学和转移性疾病状态定义的患者亚组中，我们进行了自举建模，以确定人绒毛膜促性腺激素浓度的治疗前阈值，并确定具有大于 80%耐药风险（即阳性预测值 [PPV] 为 0.8）的患者组对单药化疗。
在 5025 例低危妊娠滋养细胞肿瘤患者中，我们确定了 431 例具有 FIGO 风险评分 5 或 6 的妊娠滋养细胞肿瘤患者。所有患者的随访时间均至少为 2 年。351 例患者中有 141 例（40%）对单药治疗产生耐药，需要联合化疗才能缓解。单变量和多变量逻辑回归显示转移性疾病状态（多变量逻辑回归分析，优势比 [OR] 1.9 [95%CI 1.1-3.2]，p=0.018）、绒毛膜癌组织学（3.7 [1.9-7.4]，p=0.0002）和治疗前人绒毛膜促性腺激素浓度（2.8 [1.9-4.1]，p<0.0001）是对单药治疗耐药的显著预测因素。在没有转移疾病且没有绒毛膜癌的患者中，治疗前人绒毛膜促性腺激素浓度为 411000 IU/L 或更高时，PPV 为 0.8，而在有转移或绒毛膜癌的患者中，治疗前人绒毛膜促性腺激素浓度为 149000 IU/L 或更高时，对单药治疗耐药的 PPV 也为 0.8。
大约 60% 的 FIGO 风险评分 5 或 6 的妊娠滋养细胞肿瘤患者通过单药治疗可达到缓解；几乎所有其余患者均通过后续的联合化疗获得完全缓解。原发联合化疗应仅用于具有转移疾病和绒毛膜癌的患者，无论其治疗前人绒毛膜促性腺激素浓度如何，或用于我们新的预测因素定义的患者。
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