妊娠滋养细胞肿瘤药物治疗的现状及进展
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摘要
妊娠滋养细胞肿瘤(gestational trophoblastic neoplasia,GTN)是一类少见的恶性肿瘤,也是较早即可通过化疗治愈的肿瘤。国内外指南建议,在选择化疗方案的时候应依据于危险分层,低危GTN患者首选单药化疗。在2018年FIGO关于GTN诊治指南更新中,强调了对低危患者的进一步分层处理。对于5～6分及病理诊断为绒癌的患者,单药化疗的耐药率增加,可以放宽标准直接选择联合化疗。随着肿瘤治疗的进展,新药物、新方法也在GTN中应用,但资料仍然比较有限。多重耐药、复发的GTN患者仍然是治疗的难点。对这些患者,大剂量化疗联合自体干细胞移植可能是一个治疗选择。免疫治疗的成功报道也是鼓舞人心的,有可能成为高危、耐药患者的新选择。不过,GTN中免疫检测点抑制剂的作用机制并不完全清楚,治疗的长期疗效、毒副反应和对远期生育力的影响均尚不明确。免疫治疗在整个GTN治疗中的地位仍然需要探讨。
Gestational trophoblastic neoplasia(GTN) is a group of rare malignant tumors. It was the first metastatic cancer to be cured by chemotherapy. The choice of chemotherapy is based on risk stratification. The majority of low risk patients can be cured with single agent chemotherapy. In the updated GTN guidelines revised by FIGO in 2018, further stratification of low-risk patients was highlighted. Higher FIGO score(5～6) and clinicopathologic diagnosis of choriocarcinoma are both associated with an increased risk of resistance to single agent chemotherapy. Lowering the threshold for the use of multiple agent chemotherapy in these low-risk patients can be considered. With the progress in cancer treatment, new drugs and methods are also applied in GTN, but the data are still limited. Multi-drug resistance and recurrence patients remain difficult to cure. High-dose chemotherapy combined with autologous stem cell transplantation may be an option for these patients. Recent work suggests that checkpoint immunotherapies may also save some of these patients. However, the mechanism of checkpoint inhibitors is poorly understood, and the long-term efficacy or side effects of treatment is under cleared. The status of immunotherapy in the treatment of GTN remains to be explored.
Gestational trophoblastic neoplasia(GTN) is a group of rare malignant tumors. It was the first metastatic cancer to be cured by chemotherapy. The choice of chemotherapy is based on risk stratification. The majority of low risk patients can be cured with single agent chemotherapy. In the updated GTN guidelines revised by FIGO in 2018, further stratification of low-risk patients was highlighted. Higher FIGO score(5～6) and clinicopathologic diagnosis of choriocarcinoma are both associated with an increased risk of resistance to single agent chemotherapy. Lowering the threshold for the use of multiple agent chemotherapy in these low-risk patients can be considered. With the progress in cancer treatment, new drugs and methods are also applied in GTN, but the data are still limited. Multi-drug resistance and recurrence patients remain difficult to cure. High-dose chemotherapy combined with autologous stem cell transplantation may be an option for these patients. Recent work suggests that checkpoint immunotherapies may also save some of these patients. However, the mechanism of checkpoint inhibitors is poorly understood, and the long-term efficacy or side effects of treatment is under cleared. The status of immunotherapy in the treatment of GTN remains to be explored.
引文
[1] Ngan HYS, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and management of gestational trophoblastic disease [J]. Int J Gynaecol Obstet, 2018, 143(S2):79-85.
[2] Sung HC, Wu PC, Ho TH. Treatment of choriocarcinoma and chorioadenoma destruens with 6-mercaptopurine and surgery. A clinical report of 93 cases [J]. Chin Med J, 1963, 82:24-38.
[3] Sung HC, Wu PC, Yang HY. Reevaluation of 5-fluorouracil as a single therapeutic agent for gestational trophoblastic neoplasms [J]. Am J Obstet Gynecol, 1984, 150(1):69-75.
[4] Eysbouts YK, Massuger L, Thomas C, et al. Dutch risk classification and FIGO 2000 for gestational trophoblastic neoplasia compared [J]. Int J Gynecol Cancer, 2016, 26(9):1712-1716.
[5] Ngan HY, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and management of gestational trophoblastic disease [J]. Int J Gynaecol Obstet, 2015, 131(S2):123-126.
[6] 李洁,向阳. 低危妊娠滋养细胞肿瘤化疗现状及耐药发生相关因素[J]. 中国实用妇科与产科杂志, 2015, 31(11):1052-1054.
[7] Lawrie TA, Alazzam M, Tidy J, et al. First-line chemotherapy in low-risk gestational trophoblastic neoplasia [J]. Cochrane Database Syst Rev, 2016, 6:CD007102.
[8] Aghajanian C. Treatment of low-risk gestational trophoblastic neoplasia [J]. J Clin Oncol, 2011, 29(7):786-788.
[9] Sita-Lumsden A, Short D, Lindsay I, et al. Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009 [J]. Br J Cancer, 2012, 107(11):1810-1814.
[10] Strohl AE, Lurain JR. Postmolar choriocarcinoma: an independent risk factor for chemotherapy resistance in low-risk gestational trophoblastic neoplasia [J]. Gynecol Oncol, 2016, 141(2):276-280.
[11] Taylor F, Grew T, Everard J, et al. The outcome of patients with low risk gestational trophoblastic neoplasia treated with single agent intramuscular methotrexate and oral folinic acid [J]. Eur J Cancer, 2013, 49(15):3184-3190.
[12] Li L, Wan X, Feng F, et al. Pulse actinomycin D as first-line treatment of low-risk post-molar non-choriocarcinoma gestational trophoblastic neoplasia [J]. BMC cancer, 2018, 18(1):585.
[13] Alifrangis C, Agarwal R, Short D, et al. EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis [J]. J Clin Oncol, 2013, 31(2):280-286.
[14] Even C, Pautier P, Duvillard P, et al. Actinomycin D, cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia [J]. Eur J Cancer, 2014, 50(12):2082-2089.
[15] 孔雨佳,向阳. 高危及耐药性妊娠滋养细胞肿瘤患者的治疗策略 [J]. 现代妇产科进展, 2017, 26(7):550-555.
[16] Yang J, Xiang Y, Wan X, et al. Primary treatment of stage IV gestational trophoblastic neoplasia with floxuridine, dactinomycin, etoposide and vincristine (FAEV): A report based on our 10-year clinical experiences [J]. Gynecol Oncol, 2016, 143(1):68-72.
[17] Bolze PA, Attia J, Massardier J, et al. Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases [J]. Eur J Cancer, 2015, 51(13):1725-1731.
[18] Kong Y, Yang J, Jiang F, et al. Clinical characteristics and prognosis of ultra high-risk gestational trophoblastic neoplasia patients: a retrospective cohort study [J]. Gynecol Oncol, 2017, 146(1):81-86.
[19] Singh K, Warnock C, Ireson J, et al. Experiences of women with gestational trophoblastic neoplasia treated with high-dose chemotherapy and stem cell transplantation: a qualitative study [J]. Oncol Nurs Forum, 2017, 44(3):375-383.
[20] Yamamoto E, Niimi K, Fujikake K, et al. High-dose chemotherapy with autologous peripheral blood stem cell transplantation for choriocarcinoma: a case report and literature review [J]. Mol Clin Oncol, 2016, 5(5):660-664.
[21] Yamamoto E, Niimi K, Fujikake K, et al. Erratum: High-dose chemotherapy with autologous peripheral blood stem cell transplantation for choriocarcinoma: a case report and literature review[J]. Mol Clin Oncol, 2017, 7(3):510.
[22] Markman M. Experience with platinum-based and high-dose chemotherapy in patients with gestational trophoblastic disease: possible implications for future management [J]. J Cancer Res Clin Oncol, 2004, 130(7):383-387.
[23] Sharma P, Allison JP. The future of immune checkpoint therapy [J]. Science, 2015, 348(6230):56-61.
[24] Veras E, Kurman RJ, Wang TL, et al. PD-L1 expression in human placentas and gestational trophoblastic diseases [J]. Int J Gynecol Pathol, 2017, 36(2):146-153.
[25] Ghorani E, Kaur B, Fisher RA, et al. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia [J]. Lancet, 2017, 390(10110):2343-2345.
[2] Sung HC, Wu PC, Ho TH. Treatment of choriocarcinoma and chorioadenoma destruens with 6-mercaptopurine and surgery. A clinical report of 93 cases [J]. Chin Med J, 1963, 82:24-38.
[3] Sung HC, Wu PC, Yang HY. Reevaluation of 5-fluorouracil as a single therapeutic agent for gestational trophoblastic neoplasms [J]. Am J Obstet Gynecol, 1984, 150(1):69-75.
[4] Eysbouts YK, Massuger L, Thomas C, et al. Dutch risk classification and FIGO 2000 for gestational trophoblastic neoplasia compared [J]. Int J Gynecol Cancer, 2016, 26(9):1712-1716.
[5] Ngan HY, Seckl MJ, Berkowitz RS, et al. Update on the diagnosis and management of gestational trophoblastic disease [J]. Int J Gynaecol Obstet, 2015, 131(S2):123-126.
[6] 李洁,向阳. 低危妊娠滋养细胞肿瘤化疗现状及耐药发生相关因素[J]. 中国实用妇科与产科杂志, 2015, 31(11):1052-1054.
[7] Lawrie TA, Alazzam M, Tidy J, et al. First-line chemotherapy in low-risk gestational trophoblastic neoplasia [J]. Cochrane Database Syst Rev, 2016, 6:CD007102.
[8] Aghajanian C. Treatment of low-risk gestational trophoblastic neoplasia [J]. J Clin Oncol, 2011, 29(7):786-788.
[9] Sita-Lumsden A, Short D, Lindsay I, et al. Treatment outcomes for 618 women with gestational trophoblastic tumours following a molar pregnancy at the Charing Cross Hospital, 2000-2009 [J]. Br J Cancer, 2012, 107(11):1810-1814.
[10] Strohl AE, Lurain JR. Postmolar choriocarcinoma: an independent risk factor for chemotherapy resistance in low-risk gestational trophoblastic neoplasia [J]. Gynecol Oncol, 2016, 141(2):276-280.
[11] Taylor F, Grew T, Everard J, et al. The outcome of patients with low risk gestational trophoblastic neoplasia treated with single agent intramuscular methotrexate and oral folinic acid [J]. Eur J Cancer, 2013, 49(15):3184-3190.
[12] Li L, Wan X, Feng F, et al. Pulse actinomycin D as first-line treatment of low-risk post-molar non-choriocarcinoma gestational trophoblastic neoplasia [J]. BMC cancer, 2018, 18(1):585.
[13] Alifrangis C, Agarwal R, Short D, et al. EMA/CO for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis [J]. J Clin Oncol, 2013, 31(2):280-286.
[14] Even C, Pautier P, Duvillard P, et al. Actinomycin D, cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia [J]. Eur J Cancer, 2014, 50(12):2082-2089.
[15] 孔雨佳,向阳. 高危及耐药性妊娠滋养细胞肿瘤患者的治疗策略 [J]. 现代妇产科进展, 2017, 26(7):550-555.
[16] Yang J, Xiang Y, Wan X, et al. Primary treatment of stage IV gestational trophoblastic neoplasia with floxuridine, dactinomycin, etoposide and vincristine (FAEV): A report based on our 10-year clinical experiences [J]. Gynecol Oncol, 2016, 143(1):68-72.
[17] Bolze PA, Attia J, Massardier J, et al. Formalised consensus of the European Organisation for Treatment of Trophoblastic Diseases on management of gestational trophoblastic diseases [J]. Eur J Cancer, 2015, 51(13):1725-1731.
[18] Kong Y, Yang J, Jiang F, et al. Clinical characteristics and prognosis of ultra high-risk gestational trophoblastic neoplasia patients: a retrospective cohort study [J]. Gynecol Oncol, 2017, 146(1):81-86.
[19] Singh K, Warnock C, Ireson J, et al. Experiences of women with gestational trophoblastic neoplasia treated with high-dose chemotherapy and stem cell transplantation: a qualitative study [J]. Oncol Nurs Forum, 2017, 44(3):375-383.
[20] Yamamoto E, Niimi K, Fujikake K, et al. High-dose chemotherapy with autologous peripheral blood stem cell transplantation for choriocarcinoma: a case report and literature review [J]. Mol Clin Oncol, 2016, 5(5):660-664.
[21] Yamamoto E, Niimi K, Fujikake K, et al. Erratum: High-dose chemotherapy with autologous peripheral blood stem cell transplantation for choriocarcinoma: a case report and literature review[J]. Mol Clin Oncol, 2017, 7(3):510.
[22] Markman M. Experience with platinum-based and high-dose chemotherapy in patients with gestational trophoblastic disease: possible implications for future management [J]. J Cancer Res Clin Oncol, 2004, 130(7):383-387.
[23] Sharma P, Allison JP. The future of immune checkpoint therapy [J]. Science, 2015, 348(6230):56-61.
[24] Veras E, Kurman RJ, Wang TL, et al. PD-L1 expression in human placentas and gestational trophoblastic diseases [J]. Int J Gynecol Pathol, 2017, 36(2):146-153.
[25] Ghorani E, Kaur B, Fisher RA, et al. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia [J]. Lancet, 2017, 390(10110):2343-2345.