妊娠期乳腺癌的治疗与非妊娠期无异

《柳叶刀-肿瘤学》(Lancet Oncology)8月16日在线发表的一项观察研究显示，妊娠期乳腺癌与非妊娠期乳腺癌的治疗相同，并且不会明显增加对母婴的风险(Lancet Oncol. 2012 Aug. 15 [doi:10.1016/S1470-2045(12)70261-9])。

虽然妊娠期乳腺癌较为罕见(在欧洲乳腺癌病例中仅占不到1%)，但由于高龄产妇日益增多，妊娠期乳腺癌的发生率相应升高。德国乳腺研究组(German Breast Group)于2003年建立了妊娠期乳腺癌登记库，并在2009年将登记范围扩大至荷兰、英国、波兰、意大利和捷克。同一时期，比利时也建立了纳入所有妊娠期癌症病例的登记库。在这项研究中，该研究组的Sibylle Loibl博士及其同事对这些登记库中447例在妊娠期间被诊断为早期(413例)或转移性(34例)乳腺癌的患者的预后进行了评估。

诊断时的中位胎龄为24周(5~40周)，患者的中位年龄为33岁(22~51岁)。共获得368例患者的化疗数据，其中197例在妊娠期间接受化疗，171例在分娩后接受化疗。共化疗1,187个周期，其中63%在妊娠期间进行。患者在妊娠期间接受1~8个(中位数：4个)周期化疗。

在妊娠期间接受治疗的患者中，共有90%使用蒽环类抗生素；8％合用环磷酰胺、甲氨蝶呤和氟尿嘧啶；7％使用紫杉类。无1例患者在妊娠期间接受曲妥珠单抗、内分泌治疗或放疗。
选择在妊娠期间接受化疗的早期乳腺癌患者往往比选择在分娩后进行化疗的患者具有更晚期的疾病，而且肿瘤分期和淋巴结状况较差。在校正这些方面的差异后，研究者发现两组患者在无病生存率和总生存率方面均无显著差异。

妊娠期间接受化疗和分娩后接受化疗的早期乳腺癌患者，估计3年无病生存率为70.2% vs. 74.3%，估计3年总生存率为84.9% vs. 87.4%，估计5年无病生存率为61.1% vs. 64.4%，估计5年总生存率为77% vs. 82.4%。

共获得373例新生儿的数据，其中203例在子宫内暴露于化疗，170例无此暴露。妊娠期暴露组新生儿的出生体重稍低于未暴露组，但这一差异被认为不影响婴儿健康而无临床意义。此外，两组在主要出生缺陷、婴儿身高、Apgar评分、血红蛋白浓度、白细胞计数、血小板计数或脱发方面无显著差异。两组随母亲出院的婴儿比例也无显著差异(34% vs. 41%)。

妊娠期间接受化疗者的不良事件发生率高于分娩后接受化疗者(15% vs. 4%)。然而，这一差异缘于妊娠期间暴露于化疗组的早产和胎膜早破发生率较高。大部分并发症见于早产婴儿，不论化疗暴露的时间点如何。

该研究的数据不足以解释为什么接受化疗的孕产妇的早产率较高。不过，原因可能在于身心上的双重应激，以及接受化疗的孕产妇更易于发生可诱发分娩的感染。此外，细胞毒性药物可能通过一些尚不清楚的机制促进分娩。然而，两组的先兆子痫发生率相似，因此已知由细胞毒性药物诱导产生的氧化应激并非早产的诱发因素。

研究者总结指出，上述结果表明孕中期或孕晚期接受乳腺癌化疗者的妊娠预后与分娩后才接受化疗的孕产妇无显著差异，但这一结果仍有待其他研究的证实。

该研究获BANSS基金会等多家机构支持。研究者声明无经济利益冲突。

随刊述评：未来研究的方向

巴黎妊娠相关癌症网络的Olivier Mir博士和Paul Berveiller博士指出，未来研究不仅应探讨妊娠期间化疗的毒性影响，而且还应探讨细胞毒性药物在孕产妇体内的药代动力学，因为妊娠生理改变可显著影响药物分布。对于这类人群，是否应增加剂量尚不确定，因为这么做可能会导致重度血小板减少、中性粒细胞减少和感染，并对母亲和婴儿产生潜在不良影响。此外，还应探讨通过优化药物选择和给药方案是否可最大程度地降低该研究观察到的胎儿风险轻微增加(Lancet Oncol. 2012 Aug. 15 [doi:10.1016/S1470-2045(12)70331-5])。

爱思唯尔版权所有  未经授权请勿转载

By: MARY ANN MOON, Internal Medicine News Digital Network

It appears that breast cancer diagnosed during pregnancy can be treated much the same as breast cancer diagnosed in nonpregnant women without substantially raising the risks to mother or child, according to a study published online August 16 in the Lancet Oncology .

This conclusion, from an observational study involving 447 European women included in registries of cancers diagnosed during pregnancy, must still be validated in other studies. But until then, the current evidence indicates that pregnancy outcomes are not significantly different between women who receive breast cancer chemotherapy during the second or third trimesters and those who wait until after delivery to start treatment, said Dr. Sibylle Loibl of the German Breast Group, Neu-Isenburg, Germany, and her associates.

In this study, infants exposed to their mothers’ breast cancer chemotherapy while in utero had slightly lower birth weights and slightly more complications than those not exposed to chemotherapy, but these differences were not clinically significant.

Breast cancer diagnosed during pregnancy is rare, estimated to occur in less than 1% of breast cancers in Europe. But its incidence is increasing in high-income countries due to the trend of women delaying childbirth until they are older, when breast cancer is more prevalent.

The German Breast Group established its Breast Cancer During Pregnancy registry in 2003 and expanded it to include cases in the Netherlands, the United Kingdom, Poland, Italy, and the Czech Republic in 2009. In the same time period, Belgium also established a registry of all cancers diagnosed during pregnancy. Dr. Loibl and her colleagues assessed outcomes in 447 cases from these registries in which women were diagnosed as having early (413 patients) or metastatic (34 patients) breast cancer while pregnant (Lancet Oncol. 2012 Aug. 15 [doi:10.1016/S1470-2045(12)70261-9]).

The median gestational age at diagnosis was 24 weeks (range, 5-40 weeks), and the median age of the women was 33 years (range, 22-51 years).

Data on chemotherapy were available for 368 women. Of these, 197 received chemotherapy while pregnant and 171 received it after delivery.

Overall, 1,187 cycles of chemotherapy were given, and 63% of these were given during pregnancy. The women received a median of four cycles (range, one to eight cycles) during pregnancy.

A total of 90% of those treated during pregnancy received an anthracyline; 8% received a combination of cyclophosphamide, methotrexate, and fluorouracil; and 7% received a taxane. None of the women received trastuzumab, endocrine therapy, or radiotherapy during pregnancy.

Women with early breast cancer who opted for chemotherapy during pregnancy tended to have more advanced disease, with more unfavorable tumor stage and nodal status, than did those who chose to begin chemotherapy after delivery. After the data were adjusted to account for this difference, the researchers found no significant difference between the two groups in disease-free or overall survival.

The estimated 3-year disease-free survival was 70.2% in women with early disease who underwent chemotherapy while pregnant and 74.3% in those who waited until after delivery. Similarly, the estimated overall 3-year survival was 84.9% in women with early breast cancer who underwent chemotherapy while pregnant and 87.4% in those who delayed chemotherapy until after delivery.

The estimated 5-year disease-free survival was 61.1% in women who had chemotherapy while pregnant and 64.4% in those who waited, and the estimated 5-year overall survival was 77% and 82.4%, respectively.

Data were available for 373 newborns, of whom 203 had been exposed to chemotherapy in utero and 170 had not.

Birth weight was slightly lower in the exposed than in the nonexposed infants, but this difference was judged to be "clinically irrelevant" because it didn’t affect the health of the babies, Dr. Loibl and her associates said.

Moreover, there were no significant differences between the two groups in major birth defects, infant height, Apgar scores, hemoglobin concentration, leukocyte counts, thrombocyte counts, or alopecia. And there was no significant difference in the proportion of infants discharged with their mothers (34% vs. 41%).

Adverse events occurred more often when chemotherapy was received during pregnancy (15%) than when it was delayed (4%). However, this difference was attributed to the higher rates of preterm labor and premature rupture of the membrane among exposed pregnancies. "Most complications were reported in babies who were delivered prematurely, regardless of exposure to chemotherapy," the investigators said.

The data were not adequate to determine why women who received chemotherapy had a higher rate of preterm delivery. Both physical stress and psychological stress may have played a role, and it is possible that women who received chemotherapy were more prone to infections that may have triggered labor.

In addition, the cytotoxic agents themselves may have hastened labor through some as yet unknown mechanism. However, the rate of preeclampsia was similar between the two groups, so oxidative stress, which is known to be induced by cytoxic agents, was not responsible.

Further study of the data being collected in the registries of cancers diagnosed during pregnancy will likely shed light on these issues. Dr. Loibl and her colleagues are now performing a matched-pair analysis to assess whether the prognosis of breast cancer in nonpregnant women differs from that in pregnant women when the latter are treated according to current guidelines.

This study was supported by BANSS Foundation, University Hospital Frankfurt, the German Breast Group, Research Foundation-Flanders, Clinical Research Fund-UZ Gasthuisberg, and the Belgian Cancer Plan. No financial conflicts of interest were reported.

VIEW ON THE NEWS
Direction of Future Research

Future studies should address not just the toxic effects of chemotherapy during pregnancy but also the pharmacokinetics of cytotoxic agents in pregnant women, because the physiologic changes of pregnancy can greatly affect drug disposition, said Dr. Olivier Mir and Dr. Paul Berveiller.

"Whether doses should be increased in this population is uncertain because such increases could result in severe thrombocytopenia, neutropenia, and infection, with potentially devastating consequences for both mother and baby," they noted.

More research also is needed to determine whether the slightly increased fetal risks identified by Dr. Loibl and her colleagues could be minimized with better drug selection and dosing, they added.

Dr. Mir and Dr. Berveiller are in the Cancer Associated With Pregnancy Network, Paris. Dr. Mir is also in the department of medical oncology at Hôpital Cochin at the Université René Descartes, Paris. Dr. Mir reported ties to Roche, Pfizer, and Servier. These remarks were taken from their editorial comment accompanying Dr. Loibl’s report (Lancet Oncol. 2012 Aug. 15 [doi:10.1016/S1470-2045(12)70331-5]).