Systemic Cancer Treatment in Pregnancy

During the 6th to 34th week of pregnancy, a volume expansion of 3-4 liters evolves. Plasma volume increases by 1200 ml, total erythrocyte volume by 300 ml, and the placenta and fetal circulation require an additional 2000 ml or more. The dilution effect decreases the blood albumin concentration [33]. Another consequence is increased renal clearance [51]. Activation of relevant enzymes of the cytochrome p450 system (CYP 3A4, CYP 2C9, CYP 2A6) and uridine diphosphate glucuronosyltransferase (UGT) results in more rapid hepatic metabolism, for example of taxanes and anthracyclines [15].

Most chemotherapeutic agents are penetrating the placental barrier. This has been demonstrated for doxorubicin, daunorubicin, epirubicin, cyclophosphamide, paclitaxel (only minimally), 5-FU, capecitabine, oxaliplatin, irinotecan/SN38 (metabolite), vinblastine, cisplatin, carboplatin, and cytarabine [14, 60, 69]. Penetration into the fetal circulation must be distinguished from placental transfer. From sparse study results in humans and some data collected in monkeys, rabbits, rats, and mice, the following data can be derived (Table 4):

Despite the relevant pharmacological and pharmacokinetic peculiarities in pregnant women, no fundamental changes in dosages are recommended for systemic anticancer agents compared with use in non-pregnant women. Chemotherapy dosing is based on current body weight, and the Area Under the Curve (AUC) for carboplatin dosing is unchanged from non-pregnant patients [16].

General symptoms such as fatigue and shortness of breath as well as blood count changes, e.g., mild anemia or thrombocytopenia, can occur both pregnancy-associated and in the early phase of acute leukemia. This carries the risk of delayed diagnosis and therefore requires special clinical attention, especially since any delay in induction chemotherapy is associated with a reduction in the rate of complete remissions [78].

CML accounts for 10% of leukemias in pregnancy. During pregnancy, the use of tyrosine kinase inhibitors is contraindicated due to the teratogenic risk and an incidence of more than 10% serious adverse events [1]. For male patients of childbearing potential, the possibility of sperm cryopreservation should be discussed at the time of initial diagnosis [64]. For CML patients of childbearing potential, individualized measures are needed to allow for the possibility of remission maintenance during pregnancy without the use of TKIs. Interruption of therapy is only recommended in cases of stable molecular remission with a BCR-ABL1 transcript level < 0.01%. In cases with a BCR-ABL1 transcript level of 0.01-0.1%, therapy should initially be intensified to achieve a level below this threshold. Thus, in patients on imatinib therapy seeking pregnancy during a treatment break with stable molecular remission, a switch to a second-generation TKI should be considered to allow deeper and longer-lasting molecular remission [43]. If stable for 3-6 months, remission maintenance over a 9-month gestation is likely. If molecular remission is lost during the break in therapy in a pregnant woman, the time to delivery should be bridged without TKI resumption, if necessary with interferon-alpha. The use of PEG-IFN is controversial and should be avoided because of the accumulation of polyethylene glycol in pregnancy. If necessary, bridging cytoreduction with leukapheresis is possible in individual cases of significant leukocytosis. Since relatively low placental permeability has been demonstrated for imatinib and nilotinib, the use of these substances after the 16th week of pregnancy may be considered in selected individual cases under very strict indication and risk-benefit analysis [1]. Dasatinib should generally not be used in pregnancy due to placental permeability and the high teratogenic risk. The use of bosutinib and newer TKIs is also contraindicated. Current data on the outcome of TKI exposure during pregnancy have been compiled [22].

Few reports of pregnant women with primary brain tumors or brain metastases exist in the literature. Reliable epidemiological data are lacking. Among 27 documented cases in the INCIP registry, 13 were diagnosed in the 2nd trimester and 12 in the 3rd trimester. Therapeutic interventions included neurosurgery (n = 8), radiation (n = 7), and chemotherapy (n = 3). All 21 children born were described as healthy with no apparent damage, even at follow-up of up to 25 years [74]. Case series from single centers [76] as well as a systematic literature review [73] indicate that pregnancy may cause a less favorable clinical course of gliomas, but without a significant impact on prognosis [73]. Evidence-based guidelines on clinical procedures for pregnant women with primary brain tumors or brain metastases are not available.

For pregnant women in the second and third trimesters, the current data suggest that the same standard protocols should be used as for nonpregnant women.

According to the age distribution of patients with colorectal cancer, only few well-documented cases are available in the literature. A 2017 literature search revealed 119 case reports (53% colon, 44% rectal, 3% multiple) with 2nd and 3rd trimester manifestations of 88%. Among 82 patients whose therapy was described, approximately 10% received chemotherapy during pregnancy [67]. Forty-one well-documented cases, including 27 colon and 14 rectal cancers, were published from the INCIP registry [47]. Advanced stages were found in 73% of patients. Surgical intervention was performed in 51% and chemotherapy in 29% of pregnant women. Delivery of healthy infants was achieved in 33 of the 41 patients (80.5%), with section delivery in 21 cases. According to these registry data and a single-center report [40], no significant difference was found in the prognosis of pregnant patients with colorectal cancer compared with nonpregnant women.

No robust data are available on the selection of antineoplastic agents or therapy protocols suitable for drug therapy of pregnant women with colorectal carcinoma. Fluoropyrimidines such as 5-FU and capecitabine as well as irinotecan and oxaliplatin, predominantly administered in the standard FOLFOX and FOLFIRI protocols, seem to be applicable in the second and third trimesters without specific toxicities being found in the newborns [69]. EGFR antibodies such as cetuximab and panitumumab as well as agents directed against VEGF(R) such as bevacizumab, aflibercept, or ramucirumab are contraindicated, as are multikinase inhibitors that also target VEGFR (e.g., regorafenib).

The largest collection of all cases of non-small cell lung carcinoma in pregnant women documented in the literature and in a single institution published to date includes 77 patients [75]. It is estimated that 85% of all lung carcinomas in pregnant women are non-small-cell lung cancers [59]. Only 9 cases of lung carcinoma were reported from the INCIP registry in 2013, all of which were diagnosed at advanced stages [18]. The risk of metastasis to the placenta or fetus has been reported to be as high as 26% of 44 cases evaluated [12].

Evidence-based treatment recommendations for pregnant women with lung cancer are not available. Curative intended primary resections are not very promising in view of the usually advanced disease stages. Chemotherapy using carboplatin and paclitaxel is justified from the beginning of the 2nd trimester, see Chapter 6.1.6.1. Since an above-average rate of molecular aberrations such as ALK rearrangements and activating EGFR mutations is to be expected in pregnant women with NSCLC [25], the use of molecularly targeted tumor therapies seems obvious. For this, as well as for therapy with immune checkpoint inhibitors, individual case reports are available [17], from which the justification for individual therapy decisions can be derived. Reliable study data are not available.

Malignant lymphoma represents the fourth most common cancer diagnosis in pregnancy. Hodgkin and non-Hodgkin lymphomas (NHL) account for 5% and 6%, respectively, of all pregnancy-related cancers [30].

Breast cancer accounts for 39% of all malignancies in pregnant women, see Chapter 2.2. Accordingly, the literature available is extensive, providing detailed data on diagnosis and treatment, specified for surgical, radiotherapeutic, chemotherapeutic, endocrine and immunotherapeutic treatment procedures, compared to other cancers in pregnant women.

A comparison of the prognosis of pregnant (n = 662) vs. non-pregnant (n = 2081) patients with breast cancer has been published from the INCIP registry, showing no significant differences in disease-free (78% vs. 85%) and overall survival (90% vs. 94%) at 3 years [8]. These registry data also suggest that surgical interventions, chemotherapies, and local radiation were administered in almost comparable proportions. Both endocrine and HER2-targeted therapies are not recommended in pregnancy based on current knowledge [10, 61].

While surgical procedures are also permitted in the 1st trimester, although possibly associated with a higher risk of miscarriage, (only technetium is recommended for sentinel node diagnosis, due to allergic reactions described), systemic chemotherapy may only be administered from the 2nd trimester (from week 13) [38, 42]. Anthracyclines (doxorubicin and epirubicin, in combination with cyclophosphamide) and taxanes (paclitaxel and docetaxel, but not nab-paclitaxel) are indicated as for other chemotherapies in pregnancy (see above), as in nonpregnant women. Carboplatin is recommended as a case-by-case decision according to the current AGO recommendation [2]. Thus, from the 2nd trimester, standard regimens such as AC/EC followed by paclitaxel, or the additional use of carboplatin in triple-negative carcinomas, are available in the same way as in non-pregnant patients. Dose-dense administration of AC/EC (q2w) followed by weekly paclitaxel is also possible when indicated under the appropriate supportive measures [53]. 5-fluorouracil or methotrexate should not be used in pregnant women.

Endocrine therapies (tamoxifen, fulvestrant, or aromatase inhibitors) should not be administered to pregnant women.

Molecularly targeted therapies such as PARP inhibitors, CDK4-/6 inhibitors, lapatinib, neratinib, tucatinib, PI3kinase inhibitors or mTOR inhibitors are contraindicated in pregnant women, as are monoclonal antibodies (e.g. bevacizumab, trastuzumab, pertuzumab, PD1/PD-L1 inhibitors or sacituzumab govitecan). The same applies to rarely used substances such as capecitabine, eribulin or vinorelbine, for which no reliable data on their use in pregnant women are available.

Melanoma is relatively common in pregnant women worldwide. For example, the incidence in Australia (New South Wales) was 52 cases per 100,000 pregnancies in 2008 [13], but is far lower, in line with the epidemiology of malignant melanoma, in other regions of the world, for example 3-5/100,000 pregnancies in Europe [68]. From the INCIP registry, there is a report of 60 documented cases, including 14 in stage III, 16 in stage IV (27% in recurrence) [28]. Therapeutically, mainly locoregional surgery and in single cases local radiotherapy were used, while systemic therapeutics such as BRAF/MEK-targeted tyrosine kinase inhibitors or immune checkpoint inhibitors should usually be avoided due to their incalculable risks for the fetuses despite single case reports on favorable outcome [9].

Localized melanomas do not have a significantly different prognosis in pregnant women, as shown by case-control studies with up to 185 documented patients [49]. The surgical literature contains specific recommendations on the practical surgical approach in pregnant women with melanoma [24].

As a special feature of melanoma, it is recommended to carefully search for placental metastases after delivery, which have been described as well as fetal metastasis [3, 46].

The incidence of malignant ovarian tumors in pregnant women is reported to be in the order of 0.2-3.8 per 100,000 pregnancies [5]. Of the unclear adnexal tumors occurring in 0.2-2% of all pregnancies, 1-6% represent malignant neoplasia [37].

Standard chemotherapeutic treatment with carboplatin and paclitaxel has been shown to be safe in pregnant women in the second and third trimesters [21, 77]. Since VEGF (vascular endothelial growth factor) is central to embryonic and fetal development and to the regulation of amniotic fluid, the use of the VEGF inhibitor bevacizumab is contraindicated.

Radiotherapy of malignant ovarian tumors is obsolete in pregnant women.

INCIP data indicate that treatment outcome is similar to non-pregnant patients and prognosis depends on tumor stage [37].

Currently, the following recommendations result:

Surgical intervention in the early stage of malignant ovarian tumor should preferably be performed from the 16th week of pregnancy. Chemotherapy can be administered from the 2nd trimester using the same regimens as in non-pregnant women. If neoadjuvant chemotherapy is indicated for locally advanced disease, carboplatin and paclitaxel can be used for epithelial ovarian cancer or cisplatin with etoposide and bleomycin for non-epithelial malignancies [5].

The largest data collection to date includes a retrospective analysis of 13 patients (4 with osteosarcoma and 9 with soft tissue sarcoma) who received anthracyclines and/or ifosfamide for sarcoma therapy [57]. A median of 3 cycles of therapy were administered beginning at a gestational age of 19.5 +/- 4 weeks. Pregnancy complications occurred in 10/13 (76.9%) cases. Fetal growth retardation was described in 6/13 (46.2%) cases. The median gestational age at the time of preterm delivery, which occurred in all cases, was 30.8 +/- 3.8 weeks. The majority (66.7%) of neonates required intensive care. Abortion occurred in 4 patients. These patients had received prior therapy with doxo- and idarubicin beginning at 15.5 gestational weeks, whereas initiation of therapy in all other patients was significantly later (median at 21.3 weeks). The median disease-free survival was 62 months, and three patients with soft tissue sarcoma died of the disease within 4 months of diagnosis.

A cohort study of the INCIP registry analyzed 132 pregnant and 256 non-pregnant women with cervical cancer and well-balanced patient characteristics from 1990-2012 [41]. 14.4% of pregnant women were in stage IA, 47.0% in stage IB1, 18.9% in stage IB2, and 19.7% in stages II-IV. Tumor therapy could be deferred until delivery in 26.5%, 17.4% received primary surgery, 16.7% received neoadjuvant chemotherapy, and 12.9% had early delivery. Progression-free survival did not differ between pregnant and nonpregnant women. A long-term study of 21 pregnant women with cervical cancer from 1985-2000 described a 5-year survival rate of 82%, again with no significant difference from comparable nonpregnant patients [39].

An international consensus conference has developed detailed treatment recommendations in 2019 [5]. For pregnant women with cervical carcinoma in stages IA2-IB3 beyond 22 gestational weeks, in whom therapy cannot be deferred until delivery, neoadjuvant chemotherapy using carboplatin and paclitaxel is recommended.

The AWMF S3 guideline on cervical carcinoma 2022 recommends that treatment of pregnant women with cervical carcinoma should be the same as for non-pregnant women, with neoadjuvant platinum-based chemotherapy recommended from the 2nd trimester [11]. Sectional delivery preferred as the method of choice in all present recommendations. There are no randomized studies regarding maternal outcome depending on the mode of delivery. For microinvasive carcinomas, case-control studies and retrospective analyses show no worsening of prognosis by spontaneous partus. In the S3 guideline, spontaneous parturition is only recommended for microinvasive carcinomas if an R0 resection was previously performed as part of a conization. Spontaneous parturition is not recommended in the presence of microinvasive carcinoma with R1 resection or without conization due to the risk of bleeding and lymphovascular dissemination (S3-LL).

No conclusive data on pregnant patients are available for numerous other solid tumor diseases such as head and neck carcinomas, pancreatic carcinomas, neuroendocrine tumors, urothelial carcinomas, renal cell carcinomas or hepatobiliary carcinomas.

A collection of 13 pregnant women with gastric carcinoma published from the INCIP registry [55] does not allow derivation of recommendations for the oncologic care of these patients.

Thyroid carcinomas represent 3% of malignant neoplasms in pregnant women (see above), but they are almost exclusively treated without systemic agents and have no worse prognosis as compared with non-pregnant patients [62].

In the case of an existing desire to have children, options for fertility preservation in oncological patients should be discussed with the patient in the same way as for the diagnosis of the oncological disease outside the time of pregnancy. In addition to surgical conservative treatment of cervical carcinoma, possibilities include cryopreservation of ovarian tissue, which can be harvested, for example, in the course of a section.