Systemic Cancer Treatment in Pregnancy

In the 6th-34th week of pregnancy, a volume expansion of 3-4 liters develops. The plasma volume increases by 1200 ml, the total erythrocyte volume by 300 ml, the placenta and the fetal circulation require an additional 2000 ml or more. The dilution effect reduces the albumin concentration in the blood [33]. Another consequence is increased renal clearance [51]. The activation of relevant enzymes of the cytochrome p450 system (CYP 3A4, CYP 2C9, CYP 2A6) and uridine diphosphate glucuronosyltransferase (UGT) results in faster hepatic metabolization, 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-fluorouracil, capecitabine, oxaliplatin, irinotecan/SN38 (metabolite), vinblastine, cisplatin, carboplatin and cytarabine [14, 60, 69]. Transfer into the fetal circulation must be distinguished from placental transfer. Some of the information presented in Table 5 can be derived from sparse test results in humans and some data collected in monkeys, rabbits, rats and mice. An updated review was published in 2022 on the placental permeability of numerous systemically administered antineoplastic drugs [94].

Despite the relevant pharmacological and pharmacokinetic peculiarities in pregnant women, no substantial changes in dosage are recommended for systemic anticancer agents compared to their use in non-pregnant women. Chemotherapy dosing is based on current body weight or surface, and the area under the curve (AUC) for carboplatin dosing is unchanged compared to non-pregnant patients [16].

General symptoms such as fatigue and shortness of breath as well as blood count changes in the form of 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 particular clinical attention, especially as any delay in induction chemotherapy is associated with a reduction in the rate of complete remissions [78]. A treatment algorithm is shown in Figure 1.

Chronic myeloid leukemia (CML) accounts for 10% of all leukemias during pregnancy. During pregnancy, the use of tyrosine kinase inhibitors (TKIs) is contraindicated due to the teratogenic risk and an incidence of over 10% for serious events [1]. In patients with desire to have children, the possibility of sperm cryopreservation should be discussed at the time of initial diagnosis [64]. For female CML patients desire to have children, individualized measures are required to allow the possibility of maintaining remission during pregnancy without the use of TKIs. Treatment interruption 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 in order to achieve a level below this threshold. Thus, patients undergoing imatinib therapy who are seeking pregnancy during a treatment break with a stable molecular remission should consider switching to a second-generation TKI in order to achieve a deeper and longer-lasting molecular remission [43]. If stable over 3-6 months, maintenance of remission over the course of pregnancy is likely. If molecular remission is lost during the treatment break in a pregnant woman, the time until delivery should be bridged without TKI resumption - if indicated, with interferon-alpha (IFN). The use of pegylated (PEG-)IFN is controversial and should be avoided, if possible, due to the accumulation of polyethylene glycol during pregnancy. If necessary, bridging cytoreduction with leukapheresis is an option in individual cases of significant leukocytosis. As imatinib and nilotinib have only been shown to have minimal placental permeability, the use of these substances after the 16th week of pregnancy can be considered in selected individual cases under very strict indications and risk-benefit analysis [1]. Dasatinib should generally not be used during pregnancy due to its placental permeability and high teratogenic risk. The use of bosutinib and newer TKIs is also contraindicated. Data on the outcome of different treatment regimens for CML during pregnancy have recently been compiled [22, 80].

There are only a few reports of pregnant women with primary brain tumors or brain metastases in the literature. Reliable epidemiologic data are lacking. Among 27 documented cases in the INCIP registry, 13 were diagnosed in the 2nd and 12 in the 3rd trimester. Neurosurgical interventions (n = 8), radiotherapy (n = 7) and chemotherapy (n = 3) were used therapeutically. All 21 children born were described as healthy with no apparent impairment, also after a follow-up of up to 25 years [74]. Case series from individual centers [76] as well as a systematic literature review [73] indicate that pregnancy can lead to a poorer clinical course of gliomas, without, however, having a significant impact on the prognosis [73]. Evidence-based guidelines on the clinical procedure for pregnant women with primary brain tumors or brain metastases are not available.

For pregnant women in the second and third trimester, current data support the recommendation to use the same standard treatment protocols as for non-pregnant women.

In accordance with the age distribution of patients with colorectal cancer (CRC), only a few properly documented cases of CRC in pregnant women are available in the literature. A literature search from 2017 revealed 119 case reports (53% colon, 44% rectum, 3% multiple), with first diagnosis in the 2nd and 3rd trimester in 88%. Of 82 patients whose treatment was described, around 10% received chemotherapy during pregnancy [67]. The INCIP registry published 41 well-documented cases, including 27 colon and 14 rectal carcinomas [47]. Advanced stages were found in 73% of patients. Surgery was performed in 51% and chemotherapy in 29% of pregnant women. The birth of healthy children 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 CRC compared to non-pregnant women.

No reliable data are available on the selection of antineoplastic substances or treatment protocols that are suitable for the drug treatment of pregnant women with CRC. Fluoropyrimidines such as 5-FU and capecitabine, as well as irinotecan and oxaliplatin, mainly administered in the standard protocols FOLFOX and FOLFIRI, appear to be commonly used in the second and third trimester without any specific toxicities being found in the newborns [69]. EGFR antibodies such as cetuximab and panitumumab as well as substances directed against VEGF(R) such as bevacizumab, aflibercept or ramucirumab are contraindicated, as are multikinase inhibitors directed also against VEGFR (e.g., regorafenib).

The largest published collection to date of all cases of non-small cell lung cancer (NSCLC) in pregnant women documented in the literature and in a single institution includes 77 patients [75]. It is estimated that 85% of all lung cancers in pregnant women are NSCLC [59]. Only 9 cases of lung cancer 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 is reported to be up to 26% of 44 cases evaluated [12].

There are no evidence-based treatment recommendations for pregnant women with lung cancer. In view of the generally advanced stages of the disease, curative primary resections are not very promising. 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], it is obvious to consider the use of molecularly targeted tumor therapies. Individual case reports are available [17], from which the justification for individual treatment decisions can be derived. Reliable study results are not available. Comprehensive registry data on the use of immune checkpoint inhibitors (ICI) against PD1, PD-L1 or CTLA4 show no higher overall rates of negative effects on pregnancy, fetuses or newborns than systemically administered chemotherapeutic agents, but an increased rate of premature births after the use of combined checkpoint blockade against PD1 and CTLA4 has been reported [84]. Nevertheless, the use of ICI in pregnant women cannot be recommended, especially as no long-term follow-up studies are yet available.

• Malignant lymphomas are the fourth most common cancer diagnosis in pregnancy. Hodgkin's and non-Hodgkin's lymphomas (NHL) account for 5% and 6% respectively of all pregnancy-related cancers [30]. A treatment algorithm is shown in Fig. 2.

Breast cancer accounts for 39% of all malignancies in pregnant women, see chapter 2.2. Accordingly, specific publications available today are extensive, providing detailed data on diagnostics and therapy, specified for surgical, radiotherapeutic, chemotherapeutic, endocrine and immunotherapeutic treatment procedures, in comparison to other cancers in pregnant women. Long-term studies on children who were exposed to chemotherapy in utero for the treatment of their mother's breast cancer show no negative effects of this therapy on their state of health [85].

A comparison of the prognosis of pregnant (n = 662) vs. non-pregnant (n = 2081) patients with breast cancer was published from the INCIP registry, which shows no significant difference in disease-free (78% vs. 85%) and overall survival (90% vs. 94%) after 3 years [8]. These registry data also indicate that surgical interventions, chemotherapy and local radiotherapy were administered in approximately comparable proportions. Both endocrine and HER2-targeted therapies are not recommended during pregnancy according to current knowledge [10, 61].

While surgical procedures are also permitted in the 1st trimester, potentially associated with a higher risk of miscarriage (for sentinel node staging, only technetium is recommended due to allergic reactions described), systemic chemotherapy may only be administered from the 2nd trimester (from week 13 of pregnancy) [38, 42]. Anthracyclines (doxorubicin and epirubicin), in combination with cyclophosphamide, and taxanes (paclitaxel and docetaxel, but not nab-paclitaxel) are, as with other chemotherapies in pregnancy (see above), indicated as in non-pregnant women [83]. Carboplatin is used on a case-by-case basis according to the current AGO recommendation [2]. Thus, standard regimens such as AC/EC followed by paclitaxel or the additional use of carboplatin in triple-negative carcinomas can be applied from the 2nd trimester onwards in the same way as in non-pregnant patients. Dose-dense administration of AC/EC (q2w), followed by weekly paclitaxel, is also accepted, if indicated, combined with 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, PI3 kinase 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). More rarely applied substances such as capecitabine, eribulin or vinorelbine, for which there are no reliable data on their use in pregnant women, should be avoided.

A treatment algorithm is shown in Figure 3.

Melanoma is relatively common in pregnant women worldwide. For example, the incidence in Australia (New South Wales) in 2008 was 52 cases per 100,000 pregnancies [13], but in line with the epidemiology of malignant melanomas, it is far lower in other regions of the world, for example 3-5/100,000 pregnancies in Europe [68]. The INCIP registry has reported 60 documented cases, including 14 in stage III and 16 in stage IV (27% in relapse) [28]. An analysis of 1406 pregnant melanoma patients from the Californian cancer registry showed no negative impact of pregnancy on overall survival compared to more than 10,000 non-pregnant women in this registry [87]. Therapeutically, mainly locoregional surgery and, in individual cases, local radiotherapy are used, while systemic therapeutics such as BRAF/MEK-targeted tyrosine kinase inhibitors or immune checkpoint inhibitors should generally be avoided due to their incalculable risks for the fetus, despite isolated favorable case reports [9]. For further information on immune checkpoint inhibitors, see chapter 6.1.5 (lung cancer).

Localized melanomas in particular 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 procedures for pregnant women with melanoma [24].

As a special feature of malignant melanomas, it is recommended to look carefully 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 approximately 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 a malignant neoplasm [37].

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

Local radiotherapy of malignant ovarian tumors is obsolete in pregnant women.

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

The current recommendations are as follows:

Surgical interventions in the early stages of a 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 for 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]. Updated recommendations on the diagnostic, surgical and drug treatment of pregnant women with ovarian cancer were published in 2024 by the European Society of Gynecologic Oncology (ESGO) together with the European Society of Medical Oncology (ESMO) and the European Society of Pathology (ESP) [88].

A treatment algorithm is shown in Figure 4.

The largest data collection to date comprises 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 treatment cycles were administered starting 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%) of 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 the newborns required intensive care. Abortion occurred in 4 patients. These patients had previously received treatment with doxorubicin and ifosfamide starting at 15.5 weeks, while all other patients started treatment significantly later (median 21 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.

In a cohort study of the INCIP registry, 132 pregnant women and 256 non-pregnant women with cervical cancer and comparable patient characteristics from the years 1990-2012 were analyzed [41]. 14.4% of the pregnant women were in FIGO stage IA, 47.0% in stage IB1, 18.9% in stage IB2 and 19.7% in stages II-IV. In 26.5%, tumor therapy could be postponed until delivery, 17.4% were treated with primary surgery, 16.7% received neoadjuvant chemotherapy and 12.9% had a premature delivery. There was no difference in progression-free survival between pregnant and non-pregnant women. In a long-term study of 21 pregnant women with cervical carcinoma from 1985-2000, a 5-year survival rate of 82% was described, again with no significant difference to comparable non-pregnant patients [39].

An international consensus conference developed detailed treatment recommendations in 2019 [5]. Neoadjuvant chemotherapy using carboplatin and paclitaxel is recommended for pregnant women with cervical carcinoma in stages IA2-IB3 beyond the 22nd week of pregnancy for whom treatment cannot be postponed until delivery.

The AWMF S3 guideline on cervical carcinoma 2022 recommends treating pregnant women with cervical carcinoma similarly to non-pregnant women, with neoadjuvant, platinum-based chemotherapy recommended from the 2nd trimester onwards [11]. All current recommendations support a caesarean section as the delivery method of choice. There are no randomized studies on maternal outcomes depending on the mode of delivery. In the case of microinvasive carcinomas, case-control studies and retrospective analyses show no deterioration in prognosis as a result of spontaneous parturition. In the S3 guideline on cervical carcinoma, spontaneous delivery is only recommended for microinvasive carcinomas if an in sano resection was previously performed as part of a conization. Spontaneous delivery is not recommended in the presence of a microinvasive carcinoma with R1 resection or without conization due to the risk of bleeding and the risk of lymphovascular dissemination [11].

A treatment algorithm for cervical cancer in pregnancy is shown in Figure 5.

No substantial data on pregnant patients is available for numerous other solid malignancies such as head and neck carcinomas, pancreatic carcinomas, neuroendocrine tumors, urothelial carcinomas, renal cell carcinomas or hepatobiliary cancer.

A collection of 13 pregnant women with gastric carcinomas published from the INCIP registry [55] does not allow any recommendations to be derived for the oncological care of these patients.

Although thyroid carcinomas represent 3% of malignant neoplasms in pregnant women (see above), they are almost exclusively treated without systemic antineoplastic agents. Pregnant patients with thyroid cancer do not have a different prognosis compared to non-pregnant patients [62].

In the case of desire to have children, fertility preservation options for oncological patients should be discussed with the patient in the same way as when the oncological disease is diagnosed outside the time of pregnancy. Recommendations for fertility preservation have been published for patients under the age of 25 [90]. In addition to conservative surgical treatment of cervical cancer, other options include cryopreservation of ovarian tissue, which can be removed during a caesarean section, for example, see Onkopedia Fertility Preservation (https://www.onkopedia.com/de/onkopedia/guidelines/fertilitaetserhalt/@@guideline/html/index.html).