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Cancer Treatment and Immunotherapy during Pregnancy
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14102080

According to McCormik and Peterson (2018), the most common cancers of reproductive age in women are melanoma, breast cancer (the most common gestational cancer and reaches 20% of cases), thyroid cancer, cervical cancer, and lymphomas (most commonly Hodgkin’s lymphoma). A pregnancy that coexists with cancer is not an ordinary pregnancy and consists of a complex medical condition. In the majority of these cases, various therapeutic and ethical dilemmas arise.

immunotherapy cancer pregnancy gestation chemotherapy during pregnancy

1. Pregnancy and Anticancer Drug Treatment for the Breast Cancer

There are four categories of oncology drugs used to treat breast cancer (Figure 1), such as [1][2]:
Figure 1. Breast cancer and pregnancy FAC: Fluoroucacil, Adriamycin, Cytoxan; AC: Doxorubicin, Cyclophosphamide.

1.1. The Adjuvant Oncology Drugs

These are preparations that aim to restore the body’s normal immune defenses.
Peccatori and colleagues (2009) studied the safety of administering an antineoplastic–immunomodulatory factor for treating breast cancer in pregnant women. This agent is widely known as epirubicin and proved to be quite safe and effective during pregnancy, without exhibiting a significant proportion of embryotoxicity. The initiation of the treatment was made after the first trimester of pregnancy. The dosage of epirubicin administered to women with breast cancer was 35 mg/m weekly [3]. Hahn and colleagues (2006) studied the safety of administrating a chemotherapy treatment for breast cancer, known as FAC chemotherapy regiment (Fluorouracil, Adriamycin, and Cytoxan), during pregnancy. The results indicated that administering this therapy is safe for both the mother and the fetus during the second and third trimester of the pregnancy [4]. AC (doxorubicin, cyclophosphamide) and EC (epirubicin, cyclophosphamide) were proven to be equally safe [2].
Another widely used chemotherapy for breast cancer is CMF (cyclophosphamide, methotrexate, 5-fluorouracil), contraindicated strictly in the first trimester of pregnancy as it is associated with irreversible damage to the fetus and in some cases with death. However, scientists do not prohibit the administration (with simultaneous observance of strict safety measures) during the second and the third trimester [2][5].

1.2. Hormonal Oncology Drugs

The administration of hormonal oncological drugs is realized mainly after a mastectomy or in the advanced stages of the disease. The hormonal agents that are administered in such cases are tamoxifen, anastrozole, letrozole, and exemestane. The ASCO recommends delaying the administration of hormonal therapy after childbirth, as damage to the fetus may occur [6]. More specifically, tamoxifen administration, especially during the first three months of pregnancy, has been closely associated with the development of neonatal congenital malformations [7]. Anastrozole was associated with the phenomenon of spontaneous abortion, late fetal development, and adverse malformations of the fetal genital organs [8]. Letrozole has been blamed for high embryotoxicity and teratogenicity [9], while exemestane appears to be responsible for both fetal and maternal deaths [10].

1.3. Oncology Drugs against HER-2 Type Breast Cancer

The most common therapeutic approach for women with HER-2 type breast cancer is the administration of the chemotherapeutic form, with lapatinib and/or trastuzumab for one year [11]. Many studies have shown that it is safe to administer this treatment during pregnancy. However, there are other studies that accuse it of spontaneous abortions, while it is considered that this field needs further investigation [12][13].

1.4. Oncology Drugs Related to Metastatic Breast Cancer

A rare situation, with little scientific data, is metastatic breast cancer during pregnancy. Azim and Peccatori (2008) describe the relatively safe administration of anthracyclines, taxanes, epirubicin, and vinorelbine after the first three months of gestation [14].

2. Pregnancy and Anti-Cancer Drug Treatment for Melanoma

Melanoma is an aggressive form of skin cancer and constitutes one of the most common cancers in pregnant women. Treating melanoma includes surgery and is followed by drug treatment in uncontrolled cases, especially in cases of metastases [15]. The oncology drugs used to treat melanoma are (1) dabrafenib, which is strictly contraindicated during pregnancy, as it has been shown to be teratogenic [15][16] and (2) ipilimumab, which should be administered in accordance with strict protocols, as it is responsible for fetal death and premature birth [15]; (3) imatinib is responsible for a large proportion of congenital malformations [17][18]. (4) Cisplatin has been shown to be responsible for miscarriages and teratogenesis [19]. Finally, (5) dacarbazine, which is considered to be the most effective approach in the treatment of metastatic melanoma and did not appear to be responsible for fetal deaths or fetal malformations. It is usually combined with other chemotherapeutic agents, such as bleomycin, vincristine, and lomustine [20][21][22] (Figure 2).
.

Figure 2. Pregnancy and Melanoma.
As a guideline, chemotherapy for melanoma should be postponed to the second or third trimester of pregnancy. The use of chemotherapeutic drugs in the first trimester has been associated with a significantly increased risk of miscarriage and congenital malformations in the newborn [20][21][22].

3. Pregnancy and Anti-Cancer Drug Treatment for the Cervix 

Treatment with cisplatin during pregnancy appears to be associated with low-birth-weight neonates. Additionally, administrating cisplatin and paclitaxel seems to be responsible for embryonic congenital malformations (such as hearing loss, retroperitoneal embryonal rhabdomyosarcoma, and a heterozygous mutation in the gene GJB2) [23]. However, cisplatin is the most widely used chemotherapeutic approach for cervical cancer during the second and third trimester of gestation [24]. The combination of paclitaxel–carboplatin was charged with the evolution of preterm labor, preeclampsia, intrauterine growth retardation of fetus, and transient leukopenia in the infant, when undergoing the second or third trimester of pregnancy, which makes it a less safe option [24] (Figure 3).
Figure 3. Pregnancy and Cervical Cancer.

4. Pregnancy and Anti-Cancer Drug Treatment for Ovarian Cancer

Ovarian cancer is estimated to be the fifth most common form of cancer during pregnancy. The chemotherapeutic approach to the disease initiates after the first trimester of pregnancy [25]. In cases of epithelial ovarian cancer, the chemotherapeutic intervention always follows surgery [25]. The normal practice constitutes administering a combination of two types of oncological pharmaceuticals. A frequent combination involves the compound platinum (usually cisplatin or carboplatin) with another type which is called taxane, such as paclitaxel or docetaxel [26]. The most commonly used oncology drugs in the medical practice for treating epithelial ovarian cancer are paclitaxel coupled to albumin, althetamine, capecitabine, cyclophosphamide, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melfalan, pemetrexed, topotecan, and vinorelbine [26] (Figure 4).
Figure 4. Pregnancy and Ovarian Cancer.
If this type of cancer is diagnosed during five weeks of gestation after an exploratory laparotomy, chemotherapy paclitaxel and carboplatin can be administered to the patient after the 17th week of gestation with relatively safety, with no apparent side effects to both the pregnant woman and the fetus [27]. Many studies link the administration of cisplatin during pregnancy with fetal malformations [28]. Serkies et al. (2011) studied the effect of paclitaxel and cisplatin on the treatment of non-epithelial ovarian cancer during pregnancy. The authors found that there was no teratogenic fetal effect from the drugs [29]. Furthermore, etosopide appeared to have no effect on pregnancy if administered after the first trimester. On the other hand, a case of fetal exposure to bleomycin and etoposide in the period of 25 to 28 weeks of gestation was reported, in which cerebral atrophy was caused [30].

5. Pregnancy and Anti-Cancer Drug Treatment for Thyroid Cancer

A proportion of 10% of thyroid cancer is diagnosed during gestation. This type of cancer is second in its frequency during gestation [31].
The treatment of choice in thyroid cancer is surgery (total or partial resection of the gland) (in combination or not with radiotherapy), which is usually postponed until the end of childbirth unless the course of the disease is rapid and aggressive [32]. The oncological-pharmacological treatment approach for this cancer is a rare choice, and it is usually carried out in conjunction with radiotherapy. The oncological pharmaceutical compositions used mostly to address bone thyroid cancer and anaplastic thyroid cancer are the following: dacarbazine (cytotoxic agent, contraindicated strictly in pregnancy cases), vincristine (charged for embryotoxicity or teratogenic), cyclophosphamide (charged for embryonic teratogenesis, and carcinogenicity), streptozoic, doxorubicin, fluoroulacil, paclitaxlel, docetaxel, and carboplatin. The oncological pharmacological approach to thyroid cancer is avoided during pregnancy [33][34][35].

6. Pregnancy and Anti-Cancer Drug Treatment of Lymphomas

According to Pereg and colleagues (2007), lymphoma is the fourth most common form of cancer diagnosed during pregnancy. Radiotherapy and chemotherapy in the first three months of the pregnancy have been associated with high rates of fetal congenital malformations. Therefore, these are strictly contraindicated. Upon completion of the first three months of gestation, and as time passes, the risk appears to be tempered [36]. The most widespread lymphoma diagnosed during pregnancy is lymphoma Hodgkin, and the most frequent chemotherapeutic approach comes in the form of doxorubicin–bleomycin–vinblastine and dacarbazine, or otherwise, ABVD [37][38] (Figure 5).
Figure 5. Pregnancy and lymphomas. ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine; MOP: mechloretamine, vincristine, procarbazine, prednisone; CVP: cyclophosphamide, vincristine and prednisone; CHOP: cyclophosphamide, vincristine, prednisone, and adriamycin.
According to a case study, this chemotherapy regimen was administered during a twin pregnancy at 28 weeks and 3 days. Two cycles of treatment were administered at an interval of about two weeks. The male infant developed postpartum left heart malfunction, which was restored after four weeks. On the other hand, the female infant did not develop a heart malfunction [39]. A larger study revealed the effects of lymphoma chemotherapy (ABVD and MOPP, i.e., mechloretamine, vincristine, procarbazine, and prednisone). They were studied during pregnancy in a total of 84 offspring. The results of the study proved the safety of this chemotherapy for lymphomas during pregnancy. The children were all healthy after a long run of 29 years [40].
Non-Hodgkin lymphomas have not been shown to be particularly common during a pregnancy [38]. When lymphoma is still in its infancy, and the patient remains asymptomatic, it is recommended that the treatment approach be postponed until after delivery [41]. On the other hand, when there is an advanced stage lymphoma, the administration of treatment regimens is deemed necessary, and some of the following are selected:
  • Cyclophosphamide, vincristine, and prednisone (CVP): This therapeutic option does not appear to present significant defects in fetuses if administered after the first three months of gestation [41]. However, it is reported that it can adversely affect the fertility of people of a reproductive age. At the same time, the pregnant woman receiving treatment may experience the following: neutropenia, thrombocytopenia, anemia, alopecia, insomnia, fatigue, peripheral neuropathy, etc. Therefore, the treating physician should be suspicious and closely monitor the progress of the patient [42];
  • Cyclophosphamide, vincristine, prednisone, and adriamycin (CHOP): This scheme has proven to be safe if administered after the first trimester but not earlier [41];
  • Methotrexate in high doses: This approach is chosen when lymphoma is at an advanced stage, but unfortunately, methotrexate administration during pregnancy is a safe option for the pregnant women, yet it is usually avoided due to increased adverse effects during pregnancy [43][44].

7. Pregnancy and Other Cancers

The anti-cancer drug approaches for the most common cancers during pregnancy were discussed above. What follows is a report on the less common but equally important cancers which may occur and complicate pregnancy.

8. Pregnancy and Lung Cancer

This form of cancer does not often occur during pregnancy, and the number of studies on this subject is extremely limited [2][45]. Statistics confirm that half of these cases are positively related to a medical history of smoking. The NSCLC (non-small cell lung cancer)- type adenocarcinoma is the most common form of lung cancer, which, indeed, correspond to 80% of lung cancer cases during gestation [46]. There are some chemotherapeutic regimens that can be safely administered to pregnant women after the end of the first trimester of pregnancy [2][24][45]. The schemes that are mostly used include cisplatin or carboplatin in combination with paclitaxel, docetaxel, vinorelbine, gemcitabine, or etoposide [2][45]. The effects on fetuses are transient respiratory distress and congenital malformations, and both of these are related to the administration of the regimens during the first three months of pregnancy [47].

9. Pregnancy and Brain Tumors

Due to the rarity of this type of cancer in pregnant women, not many cases have been studied [2]. However, this condition, due to its specificity, continues to be a major clinical challenge [48] (Figure 6).
Figure 6. Pregnancy and brain tumors. TMZ: Temozolomide; PCV: Procarbazine, Lomustine and Vicristin.

10. Pregnancy and Leukemia

Leukemia occurs in an amount of about one in a thousand pregnant women, and mostly in acute and especially medullary forms [49]. Regarding chemotherapy drugs, they should be avoided during the first three months of pregnancy and weeks before parturition [49]. Regarding chronic leukemia, the most common chemotherapy drug is imatinib (tyrosine inhibitor–kinase). How closely the administration of this is related to the appearance of fetal congenital malformations and spontaneous abortion is another controversial issue [17]. There have been observed infants who were perfectly normal and infants with serious and complex teratogenesis [50]. Similar results have been found in pregnancy studies after the administration of another tyrosine-kinase inhibitor, nilotinib [51] (Figure 7).
Figure 7. Pregnancy and Leukemia.
Acute leukemia is an aggressive form of cancer, and chemotherapy should be started as soon as possible; time delays are considered unacceptable. Acute myeloid leukemia (AML) is the most common leukemia diagnosed during pregnancy because it represents more than two-thirds of leukemia cases during pregnancy and has a frequency of 1 in 75,000–100,000 [38][52]. It should be organized within an oncology drug plan, which is separate for each clinical situation, while normally, the administration of daunorubicin or idarubicin in combination with cytarabine constitutes the first-line chemotherapy [52].

11. Pregnancy and Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with unique molecular pathogenesis, clinical manifestations, and therapeutic approaches. It is characterized by the proliferation of malignant promyelocytes in the bone marrow that carries a chromosomal shift or the PML/RARA gene (diagnostic criterion). Treating pregnant women with acute promyelocytic leukemia (APL) is an extremely difficult situation, where there is limited evidence. The studies found in the literature are limited, and usually concern only a few series of patients [53].
The oncological pharmaceutical disease approach constitutes mostly administering the all-trans retinoic acid (ATRA), frequently combined with other drugs such as daunorubicin or idarubicin, anthracycline, and arsenic trioxide (ATO) [40][54]. Analyzing the results of various studies, it appears that the administration of all-trans-retinoic acid during the last two trimesters of a pregnancy does not cause serious adverse maternal or fetal effects [38][54][55][56].

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