A Case Report of Metastatic Gastric Cancer Treated with Pembrolizumab during Pregnancy

Abstract

Introduction

Immune checkpoint inhibitors are extensively used in present-day clinical practice for treating many types of cancers at different stages. To date, there are scarce data on the use of immunotherapy in pregnancy. Immune-related adverse events are a typical consequence of this therapy miming autoimmune diseases.

Case Presentation

A 35-year-old woman (G1P0) diagnosed with gastric carcinoma underwent neoadjuvant chemotherapy followed by surgery. During follow-up, axillary metastasis was discovered, radiotherapy failed, and consequently immunotherapy was started. Concurrently, pregnancy ensued. Despite potential risks, the patient opted to continue immunotherapy and the pregnancy. At 31 weeks, fetal bowel dilation was noted. Subsequently, the fetus also developed fetal growth restriction. A cesarean section was performed at 35 weeks. The newborn required repeated bowel resections for necrotizing enterocolitis, necessitating extensive medical intervention. The mother continues pembrolizumab treatment with a positive response.

Conclusion

To the best of our knowledge, this might constitute a possible case of a fetal immune-related adverse event after immunotherapy in utero exposure.

Established Facts

• During pregnancy, the maternal immune system undergoes significant changes to protect against pathogens while tolerating the semi-allogeneic fetus.

• Cancer can exploit pathways involved in fetomaternal tolerance.

Novel Insights

• Immunotherapy can lead to immune-related adverse events that may negatively impact the fetus or future pregnancies, and they are yet to be defined.

• Fetal bowel dilation may be the result of a gastrointestinal immune-related adverse event after pembrolizumab in utero exposure.

Introduction

Pregnancy-related cancer presents a challenging clinical scenario and a rare condition, with an incidence of approximately 140 cases per 100,000 pregnancies [1]. Malignant melanoma, breast cancer, and cervical cancer are the most frequently encountered malignancies during pregnancy [2]. However, this incidence is on the rise due to two main factors: women are increasingly delaying childbirth to later stages of life, and noninvasive prenatal tests can now incidentally detect cancers early in pregnancy [3, 4]. Over the past decade, various immunotherapies, such as immune checkpoint inhibitors (ICIs), have become available for treating many types of cancer. Yet, there is still a lack of comprehensive data regarding the potential impact of these immunotherapies on pregnancy, the developing fetus, and fertility. Indeed, the use of immunotherapies, particularly those targeting immune checkpoints, has been associated with a wide range of immune-related adverse events (irAEs), which could be especially relevant during pregnancy, because the maternal immune system needs to develop tolerance to the semi-allogeneic fetus [5]. Thus, treatment with immunotherapy might hinder the establishment of fetomaternal tolerance, with potential consequences for both the mother and the fetus. Additionally, there is limited knowledge about the direct effects of these drugs on the fetus. As the indications for immunotherapy are expanding, there is a growing need to understand its effects on pregnancy and fertility. To address this, the authors aim to report the case of a patient with advanced malignant gastric carcinoma treated with pembrolizumab during pregnancy.

Case Report

In 2021, a 35-year-old woman (G1P0) was diagnosed with poorly differentiated gastric carcinoma (stage pT3pN1, tumor regression grading 5). She underwent neoadjuvant chemotherapy with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT regimen), followed by total gastrectomy and lymphadenectomy, and completed adjuvant chemotherapy in March 2022. During an oncological follow-up in November 2022, she reported right arm pain, which prompted an MRI revealing a 5 × 5 × 7 cm axillary mass compressing the subclavian vein and artery. The mass was confirmed as metastasis upon biopsy. In December 2022, during a PET-FGD examination, an abnormal uptake was observed in the right ovary, and the patient was referred to the Gynecological Oncological Unit at Sant’Orsola Hospital. Subsequent transvaginal ultrasound revealed two solid ovarian masses, both displaying benign characteristics. Scheduled gynecological follow-ups indicated consistent ultrasound findings. The stereotactic radiotherapy was ineffective in treating the axillary mass, leading to the initiation of pembrolizumab immunotherapy (200 mg every 21 days) in January 2023. By March 2023, MRI results showed a reduction in axillary metastasis. In June 2023, a viable intrauterine pregnancy was diagnosed, and she was referred for consultation to the Maternal-Fetal Unit at Sant’Orsola Hospital.

The patient was evaluated by a multidisciplinary team including oncologists, obstetricians, and neonatologists, who assessed the risks and benefits of continuing pembrolizumab during pregnancy, taking into account both maternal and fetal health. The existing literature was reviewed and discussed with the patient, emphasizing the uncertainty of pembrolizumab's effects on pregnancy. Despite counseling regarding possible risks associated with metastatic cancer and pembrolizumab administration in pregnancy, she opted to continue immunotherapy and the pregnancy. The patient continued to receive the same dose of pembrolizumab as before, with strict monitoring by the multidisciplinary team to ensure the safety and efficacy of the treatment during pregnancy. Fetal anatomy evaluations at 16 and 20 weeks were normal, although the second-trimester ultrasound revealed an increased uterine artery pulsatility index. She developed gestational hypothyroidism and started taking levothyroxine. Moreover, there was a gradual decline in her platelet count, and at 30 weeks of gestation, while recovering in the Obstetric Department for a flu-like syndrome and fever, severe thrombocytopenia was observed, leading to discontinuation of enoxaparin. Despite negative tests for antibodies against platelet factor 4 and glycoprotein complex (GPIIb/IIIa and GPIb/IX), the cause of thrombocytopenia remained unclear, raising suspicion of immunotherapy involvement. During recovery, she was administered antenatal corticosteroids for fetal lung maturation. At 31 weeks, a dilation of the small bowel measuring 12.5 mm was noted, with normal bowel walls and no hyperechoic content or abnormal peristaltic movements observed. A detailed study of fetal anatomy was conducted at the time of the bowel dilation observation, and no other anomalies were detected. Subsequently, the patient underwent weekly obstetric ultrasounds, showing the following measurements of the bowel dilation: 32 weeks – 13.8 mm, 33 weeks – 12.5 mm, and 34 weeks and 5 days – 12.6 mm (Fig. 1). Despite the last dose of pembrolizumab being administered at 32 weeks, the bowel dilation did not show significant improvement. Moreover, at 32 weeks, the estimated fetal weight was 1,637 g, corresponding to the 30th percentile according to Hadlock’s nomogram. Successive follow-ups revealed a fetal growth restriction (FGR) with a low cerebroplacental ratio but always a normal umbilical artery pulsatility index. At 35 weeks, an elective cesarean section along with a right adnexectomy and peritoneal biopsies were performed; the timing of delivery was handled in agreement with the oncologists. The pathologist's findings revealed normal right adnexa and negative peritoneal biopsies. Macroscopic and microscopic examinations of the placenta showed no abnormalities. The newborn was a girl with an arterial cord blood gas pH of 7.20 and a base excess of −3.9 mmol/L. The 1- and 5-min Apgar scores were 9 and 10, respectively. The baby weighed 1,685 g at birth. Consequently, she was admitted to the neonatal intensive care unit. On the 7th day of life, she experienced vomiting, anorexia, episodes of apnea, and a poor clinical condition, raising suspicion of necrotizing enterocolitis (NEC). She underwent a 20-cm ileal resection, beginning 15 cm proximally from the ileocecal valve, along with a double ileostomy and appendicectomy. Histologic analysis confirmed the extensive necrosis of the mucosa and submucosa, vascular congestion, and inflammation signs. The immediate postoperative period was marked by severe metabolic acidosis, glycemic instability, hypoalbuminemia, and anemia, necessitating intensive treatment with multiple transfusions of red blood cells and platelets. There was a progressive increase in intensive support with the addition of dobutamine, hydrocortisone, and furosemide. Subsequently, inflammation indices increased, and blood cultures tested positive for Klebsiella pneumoniae. As a result, antibiotic therapy was administered. Thereafter, due to nonfunctioning stomas with drainage providing enteric material and peritonitis, surgical exploration was performed suspecting intestinal perforation, which was confirmed at the time of surgery. She underwent further intestinal resection upstream of the proximal ileostomy. Postoperative brain MRI revealed severe and widespread parenchymal suffering with multiple ischemic insults and hemorrhagic foci, indicating extensive damage of the cortex and brainstem. Electroencephalography showed a diffusely slowed pattern, but no critical episodes. Echocardiography revealed a small patency at the level of the interatrial septum with a left-right shunt. Meanwhile, because of increased inflammation indices, a new blood culture was made and was positive for Staphylococcus epidermidis; specific antibiotic therapy was initiated with progressive improvement in the following days. All neonatal infections may have been secondary to immunosuppression related to the underlying condition and treatment, though it is difficult to definitively attribute them solely to pembrolizumab. Throughout the neonate’s recovery, her glucose level remained persistently high and difficult to control with insulin infusion. Although genetic testing for neonatal diabetes was negative, an abdominal MRI revealed findings of pancreatic hypoplasia. The neonate underwent recanalization surgery and resection of a stenotic portion of the descending colon. Histologic analysis demonstrated reepithelization of the mucosa and modest signs of chronic inflammation with apoptosis in some glandular crypts. At the time of publication of the article, she is still hospitalized, whereas the mother is continuing immunotherapy with pembrolizumab. On the follow-up CT scan, her metastasis in the axillary cavity further decreased in size to 3.3 × 2.8 cm, and no new metastases were observed. Although possible side effects were anticipated given the limited data on the use of pembrolizumab during pregnancy, the bowel dilation and subsequent neonatal complications were not predictable. These issues are suspected to be related to in utero exposure to pembrolizumab, representing a potential fetal irAE.

Fig. 1.

Fetal bowel dilation and its ultrasound appearance through follow-ups. a 31 weeks d = 12.5 mm. b 32 weeks d = 13.8 mm. c 33 weeks d = 12.5 mm. d 34 weeks + 5 days d = 12.6 mm. The arrow signals bowel dilation.

Discussion

This case report highlights the complexity of managing cancer during pregnancy, emphasizing the potential risks of immunotherapy to the fetus and the necessity for multidisciplinary care and close monitoring. It also underscores the need for further investigation into potential adverse neonatal outcomes, particularly irAEs. ICIs are monoclonal antibodies that bolster the body’s antitumor immune response by blocking intrinsic inhibitors of immunity, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), or its ligand, programmed cell death ligand 1 (PD-L1) [6]. CTLA-4 regulates the intensity of early stages of T-cell activation, and by blocking CTLA-4 with monoclonal antibodies, regulatory T cell (Treg)-mediated immune suppression is inhibited, whereas CD4+ and CD8+ T-cell effector function is promoted [7, 8]. PD-1 inhibits T cells in later stages of the immune response. High expression of PD-L1 has been observed in various malignant tumors, and by impeding the interaction between PD-1 and PD-L1, ICIs have proved significant antitumor effects [6, 9, 10]. Several ICIs have received approval from the European Medicines Agency: ipilimumab (CTLA-4 inhibitor), nivolumab and pembrolizumab (PD-1 inhibitors), and atezolizumab, avelumab, and durvalumab (PD-L1 inhibitors). To date, limited information exists regarding the use of immunotherapy during pregnancy, derived by animal studies and case reports. Consistent with their immune system-mediated mechanisms of action, these drugs are known to elicit irAEs, many of which are not yet fully described [11]. The most frequently reported irAEs include endocrine, cutaneous, gastrointestinal, hepatic, neurological, and pulmonary adverse effects, which on occasion may be life threatening or fatal [12, 13]. These side effects persist in some patients despite withholding therapy and using immunosuppressive and immune-modulating agents [14]. While prednisone doses of up to 20 mg/day are generally regarded as safe during pregnancy, severe irAEs often necessitate much higher doses (1–2 mg/kg) [15, 16]. In addition, during pregnancy, these medications have been linked to a higher risk of gestational diabetes, fetal oral-facial clefts (if exposed during the first trimester), and dysfunction of the hypothalamic-pituitary-adrenal axis [16]. PD-1 and its ligands form coinhibitory pathways that play a crucial role in regulating T-cell activation, peripheral tolerance, and immune-mediated tissue damage, all vital for fetomaternal tolerance and pregnancy maintenance [17]. Interactions between decidual stromal cells and CD4+ T cells through the PD-1-PD-L1 pathway create an immunosuppressive environment at the maternal-fetal interface, favoring implantation [17, 18]. Dysfunctional PD-1-PD-L1 pathway can lead to adverse pregnancy outcomes [19]. Similarly, CTLA-4 and its ligands, predominantly expressed by Tregs in the decidua, contribute to fetomaternal tolerance, particularly in early pregnancy [19]. T cells play a pivotal role in the adaptive immune response within the decidua, with a delicate balance between T helper 1, Th2, and Th17 cells, along with Tregs, being crucial for normal pregnancy [20]. Dysregulation of these pathways may contribute to conditions such as preeclampsia, preterm labor, and spontaneous abortion [20]. Another aspect to consider regarding fetal risks associated with ICI treatment during pregnancy is the influence of the molecular weight and IgG subtype of the monoclonal antibodies used [19]. Due to their size exceeding the limit for simple diffusion, monoclonal antibodies need to be actively transported across the placental barrier [21, 22]. Since this mechanism relies on fetal Fc receptors, which are absent during the first 14 weeks of pregnancy, fetuses are relatively protected during organogenesis [22]. The highest rate of transplacental transmission typically occurs during the late second and third trimesters [22]. Consequently, fetal exposure to ICIs might induce irAEs in the neonate, as observed in studies by Xu et al. [23]. Additionally, ICI treatment often results in increased production of interferon-gamma, which theoretically could contribute to implantation failure, miscarriage, fetal stress, preeclampsia, and preterm labor [24, 25]. A review of the literature on fetal outcomes of in utero exposure to ICIs indicates that these agents can potentially cause obstetric complications, such as FGR and preterm birth, and might lead to immune dysfunction in neonates, including immune-related gastroenterocolitis and congenital hypothyroidism. To date, there are nine published case reports of women who either conceived while on ICI treatment (n = 4) or initiated treatment during pregnancy (n = 5), including two twin pregnancies. The characteristics of all patients and detailed information about their immunotherapy treatments are summarized in Table 1. Recently, Baarslag et al. [26] argued that the use of ICIs in pregnancy might trigger irAEs in offspring, even several months after birth, emphasizing the need for cautious administration of these drugs during pregnancy and close monitoring for symptoms in newborns. Indeed, factors such as the necessity of treatment initiation during pregnancy, expected maternal benefits, and timing of exposure during gestation must be carefully considered in treatment decisions. Though challenging to define, we strongly question the potential correlation of NEC with late FGR, late preterm birth, and low birth weight, deeming it highly unlikely. The histological features of NEC are known to be nonspecific and could be associated with various underlying causes. We suspect that the prenatal bowel dilation observed in the case report was linked to the administration of pembrolizumab during pregnancy. To our knowledge, this could represent a potential fetal irAE following in utero exposure to anti-PD1 therapy. Patients should be counseled on the potential risks of taking immunotherapy during conception and pregnancy, including possible fetal and neonatal complications. A thorough evaluation by a multidisciplinary team is crucial for informed decision-making. Plus, fetal surveillance should be intensified with frequent ultrasounds to monitor growth and organ development, as well as regular maternal checkups to screen for potential adverse effects of the treatment. Coordination with neonatologists for postnatal care planning is also essential. Conducting prospective trials of immune checkpoint therapy in pregnant cancer patients is unethical due to the potential harm to the fetus. However, as the use of immunotherapy becomes more widespread, conception and pregnancy during cancer treatment may become more frequent and retrospective analyses of pregnancy outcomes would add valuable insights to the limited data available in this field.

Table 1.

Case reports of treatment with ICIs for cancer during pregnancy

Author/date	Immunotherapy administered	Type of malignancy	Age at pregnancy (years)	GA at immunotherapy	GA at delivery	Mode of delivery	Obstetric complication	Fetal outcome
Mehta et al., 2018 [27]	Ipilimumab	Melanoma stage IV	33	Before pregnancy–9 w	Term	SVD	None	Healthy
Menzer et al., 2018 [28]	Nivolumab, ipilimumab	Melanoma stage IV	34	21 w–24 w	24 w + 2 d	CS	Preterm delivery, IUGR	RDS, IVH grade II, ROP grade II. At 6 months, slight delay in motor development
Bucheit et al., 2020 [29]	Nivolumab, ipilimumab	Melanoma stage IV	32	Before pregnancy–delivery	32 w	CS	IUGR	Twin A, twin B: healthy
Xu et al., 2019 [23]	Nivolumab	Melanoma stage IV	32	Before pregnancy–7 w + 6 days	33 w	CS	IUGR	Congenital hypothyroidism (due to immune-related thyroiditis?)
Burotto et al., 2018 [30]	Nivolumab, ipilimumab	Melanoma stage IV	34	9 w–II trimester	32 w	CS	Preterm delivery, IUGR	Healthy
Haiduk et al., 2021 [31]	Nivolumab	Uveal melanoma stage IV	39	Before pregnancy–6 w	30 w	CS	HELLP syndrome, preterm delivery, IUGR	Twin A: healthy; twin B: upper limb malformation (strangulation by amniotic cord)
Anami et al., 2021 [32]	Pembrolizumab	Melanoma stage IV	40	21 w–27 w	28 w	CS	Preterm delivery	Healthy
Baarslag et al., 2023 [26]	Pembrolizumab	Melanoma stage IIIb	26	16 w–delivery	37 w	SVD	Maternal hypophysitis/adrenalitis, cholestasis	At the age of 4 months, he developed immune-related gastroenterocolitis
Polnaszek et al., 2021 [33]	Pembrolizumab	Placental site trophoblastic tumor stage I	23	Probably 4 w–6 w	39 w + 4 d	VBAC	None	NA

CS, cesarean section; d, days; GA, gestational age; IVH, intraventricular hemorrhage; FGR, fetal growth restriction; NA, not applicable; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; SVD, spontaneous vaginal birth; VBAC, vaginal birth after cesarean section; w, weeks.

Statement of Ethics

Ethical approval is not required for this study in accordance with local guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

L.P.: substantial contributions to the conception of the work, the acquisition, analysis, and interpretation of data for the work, and drafting of the work.

L.V.: substantial contributions to the acquisition of data for the work and drafting of the work.

E.C.: substantial contributions to the conception of the work and reviewing the work critically for important intellectual content.

All authors: final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author (L.V.).