Oncologic Surgery for Lower Gastrointestinal Tumors during Pregnancy: A Literature Review

Lower GI cancers during pregnancy are challenging because the carcinoma may be in closer proximity to the uterus, such as rectal cancer, and there is an additional risk of direct uterine tumor infiltration or compression. The pathologic characteristics and prognosis of patients diagnosed with malignancy during pregnancy are generally comparable to those of age- and stage-matched non-pregnant patients [1, 2].

Colorectal cancer (CRC) is one of the most common malignancies diagnosed during pregnancy and therefore requires special attention in terms of optimal diagnosis and treatment. The incidence of CRC is reported to be 2 per 100,000 pregnancies [3]. The pooled risk was 0.002% in a systematic review by Pellino et al. [4]. A recent Swedish nationwide case-control study demonstrated that early-onset CRC (age at diagnosis: 18–49 years) is associated with risk of both adverse pregnancy (pre-eclampsia, C-section) and worse neonatal outcomes (preterm birth). There was no association to congenital malformation found [1]. The correct diagnosis of colon or rectal cancer during pregnancy is complicated by the fact that many symptoms of malignancy mimic the symptoms of pregnancy, including nausea/vomiting, abdominal pain, anemia, and fatigue. The gravid uterus may complicate the physical examination during pregnancy. The most common clinical manifestations include abdominal pain, nausea and vomiting, and altered intestinal peristalsis, as is often seen in normal pregnancy [2]. The role of estrogen and progesterone as growth factors during pregnancy is controversial concerning carcinogenesis [5, 6]. After all, this usually leads to late diagnosis in advanced stages and a correspondingly poor prognosis. In addition, physicians are often reluctant to order appropriate diagnostic tests or imaging for fear that laboratory results may be inaccurate or that radiologic studies may be harmful [7]. In principle, chemotherapy is also possible during pregnancy, but this must be carefully considered and ideally postponed until after delivery as adjuvant therapy, as long as it is oncologically justified. Radiation therapy is contraindicated. Because high radiation exposure is associated with teratogenesis, miscarriage, and possible mental retardation as well as the development of malignancies in the exposed child, it is common clinical practice to postpone radiotherapy, e.g., for rectal cancer, until the puerperium, if the uterus cannot be shielded or if postponing radiotherapy would not significantly affect the outcome [8]. Most patients with CRC during pregnancy undergo oncologic resection with anastomosis, possibly with stoma. However, there is no indication of a caesarian section in this situation.

Pregnancy may limit the use of diagnostic and therapeutic standards. While ultrasound and magnetic resonance imaging (MRI) of the abdomen can be used safely, computed tomography for staging should be avoided because of the high radiation dose to the fetus [9‒11]. Although studies evaluating the safety of MRI during pregnancy have shown no adverse effects, it is good practice to avoid non-urgent MRI, especially during the first trimester. Gadolinium is contraindicated in pregnancy due to its known teratogenicity [12]. However, the radiation dose used in diagnostic radiology, including computed tomography, is very low (less than 500 mGy), and evidence-based guidelines suggest that the risk of adverse fetal effects, particularly teratogenesis or fetal loss, is low at radiation doses used for diagnostic purposes [12]. Colonoscopy is feasible during pregnancy and should always be performed when there is a clear clinical indication [6, 13, 14]. Nevertheless, it is still underused, especially considering that such symptoms like rectal bleeding (derived from hemorrhoids or anal thrombosis) are not uncommon and often occur during both pregnancy and lactation (affecting up to 40% of women) [15]. The value of tumor markers such as CEA and CA19-9 is discussed controversial during pregnancy. On the one hand, studies suggest CEA and CA19-9 (contrary to tumor markers in gynecological malignancies) to be independent during pregnancy and thus remain reliable for monitoring malignancy in pregnant women [16‒18]. On the other hand, there are hints that higher levels of CEA can be detected in multigravida patients [19].

Gestational age and tumor stage are relevant in selecting the best treatment modality. To treat the mother in the best possible way and to minimize side effects on the fetus, the treatment of CRC during pregnancy must take into account many aspects, including the stage of pregnancy, the elective or emergency presentation, the progression of the disease, and the patient’s wishes. In the curable stage, primary oncologic resection with lymphadenectomy is recommended, especially for patients diagnosed in early pregnancy (before 20 weeks of gestation). Surgical resection is indicated immediately after diagnosis to minimize the progression of the malignancy. It has been reported that the incidence of preterm delivery and low birth weight after surgery is twice that of normal pregnancies [20]. Abortion should be considered at the patient’s request, after careful information and explanation. Adjuvant chemotherapy depends on the stage of the cancer. According to the current German guidelines for CRC, adjuvant chemotherapy can be discussed for patients with UICC stage II colon cancer who either had pT4 tumors or pT3 tumors with so-called risk factors such as emergency surgery, less than 12 resected lymph nodes, poor quality of the mesorectal preparation, tumor perforation, or histopathologically documented lymphatic or blood vessel infiltration as well as undifferentiated tumors [21]. The recommended therapy of choice is capecitabine. In UICC stage III tumors (with positive nodal metastases), adjuvant chemotherapeutic treatment is always recommended, either suggesting the 5-FU/folinic acid/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (CAPOX) regime [21]. In patients at low risk of recurrence with T1-3 and N1 stage, a treatment interval of 3 months can be performed; in patients at high risk of recurrence (T4 and/or N2), 6 months of chemotherapy is recommended. Nevertheless, there are little data from case reports focusing on the safe chemotherapeutic treatment with these regimens in pregnant patients [22, 23].

The application of chemotherapy for CRC during pregnancy has been reported with no observable adverse effects on the fetus, but these are always highly individualized decisions. If oncologically warranted and if the tumor is still localized or at an early stage, postponement of surgery may be considered to reduce the anesthetic risks to the fetus and the mother.

In pregnancies with a duration of ≥20 weeks, it is recommended to postpone surgery until the birth of a viable fetus (28–30 weeks). At the same time, medical support (glucocorticoid administration) is given to initiate fetal lung maturation. In later diagnosis, surgery can be postponed to the earliest possible time, when the fetus is viable (approximately 32 weeks after gestation). The neonatology aspects of induced preterm birth, including the high risk of preterm complications, such as cerebral hemorrhage, pulmonary hypoplasia, and necrotizing enterocolitis, must be included in the multidisciplinary discussion [24].

The choice between vaginal delivery and cesarean section is controversial. Arguments for cesarean delivery include the avoidance of high pressure or trauma to the tumor during vaginal delivery. This may also reduce damage to the patient [25]. Resection of the tumor should usually be performed 1–2 weeks after vaginal delivery when involution of the uterus and resolution of vascular congestion in the small pelvis is complete. In advanced stages of the tumor, when adjuvant therapy is required, the focus is on saving the mother’s life and improving the prognosis as much as possible. Therefore, in the later stages of pregnancy, the best option is adjuvant therapy or early delivery followed by chemotherapy. The most challenging clinical scenarios may occur when CRC diagnosis reveals synchronous hepatic metastasis or peritoneal carcinomatosis. Nevertheless, as mentioned before, there is only a little evidence on how to proceed in such situations. In the case of liver metastases, sequential treatment is the most promising therapeutic option. There are no strong data on which sequence to prefer; however, compared to non-pregnant patients, the resection of the primary tumor followed by chemotherapy and hepatic surgery has been published so far [22]. The optimal time point for abdominal surgery is the early second trimester [26], while data suggests that chemotherapy can be safely administered after 12–14 weeks of gestation until 1–3 weeks before the anticipated delivery of the child [26]. For peritoneal carcinomatosis, case reports describe the primary surgical approach via cytoreductive surgery [27] with adjuvant chemotherapy. Adjuvant chemotherapy depends on the stage of the cancer.

The oncologic-surgical procedure for CRC in pregnant patients does not differ from the usual procedure for non-pregnant women but may vary depending on the stage, location, and urgency of the necessary therapy, e.g., in the case of bleeding or covered perforation of the tumor, as well as the duration of pregnancy. In principle, surgery should be performed without delay, if possible, during pregnancy, to prevent the progression of the disease before adjuvant therapy. Emergency resection of CRC with acute bowel obstruction is always associated with high morbidity and mortality, even in non-pregnant women [24]. For stenosing CRC with ileus, different types of emergency interventions are recommended. Due to the high morbidity of primary oncologic colon resection during pregnancy, bridging techniques should be evaluated [28]. Patients with left-sided obstructive colon cancer are traditionally treated with a decompressive stoma or stent implantation. The timing of the section should be determined by interdisciplinary consensus. In the few cases described, late preterm delivery was often accepted in the presence of advanced tumor disease and the need for timely oncologic therapy [24].

Due to the limited data available, there is no reliable evidence regarding the exact surgical approach, particularly for open versus minimally invasive resections. The resulting risk to the fetus must always be carefully weighed against successful tumor resection [24, 29, 30]. There are case series describing robot-assisted oncologic colon resection as a viable approach for resectable and non-metastatic tumors [31]. After delivery, treatment should be continued according to standard guidelines for CRC [21]. In all of these actions, the health of the fetus should always be the priority. Figure 1 summarizes the possible diagnostic and therapeutic algorithms depending on the stage of tumor spread, elective or emergencies, and the time point of diagnosis during pregnancy.

Rectal cancer during pregnancy is a particularly complex situation for the mother and the fetus. A systematic review by Pellino et al. [4] which included 79 publications and 119 patients with CRC during pregnancy, found that patients with rectal cancer had a significantly longer overall survival compared to colon cancer (73 vs. 26 months; p = 0.0072). Although, in analogy to colon cancer, there is no high-level evidence for the management of rectal cancer during pregnancy as there are few management options and algorithms in the current literature, only.

Patients diagnosed with rectal cancer in the first trimester have the option of terminating the pregnancy and managing the cancer as in non-pregnant patients or proceeding with surgery if imaging indicates that the tumor can be resected primarily. The need for chemotherapy depends on the final histology and can be started in the second and third trimesters [32]. However, little is known about the long-term effects of chemotherapy on the fetus. Radiation therapy is contraindicated during pregnancy. For patients diagnosed in the second trimester of pregnancy, delaying treatment until after delivery can put the patient at serious risk and pose a significant danger of disease progression in the pro-angiogenic state of pregnancy [12]. In these situations, neoadjuvant chemoradiation would be the standard treatment, but the preservation of pregnancy in this case means that radiotherapy is only possible in the adjuvant setting. It should be noted that rectal cancer surgery can be performed in the second trimester. For patients diagnosed in the third trimester, it may be considered appropriate to wait until the pregnancy is 32 weeks after gestation to allow for fetal lung maturation. Delivery can then take place, followed by treatment of rectal cancer as in non-pregnant women [12]. Optimal management of rectal cancer in pregnancy requires well-considered, individualized strategies and approaches based on gestational age and after thorough consultation with the patient. Surgical management should be considered on a case-by-case basis with careful consideration of timing, consent, and multidisciplinary consensus.

As with CRC, there is no broad evidence base for the precise surgical oncologic resection strategy for rectal cancer. However, both anterior rectal resections and abdominoperineal extirpations have been described in relevant reviews [4]. Surgical approaches for simultaneous hepatic metastases have also been suggested as feasible [4]. Robot-assisted resections also appear possible [31].

The treatment of CRC during pregnancy raises profound ethical and medico-legal questions due to the different and often conflicting interests of the mother and fetus. Treatment depends on the patient’s age, desire for future pregnancy, gestational age, tumor stage, and ethical beliefs. It also depends on surgical and technical difficulties and the need for elective or emergency surgery. Individualized management by a multidisciplinary team is therefore essential. It is absolutely essential that pregnant patients diagnosed with CRC should be referred to specialized high volume/experienced centers with colorectal surgery, gastrointestinal oncology, gynecology, and neonatology for the best treatment options for both the patient and the child.

Patrick S. Plum, Seung-Hun Chon, Hakan Alakus, Matthias Mehdorn, Sigmar Stelzner, René Thieme, Nicole Kreuser, and Ines Gockel declare that they have no conflicts of interest.

This study was not supported by any sponsor or funder.

Idea, conception, and manuscript writing: P.S.P. and I.G. Literature research: P.S.P., S.-H.C., H.A., M.M., S.S., R.T., N.K., and I.G. Editing manuscript: S.-H.C., H.A., M.M., S.S., R.T., and N.K. Graphics: P.S.P. and N.K. All the authors have read and agreed to the published version of this manuscript.