Metastatic colorectal cancer during pregnancy: A tertiary center experience and review of the literature

Short abstract

Background

Colorectal cancer during pregnancy is rare. Diagnosis may be delayed and clinicians are faced with unique challenges when formulating management plans, having to consider the well-being of both fetus and mother.

Cases

Our series outlines five cases of metastatic colorectal cancer during pregnancy. There was one patient who presented in each of the first, second and third trimesters, whilst the remaining were post-partum. Diagnosis was difficult as the patients were either asymptomatic or their symptoms were misconstrued as features of pregnancy. Two patients received chemotherapy while pregnant but only one had a successful delivery. Survival of patients in this series ranged between 1 and 35 months from diagnosis.

Conclusion

Women with gestational colorectal cancer are often diagnosed at an advanced stage and have a poor prognosis.

Introduction

The diagnosis of colorectal cancer during pregnancy is uncommon, occurring in approximately 1/13,000 pregnancies.^1,2 Whilst over 300 cases of gestational colorectal cancers have been reported, few detailed their experience with chemotherapy. Given the paucity of data, there are no guidelines regarding the use of chemotherapy in this setting. This can lead to a management dilemma for clinicians who must balance the benefits and risks of treatment of the malignancy in the mother with the welfare of the pregnancy and fetus. Herein, we describe a case series of five patients presenting to a tertiary institution with metastatic colorectal cancer during pregnancy.

Cases

Case 1

Two months after delivering a healthy baby at term, a 29-year-old woman was diagnosed with metastatic rectal cancer. During the second trimester, she developed nausea, anorexia and fatigue, which continued throughout the rest of her pregnancy and was associated with 15 kg weight loss. However, no investigations were performed until after she reported a rapidly growing epigastric mass 4 weeks post-delivery. A computed tomography (CT) revealed bi-lobar liver metastases and at sigmoidoscopy a large 4 cm rectal mass was found. Biopsy of the rectal lesion confirmed adenocarcinoma. Her carcinoembryonic antigen (CEA) level was 7120 µg/L (reference range: <5.0 µg/L). Her case was reviewed in the hepatobiliary multidisciplinary meeting where her liver disease was deemed unresectable. She stopped breastfeeding to commence chemotherapy but died 35 months later.

Case 2

At 37 weeks' gestation, a 32-year-old woman presented with a 1-week history of intermittent abdominal pain and was found, on routine examination to have a tender epigastric mass. She had no other associated symptoms. Iron deficiency had been noted and treated with oral iron supplement from the second trimester. Investigations including an abdominal ultrasound and magnetic resonance imaging (MRI) scan revealed innumerable liver lesions consistent with metastases. CEA was 1170 µg/L. She was immediately induced resulting in a forceps-assisted vaginal delivery. She subsequently underwent a biopsy of her liver lesion revealing adenocarcinoma. A colonoscopy detected a 3 cm primary tumor in the sigmoid colon, biopsy of which also revealed adenocarcinoma. She breastfed for 1 week prior to commencing chemotherapy but died 11 months later.

Case 3

A 25-year-old woman presented at 19 weeks' gestation with a 6-week history of right upper quadrant abdominal pain, bloody diarrhea and severe iron deficiency anemia. An abdominal ultrasound revealed multiple liver lesions, confirmed on MRI, which also noted a mass within the left colon. A sigmoidoscopy demonstrated a near-obstructing 6 cm lesion in the descending colon. Histology revealed a moderately-differentiated adenocarcinoma. There was a strong family history of colorectal cancer hence genetic counseling was pursued. A germline adenomatous polyposis coli gene mutation was detected consistent with familial adenomatous polyposis (FAP). She was commenced on chemotherapy with standard, full-dose FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) at 20 weeks' gestation. She tolerated chemotherapy well apart from an episode of central venous catheter associated sepsis and the disease responded to treatment. Sadly, she suffered a stillbirth at 33 weeks' gestation, after six cycles of chemotherapy. The fetus weighed 1718 g (16th percentile for weight). The placental analysis revealed fetal thrombotic vasculopathy (FTV) from an undetermined cause but no thrombosis was seen in the fetal organs. On autopsy, there was no evidence of intrauterine growth restriction (IUGR) and the fetus was found to be morphologically normal. Array comparative genomic hybridization (CGH) testing excluded gross chromosomal abnormalities but there was insufficient DNA sample for a full analysis. The stillbirth was attributed to placental insufficiency secondary to FTV from an undetermined cause. The patient had three prior pregnancies, of which, two miscarried (at 8 and 12 weeks' gestation) and a third suffered with micrognathia, IUGR, gastroschisis and right hand syndactyly. Her only surviving child was delivered at 36 weeks' gestation with a birth weight of 1979 g (2nd percentile for weight). Placental analysis and his array CGH test were normal. No specific cause was found for his congenital anomalies and IUGR. After the stillbirth, the patient went on to have further chemotherapy with biologics and novel drugs in clinical trials. She died 31 months after her diagnosis.

Case 4

A day after spontaneous vaginal delivery of a healthy baby at 37 weeks' gestation, a 31-year-old woman developed severe right upper quadrant abdominal pain and was found to have a palpable abdominal mass. On direct questioning, she reported a 2-week history of bleeding per rectum but no other symptoms. Her first trimester nausea and vomiting had settled but she had not gained any weight throughout the pregnancy. She was found on ultrasound and CT to have a large left pelvic mass and innumerable liver lesions. A colonoscopy revealed a fungating 5 cm sigmoid tumor and biopsy demonstrated adenocarcinoma. CEA was 8220 µg/L. Her condition deteriorated and she died 1 month after delivery from progression of her extensive metastatic malignancy, having received only one cycle of chemotherapy.

Case 5

An asymptomatic 34-year-old woman was found to have a non-specific 5 cm liver lesion during her 11 weeks fetal morphology scan. After weighing the risks and benefits, a decision was made to monitor the lesion. A follow-up ultrasound and MRI at 22 weeks' gestation showed that the lesion had doubled in size, increasing the suspicion for malignancy. Her CEA was 24 µg/L. She underwent a colonoscopy which found a 10 cm descending colon tumor confirmed to be adenocarcinoma. After discussion of the case in the hepatobiliary multidisciplinary meeting, a plan was made for chemotherapy then surgery to remove her tumors. She commenced chemotherapy with full dose FOLFOX at 23 weeks' gestation. Three weeks after the sixth uneventful cycle, labor was induced with vacuum-assisted delivery at 36 weeks' gestation. The healthy baby weighed 3020 g (78th percentile for weight), but delivery was complicated by postpartum hemorrhage. A month later, she underwent resection of the primary colonic tumor and hepatic metastasis, followed by adjuvant chemotherapy. Her disease unfortunately recurred rapidly thereafter and she died 12 months from her initial diagnosis. Her child remained well with no recognizable complications on last follow-up at 9 months of age.

Discussion

Colorectal cancer during pregnancy typically presents at an average maternal age of 31 years.¹ This might be reflective of the increasing number of women delaying childbearing to the third and fourth decades together with a rising incidence of young adults being diagnosed with colorectal cancer.³ In Australia, the average age of women who gave birth was 30.3 years in 2015, and this number is climbing.⁴ Consequently, gestational colorectal cancer may become a more common problem as part of a rising incidence of malignancy being diagnosed during pregnancy over the past few decades.³

Among colorectal cancers developing at a young age, a proportion may be due to a defined hereditary colorectal cancer syndrome or predisposing condition such as inflammatory bowel disease.^1,2 Such predisposition was found in one of our cases who had a clear indication for genetic testing for FAP. The other cases had no apparent predisposition to colorectal cancer and were not investigated for hereditary colorectal cancer syndromes. All of the patients had microsatellite stable disease, arguing against Lynch syndrome.

Four of our five patients had colon cancer, all of which were left sided. There is increased understanding of the heterogeneity of colorectal cancer at a mutational and gene expression level, with subgroups having different prognoses.⁵ However, it is unknown whether pregnancy-associated colorectal cancer is overrepresented by a specific molecular subtype and further research in this area is needed.

Compared to the general population, gestational colorectal cancer is usually diagnosed at a more advanced stage and is more commonly associated with perforation and obstruction.^1,2 This might be due to a delay in diagnosis and more rapid tumor growth during pregnancy. It has been postulated that physiologic changes supporting a normal pregnancy, such as immune tolerance and an increase in growth factors, among others, are exploited by malignant cells resulting in faster tumor growth.⁶ In addition to increasing incidence, young adults (<40 years) with colorectal cancer have a worse prognosis than older patients. The reasons for this observation are unclear but may relate to more aggressive tumor biology.⁷ Whether pregnancy in these young women further worsens the prognosis is not clear. Thus, making a prompt diagnosis of gestational colorectal cancer is vitally important but challenging for multiple reasons. Firstly, there are many overlapping signs and symptoms between pregnancy and malignancy, such as fatigue, abdominal bloating and bowel habit change. Colonic bleeding may lead to iron deficiency and/or anemia, but these may be attributed to the pregnancy and be overlooked.⁸ This may be further compounded by a lower index of suspicion of malignancy due to the younger age group. Therefore, although rare, it is critical for the clinician to consider a diagnosis of malignancy. “Red flags” such as weight loss or absence of weight gain, with or without other associated symptoms, should be carefully evaluated and promptly investigated.

The use of some investigations especially CT and colonoscopy during pregnancy must take into account the associated risks and benefits. Nonetheless, clinicians can utilize alternative diagnostic modalities such as sigmoidoscopy, ultrasound and MRI as seen in this case series.^1,2 Whilst serum CEA levels may be elevated in colorectal cancer, increases above the normal range can also be found during pregnancy and levels may vary between trimesters. However, levels rarely exceed 10 µg/L in pregnancy and should be promptly investigated.⁹

The management of gestational colorectal cancers is particularly challenging given the difficult balance between maternal health and fetal well-being. Treatment is complex, and is dependent on tumor stage, fetal gestational age, and whether emergent treatment is indicated. Furthermore, there is extremely limited data on the efficacy and safety of chemotherapy and biologic agents during pregnancy. Therefore, it is essential for multidisciplinary involvement between surgeons, pediatricians, obstetricians, radiation and medical oncologists.^1,2

The safety profile of chemotherapy drugs directed against colorectal cancer, oxaliplatin, irinotecan and 5-fluorouracil, is mostly limited to animal fetal studies revealing developmental abnormalities, delayed growth and death, especially during organogenesis.^2,3 In general terms, chemotherapy use is associated with less risk moving from the first through to the third trimester and is usually contra-indicated during the first trimester when fetal organogenesis takes place.³ It is not known whether these drugs are passed into breast milk.² Bevacizumab and anti-EGFR antibodies are common biological agents used against colorectal cancer. Their mechanism of action suggests they are likely to be associated with major fetal abnormalities. Being immunoglobulin G antibodies, placental transfer may actually increase later in pregnancy when immunoglobulin active transport takes place.³ There have been no reports of intravenous administration of these antibodies during pregnancy to date. However, intravitreal bevacizumab injections have been associated with miscarriages in the ophthalmology setting.^3,10 We did not administer these agents to any of our five cases before delivery and we believe their use cannot be recommended. For patients with gestational colorectal cancer, the mode of delivery should be considered on obstetric grounds. However, specific indications for cesarean delivery might include birth canal obstruction by tumor and tumor tracking along the anterior rectal wall as vaginal birth pressure can cause the tumor to bleed.^1,2 Due to potential complications associated with myelosuppression during delivery, chemotherapy should not be administered 3 weeks prior to expected delivery or beyond 35 weeks' gestation.^3,11

Clinical experience especially in the breast cancer setting indicates good tolerability and efficacy of chemotherapy, based on body surface area (BSA) dosing during the second and third trimesters. Nevertheless, known physiological variations in drug pharmacokinetics throughout pregnancy and transplacental transfer rates of individual cytotoxic agents raise important questions regarding the optimal drug dosage in these patients.¹² Furthermore, the volume of distribution of drugs increases, protein binding decreases, hepatic clearance changes, and renal elimination increases.³ It is unclear to what extent these changes impact chemotherapy pharmacodynamics, and currently, dosing based on BSA using the patient’s actual weight, remains the standard without empiric dose reductions or dose capping. As in non-pregnant patients, drug doses should be adjusted with any change in weight.¹²

To date, only five cases of FOLFOX chemotherapy administration during pregnancy (commencing between 13 and 24 weeks' gestation) have been reported. All had successful deliveries with no congenital malformations but one infant developed hypothyroidism requiring life-long therapy.^3,8 In our series, one of the two patients who received chemotherapy while pregnant had a stillbirth. It was unclear whether this was due to the chemotherapy or an underlying undiagnosed genetic predisposition, although we favor the latter explanation, given her pregnancy history. No previous association between 5-flurouracil or oxaliplatin and FTV has been described. However, there has been reported association between malignancy-induced hypercoagulability and placental thrombosis.¹³ Although no data are available regarding the long-term effects of in-utero exposure to chemotherapy for colorectal cancer, a mean follow-up of 18.7 years of 84 children who were exposed to chemotherapy in-utero for hematological malignancies during pregnancy did not reveal any long-term developmental, behavioral or intellectual adverse outcomes. In fact, 12 second generation children were born with no congenital abnormalities.¹⁴ At present, there are no guidelines for long-term follow-up of children of such pregnancies.

Whilst no definitive recommendations can be given, resectable colorectal malignancies, even detected prior to 20 weeks' gestation should still be considered for surgical management. Advances in surgical, anesthetic and maternal-fetal monitoring techniques have allowed surgeons to perform invasive procedures more safely in pregnant women. However, it is still important to be aware of the potential risk of abdominal surgery affecting the gravid uterus leading to fetal loss.⁸ Although no data exist specific for colorectal cancer surgery, laparoscopic abdominal surgery appears to be associated with less risk to the pregnant woman compared to open laparotomy.^15,16 The largest study to date by Sachs et al., which included nearly 20,000 women found that laparoscopic surgery was safer with fewer adverse obstetric outcomes, including miscarriage, compared to open surgery.¹⁷ When malignancies are detected later in pregnancy, surgery may be delayed until after the earliest and safest possible delivery of the fetus. The priority is to allow fetal lung maturation, with multidisciplinary team coordination to facilitate delivery between 28 and 32 weeks of gestation.^1,2 This approach is however associated with increased risk of cancer progression and thus, in the setting of resectable oligo-metastatic disease, pre-operative chemotherapy during pregnancy might be recommended, as we decided for case 5.

Due to factors including potential for stillbirth, prematurity or pregnancy termination, there is an approximately 30% fetal mortality rate in pregnancies complicated by colorectal carcinoma.⁹ To date, no direct spread to fetuses has been reported, but there has been a case of metastatic disease to the placenta.¹⁸ As such, it is advisable to check the placenta for tumor deposits following delivery. None of the patients in this case series had placental metastases.

The 5-year survival for pregnant patients with colorectal cancer appears to be similar to stage and age matched non-pregnant controls. However, there is an overall poor prognosis due to diagnosis with advanced stage disease.^1,9 For example, in a review of 42 patients with gestational colorectal cancer, median survival was less than 5 months, with majority of patients dying within 1 year of diagnosis and no patient surviving beyond 5 years.²

Conclusion

Gestational colorectal cancer presents both a diagnostic and management challenge. Physiologic and anatomic changes in pregnancy may cloud the clinical presentation leading to delayed diagnosis. Treatment decisions need to consider both the fetus and mother, which will depend on the individual circumstances of each case, taking into account the prognosis for successful maternal and fetal outcomes, with the mother being the ultimate decision maker. Greater awareness and a multidisciplinary coordinated approach are necessary to maximize both maternal and fetal outcome. Although rare, the diagnosis of colorectal cancer should be considered and promptly investigated in both pregnant and non-pregnant young adults when symptoms are reported. The experience at this institution with FOLFOX chemotherapy adds to the literature regarding its usage during pregnancy. Our series of five patients unfortunately illustrates the point that these patients are often diagnosed at an advanced stage and have a poor outcome.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

This study has been approved by the Royal Brisbane and Women’s Hospital Human Research Ethics Committee and written consent has been obtained from each patient.

Guarantor

SFL.

Contributorship

Each of the three authors has contributed to gathering information about the cases and writing up this manuscript.