ORIGINAL ARTICLE ANZJSurg.com
Synchronous colorectal liver metastases in pregnancy and post-partum Danielle E. Robson, Joel Lewin, Anthony W. Cheng, Nicholas A. O’Rourke and David J. Cavallucci Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia
Key words colorectal cancer, metastatic, pregnancy, post-partum. Correspondence Dr Danielle E. Robson, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, Queensland, Australia. Email: [email protected] D. E. Robson MBBS (Hons); J. Lewin MBBS; A. W. Cheng FRACS; N. A. O’Rourke FRACS; D. J. Cavallucci FRACS. Accepted for publication 25 April 2015. doi: 10.1111/ans.13196
Abstract Background: Metastatic colorectal cancer (mCRC) in pregnancy and post-partum is rare, but represents significant diagnostic and therapeutic challenges for clinicians. A multidisciplinary team (MDT) approach is essential. This study reports the first series in the Australasian literature, describing our experience with and management of pregnant and post-partum patients diagnosed with synchronous colorectal liver metastases (sCRLM). Method: A retrospective review of prospectively collected data for patients with sCRLM diagnosed during pregnancy or post-partum, presenting to a tertiary referral hospital between 2009 and 2014, was performed. Data regarding patient presentation, imaging, management, histopathology and survival were analysed. Patient characteristics and outcomes were reviewed, including age, presenting complaint and median survival. Results: Five patients were identified with sCRLM: three patients were diagnosed antepartum and two post-partum. Median age was 31 years (range 26–34). All patients were diagnosed with colorectal primary and synchronous liver lesions. All patients received folinic acid, fluorouracil, oxaliplatin chemotherapy, two intrapartum. One patient had both the primary lesion and liver metastases excised early post-partum. Second-line chemotherapy with folinic acid, fluorouracil, irinotecan and other biological agents was used in some cases post-partum. One patient suffered a fetal loss, while the other four had uncomplicated live births. Median survival was 7.6 months, with two patients dying shortly after delivery. Conclusion: The diagnosis of mCRC in pregnancy is challenging and survival is poor. A MDT approach to management is essential. Chemotherapy remains the mainstay of treatment from the second trimester. Rapid confirmation of diagnosis and early chemotherapy, followed by post-partum colorectal and liver resection may improve survival.
Introduction Cancer is diagnosed in approximately one in every 1000 pregnant women. Gynaecological cancers are most frequently observed, followed by melanoma.1 Metastatic colorectal cancer (mCRC) is rare, occurring in approximately 0.002% of pregnancies.1–3 However, epidemiological data indicate an increased incidence of colorectal cancer (CRC) diagnosed in pregnancy and post-partum of 26% over the last 10 years, due, at least in part, to more women falling pregnant at an advanced maternal age.1,4 Common presenting symptoms include abdominal pain or mass, constipation, nausea and vomiting, weight loss and rectal bleeding.2 Symptoms are often © 2015 Royal Australasian College of Surgeons
attributed to benign conditions associated with pregnancy, such as haemorrhoids or constipation, and may go under investigated.5 The low incidence of CRC in this age group and the symptomatic overlap with common conditions of pregnancy and the post-partum period mean that these cancers represent a significant diagnostic and therapeutic challenge and are commonly diagnosed late worsening their prognosis.6 These complex patients require multidisciplinary management including obstetric, neonatology, surgical, oncology, radiology and psychology input. To date, there are no studies reporting on the Australasian experience with these patients, and to our knowledge, there are no reports of liver resection for colorectal liver metastases (CLM) during ANZ J Surg •• (2015) ••–••
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Robson et al.
Table 1 Metastatic colorectal cancer in pregnancy and post-partum Author
Study type
Jeppesen & Østerlind1 Kanate et al.3 Minter et al.7
Case Case Case Case
Bernstein et al.8
Retrospective survey study
series series series series
Number of patients 1 1 1 1 40 (6 Duke’s D)
Treatment modality
5-fluorouracil leucovorin oxaliplatin 5-fluorouracil leucovorin Oxaliplatin 5-fluorouracil leucovorin oxaliplatin bevacizumab Not reported
pregnancy and post-partum. Existing data addressing this unique cohort of patients is largely limited to case reports worldwide. Current literature indicates that the mainstay of treatment for these patients is predominantly chemotherapy, with minimal surgical intervention reported to date (Table 1).7,8 This is attributed to advanced stage of disease at time of diagnosis and rapid disease progression. There are case reports advocating the use of both chemotherapy and surgical resection of primary CRC as effective and safe treatment modalities during pregnancy and post-partum.7,8 Reported risks of active treatment during pregnancy include teratogenicity, intra-uterine fetal demise and placental abruption.3 Other studies suggest surgical and chemotherapy treatments as having acceptable morbidity and mortality risk for the unborn child while also improving maternal survival.1 This study reports five cases of synchronous primary CRC with liver metastases (sCRLM) diagnosed during pregnancy or postpartum, highlighting the importance of early investigation of symptomatic patients during pregnancy, as well as the role of chemotherapeutic, radiological and surgical interventions.
Recorded maternal survival
Fetal outcome
12 months 3 months 5 months 11 months
Live birth Live birth Live birth Termination of pregnancy Not reported
0% 5-year survival
Table 2 Overview of key words and MeSH terms Key words Colorectal cancer
Metastasis
Metastatic colorectal cancer Pregnancy Post-partum Delivery Diagnosis Management Chemotherapy Survival
MeSH terms ‘Colorectal Cancer’[MeSH Terms] OR ‘Colorectal Carcinoma’ [MeSH Terms] OR ‘Colorectal Neoplasm’ [MeSH Terms] OR ‘Colon Cancer’ [MeSH Terms] OR ‘Rectal Cancer’ [MeSH Terms] ‘Metastasis’ [MeSH Terms] OR ‘Neoplasm Metastasis’ [MeSH Terms] AND ‘Advanced Disease’ [Key Word] ‘Metastatic Colorectal Cancer’ [Key Word] AND ‘Synchronous Colorectal Liver Metastases’ ‘Pregnancy’ ‘[MeSH Terms]’ OR ‘Pregnant’ [MeSH Terms] ‘Postpartum’[MeSH Terms] AND ‘Post Delivery’ [Key Word] ‘Obstetric Delivery’ [MeSH Terms] ‘Diagnosis’ [Text Word] AND Screening [MeSH Term] ‘Management’ [Text Word] ‘Chemotherapy’ [MeSH Terms] ‘Survival’ [MeSH Terms]
Methods A retrospective review of a prospectively collected database at the Royal Brisbane and Women’s Hospital, Australia, was performed. All women diagnosed with sCRLM during pregnancy or postpartum between 2009 and 2014 were identified. Data pertaining to patient presentation, diagnostic and staging modalities, chemotherapy, surgical management and survival outcomes were analysed. A literature review on the topic was performed using Ovid MEDLINE, EMBASE, and Cochrane databases using a combination of keywords and MeSH terms (Table 2). When diagnosed, all patients with sCRLM were discussed at a multidisciplinary team (MDT) meeting, with radiology, gastroenterology, surgical, obstetric and oncology input to arrive at a consensus for optimal management. All patients underwent colonoscopy and biopsy of the primary lesion to confirm the diagnosis of CRC. Diagnosis of liver metastases was made with magnetic resonance imaging (MRI). If the patient was post-partum, MRI was performed using liver-specific contrast (Gd-EOB-DTPA, Primovist or Eovist, Bayer, Leverkusen, Germany) and extrahepatic metastatic disease identified with positron emission tomography.
Results Five cases of sCRLM during pregnancy or post-partum were identified between 2009 and 2014 (Table 3). The median age was 31
years and all patients were non-smokers. Three patients were diagnosed during pregnancy and the other two post-partum. The postpartum period was defined as 6 weeks post delivery date.10 The most common presenting complaint was a right upper quadrant (RUQ) mass, detectable in all five patients. After diagnosis, patients invariably reported a longer history of symptoms relating to the primary cancer, such as abdominal pain, weight loss and rectal bleeding. The number, size and location of liver metastases were variable between patients. Two patients had a single, large metastasis, with another patient having at least 30 small liver metastases identified on imaging. All patients were managed with chemotherapy. One patient underwent resection of her liver metastases and primary tumour post-partum (Table 4). Four patients had live births. One patient suffered an intra-uterine fetal death.
Case one A 34-year-old woman 1-day post spontaneous vaginal delivery was noted to have a large palpable mass in the RUQ and associated pain on inspiration. She reported a 2-week history of rectal bleeding and right-sided abdominal pain. She also reported significant nausea, vomiting, diarrhoea and unexplained weight loss throughout the pregnancy. Computed tomography (CT) imaging revealed an irregu© 2015 Royal Australasian College of Surgeons
sCRLMs in pregnancy and post-partum
3
lar large mass in the sigmoid colon and associated enlarged left common iliac node measuring 13 mm. CT also showed multiple large, bilobar liver lesions consistent with metastases. Tissue biopsies during colonoscopy confirmed adenocarcinoma in the sigmoid colon. She received a single cycle of folinic acid, fluorouracil, oxaliplatin (FOLFOX) chemotherapy before returning home overseas to continue treatment. Her disease quickly progressed and she died 37 days after diagnosis and 38 days after delivering a healthy baby.
Table 3 Patient characteristics and outcomes Median age Median CEA at diagnosis† Fetal outcome Live birth Intra-uterine death Presenting complaint‡ Palpable RUQ mass Epigastric pain RUQ abdominal pain Short of breath Fevers Nausea Vomiting Symptoms from primary‡ Rectal bleeding Abdominal pain Weight loss Diarrhoea Primary location (colon : rectum) Tumour grade Poorly differentiated Moderately differentiated Well differentiated Number of liver metastases 1 2–5 >5 Median size of the largest liver metastasis (cm) Presence of metastases > 5 cm diameter Median survival (months)§ Maternal deaths
31 (26–34) 4115 (24–8220) 4 1 5 2 2 1 1 1 1
Case two A 29-year-old woman was referred to hospital by her general practitioner (GP) after presenting with epigastric discomfort and a palpable mass in the RUQ extending below the umbilicus post-partum. She reported symptoms of abdominal pain, fatigue, nausea, vomiting and 15-kg weight loss during the last 2 months of her pregnancy. Rectal examination revealed a palpable mass with blood. Staging CT scan revealed extensive, bilobar metastatic disease of the liver as well as multiple lung metastases. Flexible sigmoidoscopy and biopsy confirmed a 4 cm fungating, non-obstructing rectal adenocarcinoma. She was commenced on folinic acid, fluorouracil, irinotecan (FOLFIRI) chemotherapy for 18 cycles until a progress CT scan revealed progression of liver metastases. She was then commenced on FOLFOX with a partial response based on declining carcinoembryonic antigen (CEA) level and reduced volume of liver disease on progress CT scan. Transarterial chemoembolization was performed to the liver metastases and the patient remains on chemotherapy at 30 months post diagnosis.
Case three
2 1 1 2 4:1 1 3 1 2 2 1 8.1 (7.00–22.7) 3 7.6 (1.2–30.0) 2
†Carcinoembryonic antigen level was not recorded in one patient. ‡Individual patients could have multiple presenting complaints or symptoms from the primary. §Median survival was calculated from the time of diagnosis to the time of most recent follow-up. CEA, carcinoembryonic antigen; RUQ, right upper quadrant.
A 34-year-old woman presented to her GP at 14 weeks gestation complaining of recurrent RUQ pain and palpable mass for several months. Outpatient ultrasound revealed a large hepatic mass and subsequent MRI confirmed bilobar liver disease. Colonoscopy showed a partially obstructing rectosigmoid tumour with biopsy confirming the diagnosis of adenocarcinoma. Following investigations, she underwent six cycles of FOLFOX chemotherapy. She delivered a healthy baby at 34 weeks gestation by induced spontaneous vaginal delivery. Restaging CT scan immediately post delivery showed bilobar liver metastases, predominantly in the left lobe, the largest of which had increased in size to 9.5 × 14 × 9 cm. She had no extrahepatic metastatic disease. A week later she underwent a successful open extended left hepatectomy, with histopathology confirming mCRC with clear margins. She was discharged without complication and underwent three more cycles of adjuvant chemotherapy before undergoing successful R0 resection of the primary via laparoscopic high anterior resection 6 weeks later. As the patient was deemed high risk for recurrence, a further course of chemotherapy after the primary resection was recommended by oncology. She currently remains disease free on adjuvant chemotherapy.
Table 4 Management of metastatic colorectal cancer in pregnancy and post-partum Case
1 2
Chemotherapy agent
Trimester agent given
Surgical intervention
Maternal outcome
Deceased Alive with disease
Live birth Live birth
38 days 30 months
Alive with disease
Live birth
8 months
Alive with disease
5 months
Deceased
Intra-uterine death Live birth
Post delivery Post delivery
3
FOLFOX FOLFIRI FOLFOX FOLFOX
4
FOLFOX
2, post delivery
Nil Transarterial chemoembolization Open extended left hepatectomy and R0 excision of primary Nil
5
FOLFOX + Bevacizumab, FOLFIRI
Post delivery
Nil
2, 3, post delivery
FOLFIRI, folinic acid, fluorouracil, irinotecan; FOLFOX, folinic acid, fluorouracil, oxaliplatin.
© 2015 Royal Australasian College of Surgeons
Fetal outcome
Follow-up
5 months
4
Case four A 26-year-old woman presented to a regional hospital at 19 weeks gestation, reporting RUQ pain, shortness of breath and fevers on a background of 6 weeks of bloody diarrhoea. An enlarged palpable liver was noted on examination with CT scan revealing large, bilobar intrahepatic lesions, the largest in segment six measuring 7.3 × 7.0 × 8.4 cm. No extrahepatic disease was detected on CT. Colonoscopy revealed a 60 mm fungating, partially obstructing tumour in the descending colon, with multiple surrounding polyps. She was positive for familial adenomatous polyposis. The patient commenced on FOLFOX chemotherapy 2 weeks after diagnosis, with her liver metastases deemed unresectable. She responded well to chemotherapy as demonstrated by a declining CEA level. However, she suffered an intra-uterine fetal loss at 33 weeks. She continued to respond to chemotherapy post delivery (restaging CT showed a reduction in liver metastases) and is currently alive with disease over 5 months post diagnosis.
Case five A 31-year-old woman presented at 37 weeks gestation with a palpable RUQ mass, nausea and epigastric pain. Abdominal ultrasound showed multiple, hypoechoic hepatic nodules up to 2.5 cm in diameter. MRI demonstrated thickening of the sigmoid colon and associated lymphadenopathy and multiple hepatic lesions consistent with metastases. Given the patients’ clinical presentation and imaging findings, colonic adenocarcinoma with hepatic metastases was the favoured diagnosis and as such, she was induced immediately and delivered a healthy baby boy. Following delivery, staging CT revealed multiple bilateral pulmonary nodules consistent with metastases. Colonoscopy and biopsy of the colonic lesion confirmed invasive adenocarcinoma. Two weeks following colonoscopy, she proceeded to 11 cycles of FOLFOX with bevacizumab, followed by three cycles of 5-fluorouracil and bevacizumab. She was changed to FOLFIRI due to disease progression; however, she died 5 months later of fulminant liver failure.
Discussion This series examines five patients with sCRLM in pregnancy or post-partum treated at a single tertiary hospital. CRC is often detected late in pregnant and post-partum women, such that their presenting symptoms may be related to metastatic disease.7,11 This was certainly the case in the current series, with all five patients presenting with a palpable RUQ mass. Late diagnosis is likely related to the common symptoms associated with primary CRC, such as altered bowel habit, bleeding, fatigue and abdominal discomfort, being incorrectly attributed to the pregnancy. Several patients in this series reported symptoms likely resulting from their primary CRC such as rectal bleeding, weight loss, abdominal pain and diarrhoea during their routine antenatal and postnatal care, but were still diagnosed very late, with unresectable or borderline resectable metastatic disease. Abdominal pain, rectal bleeding in conjunction with haemorrhoids and altered bowel habit are frequently reported in pregnancy, but care should be taken in attributing these solely to pregnancy
Robson et al.
without careful examination at the very least including external inspection of the anus and digital rectal examination.7,12,13 Furthermore, weight loss remains an uncommon finding during pregnancy and its presence, in combination with the symptoms mentioned earlier, should lower the threshold for obtaining an endoscopic examination. Two of our patients reported weight loss in conjunction with altered bowel habit and rectal bleeding. Earlier detection could result in earlier and potentially curative intervention and thus increased likelihood of improved survival. Women are seen regularly by health practitioners throughout the term of their pregnancy, undergoing various screening tests and regular clinical review. Thus, there is an opportunity to identify high-risk patients reporting these symptoms who would warrant further investigation. The treatment of mCRC in pregnancy is challenging. These patients require local control of the primary lesion, regional management of the liver and systemic treatment with an early multidisciplinary decision made regarding treatment intent. Based on our small series and the reviewed literature, very few of these women will undergo surgical intervention and most will be managed with palliative intent. Several studies have shown improved long-term survival in pregnant or post-partum patients undergoing chemotherapy and R0 resection of non-mCRC.1,7 Standard chemotherapy, such as FOLFOX, used during the second or third trimester of pregnancy appears safe and the longterm growth and development milestones of children exposed to this chemotherapy regimen antenatally are comparable with children of the same age not exposed.1,14 The addition of biological therapies such as bevacizumab, cetuximab or panitumumab is not recommended during pregnancy due to the high risk of fetal loss.14 Considering the relatively modest survival gain of these agents in addition to standard chemotherapy, withholding their use until the post-partum period would not be expected to preclude treatment with curative intent. To our knowledge, there are currently no reports of liver resection for sCRLM during pregnancy and the oncological rationale for such an intervention seems limited. Surgical resection of primary CRC during pregnancy has been reported as safe in patients diagnosed prior to 20 weeks gestation.7 However, hepatic resection for sCRLM during pregnancy presents a potentially higher risk approach to both mother and unborn fetus if major complications occur. The hyperdynamic circulation of pregnancy may increase the risk of excessive bleeding during hepatic resection. During pregnancy, maternal plasma volume increases by 45–50%,15 cardiac output by 30–50%16,17 and hepatic and renal perfusion are also increased.18 A low central venous pressure (CVP) during hepatic resection, which is desirable to minimize bleeding during parenchymal transection,19 can be misleading due to dilated systemic and respiratory circulations during pregnancy.20 In fact, the CVP in the third trimester may be decreased due to compression of the inferior vena cava by the gravid uterus. A further consideration in the altered physiology of pregnancy is the impact of potential maternal haemorrhage during liver resection on placental blood flow and the fetus. As the uterine vasculature is dilated during pregnancy, there is minimal capacity to increase blood flow by reducing resistance.20,21 Thus during pregnancy, the control of placental blood flow is not by autoregulation, but will vary lin© 2015 Royal Australasian College of Surgeons
sCRLMs in pregnancy and post-partum
early with maternal systemic arterial pressure.22 Aggressive resuscitation is advocated for trauma resulting in haemorrhage during pregnancy to maintain uteroplacental perfusion and fetal oxygenation.23 These factors would likely prevent consideration of liver resection for sCRLM during pregnancy. One patient (case 3) presented with sCRLM at 14 weeks gestation and represented a rare case where surgical intervention with curative intent post delivery was feasible. Major open liver resection occurred 3 weeks post-partum, with the primary colonic malignancy laparoscopically resected 8 weeks post-partum. Both procedures had clear margins on histopathology. The rationale for this ‘liver first’ approach was to prevent progression of already borderline resectable liver disease becoming unresectable and precluding a curative approach. Several cohort studies have shown similar survival for selected patients with synchronous mCRC undergoing liver-first resection compared with the normal ‘primary first’ approach.24–27
Conclusion The prognosis of mCRC in pregnancy remains poor. Obstetric and neonatology input is vital when patients present during pregnancy and decide to continue with the pregnancy and an MDT approach is essential to optimize outcomes for both the patient and her unborn child. Antenatal chemotherapy and resection of the primary lesion can be performed safely, but surgical management of liver metastases should be delayed until the post-partum period. Treatment efforts should therefore be directed towards maximizing the possibility for these patients to receive curative management where possible while understanding that palliation is the likely outcome.
References 1. Jeppesen JB, Østerlind K. Successful twin pregnancy outcome after in utero exposure to FOLFOX for metastatic colon cancer: a case report and review of the literature. Clin. Colorectal Cancer 2011; 10: 348–52. 2. Vitoratos N, Salamalekis E, Makrakis E, Creatsas G. Sigmoid colon cancer during pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 2002; 104: 70–2. 3. Kanate AS, Auber ML, Higa GM. Priorities and uncertainties of administering chemotherapy in a pregnant woman with newly diagnosed colorectal cancer. J. Oncol. Pharm. Pract. 2009; 15: 5–8. 4. Dahling MT, Xing G, Cress R, Danielsen B, Smith LH. Pregnancyassociated colon and rectal cancer: perinatal and cancer outcomes. J. Matern. Fetal Neonatal Med. 2009; 22: 204–11. 5. Abramowitz L, Sobhani I, Benifla JL et al. Anal fissure and thrombosed external hemorrhoids before and after delivery. Dis. Colon Rectum 2002; 45: 650–5. 6. Khodaverdi S, Valeshabad AK, Khodaverdi M. A case of colorectal cancer during pregnancy: a brief review of the literature. Case Rep. Obstet. Gynecol. 2013; 2013: 626393. 7. Voulgaris E, Pentheroudakis G, Pavlidis N. Cancer and pregnancy: a comprehensive review. Surg. Oncol. 2011; 20: e175–85.
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8. Minter A, Malik R, Ledbetter L, Winokur TS, Hawn MT, Saif MW. Colon cancer in pregnancy. Cancer Control 2005; 12: 196–202. 9. Bernstein MA, Madoff RD, Caushaj PF. Colon and rectal cancer in pregnancy. Dis. Colon Rectum 1993; 36: 172–8. 10. Harris P, Nagy S, Vardaxis NJ. Mosby’s Dictionary of Medicine, Nursing and Health Professions. New South Wales: Elsevier Australia, 2009. 11. Saif MW. Management of colorectal cancer in pregnancy: a multimodality approach. Clin. Colorectal Cancer 2005; 5: 247–56. 12. De Jonge HJ, Oosterwijk PR, Meijssen M, Flierman A. [Rectal bleeding during pregnancy]. Ned. Tijdschr. Geneeskd 2014; 158: A6758. 13. Cappell MS, Colon VJ, Sidhom OA. A study at 10 medical centers of the safety and efficacy of 48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of fetal outcome and with comparison to control groups. Dig. Dis. Sci. 1996; 41: 2353–61. 14. Amant F, Han SN, Gziri MM, Dekrem J, Van Calsteren K. Chemotherapy during pregnancy. Curr. Opin. Oncol. 2012; 24: 580–6. 15. Clapp JF 3rd, Seaward BL, Sleamaker RH, Hiser J. Maternal physiologic adaptations to early human pregnancy. Am. J. Obstet. Gynecol. 1988; 159: 1456–60. 16. Clark SL, Cotton DB, Lee W et al. Central hemodynamic assessment of normal term pregnancy. Am. J. Obstet. Gynecol. 1989; 161 (6 Pt 1): 1439–42. 17. Easterling TR, Watts DH, Schmucker BC, Benedetti TJ. Measurement of cardiac output during pregnancy: validation of Doppler technique and clinical observations in preeclampsia. Obstet. Gynecol. 1987; 69: 845–50. 18. Davison JM, Hytten FE. The effect of pregnancy on the renal handling of glucose. Br. J. Obstet. Gynaecol. 1975; 82: 374–81. 19. Jones RM, Moulton CE, Hardy KJ. Central venous pressure and its effect on blood loss during liver resection. Br. J. Surg. 1998; 85: 1058– 60. 20. Assali NS, Brinkman CR. The uterine circulation and its control. In: Longo LD, Bartels H, (eds). Respiratory Gas Exchange and Blood Flow in the Placenta. Bethesda, MD: NIH, 1972; 121. 21. Pearlman MD, Tintinalli JE, Lorenz RP. Blunt trauma during pregnancy. N. Engl. J. Med. 1990; 323: 1609–13. 22. Thurlow JA, Kinsella SM. Intrauterine resuscitation: active management of fetal distress. Int. J. Obstet. Anesth. 2002; 11: 105–16. 23. Weinberg L, Steele RG, Pugh R, Higgins S, Herbert M, Story D. The pregnant trauma patient. Anaesth. Intensive Care 2005; 33: 167–80. 24. Brouquet A, Mortenson MM, Vauthey J-N et al. Surgical strategies for synchronous colorectal liver metastases in 156 consecutive patients: classic, combined or reverse strategy? J. Am. Coll. Surg. 2010; 210: 934–41. 25. Verhoef C, van der Pool AE, Nuyttens JJ, Planting AS, Eggermont AM, de Wilt JH. The ‘liver-first approach’ for patients with locally advanced rectal cancer and synchronous liver metastases. Dis. Colon Rectum 2009; 52: 23–30. 26. Mentha G, Roth AD, Terraz S et al. ‘Liver first’ approach in the treatment of colorectal cancer with synchronous liver metastases. Dig. Surg. 2008; 25: 430–5. 27. De Jong MC, van Dam RM, Maas M et al. The liver-first approach for synchronous colorectal liver metastasis: a 5-year single-centre experience. HPB (Oxford). 2011; 13: 745–52.
Synchronous colorectal liver metastases in pregnancy and post-partum Danielle E. Robson, Joel Lewin, Anthony W. Cheng, Nicholas A. O’Rourke and David J. Cavallucci Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia
Key words colorectal cancer, metastatic, pregnancy, post-partum. Correspondence Dr Danielle E. Robson, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, Queensland, Australia. Email: [email protected] D. E. Robson MBBS (Hons); J. Lewin MBBS; A. W. Cheng FRACS; N. A. O’Rourke FRACS; D. J. Cavallucci FRACS. Accepted for publication 25 April 2015. doi: 10.1111/ans.13196
Abstract Background: Metastatic colorectal cancer (mCRC) in pregnancy and post-partum is rare, but represents significant diagnostic and therapeutic challenges for clinicians. A multidisciplinary team (MDT) approach is essential. This study reports the first series in the Australasian literature, describing our experience with and management of pregnant and post-partum patients diagnosed with synchronous colorectal liver metastases (sCRLM). Method: A retrospective review of prospectively collected data for patients with sCRLM diagnosed during pregnancy or post-partum, presenting to a tertiary referral hospital between 2009 and 2014, was performed. Data regarding patient presentation, imaging, management, histopathology and survival were analysed. Patient characteristics and outcomes were reviewed, including age, presenting complaint and median survival. Results: Five patients were identified with sCRLM: three patients were diagnosed antepartum and two post-partum. Median age was 31 years (range 26–34). All patients were diagnosed with colorectal primary and synchronous liver lesions. All patients received folinic acid, fluorouracil, oxaliplatin chemotherapy, two intrapartum. One patient had both the primary lesion and liver metastases excised early post-partum. Second-line chemotherapy with folinic acid, fluorouracil, irinotecan and other biological agents was used in some cases post-partum. One patient suffered a fetal loss, while the other four had uncomplicated live births. Median survival was 7.6 months, with two patients dying shortly after delivery. Conclusion: The diagnosis of mCRC in pregnancy is challenging and survival is poor. A MDT approach to management is essential. Chemotherapy remains the mainstay of treatment from the second trimester. Rapid confirmation of diagnosis and early chemotherapy, followed by post-partum colorectal and liver resection may improve survival.
Introduction Cancer is diagnosed in approximately one in every 1000 pregnant women. Gynaecological cancers are most frequently observed, followed by melanoma.1 Metastatic colorectal cancer (mCRC) is rare, occurring in approximately 0.002% of pregnancies.1–3 However, epidemiological data indicate an increased incidence of colorectal cancer (CRC) diagnosed in pregnancy and post-partum of 26% over the last 10 years, due, at least in part, to more women falling pregnant at an advanced maternal age.1,4 Common presenting symptoms include abdominal pain or mass, constipation, nausea and vomiting, weight loss and rectal bleeding.2 Symptoms are often © 2015 Royal Australasian College of Surgeons
attributed to benign conditions associated with pregnancy, such as haemorrhoids or constipation, and may go under investigated.5 The low incidence of CRC in this age group and the symptomatic overlap with common conditions of pregnancy and the post-partum period mean that these cancers represent a significant diagnostic and therapeutic challenge and are commonly diagnosed late worsening their prognosis.6 These complex patients require multidisciplinary management including obstetric, neonatology, surgical, oncology, radiology and psychology input. To date, there are no studies reporting on the Australasian experience with these patients, and to our knowledge, there are no reports of liver resection for colorectal liver metastases (CLM) during ANZ J Surg •• (2015) ••–••
2
Robson et al.
Table 1 Metastatic colorectal cancer in pregnancy and post-partum Author
Study type
Jeppesen & Østerlind1 Kanate et al.3 Minter et al.7
Case Case Case Case
Bernstein et al.8
Retrospective survey study
series series series series
Number of patients 1 1 1 1 40 (6 Duke’s D)
Treatment modality
5-fluorouracil leucovorin oxaliplatin 5-fluorouracil leucovorin Oxaliplatin 5-fluorouracil leucovorin oxaliplatin bevacizumab Not reported
pregnancy and post-partum. Existing data addressing this unique cohort of patients is largely limited to case reports worldwide. Current literature indicates that the mainstay of treatment for these patients is predominantly chemotherapy, with minimal surgical intervention reported to date (Table 1).7,8 This is attributed to advanced stage of disease at time of diagnosis and rapid disease progression. There are case reports advocating the use of both chemotherapy and surgical resection of primary CRC as effective and safe treatment modalities during pregnancy and post-partum.7,8 Reported risks of active treatment during pregnancy include teratogenicity, intra-uterine fetal demise and placental abruption.3 Other studies suggest surgical and chemotherapy treatments as having acceptable morbidity and mortality risk for the unborn child while also improving maternal survival.1 This study reports five cases of synchronous primary CRC with liver metastases (sCRLM) diagnosed during pregnancy or postpartum, highlighting the importance of early investigation of symptomatic patients during pregnancy, as well as the role of chemotherapeutic, radiological and surgical interventions.
Recorded maternal survival
Fetal outcome
12 months 3 months 5 months 11 months
Live birth Live birth Live birth Termination of pregnancy Not reported
0% 5-year survival
Table 2 Overview of key words and MeSH terms Key words Colorectal cancer
Metastasis
Metastatic colorectal cancer Pregnancy Post-partum Delivery Diagnosis Management Chemotherapy Survival
MeSH terms ‘Colorectal Cancer’[MeSH Terms] OR ‘Colorectal Carcinoma’ [MeSH Terms] OR ‘Colorectal Neoplasm’ [MeSH Terms] OR ‘Colon Cancer’ [MeSH Terms] OR ‘Rectal Cancer’ [MeSH Terms] ‘Metastasis’ [MeSH Terms] OR ‘Neoplasm Metastasis’ [MeSH Terms] AND ‘Advanced Disease’ [Key Word] ‘Metastatic Colorectal Cancer’ [Key Word] AND ‘Synchronous Colorectal Liver Metastases’ ‘Pregnancy’ ‘[MeSH Terms]’ OR ‘Pregnant’ [MeSH Terms] ‘Postpartum’[MeSH Terms] AND ‘Post Delivery’ [Key Word] ‘Obstetric Delivery’ [MeSH Terms] ‘Diagnosis’ [Text Word] AND Screening [MeSH Term] ‘Management’ [Text Word] ‘Chemotherapy’ [MeSH Terms] ‘Survival’ [MeSH Terms]
Methods A retrospective review of a prospectively collected database at the Royal Brisbane and Women’s Hospital, Australia, was performed. All women diagnosed with sCRLM during pregnancy or postpartum between 2009 and 2014 were identified. Data pertaining to patient presentation, diagnostic and staging modalities, chemotherapy, surgical management and survival outcomes were analysed. A literature review on the topic was performed using Ovid MEDLINE, EMBASE, and Cochrane databases using a combination of keywords and MeSH terms (Table 2). When diagnosed, all patients with sCRLM were discussed at a multidisciplinary team (MDT) meeting, with radiology, gastroenterology, surgical, obstetric and oncology input to arrive at a consensus for optimal management. All patients underwent colonoscopy and biopsy of the primary lesion to confirm the diagnosis of CRC. Diagnosis of liver metastases was made with magnetic resonance imaging (MRI). If the patient was post-partum, MRI was performed using liver-specific contrast (Gd-EOB-DTPA, Primovist or Eovist, Bayer, Leverkusen, Germany) and extrahepatic metastatic disease identified with positron emission tomography.
Results Five cases of sCRLM during pregnancy or post-partum were identified between 2009 and 2014 (Table 3). The median age was 31
years and all patients were non-smokers. Three patients were diagnosed during pregnancy and the other two post-partum. The postpartum period was defined as 6 weeks post delivery date.10 The most common presenting complaint was a right upper quadrant (RUQ) mass, detectable in all five patients. After diagnosis, patients invariably reported a longer history of symptoms relating to the primary cancer, such as abdominal pain, weight loss and rectal bleeding. The number, size and location of liver metastases were variable between patients. Two patients had a single, large metastasis, with another patient having at least 30 small liver metastases identified on imaging. All patients were managed with chemotherapy. One patient underwent resection of her liver metastases and primary tumour post-partum (Table 4). Four patients had live births. One patient suffered an intra-uterine fetal death.
Case one A 34-year-old woman 1-day post spontaneous vaginal delivery was noted to have a large palpable mass in the RUQ and associated pain on inspiration. She reported a 2-week history of rectal bleeding and right-sided abdominal pain. She also reported significant nausea, vomiting, diarrhoea and unexplained weight loss throughout the pregnancy. Computed tomography (CT) imaging revealed an irregu© 2015 Royal Australasian College of Surgeons
sCRLMs in pregnancy and post-partum
3
lar large mass in the sigmoid colon and associated enlarged left common iliac node measuring 13 mm. CT also showed multiple large, bilobar liver lesions consistent with metastases. Tissue biopsies during colonoscopy confirmed adenocarcinoma in the sigmoid colon. She received a single cycle of folinic acid, fluorouracil, oxaliplatin (FOLFOX) chemotherapy before returning home overseas to continue treatment. Her disease quickly progressed and she died 37 days after diagnosis and 38 days after delivering a healthy baby.
Table 3 Patient characteristics and outcomes Median age Median CEA at diagnosis† Fetal outcome Live birth Intra-uterine death Presenting complaint‡ Palpable RUQ mass Epigastric pain RUQ abdominal pain Short of breath Fevers Nausea Vomiting Symptoms from primary‡ Rectal bleeding Abdominal pain Weight loss Diarrhoea Primary location (colon : rectum) Tumour grade Poorly differentiated Moderately differentiated Well differentiated Number of liver metastases 1 2–5 >5 Median size of the largest liver metastasis (cm) Presence of metastases > 5 cm diameter Median survival (months)§ Maternal deaths
31 (26–34) 4115 (24–8220) 4 1 5 2 2 1 1 1 1
Case two A 29-year-old woman was referred to hospital by her general practitioner (GP) after presenting with epigastric discomfort and a palpable mass in the RUQ extending below the umbilicus post-partum. She reported symptoms of abdominal pain, fatigue, nausea, vomiting and 15-kg weight loss during the last 2 months of her pregnancy. Rectal examination revealed a palpable mass with blood. Staging CT scan revealed extensive, bilobar metastatic disease of the liver as well as multiple lung metastases. Flexible sigmoidoscopy and biopsy confirmed a 4 cm fungating, non-obstructing rectal adenocarcinoma. She was commenced on folinic acid, fluorouracil, irinotecan (FOLFIRI) chemotherapy for 18 cycles until a progress CT scan revealed progression of liver metastases. She was then commenced on FOLFOX with a partial response based on declining carcinoembryonic antigen (CEA) level and reduced volume of liver disease on progress CT scan. Transarterial chemoembolization was performed to the liver metastases and the patient remains on chemotherapy at 30 months post diagnosis.
Case three
2 1 1 2 4:1 1 3 1 2 2 1 8.1 (7.00–22.7) 3 7.6 (1.2–30.0) 2
†Carcinoembryonic antigen level was not recorded in one patient. ‡Individual patients could have multiple presenting complaints or symptoms from the primary. §Median survival was calculated from the time of diagnosis to the time of most recent follow-up. CEA, carcinoembryonic antigen; RUQ, right upper quadrant.
A 34-year-old woman presented to her GP at 14 weeks gestation complaining of recurrent RUQ pain and palpable mass for several months. Outpatient ultrasound revealed a large hepatic mass and subsequent MRI confirmed bilobar liver disease. Colonoscopy showed a partially obstructing rectosigmoid tumour with biopsy confirming the diagnosis of adenocarcinoma. Following investigations, she underwent six cycles of FOLFOX chemotherapy. She delivered a healthy baby at 34 weeks gestation by induced spontaneous vaginal delivery. Restaging CT scan immediately post delivery showed bilobar liver metastases, predominantly in the left lobe, the largest of which had increased in size to 9.5 × 14 × 9 cm. She had no extrahepatic metastatic disease. A week later she underwent a successful open extended left hepatectomy, with histopathology confirming mCRC with clear margins. She was discharged without complication and underwent three more cycles of adjuvant chemotherapy before undergoing successful R0 resection of the primary via laparoscopic high anterior resection 6 weeks later. As the patient was deemed high risk for recurrence, a further course of chemotherapy after the primary resection was recommended by oncology. She currently remains disease free on adjuvant chemotherapy.
Table 4 Management of metastatic colorectal cancer in pregnancy and post-partum Case
1 2
Chemotherapy agent
Trimester agent given
Surgical intervention
Maternal outcome
Deceased Alive with disease
Live birth Live birth
38 days 30 months
Alive with disease
Live birth
8 months
Alive with disease
5 months
Deceased
Intra-uterine death Live birth
Post delivery Post delivery
3
FOLFOX FOLFIRI FOLFOX FOLFOX
4
FOLFOX
2, post delivery
Nil Transarterial chemoembolization Open extended left hepatectomy and R0 excision of primary Nil
5
FOLFOX + Bevacizumab, FOLFIRI
Post delivery
Nil
2, 3, post delivery
FOLFIRI, folinic acid, fluorouracil, irinotecan; FOLFOX, folinic acid, fluorouracil, oxaliplatin.
© 2015 Royal Australasian College of Surgeons
Fetal outcome
Follow-up
5 months
4
Case four A 26-year-old woman presented to a regional hospital at 19 weeks gestation, reporting RUQ pain, shortness of breath and fevers on a background of 6 weeks of bloody diarrhoea. An enlarged palpable liver was noted on examination with CT scan revealing large, bilobar intrahepatic lesions, the largest in segment six measuring 7.3 × 7.0 × 8.4 cm. No extrahepatic disease was detected on CT. Colonoscopy revealed a 60 mm fungating, partially obstructing tumour in the descending colon, with multiple surrounding polyps. She was positive for familial adenomatous polyposis. The patient commenced on FOLFOX chemotherapy 2 weeks after diagnosis, with her liver metastases deemed unresectable. She responded well to chemotherapy as demonstrated by a declining CEA level. However, she suffered an intra-uterine fetal loss at 33 weeks. She continued to respond to chemotherapy post delivery (restaging CT showed a reduction in liver metastases) and is currently alive with disease over 5 months post diagnosis.
Case five A 31-year-old woman presented at 37 weeks gestation with a palpable RUQ mass, nausea and epigastric pain. Abdominal ultrasound showed multiple, hypoechoic hepatic nodules up to 2.5 cm in diameter. MRI demonstrated thickening of the sigmoid colon and associated lymphadenopathy and multiple hepatic lesions consistent with metastases. Given the patients’ clinical presentation and imaging findings, colonic adenocarcinoma with hepatic metastases was the favoured diagnosis and as such, she was induced immediately and delivered a healthy baby boy. Following delivery, staging CT revealed multiple bilateral pulmonary nodules consistent with metastases. Colonoscopy and biopsy of the colonic lesion confirmed invasive adenocarcinoma. Two weeks following colonoscopy, she proceeded to 11 cycles of FOLFOX with bevacizumab, followed by three cycles of 5-fluorouracil and bevacizumab. She was changed to FOLFIRI due to disease progression; however, she died 5 months later of fulminant liver failure.
Discussion This series examines five patients with sCRLM in pregnancy or post-partum treated at a single tertiary hospital. CRC is often detected late in pregnant and post-partum women, such that their presenting symptoms may be related to metastatic disease.7,11 This was certainly the case in the current series, with all five patients presenting with a palpable RUQ mass. Late diagnosis is likely related to the common symptoms associated with primary CRC, such as altered bowel habit, bleeding, fatigue and abdominal discomfort, being incorrectly attributed to the pregnancy. Several patients in this series reported symptoms likely resulting from their primary CRC such as rectal bleeding, weight loss, abdominal pain and diarrhoea during their routine antenatal and postnatal care, but were still diagnosed very late, with unresectable or borderline resectable metastatic disease. Abdominal pain, rectal bleeding in conjunction with haemorrhoids and altered bowel habit are frequently reported in pregnancy, but care should be taken in attributing these solely to pregnancy
Robson et al.
without careful examination at the very least including external inspection of the anus and digital rectal examination.7,12,13 Furthermore, weight loss remains an uncommon finding during pregnancy and its presence, in combination with the symptoms mentioned earlier, should lower the threshold for obtaining an endoscopic examination. Two of our patients reported weight loss in conjunction with altered bowel habit and rectal bleeding. Earlier detection could result in earlier and potentially curative intervention and thus increased likelihood of improved survival. Women are seen regularly by health practitioners throughout the term of their pregnancy, undergoing various screening tests and regular clinical review. Thus, there is an opportunity to identify high-risk patients reporting these symptoms who would warrant further investigation. The treatment of mCRC in pregnancy is challenging. These patients require local control of the primary lesion, regional management of the liver and systemic treatment with an early multidisciplinary decision made regarding treatment intent. Based on our small series and the reviewed literature, very few of these women will undergo surgical intervention and most will be managed with palliative intent. Several studies have shown improved long-term survival in pregnant or post-partum patients undergoing chemotherapy and R0 resection of non-mCRC.1,7 Standard chemotherapy, such as FOLFOX, used during the second or third trimester of pregnancy appears safe and the longterm growth and development milestones of children exposed to this chemotherapy regimen antenatally are comparable with children of the same age not exposed.1,14 The addition of biological therapies such as bevacizumab, cetuximab or panitumumab is not recommended during pregnancy due to the high risk of fetal loss.14 Considering the relatively modest survival gain of these agents in addition to standard chemotherapy, withholding their use until the post-partum period would not be expected to preclude treatment with curative intent. To our knowledge, there are currently no reports of liver resection for sCRLM during pregnancy and the oncological rationale for such an intervention seems limited. Surgical resection of primary CRC during pregnancy has been reported as safe in patients diagnosed prior to 20 weeks gestation.7 However, hepatic resection for sCRLM during pregnancy presents a potentially higher risk approach to both mother and unborn fetus if major complications occur. The hyperdynamic circulation of pregnancy may increase the risk of excessive bleeding during hepatic resection. During pregnancy, maternal plasma volume increases by 45–50%,15 cardiac output by 30–50%16,17 and hepatic and renal perfusion are also increased.18 A low central venous pressure (CVP) during hepatic resection, which is desirable to minimize bleeding during parenchymal transection,19 can be misleading due to dilated systemic and respiratory circulations during pregnancy.20 In fact, the CVP in the third trimester may be decreased due to compression of the inferior vena cava by the gravid uterus. A further consideration in the altered physiology of pregnancy is the impact of potential maternal haemorrhage during liver resection on placental blood flow and the fetus. As the uterine vasculature is dilated during pregnancy, there is minimal capacity to increase blood flow by reducing resistance.20,21 Thus during pregnancy, the control of placental blood flow is not by autoregulation, but will vary lin© 2015 Royal Australasian College of Surgeons
sCRLMs in pregnancy and post-partum
early with maternal systemic arterial pressure.22 Aggressive resuscitation is advocated for trauma resulting in haemorrhage during pregnancy to maintain uteroplacental perfusion and fetal oxygenation.23 These factors would likely prevent consideration of liver resection for sCRLM during pregnancy. One patient (case 3) presented with sCRLM at 14 weeks gestation and represented a rare case where surgical intervention with curative intent post delivery was feasible. Major open liver resection occurred 3 weeks post-partum, with the primary colonic malignancy laparoscopically resected 8 weeks post-partum. Both procedures had clear margins on histopathology. The rationale for this ‘liver first’ approach was to prevent progression of already borderline resectable liver disease becoming unresectable and precluding a curative approach. Several cohort studies have shown similar survival for selected patients with synchronous mCRC undergoing liver-first resection compared with the normal ‘primary first’ approach.24–27
Conclusion The prognosis of mCRC in pregnancy remains poor. Obstetric and neonatology input is vital when patients present during pregnancy and decide to continue with the pregnancy and an MDT approach is essential to optimize outcomes for both the patient and her unborn child. Antenatal chemotherapy and resection of the primary lesion can be performed safely, but surgical management of liver metastases should be delayed until the post-partum period. Treatment efforts should therefore be directed towards maximizing the possibility for these patients to receive curative management where possible while understanding that palliation is the likely outcome.
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