Outcomes of gynecological and breast cancer among female patients with cirrhosis: Scoping review of the literature

Abstract

Background:

The incidence of gynecological and breast cancers is on the rise in addition to a rise in the incidence of cirrhosis among women. Women with cirrhosis are generally excluded from clinical trials therefore little is known about the oncologic and/or liver-related outcomes in this population. The aim of this study was to review the current literature regarding treatment and survival outcomes in females with gynecological or breast cancer with underlying cirrhosis.

Methods:

An electronic search was conducted for studies reporting outcomes among females with cirrhosis and gynecological and breast cancer. References were reviewed for relevant publications. Studies were reviewed and data were extracted from publications.

Results:

Three thousand one hundred ninety one articles were identified, and five studies were reviewed in full. Thirty unique patients were identified. Ten patients with breast cancer were identified, 9/10 patients did not have cancer recurrence in the follow-up period, and 1/10 did not have follow up. 1/10 patient's received chemotherapy and developed degree II abnormal liver function and bone marrow suppression. 2/9 patients experienced postoperative complications, one had worsening thrombocytopenia and one developed mild encephalopathy. Nienteen patients with ovarian cancer all received surgery and chemotherapy. 10/19 had postoperative complications and 1/19 died in follow-up period. One patient had a neuroendocrine uterine cancer stage IV who died after one cycle of chemotherapy.

Conclusion:

There is limited data on the outcomes and management of patients with both cirrhosis and gynecological or breast cancers. Therefore, further work is necessary to address these gaps in clinical practice to improve patient care.

Plain language summary

Lay Summary: There is an increase in both cirrhosis and gynecological and breast cancer. However, there are scarce reports on survival outcomes and treatment in these patients. We completed a review of the literature and found very limited information on this topic. Given that there is limited data available on the topic, we were unable to draw any meaningful conclusions. In the small cohort we demonstrated that patients with either Child Pugh Class A or B cirrhosis with Stage I or II cancer had favorable outcomes in regard to cancer recurrence. Therefore, large scale studies are needed to generate robust data for this population.

Introduction

Gynecological and breast cancers continue to have high incidence and mortality rates among Canadian female patients. In Canada, it is estimated that breast cancer will comprise 25% of newly diagnosed cancers annually for females, with uterus cancer accounting for 7.2%, ovarian cancer for 2.7%, and cervical cancer for 1.3% (1). Many of these patients often have underlying comorbidities and given the increase in the prevalence of cirrhosis especially among post-menopausal women, there is now increased focus on defining the outcomes of women with cirrhosis and various cancers (2,3). The number of women with cirrhosis is increasing due to metabolic dysfunction associated steatotoic liver disease (MASLD) and alcoholic associated liver disease (ALD) (4). While the mechanism is not completely understood, patients with cirrhosis may be at an increased risk of developing gynecological and breast cancers due to the association with estrogen levels (5,6). Unfortunately, patients with cirrhosis are often excluded from clinical trials due to safety concerns, interaction with medications, variable heterogeneity amongst patient with cirrhosis, and altered pharmacokinetics (7, 8, 9). Therefore, clinical guidelines may not apply to this population and hence there is no evidence to base decisions on for managing these patients with concurrent cancers. In particular, cirrhosis presents with unique challenges in diagnosing and treating cancers. For instance, early detection of cancers may be missed due to overlapping symptoms of cirrhosis including abdominal pain and bloating (8). Furthermore, achieving curative intent requires surgical resection. However, individuals with cirrhosis experience higher postoperative complications and surgical risks (9). Also, the existing surgical risk stratification tools are derived from the Department of Veteran's Affair database, which do not take into account female-specific diseases (10). In addition, chemotherapy is the mainstay treatment for cancer, yet there is an increased risk of drug toxicity that can worsen underlying cirrhosis (8). With worsening hepatic function, there are increased mortality and complication rates. As such, there remains a need to address these gaps in clinical practice to optimize the care we provide to females with gynecological cancer and breast cancer with underlying cirrhosis.

Current studies recommend considering treatment in those with Child-Pugh A or B and early-stage cancers in various cancers (11). As a result, we conducted a scoping review to describe the epidemiology, management, and survival outcomes in females with gynecological or breast cancer with underlying cirrhosis.

Methods

Search strategy/Study selection

A scoping review was completed and followed Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. An electronic search of PubMed (1974–present), MEDLINE (1946–present), EMBASE (1974–present),

EBM Reviews–Cochrane Central Register of Controlled Trials (1946–present) and EBM Reviews–Cochrane Database of Systematic Reviews (2005–present) were conducted for studies reporting cirrhosis and treatment in female specific cancers.

The medical subject headings (MeSH) searched include, “cirrhosis” combined with “breast cancer” OR “cervical cancer” OR “uterine cancer” OR “ovarian cancer” OR “vaginal cancer” OR “vulvar cancer” OR “gestational trophoblastic disease” AND “surgery” OR “treatment” OR “management.” From these initially selected articles, the references were analyzed to identify additional relevant articles. Studies were included if the following criteria were met: (1) studies evaluating patients with either gynecological cancers or breast cancer with underlying cirrhosis, (2) studies reporting treatment, management, and surgical outcomes, (3) females, and (4) studies published in English. Exclusion criteria included patients less than age 18, males, and articles not in English. Those that met the criteria were reviewed in full.

Data collection and analysis

A single investigator (MJ) extracted and tabulated the following data: (1) age at cancer diagnosis, (2) details of the underlying liver disease (Child Pugh Turcotte scores (CPT)/Model for End-stage Liver Disease – Sodium (Meld-Na)), decompensation of cirrhosis (ascites, encephalopathy, variceal bleed, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome), etiology of cirrhosis (hepatitis B/C, ALD, MASLD, genetic, autoimmune, and biliary disorder) diagnosed in medical record, patients listed for transplant, (3) type of cancer (site, stage, histology), (4) surgical and/or medical treatment of cancer, (5) complications of treatment and recurrence of cancer.

Results

The search strategy identified 3191 articles, of these, five studies were selected for data extraction (12, 13, 14, 15, 16). Studies were excluded as per exclusion criteria described under search strategy/study selection in the methods. See Figure 1 for search study.

Figure 1: PRISMA flow diagram for literature search.

See Table 1 for the included study characteristics. Of these five studies, three were case reports, one was a single centre prospective study in Mansura, Egypt from 2011 to 2013, and one was a single centre retrospective study in California, United States from 2013 to 2019. Three studies focused exclusively on breast cancer, one on ovarian cancer and one on uterine cancer. A total of 30 unique patients were identified. Of these 30 patients, the etiology of cirrhosis was chronic hepatitis C in 19/30, alcohol use in 2/30, Wilson's disease in 1/30, and unknown in 8/30. The median age for patients with ovarian cancer was 58 years and for those with breast cancer was 59 years. Additionally, there was one patient aged 49 with uterine cancer. Other demographics were not available for patients.

Table 1:

Outcomes from included studies of gynecological and breast cancer in patients with cirrhosis

Studies	Study type	Demographics	Cirrhosis history	Cancer history	Treatment	Complications	Follow up
Veluvolu et al. (12)	Case report	57-year-old female	Etiology: secondary to alcohol use Complications: abdominal ascites, oesophageal varices, portal hypertension, mild splenomegaly, body wall oedema, low blood pressure, elevated INR and scleral icterus	Stage IIA (cT2, cN0, cM0, G2, ER: Positive, PR: Negative, HER2: Negative), left breast cancer (3.4 cm mass)	Prescription dose was 25 Gy in a single fraction on a linear accelerator targeting the PTV. Following month started endocrine therapy with goserelin, as a 3.6 mg subcutaneous injection given every 28 days. Started on 1 mg anastrozole PO daily a couple of weeks later	Thickening and pruritis of the skin over the treated region noticed two months following SABR. Palbociclib 125 mg added to treatment 21 days	Mammography and ultrasound at 7 months post SABR showed no discrete mass in the area of concern. No clinical or radiographic evidence of recurrence
Sinescu et al. (13)	Case report	49-year-old female	Etiology: secondary to alcohol use	Small cell neuroendocrine tumor, expanded on all the layers of the uterus wall, invasion of annexes, metastases both lungs, hepatic, rib and peritoneal carcinomatoses	One standard dose of chemotherapy	N/A	Low compliance to the indicated therapy and died 1 month after one dose of chemotherapy
Li et al. (14)	Case report	40-year-old female	Etiology: secondary to Wilson's Disease Treated with sodium dimercaptosulphonate decoppering. In 2003, received a splenectomy due to splenomegaly and hypersplenism	Stage IIa (pT2N0M0 triple negative), left breast cancer, (2.0 × 1.5 cm)	Mastectomy and six cycles of Paclitaxel after operation (80 mg m−2 weekly)	Degree II abnormal liver function and degree I to II bone marrow suppression	N/A
Refky et al. (15)	Single centre prospective study	19 patients - median age 58 years old	Etiology: Chronic Hepatitis C, Child Pugh Class A	Stage I – 9/19, Stage II – 5/19, Stage III – 5/19, Stage IV – 0/19. Serous – 17/19, Mucinous – 1/19, Clear Cell – 1/19 G1 – 5/19, G2 – 3/19, G3 – 11/19 R0 – 14/19, R1 and or R2 –5/19	All the patients underwent primary debulking surgery followed by six cycles of chemotherapy	Intraoperative bleeding mean: 463 mL Urological complications – 1/19, Vascular complications – 2/19, Visceral organs resection – 4/19, Length of stay in ICU median – 4 days, GIT fistula or leakage – 1/19, Wound complications –1/19, Lymphorrhea – 0/19, Thrombo-embolic events – 1/19	1/19 discontinued chemo due to intolerance, 2/19 recurrence of cancer, 1/19 death Disease-free survival was 19.9–26.7 months Overall survival was 21.6–25.7 months
Olimpiadi et al. (16)	Single Centre Retrospective Study	1: 67 year old 2: 65 year old 3: 68 year old 4: 60 year old 5: 58 year old 6: 57 year old 7: 47 year old 8: 64 year old	1. MELD-Na 16 at diagnosis, Child Pugh at diagnosis A, MELD- Na after surgery 24, Child Pugh before surgery: A, Transplanted 2: MELD-Na 23 at diagnosis, Child Pugh at diagnosis B, MELD- Na after surgery 18, Child Pugh before surgery: B, Listed for transplant 3: MELD-Na 19 at diagnosis, Child Pugh at diagnosis B, MELD- Na after surgery 23, Child Pugh before	1: IDCA, DCIS, cT1N0M0 (IA), ypT0N0M0 (0), ER 80, PR 100, HER2 0 2: IDCA, DCIS, cT2N0M0 (HA), PT2N0M0 (HA), ER 100, PR 80, HER2 0 3: IDCA, DCIS, cT1N0M0 (IA), pT1bN0M0 (IA), ER 100, PR 100, HER2 0 4: DCIS, cTisN0M0 (0), pTisN0M0 (0), ER 100, PR 98, HER 2 N/A	1: R total mastectomy, R SLNB, aromatase inhibitor, 2: R wire localized segmental mastectomy, R SLNB, aromatase inhibitor, XRT 3: R wire localized segmental mastectomy, R SLNB, aromatase inhibitor, XRT 4: L wire localized segmental mastectomy, aromatase inhibitor	1. None 2. None 3. None 4. None 5. None 6. Encephalopathy 7. None 8. Tachycardia, low platelet count (46), platelet transfusion	1. Alive, no recurrence 2. Alive, no recurrence 3. Alive, no recurrence 4. Alive, no recurrence 5. Alive, no recurrence 6. Not Alive, no recurrence 7. Alive, no recurrence 8. Alive, no recurrence
			surgery: C, Transplanted 4: MELD-Na 7 at diagnosis, Child Pugh at diagnosis A, MELD- Na after surgery 6, Child Pugh before surgery: A, Not listed for transplant 5: MELD-Na 16 at diagnosis, Child Pugh at diagnosis B, MELD-Na after surgery unknown, Child Pugh before surgery: unknown, Not listed for transplant 6: MELD-Na 21 at diagnosis, Child Pugh at diagnosis B, MELD- Na after surgery 23, Child Pugh before surgery: C, Passed away before getting listed 7: MELD-Na 11 at diagnosis, Child Pugh at diagnosis A, MELD- Na after surgery 9, Child Pugh before surgery: A, Not listed for transplant 8: MELD-Na 14 at diagnosis, Child Pugh at diagnosis A, MELD-Na after surgery 15, Child Pugh before surgery: A, Not listed for transplant	5: ILCA, cT1N0M0 (IA), pT1cN0(i+)M0 (IA), ER 99, PR 50, HER2 0 6: IDCA, DCIS, cT1N0M0 (IA), pT1cN0M0 (IA), ER 100, PR 98, HER2 0 7: ILCA, cT1N0M0 (IA), pT1cN0M0 (IA), ER 100, PR 100, HER2 0 8: DCIS, cTisN0M0 (0), pTisN0M0 (0), ER 95, PR 90, HER2 N/A	5: R wire localized segmental mastectomy, R SLNB, aromatase inhibitor, XRT 6: L total mastectomy, L SLNB, aromatase inhibitor 7: L wire localized segmental mastectomy, L SLNB, Tamoxifen, XRT 8: R wire localized segmental mastectomy, aromatase inhibitor, XRT

Of the 10 patients with breast cancer, 4 were Child Pugh A, 4 were Child Pugh B, and 2 were unknown. Breast cancer staging was determined as stage 0 in 3/10 patients, stage I in 4/10 patients, and stage II in 3/10 patients. We identified that 9/10 patients received surgery, 7/10 received endocrine therapy, 6/10 received radiation in addition to surgery and/or endocrine therapy, and 1/10 received chemotherapy in addition to surgery. Furthermore, 1/10 patients had no recurrence at 7 months, 8/10 patients had no recurrence at median 30.5 months, and follow up was not documented in one patient. The patient who underwent chemotherapy developed degree II abnormal liver function and degree I to II bone marrow suppression. In addition, 2/9 patients experienced postoperative complications, one developed worsening thrombocytopenia and tachycardia and the second patient developed mild encephalopathy, both of which resolved. During the study period of 30.5 months, two patients underwent liver transplantation, one at 7.5 months and another at 18.9 months post breast cancer surgery. There was one patient death due to worsening hepatic decompensation, however, this was greater than 6 months after breast surgery.

There was one case report on neuroendocrine uterine cancer in a patient with cirrhosis. This patient had Stage IV cancer and due to low adherence to therapy, only received one cycle of chemotherapy and died 1 month later.

Ovarian cancer among females with cirrhosis was evaluated in one prospective study of 19 patients. All patients in this study had chronic hepatitis C and had Child-Pugh A disease. Of the 19 patients, 9 had stage I, 5 stage II, and 5 stage III. All patients underwent debulking surgery and received six cycles of chemotherapy. During surgical admission, 1/19 patients had urological complications, 2/19 had vascular complications, 4/19 had visceral organ resection, 1/19 had gastrointestinal fistula or leakage, 1/19 had wound complications, and 1/19 had a thrombo-embolic event. The median length of ICU admission was 4 days. At the long-term follow-up at 24 months, 1/19 had to discontinue chemotherapy due to intolerance, 2/19 had recurrence of cancer, and 1/19 died.

Discussion

Our results demonstrate that there is limited data on management and outcomes of females with underlying cirrhosis who have associated gynecological or breast cancer. From the small sample size, we determined that most patients with either Child Pugh Class A or B cirrhosis with Stage I or II cancer had favourable outcomes in regard to cancer recurrence. We also observed complications in a small cohort of patients with uterine cancer and the majority of complications occurred during the surgical admission. In terms of surgical complications, these were similar in patients with and without cirrhosis undergoing treatment for ovarian cancer. However, it's important to note that other studies lacked a comparison group for meaningful analysis. Among patients with breast cancer, one patient experienced thrombocytopenia and another had mild hepatic encephalopathy during surgical admission. In terms of patient deaths, one patient died 6 months post surgery due to worsening hepatic decompensation without liver transplant available.

These results are consistent with previous studies investigating the association between cirrhosis and colon or lung cancer. In particular, these studies showed that patients with CTP A responded well to treatment of their underlying cancer (17,18). Unfortunately, despite the growing prevalence of female cancers, females with breast and gynecological cancer have largely been under investigated in this context.

While we acknowledge the importance of expanding the literature on this subject, there were limitations to our study. Specifically, our results were mainly from studies on breast cancer, with limited data on ovarian and uterine cancers. In addition, the majority of studies extracted were case reports, which lack high-quality evidence to make informed clinical conclusions. Our search strategy also did not find any articles specific to cervical cancer, vaginal, or gestational trophoblastic neoplasia. Furthermore, only one study had a comparison group, therefore it was challenging to draw meaningful conclusions.

Our scoping review is critical in identifying gaps in our knowledge regarding the treatment of gynecological and breast cancers in females with underlying cirrhosis. As a result, we intend to address these gaps through future research in this area, with the aim of generating more robust data to inform the management of these types of cancers.

Funding Statement

N/A

Contributions:

Conceptualization, M Jogendran and JA Flemming; Methodology, M Jogendran and JA Flemming; Investigation, M Jogendran and JAF; Writing – Original Draft, M Jogendran; Writing – Review & Editing, JA Flemming; Supervision, JA Flemming.

Ethics Approval:

N/A

Informed Consent:

N/A

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

Data generated and analyzed during this study are available in published study.

Funding:

N/A

Disclosures:

N/A

Peer Review:

N/A

Animal Studies:

N/A