The Lynx Group

Exploring Gender-Based Differences in the Incidence, Diagnosis, and Treatment of Cholangiocarcinoma

October 2020, Vol 11, No 5

Cholangiocarcinoma (CCA) is a rare type of cancer that arises from the intrahepatic or extrahepatic biliary ductal epithelium, accounting for approximately 10% to 15% of all primary hepatic malignancies.1,2 CCA is classified as intrahepatic or extrahepatic CCA. In the United States, the incidence of CCA has been rising consistently since 1973.2

Recently, increased emphasis has been placed on understanding potential differences between men and women in the diagnosis, treatment, and outcomes of all diseases, including cancer. The incidence of CCA is higher among men compared with women, with an increased disparity observed with increasing age.3 Based on an updated analysis of data from the 2000 to 2011 Surveillance, Epidemiology, and End Results (SEER) registry, the annual incidence of patients with intrahepatic CCA aged ≥80 years was 9.8 per 100,000 persons among men compared with 6.9 per 100,000 persons among women; during that period, the incidence of extrahepatic CCA was 10.4 per 100,000 persons among men compared with 7.0 per 100,000 persons per year among women.3

The increasing incidence of CCA in the United States was most evident in Asian patients aged ≥80 years, with an intrahepatic CCA incidence of 13.8 per 100,000 persons per year versus 7.2 per 100,000 persons per year in non-Hispanic white patients. The extrahepatic CCA incidence was 12.9 per 100,000 persons per year in Asian patients compared with 7.6 per 100,000 persons per year in non-Hispanic whites.3

Diagnosis, Treatment, and Patient Outcomes

In 2014, the Cholangiocarcinoma Foundation created the International Cholangiocarcinoma Patient Registry (ICPR), which is designed to collect relevant clinical and scientific information, including next-generation sequencing data, from patients with CCA. Findings from this database include an increased incidence of intrahepatic CCA, a history of other cancers, a history of diabetes, and exposure to toxins or chemicals among women diagnosed with CCA compared with men.4 Women had a lower incidence of ductal or perihilar CCA and were less likely to have a history of smoking or heavy alcohol consumption. Furthermore, compared with men, women were more likely to be diagnosed with stage II/IIIA disease and less likely to be diagnosed with stage I, stage IIIB, or stage IIIC disease.4

In patients with intrahepatic CCA, the use of portal lymphadenectomy is encouraged for staging purposes. A study of 152 patients with CCA revealed that tumor grade, male sex, and age >60 years were all significantly associated with high rates of lymph node metastases, which are predictive of decreased overall survival (OS).5

In an interview with Value-Based Cancer Care, Imane El Dika, MD, Assistant Attending Physician, Memorial Sloan Kettering Cancer Center, New York, NY, and Angela Lamarca, MD, PhD, MSc, Consultant, Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom, provided expert commentary regarding the diagnosis and treatment of patients with CCA.

Data from the ICPR revealed that women are more likely to undergo next-generation sequencing testing, and to test positive for alterations in TP53, IDH1, and KRAS, compared with men.4

In individuals with CCA, the only potentially curative treatment is complete surgical resection, but only approximately 30% of patients are diagnosed with resectable tumors,4 leaving 70% of patients who require alternative treatment options.

The ICPR data show that women are more likely than men to receive treatment with platinum-based therapy, such as the XELOX or CAPOX regimen (intravenous oxaliplatin and oral capecitabine) regimen, fluorodeoxyuridine, and HER2-directed therapy.4 In addition, women were less likely than men to undergo surgical resection and to receive treatment with vascular endothelial growth factor inhibitors or with tyrosine kinase inhibitors.4

For patients with advanced biliary cancer, the standard of care is systemic chemotherapy with gemcitabine plus cisplatin.6 Results from the phase 3, randomized ABC-02 clinical trial demonstrated a significantly longer median OS with gemcitabine plus cisplatin compared with gemcitabine alone (11.7 months vs 8.1 months, respectively; P <.001). In the adjuvant setting, results from the randomized, controlled, multicenter, phase 3 BILCAP clinical trial, which included patients with intrahepatic CCA, demonstrated an increased median OS with capecitabine versus observation (51 months vs 36 months, respectively).7

Notably, adjustments for sex were taken into consideration in the sensitivity analyses, suggesting a potential influence of sex on these findings.7 In this study, only 29% of the patients were women, who had better OS and relapse-free survival compared with men.7

The results of the Bile Duct Cancer Adjuvant Trial, which included patients with extrahepatic CCA, did not demonstrate survival differences between those who received gemcitabine adjuvant chemotherapy and those who were managed with observation only.8

The results of the PRODIGE 12-ACCORD 18-UNICANCER GI clinical trial also did not demonstrate a survival benefit with adjuvant gemcitabine plus oxaliplatin compared with observation only.9 In this study, the ratio of men to women was 60% to 40%, respectively.9

The results of the multicenter, open-label, phase 2 clinical trial, which was designed to evaluate the efficacy of the XELOX regimen as second-line therapy for patients with advanced intrahepatic or extrahepatic CCA, or gallbladder cancer that did not respond to first-line treatment with gemcitabine plus cisplatin, demonstrated the tolerability of the XELOX regimen.10 In this study, only 38% of the patients were women. The most frequently reported adverse events were grade 1 or 2, with thrombocytopenia and neuropathy having the highest incidence. The disease control rate was 52%; the overall response rate (ORR) was 14%.10

The CAPOX regimen was found to be well-tolerated and active among patients with advanced extrahepatic CCA and gallbladder carcinoma, but less so among those with intrahepatic CCA.11 A prospective, multicenter, phase 2 clinical trial was conducted that included 27 men and 39 women, with more women than men having gallbladder cancer (67% vs 33%, respectively) and slightly more women than men having intrahepatic CCA (56% vs 44%, respectively). Among patients with intrahepatic CCA, 33% had stable disease. The response rate was 27% in patients with extrahepatic CCA or gallbladder carcinoma, with 49% having stable disease.11

The median OS was 16.8 months among patients with extrahepatic CCA and 5.2 months among those with intrahepatic CCA.11 The most frequently reported grade 3 or 4 adverse event was peripheral sensory neuropathy. At least 1 treatment cycle was delayed because of oxaliplatin- and/or capecitabine-related adverse events, resulting in oxaliplatin dose reductions in 30.8% of patients and capecitabine dose reductions in 46.2% of patients.11

Among patients with unresectable intrahepatic CCA, hepatic arterial infusion of floxuridine plus systemic gemcitabine and oxaliplatin contributed to a median progression-free survival (PFS) of 11.8 months, with a 6-month PFS rate of 84.1%.12 This single-arm, phase 2 clinical trial included more women than men (66% vs 34%, respectively). Overall, 58% of patients achieved a partial radiographic response and 84% achieved disease control at 6 months.12 Grade 4 adverse events necessitating withdrawal from the study included portal hypertension, gastroduodenal artery aneurysms, and infection in the pump pocket.12

Results from a retrospective analysis of data from 9 patients with advanced gallbladder cancer, including 7 women who had HER2-neu gene overexpression or amplification, demonstrated partial or complete responses in 5 patients who received trastuzumab therapy (a HER2-targeted therapy).13 The duration of response varied from ≥8 to 168 weeks (median, 40 weeks), and 3 patients are still receiving therapy.13 Other HER2-directed therapies included lapatinib and pertuzumab. One patient who received lapatinib had a mixed response; this patient had a HER2/neu mutation V777L.13 No responses were reported in 5 patients (all men) with CCA after HER2-targeted therapy.13 These findings suggest that women with CCA may respond better than men to HER2-targeted therapy, but additional studies are warranted.

Among 4 patients with CCA and mismatch repair-deficient (dMMR) tumors, pembrolizumab, an anti–programmed-cell death 1 (PD-1) antibody, contributed to 1 complete response and 3 patients with stable disease.14 Based on these findings, pembrolizumab is an option for patients with metastatic or unresectable microsatellite instability-high (MSI-H) or dMMR biliary tract tumors, despite limited supporting data. No information was available about patient sex; therefore, additional analyses are warranted to explore potential sex effects related to PD-1 inhibitor therapy in patients with CCA and MSI-H or dMMR tumors.

In a multicenter, open-label, phase 2 clinical trial of 61 patients, treatment with infigratinib—a selective inhibitor of the fibroblast growth factor receptor (FGFR)—was associated with an ORR of 14.8%, a disease control rate of 75.4%, and a median PFS of 5.8 months in patients with advanced or metastatic CCA and FGFR2 fusions or other alterations, after disease progression with previous therapy.15 In this study, 57.4% of the patients were women.15 No differences were noted in the response rate in women versus men.15

The results of an open-label, multicenter, phase 2 clinical trial of 146 patients with previously treated, locally advanced or metastatic CCA and FGFR2 fusions or rearrangements demonstrated an ORR of 35.5%, a disease control rate of 82%, and a median PFS of 6.9 months after treatment with pemigatinib.16 Women represented 58% of the study population. This study included 61% (65 of 107) of women who had FGFR2 fusions or rearrangements.16

Derazantinib, an orally bioavailable multikinase inhibitor with potent pan-FGFR activity, contributed to an ORR of 20.7%, a disease control rate of 82.8%, and a median PFS of 5.7 months in a study of 29 patients with advanced, unresectable intrahepatic CCA and FGFR2 fusions whose disease progressed after chemotherapy.17 In this study, 62.1% of the participants were women.

A study analyzing CCA data from the SEER database showed that the median OS was 4 months in patients with intrahepatic CCA versus 8 months in patients with extrahepatic CCA.2 Furthermore, the OS decreased with age, with improved survival outcomes reported among patients with extrahepatic CCA versus intrahepatic CCA. Women had a significantly lower risk for mortality compared with men, and African Americans had the highest mortality risk.2 In this analysis, Hispanic women had the best 5-year survival outcomes.2

Adverse Events

Treatment with infigratinib has been associated with hyperphosphatemia, fatigue, stomatitis, and alopecia. Eye and nail toxicities, including blurred vision, onychomadesis, and dry eye, also have been reported.15

After treatment with pemigatinib, patients have reported adverse events, including hyperphosphatemia, alopecia, dysgeusia, diarrhea, fatigue, stomatitis, dry mouth, and nail toxicities.16 Fatigue, eye-related adverse events, and hyperphosphatemia have been associated with derazantinib, another FGFR inhibitor.17

A systematic review of 34 studies about the effect of alopecia on the patient revealed that this dermatologic disorder can be associated with serious psychological consequences, especially depression and anxiety.18 Patients with alopecia reported poor body image, low self-esteem, and decreased quality of life (QOL). Patients who had loss of their eyebrows and eyelashes may report issues with identity, because these features are known to help define an individual’s face.18

Furthermore, hair is an essential aspect of many women’s identities. Personality, femininity, attractiveness, and sexuality have been linked to a woman’s hair to a greater degree than for a man.18 In a study that followed a group of women who had hair loss associated with chemotherapy, most had reactions of unpreparedness, shock, embarrassment, and loss of sense of self.19 Hair loss is associated with social values and cultural beliefs. In fact, for some women, loss of their hair has been reported to be more difficult psychologically and more traumatic than the actual loss of a breast because of breast cancer.20

Nail changes may vary based on the treatment dose, type, and duration.21 Common dermatologic changes observed after radiation therapy include increased photosensitivity, peeling, redness, and thin or fragile skin.21 Changes that are often associated with chemotherapy include very dry skin, redness, peeling, rash, changes in pigmentation or skin tone, and increased photosensitivity. Fingernails and toenails may become weak or discolored and/or break or develop ridges.21 These changes are often temporary, returning to normal approximately 6 months after treatment has been terminated.21

The results of a questionnaire-based study of 1063 patients with nail disorders revealed that QOL was affected significantly more often in patients with multiple nails involved in the disorder among all patients aged 60 to 79 years, and in women.22

Fatigue has been associated with psychological distress and reduced QOL among women with breast cancer who receive chemotherapy.23 Although fatigue has been shown to improve for many patients during the year after treatment completion, some survivors can have fatigue for months to years after successful therapy.24,25 The results of studies that evaluated long-term survivors of cancer demonstrate that 25% to 34% of these patients have persistent fatigue for up to 10 years after their cancer diagnosis.26,27

Furthermore, fatigue has been shown to have a negative effect on mood, daily activities, work, and social relationships, which contribute to significant impairments in QOL during and after cancer therapy.28-30 Fatigue may also be predictive of decreased survival.31,32 Cancer-related fatigue can have mental, emotional, and physical manifestations, including diminished concentration or attention, decreased interest or motivation to engage in usual activities, emotional lability, and generalized weakness.25

Results from a survey-based study of patients with cancer aged 51 to 70 years demonstrated a considerable effect of cancer diagnosis on labor-force participation.33 The survey showed that working men were more likely to quit their job in the year they are diagnosed with cancer (10.1%; 95% confidence interval [CI], 6.9-13.4) and in the year after diagnosis (5.0%; 95% CI, 1.5-8.5). By contrast, working women were more likely to quit their job immediately after a cancer diagnosis (18.6%; 95% CI, 13.1-24.0).33 These results suggest a degree of discrimination in the workplace between men and women.

In a study of women with breast cancer, a woman’s work status was influenced 1 year after diagnosis, highlighting the importance of considering potential work concerns and financial stresses that continue to affect patients after a cancer diagnosis.34 In a prospective study, work ability scores have been shown to increase significantly (P <.001) in men and women with cancer over time.35 Compared with men, however, women exhibited significantly (P = .002) improved scores.35

The results of a meta-analysis demonstrate that the diagnosis and treatment of cancer are associated with changes in a patient’s life, daily activities, relationships, family roles, and work.36 Furthermore, a patient’s condition during treatment has been shown to affect certain aspects of everyday life, including family life, communication with family members, and social activities.37

Women’s experiences with cancer are interwoven with broader social perceptions about their role in their own health and assumptions about contributing causes in various types of cancer.38 Social expectations placed on women suggest that they can manage their health and deal with illness when it arises. Therefore, women may be blamed and told not to feel guilty or to be surprised when they receive a cancer diagnosis.38

Similar experiences may occur during treatment, when women undergo life changes when they experience the implications of cancer, and how it is to feel or look as a person with cancer. Interviews with women with cancer reveal the inability to mask the “humiliating” side effects and the effect of cancer on their daily lives.38

Some women also experience social expectations to focus on reinstating their femininity and to conceal cancer-related effects, which minimize the emphasis on dealing with cancer and with their emotional well-being.38 Additional studies are warranted to understand women’s experiences with cancer, and the physical, social, and emotional effects on them.

Conclusion

The incidence and mortality related to CCA may be diminished in women compared with men. Overall, the type of treatment received, response to therapy, and tolerability of treatment-related side effects are similar among men and women. However, experience perceived from the entire cancer journey, including the impact of treatment on daily life and treatment-related toxicity, may be different for women and men. A better understanding of these factors will inform clinicians on how to improve the QOL during therapy for women with CCA; additional studies that focus on the different effects of the disease and its management in women are needed.

References

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