Sex and gender differences in treatment intention, quality of life and performance status in the first 100 patients with periampullary cancer enrolled in the CHAMP study

The term periampullary cancer encompasses a heterogenous group of tumors arising in the pancreas, the Ampulla of Vater, distal bile duct or the periampullary duodenum. The majority of periampullary tumors are located within the pancreas. These tumors carry a dismal prognosis and afflicted patients often suffer from severe symptoms. In the United States it is estimated that pancreatic cancer will be responsible for 8% of cancer deaths in 2022. At present, it is the third leading cause of cancer death globally but is projected to rise to the second by the year 2030. Pancreatic cancer incidence is slightly higher in men than in women, with an estimated 53% of newly diagnosed patients being male [1, 2]. Biological sex modulates cancer through genetic and hormonal influences while the social constructs of gender affect the way patients and the health care system interact. Although a growing field, the influence of sex and gender on cancer evolution and response to treatment has hitherto been understudied [3]. As in many other types of cancer, men with pancreatic cancer have decreased survival in late-stage disease compared to women [4, 5]. Lifestyle factors such as smoking, excessive alcohol consumption and an unhealthy diet are more common in men, and their poorer survival has often been attributed to these factors. However, one study of pancreatic cancer conducted using a mouse model shows a clear sex difference in survival with decreased survival and increased liver metastases for male mice without exposure to extrinsic factors, further supporting that lifestyle factors alone cannot explain the differences in pancreatic cancer survival between the sexes [6].

The majority of patients with periampullary cancer present with irresectable disease, and palliative chemotherapy remains standard of care, albeit leading to only modest survival benefits. Patients with operable disease undergo surgery followed by adjuvant chemotherapy, however, most relapse and the 5-year overall survival is 5–28% globally [7]. In a recent Swedish registry study, female patients who were planned for curative pancreatic cancer surgery had significantly better long-term survival than male patients, although they were older at diagnosis (69 vs 68 years of age) [8].

Chemotherapy is given in both adjuvant and palliative settings as well as for downsizing borderline resectable tumors [9]. Combination treatment with FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin) or modified FOLFIRINOX is standard of care for fit patients, while patients with poorer performance status receive single agent chemotherapy with gemcitabine or 5-FU (Fluorouracil). For patients who are deemed unfit for FOLFIRINOX, but well enough to tolerate combination chemotherapy, gemcitabine in combination with nab-paclitaxel or capecitabin is given [9‐18]. Many patients suffer from toxicity to treatment, and even with optimal combination chemotherapy treatment the overall survival for stage IV patients is less than a year [12, 19]. Female patients are subject to a 1.5 times higher risk of serious drug side effects compared to males and in women with pancreatic cancer there is an increased risk of toxicity from 5-FU based chemotherapy [20, 21].

The aim of this study was to investigate any differences between males and females regarding demographic and clinicopathological parameters as well as treatment intention, performance status, quality of life and overall survival (OS) in the first 100 patients enrolled in the Chemotherapy, Host Response and Molecular dynamics in Periampullary cancer (CHAMP) study [22].

The CHAMP study is an ongoing prospective, single-arm observational study registered in clinicaltrials.gov as NCT03724994 [22]. All patients with a histologically or cytologically confirmed diagnosis of pancreatic or other periampullary adenocarcinoma undergoing adjuvant or palliative chemotherapy treatment in the Department of Oncology, Skåne University Hospital have been invited to participate, and the first patient was included in November 2018.

Clinical and pathology data are compiled at study entry with radiological and clinical follow-up being performed at three-month intervals. Serial blood sampling during chemotherapy treatment is performed by a dedicated research nurse and health-related quality of life (HRQoL) is assessed every three months through EORTC-QLQ-C30 (The European Organisation for Research and Treatment of Cancer Quality of life Questionnaire) [23]. In May 2022, 100 patients had been included, of whom 49 participants were female and 51 male. The latest follow-up was on 31^tst October 2022. Seventy-five patients had completed EORCT-QLQ-30 questionnaires at baseline, i.e. before the first chemotherapy cycle (6–8 weeks post-operatively for adjuvant patients). Comorbidities and risk factors were established through examination of patient charts. Cardiac comorbidity was defined as patients having a history of myocardial infarction, frequent angina pectoris or heart failure. Atrial fibrillation was not considered a comorbidity. Diabetes mellitus was considered newly diagnosed if the diagnosis was set within a year prior to the cancer diagnosis. Body mass index (BMI) was calculated and grouped according to WHO [24], underweight; < 18.4, normal weight; 18.5–24.9, overweight, 25.0–29.9, Obese; > 30. Performance status score was rated by the patients’ physician according to the Eastern Cooperative Oncology Group (ECOG) scale [25]. Histopathological re-evaluation of all cases was performed by a senior pathologist (KJ). Resected tumors were classified according to WHO classification of tumors 5^th edition [26].

The influence of sex and gender on the choice of treatment and the HRQoL of patients with pancreatic and other periampullary cancers has hitherto been little studied, but it is evident that increased awareness of these issues is vital in order to prevent gender-based bias and to achieve optimized personalized treatment. This study of the first 100 patients with periampullary adenocarcinoma enrolled in the CHAMP study shows a significant difference between men and women regarding treatment with curative intent, with less women having undergone pancreatectomy. This is in line with the findings of a previous nationwide Swedish study of patients with periampullary adenocarcinoma [8], although in that study, the significant difference between sexes was lost after adjusting for age and tumor location, with female patients being of older age and having more tumors located in the pancreatic head. In contrast, in the current study, female patients were slightly younger than male patients (66.5 vs. 68.4 years of age) and fewer women had tumors located in the pancreatic head. Moreover, no patients with a periampullary tumor originating in the duodenum has been included in the CHAMP study, since these patients receive a different chemotherapy regimen.

It has also been shown that male patients have a higher morbidity rate than female patients after pancreatectomy and that female patients with early-stage pancreatic cancer have prolonged survival after pancreatectomy [8, 28]. Our results showed no significant difference in OS between men and women after curative surgery, but a larger number of cases and a longer follow-up is needed. Also, male patients who underwent surgery tended to have a poorer performance status compared to female patients, although these findings did not reach statistical significance.

Patients with pancreatic cancer generally have an impaired HRQoL, although one study found no significant difference in the scales cognitive function or pain for female patients with pancreatic cancer compared to the general population [29]. It is also known that both short and long-term HRQoL decreases after pancreatectomy with no clear difference between the sexes [30, 31]. In this study, females generally had a decreased HRQoL compared to males, both in functional scales and symptoms before the start of treatment. Female patients also tended to experience more pain and had poorer social functioning than males before the start of adjuvant treatment. These findings are in line with the literature regarding cancer patients but is also true for women in the general population [32, 33]. Therefore, when interpreting cancer patients’ HRQoL it is important to always consider the reference population. In one study on the HRQoL of over 5000 long-term cancer survivors, adjustment to the reference population highlighted a significant and unexpected impact on male patients [34]. The finding in the present study that operated patients had higher HRQoL than palliative patients is not surprising but indicates that patients seemingly experienced a high level of recovery 6–8 weeks after extensive surgery, i.e. at the start of adjuvant chemotherapy treatment.

Since our results showed no statistical differences between the sexes regarding age, clinicopathological factors, or comorbidities, it is feasible to assume that gender plays an important role in the discrepancy of surgery given with curative intent. Of the 51 female patients included in this study, two were eligible for pancreatectomy but declined surgery and, hence, a chance of cure. It has been shown in several studies that patients with early-stage pancreatic cancer who decline surgery are generally of female sex, of older age, and/or suffer from more comorbidities [35‐37]. Symptom perception theory hypothesizes that men and women perceive and report symptoms differently due to differences in early socialization, social position, and traditional gender roles [38]. Few studies have investigated the potential associations between patient-reported HRQoL and physicians’ assessment of performance status, and even fewer have examined this association in relation to sex or gender. In one study including 115 cancer patients with a variety of diagnoses and only six gastrointestinal cancers, female sex was found to be associated with decreased HRQoL and performance status [39]. These findings are in contrast to our results, but comparisons are difficult to make given the quite diverging study populations. Men in the general population, as well as in our study, experience a better general HRQoL than women. The finding that men with poor performance status suffer from greater fatigue and a decrease in physical, emotional, and social functioning while women’s HRQoL remains unchanged with decreasing performance status is however novel and must be attributed to the complexity of gender differences. Our understanding of the impact that gender dimensions might have on HRQoL is limited, with no scales in clinical use to date. Gender is multidimensional and while many studies primarily focus on gender identity, other gender dimensions such as gender roles, behaviors and relations, should also be investigated, as they might well be more important for HRQoL. In a recent study of patients with Parkinson’s disease no associations were found between self-reported gender identity and overall HRQoL whereas an androgynous gender role orientation and higher engagement in household tasks were associated with increased HRQoL [40]. In the previously mentioned study of > 5000 long-term cancer survivors it was concluded that men had a significant loss of social and role functioning, perhaps an indication of the loss of gender role [34].

The strengths of the present study are that it is an ongoing, prospective trial with real-world data from patients with pancreatic and other periampullary cancer, making biased patient selection minimal. The limitations include a small patient number, in particular in the adjuvant group. Only 75 patients had completed EORTC-C30 questionnaires, however no significant demographic differences were seen between patients with or without completed forms. Other limitations are that we did not adjust HRQoL for the reference population and did not use tools to analyze gender dimensions or compare patients enrolled in the CHAMP study to all patients with periampullary cancer receiving chemotherapy during this time span. Since all patients included in the CHAMP study received chemotherapy, no information was available regarding surgically treated patients who may have been unfit for adjuvant chemotherapy due to post-operative complications.

The results from this study further underline the importance of gender with regard to the interaction between healthcare providers and patients, and how this interaction may affect the outcome for patients with periampullary adenocarcinoma. In this context, particular attention should be given to the selection of women for curative surgery, where a more encouraging approach might well lead to improved survival rates. The gender disparities regarding the relationship between self-perceived HRQoL and the physicians’ subjective assessment of the patients’ performance status are noteworthy, and a heightened awareness of how these factors may influence treatment decisions should be an important part of personalized medicine. In future studies, the multidimensionality of gender needs further consideration in order to gain insights into how it impacts the biological outcome for all patients.