Short summary

The project aims to examine whether an optimization of older women with ovarian cancer during their neoadjuvant chemotherapy can increase the number of patients referred to surgery. The combination of both treatments is the only potential curative treatment, but more than 40% of patients aged ≥70 are not referred to surgery. Patients are randomized 1:1 to either standard of care or Comprehensive Geriatric Assessment and derived interventions along with individual supervised exercise therapy.

Rationale

FRAGINOC is a multicenter randomized study, which focuses on older patients with ovarian cancer (OC), referred to neoadjuvant chemotherapy (NACT) before possible extensive surgery (Interval debulking surgery (IDS)). The primary aim is to evaluate if optimization during chemotherapy can improve the health status and functional capacity increasing the number of patients referred to IDS after NACT. Indeed, the combination of extensive surgery and chemotherapy is the cornerstone of curatively intended treatment in advanced OC - either as primary debulking surgery (PDS) followed by adjuvant chemotherapy (CT) or as NACT followed by interval debulking surgery (IDS) and postoperative CT. Growing attention has focused on inequality in treating younger versus older patients, as both groups benefit equally from standard treatment regimens(1-3). It has been showed that 43% of Danish EOC older patients do not undergo surgery, compared to 18% of their younger counterparts(4-6). The difference in surgical rate may be explained by fear of complications, frailty or advanced age. Almost half of the patients who are diagnosed with OC are >=70 years, usually with comorbidities that can limit their chances to complete oncological treatment. We know that older patients diagnosed with OC have to deal with the most lethal gynecological malignancy and the worse prognosis because of their age and/or frailty(5). Even though the surgical and chemotherapy treatment of OC is well established also as the best strategy for the older population, there is a shocking lack of knowledge regarding the effect of optimization during the oncological treatment and prior to surgery. Indeed, several international organizations recommend screening of older patients for frailty before the oncological treatment(7-9), in order to implement the necessary interventions to improve their complete health status to better tolerate the oncological treatment. A comprehensive geriatric assessment (CGA) is the recommended tool to detect and treat possible impairments, which can be optimized before and during treatment(10,11). But because there is a wide range from frail to fit patients in the older population, the use of short frailty screening tools could identify the patients in need of a CGA. Additionally, the focus on prehabilitation in patients with gynecological malignancies has increased, and a combination of aerobic and resistance exercise is recommended during and after oncological treatment to patients with cancer(12-14). There is increasing evidence of the positive effect of exercise in patients receiving oncological treatment; however, neither the effect of exercise, of CGA, nor the value of the short frailty screening tools have been evaluated in older patients with OC. With this project we aim to fill out the knowledge gap regarding the benefits of CGA and exercise in older women with newly diagnosed OC. Hypothesis and purposes Our hypothesis is that frail older patients with advanced EOC will benefit from a CGA and derived interventions along with an individualized exercise therapy, increasing referral to interval surgery and completing oncological treatment. The primary objective is to determine whether a CGA and tailored intervention along with an exercise therapy program can increase the proportion of patients referred to IDS. Secondary objectives are: -To evaluate whether the described intervention can increase the proportion of patients who complete oncological treatment. -To examine the performance of three validated frailty screening tests (Geriatric 8, modified Geriatric-8 (mG8), and Clinical Frailty Scale (CFS)), as well of ECOG performance status (PS) in predicting CGA identified impairments. -To establish whether CGA and tailored intervention with an exercise therapy program can: _Improve physical fitness. _Improve physical activity. _Decrease surgical and chemotherapy-related complication rates. _Enhance progression-free survival (PFS) at twelve, 24 and 36 months. _Improve quality of life. _Reduce costs associated with both surgical and oncological treatment.

Description of the cohort

Women >=70 years with advanced Epithelial Ovarian Cancer (FIGO stage III-IV) who are eligible for NACT are included from the Departments of onco-gynecology at Copenhagen University Hospital, Rigshospitalet (RH), Odense University Hospital (OUH) and Zealand University Hospital (ZUH). Exclusion criteria are severe psychiatric disease and presence of another cancer disease, or have received antineoplastic treatment (excluding surgery or endocrine therapy alone) in the preceding 3 years.

Data and biological material

Data will be collected prospectively (demographic, clinical, pathologic, and results from frailty screening, functional tests, blood tests, and intervention effects) and recorded in a predesigned REDCap database. Life-long follow-up data on overall survival will be obtained from the Danish National Patient Registry through linkage with a personal identification number. Data will include age, PS, Charlson Comorbidity Index, type and number of surgeries, number of pregnancies, body mass index, weight loss, alcohol, and smoking habits, Saltin-Grimby Physical Activity Level Scale and self-related physical fitness, Ca-125, Risk of Malignancy Index, FIGO stage, PET-CT description of tumor burden and extension.

Collaborating researchers and departments

Department of Oncology, Odense University Hospital

Department of Geriatrics, Odense University Hospital

Department of Ocupational Therapy and Physiotherapy, Odense University Hospital

Department of Ocupational Therapy and Physiotherapy, Vejle Hospital

Department of Gynecology and Obstetrics, Zealand University Hospital, Roskilde

Department of Oncology, Zealand University Hospital, Roskilde

Department of Ocupational Therapy and Physiotherapy, Zealand University Hospital, Roskilde, and Herlev Hospital

Department of Geriatrics, Zealand University Hospital, Køge

Department of Gynecology and Obstetrics, Copenhagen University Hospital

Publications associated with the project

Daviu Cobián C, Oreskov JO, Blaakaer J, Jespersen E, Jørgensen TL, Ryg J, Herrstedt J, Høgdall C, Lund CM, Seibæk L, Vinther A, Ekmann-Gade AW, Schnack TH. Impact of FRAilty screening and Geriatric assessment and INtervention in older patients with epithelial Ovarian Cancer: A multicenter randomized clinical trial protocol (FRAGINOC). J Geriatr Oncol. 2024 Apr;15(3):101713.

Jespersen E, Daviu Cobián C, Jørgensen TL, Minet LR, Schnack TH, Vinther A. Development and feasibility of an exercise therapy intervention for older women with advanced epithelial ovarian cancer referred to neoadjuvant chemotherapy prior to possible interval debulking surgery. Gynecol Oncol Rep. 2024 Jun 26;54:101441.