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Treatment algorithm in patients with ovarian cancer

Most ovarian cancer patients are diagnosed only at advanced stages when survival outcomes are worse, andwhen therapeutic decisions might prove challenging. The fundamental treatment for women with ovarian cancerincludes debulking surgery whenever possible and appropriate systemic therapy (chemotherapy, targeted andantiangiogenic agents). In the last few years, knowledge about histological and molecular characteristics of ovariancancer subtypes and stages has increased considerably. This has enabled the development and improvement ofseveral options for the diagnosis and treatment of ovarian cancer in a patient-tailored approach. Accordingly,therapeutic decisions are guided by the characteristics of the patient and the tumour, especially the molecularfeatures of the cancer subtype and disease stage. Particularly relevant are the advances in early genetic testing ofgermline and somatic mutations involved in DNA repair, and the clinical development of targeted agents. In orderto implement the best individual medical strategies, in this article, we present an algorithm of treatment options,including recently developed targeted agents, for primary and recurrent ovarian cancer patients in Belgium.


Introduction
Ovarian cancer is the fifth leading cause of cancerrelated deaths among women in Europe and the United States of America, and is the most frequent cause of death among all gynaecological cancers in Europe (Ferlay et al., 2018;American Cancer Society, 2020a). In 2018, ovarian cancer accounted for 3.7% of all new cancer cases in women in Europe (Ferlay et al., 2018). In Belgium, 752 new cases of ovarian cancer were diagnosed in (Belgian Cancer Registry, 2016. Ovarian cancer is often asymptomatic, resulting in diagnosis at advanced stages in most patients. This trend is reflected in the Belgian cancer statistics from 2016; 18.9%, 5.6%, 28.7%, and 25.1% of ovarian cancer patients were diagnosed with stage I,II, III, and IV disease, respectively (21.6% of patients had an unreported stage) (Belgian Cancer Registry, 2016). In Belgium, the five-year relative survival rate (2012)(2013)(2014)(2015)(2016) was 78.0% (95% confidence interval [CI]: 72.0-83.0) in 15-to 44-year-old patients, 52.9% (95% CI: 50.0-55.8) in 45-to 69-year-old patients, and 27.9% (95% CI: 24.8-31.1) in ≥70-year-old patients (Belgian Cancer Registry, 2016). Survival outcomes are worse in the elderly and patients with advanced-stage ovarian cancer at the time of diagnosis. Patients diagnosed with stage I disease had a five-year relative survival rate of 91.0% (survival data in Belgium, 2004Belgium, -2008 (Belgian Cancer Registry, 2012). In comparison, this rate was only 19.1% among women with stage IV disease at diagnosis.
Here, we aim to provide an overview of the current treatment landscape for ovarian cancer in Belgium to help physicians translate evidence and guidelines into individualised medical strategies for their patients.

Histological and molecular features of ovarian cancer
Ovarian cancer is a heterogeneous disease: it is comprised of tumours that can show very different morphologies, histologies, grades, and molecular characteristics (Lheureux et al., 2019). Epithelial ovarian cancer (EOC) represents approximately 90% of these malignant tumours, whereas sex-cord stromal, germ cell, and mixed-cell ovarian cancers account for the remaining 10% (Hanby et al., 2003;Rojas et al., 2016).
Ovarian cancers are staged surgically and pathologically according to two systems: the International Union Against Cancer (UICC) TNM (tumor, node, and metastasis) system of classification of malignant tumours, and the International Federation of Gynecology and Obstetrics (FIGO) staging system (Prat and FIGO Committee on Gynecologic Oncology, 2014;Brierley et al., 2017). FIGO stages are defined by the confinement of the tumour to the ovaries or fallopian tubes (stage I), the involvement of ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer (stage II), the additional cytologically or histologically confirmed spread of the tumour to the peritoneum outside of the pelvis and/or metastasis to the retroperitoneal lymph nodes (stage III), or the confirmation of distant metastasis excluding peritoneal metastases (stage IV) (Prat and FIGO Committee on Gynecologic Oncology, 2014).Ovarian cancer cells may spread to the adjacent genital organs, pelvic peritoneum, pelvic and para-aortic lymph nodes, omentum, organ, and peritoneal surfaces in the upper abdomen and thoracic pleura (Vergote et al., 2016a).

Genetic testing
Germline or somatic mutations in arrays of genes coding for proteins involved in the homologous recombination (HR) repair of double-strand DNA breaks occur in up to 40-50% of patients with HGSC and more rarely in the other epithelial subtypes (Press et al., 2008;Bell et al., 2011). The most prevalent among these are mutations in the breast cancer susceptibility genes (BRCA1/2), which are clinically validated to be of high value for predictive counselling (if germline), in particular for lifesaving preventive strategies in pre-symptomatic mutation carriers in the family. Indeed, while BRCA1/2 somatic mutations are only found in neoplastic tissue and are thus not passed on to the offspring, germline mutations may be transmitted from parents to their children (Griffiths, 2000).
The homologous recombination deficiency (HRD) diagnosis also has prognostic and therapeutic implications. ABRCA-mutated ovarian cancer has a better prognosis and an increased platinum sensitivity compared to a BRCA-wildtype cancer (Yang et al., 2011). Moreover, in BRCA-mutated ovarian cancer, platinum sensitivity can be preserved over many treatment lines in relapsing patients. BRCA1/2 mutations are synthetically lethal with the inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme: cells harbouring a BRCA loss of function undergo cell death upon PARP inhibition due to an excessive accumulation of unrepaired DNA strand breaks. In normal conditions, the HR and nonhomologous end joining (NHEJ) mechanisms repair these breaks (Faraoni and Graziani, 2018). In patients with a BRCA1/2 gene mutational loss-of-function, only the error-prone NHEJ can (incompletely) repair these breaks, resulting in the accumulation of DNA breaks and mutations that lead to cell death by synthetic lethality (Faraoni and Graziani, 2018).
Therefore, the identification of somatic and germline mutations in the BRCA1 and BRCA2 genes (and other HR genes conferring sensitivity to PARP inhibitors [PARPis]) has become an essential guide for treatment decisions (Faraoni and Graziani, 2018). fallopian tube cancer and with peritoneal cancer, ideally at diagnosis (Personalised Medicine Commission, 2019a;Personalised Medicine Commission, 2019b). NGS testing of the mutational BRCA1/2 status is recommended on both tumour DNA and germline DNA (peripheral blood cells), given that most of the BRCA1/2 mutations detected in tumours are germline (Gadducci et al., 2019;Personalised Medicine Commission, 2019b). In patients without germline or somatic BRCA1/2 mutations in recurrence setting, the Personalised Medicine Commission recommends testing the other HRD and other ovarian cancer risk genes to identify patients eligible for clinical trials and cancer genetic counselling in the relatives. An optimal molecular test for comprehensively detecting the HRD status of cancers still needs to be defined (Personalised Medicine Commission, 2019a;Personalised Medicine Commission, 2019b).
In Belgium, the Personalised Medicine Commission (ComPerMed) recommends genetic testing for all patients with invasive EOC (excluding borderline or mucinous ovarian cancers), with   in health care practices. While current standard clinical practice in many countries implies a pretest consultation with a qualified geneticist and subsequent BRCA1/2 mutation status testing (Capoluongo, 2016), it has been recently proposed that trained specialised staff at oncology units should be enabled to perform the intake and pre-test genetic counselling (Capoluongo, 2016;Capoluongo et al., 2017). One way to guarantee 100% test rates for all patients with ovarian cancer upon diagnosis would be to use "reflex" (i.e., guaranteed) tumour BRCA1/2 mutation testing as part of the pathology department work-up (Hoskins, 2018). This reflex testing requires informed consent that informs the patient on the possibility of finding germline mutations. With this adapted approach, and if turnaround time can be reduced to a maximum of three weeks, delays in proposing personalised treatment schedules could be avoided. If the test detects a potential germline mutation, the patient should be referred to a cancer geneticist for further counselling (Vergote et al., 2016b). As laparoscopic and surgical samples might be rapidly depleted and sufficient tissue is required to ensure good quality of testing, it remains key to maximally use the specimens (Aisner et al., 2016).

Treatment landscape
Fundamental principles of treatment for women with ovarian cancer include surgery to reduce the tumour bulk to no residual disease whenever possible and appropriate systemic treatment based on the ovarian cancer subtype, disease stage, biology, and patient characteristics (Lheureux et al., 2019).

First-line
Primary debulking surgery, which aims at complete resection (i.e., no residual disease), is a cornerstone of ovarian cancer therapy (Lheureux et al., 2019). Optimal primary debulking surgery is significantly associated with prolonged survival (Dogan et al., 2013). Primary surgery is also indispensable for accurate staging of ovarian cancer according to the FIGO and TNM systems (Prat and FIGO Committee on Gynecologic Oncology, 2014).The primary surgical procedure comprises an exploration of the abdomen and pelvis, which is usually followed by a total abdominal hysterectomy, a bilateral salpingooophorectomy, and an omentectomy in case of total respectability (Lheureux et al., 2019).
In women with poor general health, a high perioperative risk profile, or a low likelihood of achieving effective cytoreduction because of extensive disease (advanced stages), neo-adjuvant chemotherapy to reduce the tumour burden should precede surgery (Lheureux et al., 2019). The neoadjuvant chemotherapy should be followed by interval debulking surgery when complete resection or effective reduction to < 1cm disease is achievable (Lheureux et al., 2019). A recent pooled analysis of the long-term follow-ups of two randomised trials has validated this strategy in patients with a high tumour burden at presentation or poor performance status (Vergote et al., 2018).

Recurrence
In women with recurrent ovarian cancer, the benefit of secondary cytoreductive surgery depends on the patient population; its role remains controversial and may depend on the systemic treatment given (Dogan et al., 2013). In the recent Gynaecologic Oncology Group (GOG) 0213 study, secondary surgical cytoreduction followed by platinumbased chemotherapy did not result in longer overall survival (OS) than chemotherapy alone in patients with platinum-sensitive recurrent ovarian cancer (Coleman et al., 2019b). In this study, 84% of patients received platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance. In contrast, interim findings from the ongoing third Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent ovarian cancer (DESKTOP III) study showed that secondary surgical cytoreduction resulted in clinically meaningful increases of progression-free survival (PFS) and median time to start the first subsequent therapy in patients with a first relapse of ovarian cancer and a positive German Gynaecological Oncology Group (AGO) score (Performance Status Eastern Cooperative Oncology Group [PS ECOG] 0, ascites ≤500 ml, and complete resection at initial surgery) (Du Bois et al., 2017).Findings from these two studies suggest that secondary cytoreductive surgery may only be beneficial for patients with platinum-sensitive recurrence when complete resection is achievable (Du Bois et al., 2017;Bommert et al., 2018).

First-line
The current standard first-line systemic treatment, administered after primary debulking surgery or as neoadjuvant therapy is a platinum-based doublet intravenous chemotherapy (carboplatin and paclitaxel, every 3 weeks, or carboplatin every 3 weeks and paclitaxel weekly) with bevacizumab (Lheureux et al., 2019).
In case of intolerance to paclitaxel, alternative platinum-based doublet regimens are carboplatin treatment of platinum-sensitive relapsed ovarian cancer (European Medicines Agency). Another recent study showed a clinically relevant survival benefit in platinum-sensitive patients with germline BRCA1/2 mutations who were treated in thirdline with the association of trabectedin plus PLD compared to PLD alone (Monk et al., 2020).

Targeted and antiangiogenic agents
Treatment of first-line and recurrent ovarian cancer has now expanded to include targeted and antiangiogenic agents (Lheureux et al., 2019).The targeted agents approved by the EMA include three PARPis (olaparib, niraparib and conditional approval for rucaparib) (European Medicines Agency, 2019a; European Medicines Agency, 2019b; European Medicines Agency, 2019c). In addition, one antiangiogenic agent (bevacizumab) is also approved by the EMA (European Medicines Agency, 2019d). Pivotal trials evaluating their use in first-and further-line treatment are detailed in Tables II and III. In Europe, olaparib, niraparib and rucaparib are indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, high-grade, serous epithelial ovarian, fallopian tube, or primary peritoneal cancer (BRCAmutated for olaparib) who are in response to platinum-based chemotherapy (European Medicines Agency, 2019a; European Medicines Agency, 2019b; European Medicines Agency, 2019c). Rucaparib is also indicated as a monotherapy treatment of adult patients with platinum-sensitive, relapsed or progressive, BRCA-mutated, highgrade, epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with at least two prior lines of platinum-based chemotherapy and are unable to tolerate further platinum-based chemotherapy (European Medicines Agency, 2019c). In Belgium, olaparib is reimbursed as a single agent for maintenance treatment in patients with newly diagnosed, advanced ovarian cancer and a BRCA1/2 mutation, who have a complete or partial clinical response after first-line platinumbased chemotherapy. The randomised, double-blind, phase III trial (SOLO1 study) has shown that the use of maintenance therapy with olaparib compared with placebo provides a substantial benefit with regard to PFS in this population (Table II) (Moore et al., 2018).
Moreover, olaparib is reimbursed in Belgium as a single agent for maintenance treatment in patients with recurrent platinum-sensitive, PARP-naïve, BRCA-mutated, high-grade EOC, fallopian tube cancer or primary peritoneal cancer after at least two prior lines of platinum-based chemotherapy with docetaxel or with pegylated liposomal doxorubicin (PLD),which should be used according to the patient's/physician's treatment preferences and the patient-specific drug tolerability since each of the regimens is associated with a specific toxicity profile (Katsumata, 2003;Pignata et al., 2011).The carboplatin with PLD regimen is not reimbursed in Belgium in first-line.

Recurrence
Although surgical resection followed by first-line platinum-based chemotherapy leads to complete remission in many patients, recurrences occur in up to 70% of cases (Dogan et al., 2013).Although the recurrent disease is incurable, treatments in this setting have the intention of controlling the symptoms and the disease, to maintain the quality of life, and to prolong the treatment-free periods. Depending on the duration of the treatment-free interval before disease recurrence, patients are classically categorised into "platinum-sensitive"(relapse ≥ six months since last platinum-based treatment) versus "platinumresistant" (relapse < six months since last platinumbased treatment) (Buechel et al., 2019). Given the advances in ovarian cancer surveillance allowing for faster detection of relapse, the lack of consensus on how progression is defined, and the emergence of other first-line therapies, new guidelines do not adopt such a stringent six-month limit for defining platinum-sensitive patients (Buechel et al., 2019). Also, more patients may be incorrectly excluded from platinum-based regimens in the future as recurrences will be detected earlier (Buechel et al., 2019).
The management of recurrent ovarian cancer is less validated than that of newly diagnosed ovarian cancer (Dogan et al., 2013).After recurrence, platinum-resistant patients should receive nonplatinum-based single-agent chemotherapy (PLD, paclitaxel, topotecan or gemcitabine) (Ledermann et al., 2018).In contrast, platinum-sensitive patients may be re-challenged with platinum-based doublet chemotherapy (Ledermann et al., 2018;Lheureux et al., 2019). The intercalation of a non-platinum regimen could confer a clinically meaningful benefit to some patients with platinum-sensitive relapsed ovarian cancer and give them time to recover from platinum-related toxicities (Colombo, 2017;Romero et al., 2019). A randomised phase III study (ET743-OVA-301) demonstrated improved efficacy with an acceptable tolerance of the association of trabectedin (an antineoplastic agent) plus PLD versus PLD alone in patients with platinumsensitive relapsed ovarian cancer (Monk et al., 2010), leading to the approval of this association by the European Medicines Agency (EMA) for the      (Specenier, 2016). Niraparib and rucaparib are not yet reimbursed for that indication. Bevacizumab is indicated and reimbursed in Belgium in combination with carboplatin and paclitaxel for the first-line treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (Neyt et al., 2017;European Medicines Agency, 2019d). Bevacizumabin combined with carboplatin and gemcitabine, or carboplatin and paclitaxel is also indicated and reimbursed in Belgium for the treatment of adult patients with a first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer, who have not received prior therapy with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents. A third approved indication, which is also reimbursed in Belgium, is bevacizumab in combination with paclitaxel, topotecan or PLD for the treatment of adult patients with platinum-resistant recurrent disease and who had received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. Clinical trials are evaluating other indications for the above-mentioned targeted therapies and antiangiogenic agents as well as new agents. A phase III, randomised study (PAOLA-1 trial) has shown that the addition of olaparib to bevacizumab maintenance therapy following first-line platinumbased chemotherapy plus bevacizumab led to a statistically significant and clinically meaningful PFS benefit in patients with advanced ovarian cancer; especially in those with a BRCA mutation and in HRD-positive patients (Ray-Coquard et al., 2019). A second phase III, randomised study (PRIMA trial) has shown that patients with newly-diagnosed advanced ovarian cancer who received niraparib after a response to platinumbased chemotherapy had significantly longer PFS than those who received placebo, regardless of the presence or absence of HRD as determined by the my-Choice test (Myriad Genetics) (Gonzalez-Martin et al., 2019). A third phase III, randomised study (VELIA trial) has shown that another PARPi (veliparib) in combination with chemotherapy as initial treatment followed by veliparib maintenance therapy in patients with high-grade serous ovarian carcinoma led to significantly longer PFS than chemotherapy alone (Coleman et al., 2019a).

Conclusions
Accurate pathological and molecular testing is essential to construct multifactorial, patient-tailored