JONT Journal

Introduction

Ovarian cancer (OC) is the second most common gynecologic cancer and is the most common cause of death due to gynecologic cancer accounting for more than 50% of deaths [1-11]. OC detected at stage I has a favorable prognosis [12]. However, due to the lack of effective screening for this disease, OC is diagnosed at an advanced stage in more than 75% of cases [4,9,12-16]. Risk factors for include advancing

age, nulliparity, early menarche, late menopause, family history of OC or breast cancer, and endometriosis [4,6,8,10,14-19]. In fact, all women are subject to risk of developing OC [12]. 90% of OC are Epithelial Ovarian Cancers (EOC) [9,19]. According to the World Health Organization, there are five types of EOC including serous carcinoma, which is further classified as high-grade serous carcinoma (HGSC) or low-grade serous carcinoma (LGSC), clearcell carcinoma, mucinous carcinoma and endometrioid carcinoma [8, 11, 20]. HGSC constitutes around 75% of all OC [15,20]. The mainstay of treating OC is surgery and chemotherapy [2,13,14,19]. Several international health organizations set recommendations on the management of patients with EOC, fallopian tube and primary peritoneal cancer. We compared guidelines by the National Comprehensive Cancer Network (NCCN), the American College of Obstetricians and Gynecologists, the American Society of Clinical Oncology (ASCO), the Society of Gynecologic Oncology (SGO), the British Gynaecological Cancer Society (BGCS), the National Institute of Care and Excellence (NICE), the Royal College of Obstetricians and Gynaecologists (RCOG), the Scottish Intercollegiate Guidelines Network (SIGN), the European Society of Gynaecological Oncology (ESGO), the European Society for Medical Oncology (ESMO), the Korean Society of Gynecologic Oncology (KSGO), the Spanish Society of Medical Oncology (SEOM), the Society of Obstetricians and Gynaecologists of Canada (SOGC) and the International Federation of Gynecology and Obstetrics (FIGO) [1,4-11,13,1621]. In the interest of convenience, in this paper, OC collectively refers to EOC, fallopian tube and primary peritoneal cancer as they are managed in the same way. We designed a management guidewheel on the recommendations of treating patients with OC as per the aforementioned guidelines. This guidewheel aims to assist healthcare providers when counseling patients diagnosed with OC to provide them with a general insight on their expected course of treatment.

About this Guide Wheel

Ismail’s Guide wheel on the Management of Epithelial Ovarian Cancer Including Fallopian Tube and Primary Peritoneal Cancer integrates the recommendations of various organizations regarding the management of epithelial ovarian cancer and fallopian tube and primary peritoneal cancer. The inner wheel (Figure 1) can be rotated along the base of the guide wheel (Figure 2) to match the treatment modalities to the type of ovarian cancer, stated on the outer rim of the guide wheel, and displays the recommended steps in chronological order (Figure 3).

The types of ovarian cancer displayed on the outer rim of the guidewheel are broadly categorized as follows:

• Primary Treatment of All Ovarian Cancer, Fallopian Tube (FT) and Primary Peritoneal Cancer
• Diagnosis by Previous Surgery
• Chemotherapy for Grades 2 and 3 Endometrioid and Serous Carcinoma
• Adjuvant Therapy for Grade 1 Endometrioid Carcinoma and LGSC
• Maintenance Therapy for Stages II, III and IV After Primary Therapy
• Therapy for Persistent or Recurrent Disease
• Adjuvant Therapy of Ovarian Borderline Epithelial Tumors (Low Malignant Potential)
• The inner wheel (Figure 1) displays the different treatment modalities as follows:
• Primary Treatment: a. Surgery; b. Neoadjuvant Therapy
• Surgical Therapy: a. Surgical Staging; b. Hysterectomy; c.Fertility-Sparing Surgery; d. Unilateral Salpingooophorectomy (USO); e. Bilateral Salpingo-oophorectomy (BSO); f. Debulking; g. Cytoreduction; h. Resection; i. Completion
• Work-Up: a. Pathology (A. Histology, B. Immunohistochemistry (IHC)); b. Genetic; c. Molecular; d. T-Markers; e. Imaging
• Adjuvant Therapy: a. Chemotherapy; b. Hormonal; c. Observation; d. Systemic Therapy
• Neo-Adjuvant Therapy: a. Chemotherapy; b. Immunotherapy; c. Biological (targeted)
• Systemic Therapy
• Maintenance Therapy: a. Immunotherapy; b. Biological (targeted); c. Hormonal; d. Observation
• Therapy for Persistent/Recurrent Disease: a. Clinical Trial
• Observation
• Monitoring / Follow-Up • Care

How to Use the Guide Wheel

The back of the guidewheel (Figure 4) explains how to use Ismail’s Guidewheel on the Management of Epithelial Ovarian

Cancer Including Fallopian Tube and Primary Peritoneal Cancer. The inner wheel is rotated along the base of the guidewheel and the management of a particular ovarian cacner type is displayed in the viewing slot. The steps are in chronological order and color-coded as follows:

• Red: This is the preferred primary therapy.
• Blue: This is a feasible alternative to the primary therapy but requires greater clinical judgment.
• Black: This is usually reserved for the adjuvant therapy or therapy for recurrence.

Abbreviations used on the wheel include the following:

The FIGO 2017 classification of ovarian, fallopian tube and primary peritoneal cancer, along with the corresponding Tumors, Nodes and Metastasis system developed by the American Joint Committee on Cancer (AJCC), is displayed on the back of the wheel (Figure 4) and is listed as follows [16]:

Recommendations on Managing Patients with Epithelial Ovarian, Fallopian Tube and Primary Peritoneal Cancer Using the Guidewheel

Sector 1. Primary Treatment of All Ovarian Cancer, Fallopian Tube (FT) and Primary Peritoneal Cancer (Figure 5)

For patients with ovarian, FT or primary peritoneal cancer stages IA and IB who desire to preserve their fertility, primary treatment (1) is surgical (a) with surgical staging and USO (ad) for stage IA disease or surgical staging and BSO (ae) for stage IB disease. This is followed by further workup (1a) with pathologic staging (A) and genetic testing (b) if not done before. The next step (2) is adjuvant therapy.

Patients who do not desire to preserve their fertility must be further managed depending on the probability of optimal cytoreduction. Patients with disease stages IA-IV with optimal cytoreduction are

managed with primary treatment (1) being surgical (a). The first step (1) is surgical treatment with surgical staging (a), hysterectomy (b), BSO (e), and debulking (f). This is then followed by further workup (a) with pathologic staging (A) and genetic testing (b) if not done before. The next step (2) is adjuvant therapy.

On the other hand, patients who do not desire to preserve their fertility but are poor surgical candidates or have a low likelihood of undergoing optimal cytoreduction, management starts with neoadjuvant therapy and further steps depend on their response to the therapy. Patients demonstrating response to therapy are managed primarily (1) with neoadjuvant therapy (b). This is followed by further workup (1a) with pathologic staging (A) and genetic testing (b) if not done before. The second step (2) is surgical treatment with BSO (e), debulking (f), cytoreduction (g), and completion hysterectomy (i). The next step (3) is adjuvant therapy. The next step (4) can involve maintenance therapy.

Patients who have stable disease following neoadjuvant therapy (1b) undergo further workup (a) with pathologic staging (A) and genetic testing (b) if not done before. The second step (2) is surgical treatment with BSO (e), debulking (f), cytoreduction (g), and completion hysterectomy (i). An alternative (or) for the second step (2) is to continue neoadjuvant therapy for at least 6 cycles in total with chemotherapy (a), immunotherapy (b) or biological therapy (c). Another alternative (or) is therapy for recurrent disease (3). The next step (4) is adjuvant therapy. The next step (5) can involve maintenance therapy.

Patients with progressive disease are managed in the form of primary treatment (1) with neoadjuvant therapy (b). This is followed by further workup (a) with pathologic staging (A) and genetic testing (b) if not done before. The second step (2) is therapy for recurrent disease.

Patients who are referred with a diagnosis of OC after a surgical procedure should be further evaluated by a gynecologic oncologist and further management depends on the presence of residual disease on further workup. If patients diagnosed with stage I-IV disease and no residual disease, the first step (1) is to consider (#) surgical staging (a). This is followed by further workup (a) with pathologic staging (A) and IHC (B), genetic testing (b) if not done before, molecular testing (c), tumor markers (d), and imaging (e) as clinically indicated. The next step (2) is adjuvant therapy.

However, the management of patients who have residual disease on further workup depends on the resectability of the residual disease. If it is resectable, then primary treatment (1) is cytoreduction (g). This is followed by further workup (a) with pathologic staging (A) and IHC (B), genetic testing (b) if not done before, molecular testing (c), tumor markers (d), and imaging (e) as clinically indicated. The next step (2) is adjuvant therapy.

If the residual disease is non-resectable, then primary treatment is neoadjuvant therapy (1). This is followed by further workup (a) with pathologic staging (A) and IHC (B), genetic testing (b) if not done before, molecular testing (c), tumor markers (d), and imaging (e) as clinically indicated.

Sector 3. Chemotherapy for Grades 2 and 3 Endometrioid and Serous Carcinoma (Figure 7)

Patients with stage IA or IB grade 2 endometrioid cancer

are first managed with observation (1). An alternative (or) is systemic therapy (1). The next step (2) is best supportive care. Then, monitoring (3) is indicated. Patients with stage 1A or IB grade 3 endometrioid cancer or HGSC and those with stage IC HGSC or endometrioid cancer grades 2 or 3 are first managed with systemic therapy (1). The next step (2) is best supportive care. Then, monitoring (3) is indicated. Patients with stages II-IV are also first managed with systemic therapy (1). The next step (2) is best supportive care. Then, monitoring (3) and maintenance therapy (3) are indicated.

Sector 4. Adjuvant Therapy for Grade 1 Endometrioid Carcinoma and LGSC (Figure 8)

Adjuvant therapy for patients with grade 1 endometrioid cancer or LGSC stages IA and IB is observation (1c). The next step (2) is monitoring/follow-up. In addition to monitoring is therapy for recurrent disease (2). The preferred adjuvant therapy (1) for patients with disease stage IC is observation (c). An alternative (or 1) is systemic therapy (d) or hormonal therapy (b). The second step (2) is maintenance therapy with observation (d) or hormonal therapy (c) with letrozole, for instance. The third step (3) is monitoring and follow-up.

Patients with disease stages II-IV should receive adjuvant therapy (1) in the form of systemic therapy (d) or hormonal therapy (b). The second step (2) is maintenance therapy with observation (d) or hormonal therapy (c) with letrozole, for instance. The third step (3) is monitoring and follow-up.

Sector 5. Maintenance Therapy for Stages II, III and IV After Primary Therapy (Figure 9)

Following primary treatment of patients with stage II, III, and IV, maintenance therapy depends on whether or not bevacizumab was used during primary treatment and the presence or absence of a genetic mutation in breast cancer gene 1 (BRCA1) or 2. It also depends on the response to primary treatment. The first step (1) is further workup with imaging (e), such as CT, MRI, or PET/CT of the chest, abdomen, and pelvis. If no bevacizumab was used, there is no mutation in BRCA1/2 and the disease demonstrates complete or partial response to primary treatment, maintenance therapy (1) is observation (d) in the case of complete response. An alternative (or) to the first step (1) is biological treatment (b) with PARPi niraparib. Another alternative (or 1) is therapy for recurrent disease. The next step (2) is monitoring and follow-up.

If no bevacizumab was used, there is a mutation in BRCA1/2 and the disease demonstrates complete or partial response to primary treatment, maintenance therapy (1) is biological therapy (b) with PARPi, such as olaparib or niraparib. An alternative (or) to the first step (1) is to consider (#) observation (d) for stage II disease only. The next step (2) is monitoring and follow-up.

If there is stable or progressive disease regardless of the use of bevacizumab during primary treatment or the presence of BRCA1/2 mutation, the first step (1) of maintenance therapy is therapy for recurrent disease.

If bevacizumab was used during primary treatment, the first step (1) is further workup with imaging (e). Further management depends on the response to the primary treatment and the presence or absence of BRCA1/2 mutation. Patients with no genetic mutation and demonstrating complete or partial response to primary therapy should be assessed whether they are homologous recombination (HR) proficient or deficient. Those who are HR deficient should be managed with maintenance therapy (1) with immunotherapy (a) with bevacizumab and biological therapy (b) with olaparib. On the other hand, those who are HR proficient should receive maintenance therapy (1) with immunotherapy (a) in the form of bevacizumab. The next step (2) is monitoring regardless of the HR status.

Patients with a BRCA1/2 mutation demonstrating complete or partial response to primary thearpy should be treated with maintenance therapy (1) with biological therapy (b) with or without (±) immunotherapy (a) with bevacizumab. This is followed up by monitoring and follow-up (2).

Sector 6. Therapy for Persistent or Recurrent Disease (Figure 10)

Patients who undergo recurrence both clinically or biochemically, with rising CA125 levels, are managed depending on the use of chemotherapy during their primary treatment. Either way, further workup (1) is indicated with molecular testing (c), and imaging (e) as clinically indicated. If no chemotherapy was used, primary therapy (1) is surgery (a) with or without (±) neoadjuvant therapy (b). Otherwise, if chemotherapy was used, the next step (2) is therapy for recurrent disease with an option of clinical trial (a).

Regarding the response of the disease to platinum-based chemotherapy, it can either be platinum-resistant or platinumsensitive. Patients who progress on primary, maintenance or recurrence therapy, have stable, persistent disease or develop complete remission then relapse less than 6 months after completing chemotherapy are identified as platinum-resistant and are advised to undergo treatment for recurrent therapy (1) with clinicial trial (a). An alternative (or) is best supportive care (1). If a patient is platinum-sensitive, meaning they developed complete remission and relapsed 6 months or more after completing treatment, primary treatment (1) is therapy for recurrence with clinical trial (a). If there is evidence of relapse clinically or radiographically, secondary cytoreductive surgery (g) can be considered (#). An alternative (or) is systemic therapy (1). An alternative (or) second step (2) is maintenance therapy with immunotherapy (a) with bevacizumab and biological therapy (b) with PARPi, if not used before. An alternative (or) third step is observation (3). Finally, monitoring is indicated (4).

Sector 7. Adjuvant Therapy of Ovarian Borderline Epithelial Tumors (Low Malignant Potential) (Figure 11)

Patients with ovarian borderline epithelial tumors are managed according to the state of the surgical resection, whether it was complete or incomplete. Those who underwent complete resection and have no invasive implants can be observed (1c). The next step (2) is monitoring. Those who had a complete resection and diagnosed as LGSC are treated adjuvantly (1) with systemic therapy (d) or hormonal therapy (b). Maintenance therapy (2) with hormonal therapy (c) or observation (d). The next step (3) is monitoring. Patients diagnosed with HGSC and no residual disease, the first step (1) is adjuvant therapy with chemotherapy (a). The next step is best supportive care (2) and this is followed by monitoring (3).

Patients who underwent incomplete surgical resection of the disease are advised to undergo further workup (1) with imaging (e). If there is residual disease on imaging, then primary therapy (1) involves hysterectomy (b), resection (h) of residual disease, and completion (i) surgery or fertility-sparing surgery (c) and resection (h) of residual disease. Adjuvant therapy (1) involves systemic therapy (d) or hormonal therapy (b). The next step (2) is monitoring. If there is no residual disease on imaging, then adjuvant therapy (1) with observation (c) is warranted. The next step (2) is monitoring.

In the case of recurrent ovarian borderline epithelial tumors, observation (1) is warranted in the case of non-invasive disease while therapy for recurrent disease (1) is indicated for invasive implants or invasive carcinoma.

Discussion

OC is staged using the International Federation of Gynecology and Obstetrics (FIGO) [2,15,16,21]. Patients are either asymptomatic or can present with abdominal or pelvic pain, urinary symptoms or early satiety [3-5,11,16,21]. Several biomarkers are associated with OC, such as cancer antigen 125 (CA-125) and human epididymis protein 4 gene (HE4). CA125 is not only high in OC but can also be elevated in cases of endometriosis and pregnancy [4,14,17]. Recent studies proved that HE4 is more effective at differentiating between benign and malignant ovarian masses than CA-125 [4,9,17,20]. Various prediction models were designed to assess the risk of malignancy in ovarian masses. The Risk of Malignancy Index (RMI) only takes into consideration the CA-125 level while the Risk of Ovarian Malignancy Algorithm (ROMA) considers both CA-125 and HE4 making the latter model more sensitive [3,8,10,17,19,20]. Genetic counseling is recommended for all women with ovarian, fallopian tube or primary peritoneal cancer [16,18]. Numerous genetic mutations associated with an increased risk of OC include breast cancer gene 1 or 2 (BRCA1/2), RAD51C/D, ARID1A, BRIP1 and PALB2, among others [6,9,15,18,19]. Genetic testing for the presence of the BRCA1/2 is recommended for all women diagnosed with high-grade EOC regardless of the age at diagnosis or family history [4,9,16,18-20]. Knowing the BRCA1/2 status in a woman can help determine the response to the tumor to platinumbased chemotherapy, maintenance therapy with PARPi, and the likely prognosis [2,4,9,14,18,20]. Patients with a known mutation in BRCA1/2, RAD51C/D and BRIP1 might benefit from a riskreducing salpingo-oophorectomy (RRSO) to reduce their risk of developing both OC and breast cancer [4,6,10,14-16,18,19]. Generally, pelvic ultrasound is an initial imaging modality to help diagnose OC and if malignant disease is suspected, patients are referred for computed tomography (CT) of the chest, abdomen, and pelvis [3-5,13,14,19,21].

When a patient is diagnosed with OC, they are required to undergo complete surgical staging involving the resection of the ovaries, uterus, fallopian tubes, infracolic omentum, and bulky lymph nodes and the inspection of bowel serosa and peritoneal surfaces [3,4,7, 8,11,12,15,16,19,21]. For patients with apparent early-stage OC, a fertility-sparing procedure can be considered with comprehensive staging rather than complete surgical staging [7-9,11,12,14,15,19]. It is important to note that endometrioid carcinoma and serous tumors are associated with a high likelihood of bilateral involvement [14]. Patients are classified as having either a high or low likelihood of achieving optimal cytoreduction [13]. If optimal cytoreduction can be achieved, primary treatment can proceed with surgery, otherwise, neoadjuvant chemotherapy is recommended followed by interval cytoreductive surgery [2,4, 7,10,13,15,16,19,21]. The aim of surgical staging is to accurately stage the disease to help plan treatment and determine likely prognosis since the risk of relpase increases in patients who are incompletely staged [4,9,12]. Since EOC is highly chemosensitive, chemotherapy constitutes a major aspect of treatment [2]. Firstline chemotherapy typically includes a combination of carboplatin and paclitaxel [21]. Adjuvant chemotherapy is recommended for patients with high grade early-stage disease due to the higher risk of recurrence [2,8,9,19]. It is not necessary for patients with lowgrade early-stage OC because they generally have a better prognosis [16]. Patients with a known BRCA1/2 mutation are advised to undergo maintenance therapy with PARPi after responding to chemotherapy [9,11,14, 16,18,21]. Participation in clinical trials for women with OC is highly recommended [2,10,19,21].

The aim of surveillance of patients with OC is to monitor improvement in symptoms related to the disease and detect any recurrences that might require additional treatment [1,21]. Patients also need to be educated regarding the importance of close followup, symptoms of recurrence and the possible complications of treatment [5,9]. Recurrence occurs in 70-75% of women with EOC [14,19]. Factors associated with a higher risk of recurrence include residual macroscopic disease following resection, age of 65 years or more, and having advanced stage at diagnosis [1]. When recurrent disease is suspected, imaging with CT is advised along with measuring tumor markers, including CA-125 [1,4,15]. Those with recurrent OC might benefit from a secondary cytoreductive surgery or further chemotherapy with or without bevacizumab in addition to palliative care [4,9,12,14,16].

A management guidewheel is aimed to provide a quick and accessible resource for the treatment of patients with OC. This is similar to guidewheels we designed for abnormal pap smears, uterine, cervical and vulvar cancer [22-25]. We also designed another guidewheel to describe the management of less common OC called Ismail’s Guidewheel on the Management of Less Common Ovarian Cancers which is covered in another manuscript. We wrote several chapters on the management of cervical cancer and abnormal pap smear results [26-29]. In general, these guidewheels reflect the recommendations on managing patients in an ideal situation with all resources available. They do not provide any modifications to managing patients during the COVID-19 pandemic. Since the NCCN guidelines are continuously updated, the recommendations on this guidewheel mainly reflect the most recent guidelines.

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References

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