Prof. Yusuf Yıldırım

CAUSES & RISK FACTORS

Ovarian cancer refers to the malignant transformation and uncontrolled proliferation of any of the cell groups in the ovarium (epithelial cells, germ cells, sex-cord stromal cells and mesenchymal cells). The most common (85%) type of ovarian cancer arises from the epithelium that covers the outer surface of the ovary (called as epithelial ovarian cancer). When the expression "ovarian cancer" is used alone without specifying a particular name, this group of tumors is essentially what it meant. There are 8 subtypes of epithelial ovarian cancers: serous (most common), endometrioid (second most common), clear cell, mucinous, transitional, squamous, mixed and undifferentiated. While 85% of malignant epithelial ovarian tumors, i.e., epithelial ovarian cancers, are of the "invasive" (classic) type while 15% are of the "borderline" (or low malignant potential) type. Although ovarian cancer can be seen in young people, it often occurs in older ages. Half of the diagnosed cases are over the age of 65 (borderline patients are mostly in their 30s and 40s). The lifetime risk of developing ovarian cancer in a woman is approximately 1.3% (1/78). Although it is responsible for 2% of cancers in women, ovarian cancer is among the leading causes of cancer-related deaths (5th after lung, breast, colorectal and pancreatic cancers).

Although various risk factors are known that predispose to ovarian cancer, the process of cancer development (ovarian carcinogenesis) is not completely clear. Genetic syndromes are responsible for only 15% of ovarian cancers. In the remaining 85% of the cases, ovarian cancer occurs sporadically (randomly) without a genetic mutation. Factors that increase the risk of epithelial ovarian cancer include:

• Genetic cancer syndromes and mutations – There are some genetic syndromes or mutations that are known to be associated with an increased risk of ovarian cancer. These are Hereditary Breast-Over Cancer (HBOC) Syndrome, Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer-HNPCC), Peutz-Jegher Syndrome, HR (homologous recombination) gene mutations other than the BRCA1/2 mutation, MAP (MUTYH-Associated Polyposis)
• Family history of ovarian cancer
• Advanced age
• History of cancer
• History of infertility and IVF (in vitro fertilization)
• No childbirth
• Long years of menstruation
• History of pelvic radiotherapy
• Endometriosis –There is an increased risk of endometrioid, clear-cell and low-grade serous type ovarian cancers in endometriosis
• Smoking tobacco –There are studies reporting that smoking heightens the risk of mucinous type epithelial ovarian cancers.
• Factors with controversial impact – Obesity, diabetes, etc.

SYMPTOMS, DIAGNOSIS & STAGING

Early-stage ovarian cancer may not cause any noticeable symptoms. In advanced disease, the symptoms can be very diverse and non-specific (suggesting other diseases). Common symptoms are:

• Abdominal or pelvic pain
• Pelvic pressure or discomfort
• Feeling of bloating or tension in the abdomen
• Inability to relax after defecation
• Abdominal swelling (increased abdominal diameter due to mass or ascites)
• Eating difficulties, indigestion, feeling full quickly
• Change in bowel habits (constipation, diarrhea etc.)
• Frequent and sudden need to urinate
• Pain during sexual intercourse.

Physical examination, blood tumor markers, imaging methods and rarely biopsy and cytological examinations are used for diagnosis purposes. Sometimes, laparoscopy can be done to confirm the diagnosis, determine the extent of the disease and decide on operability. But most of the time, a preoperative diagnosis is not needed, and definitive diagnosis of ovarian cancer is reached during a laparotomy done for staging and surgical treatment. Tests and procedures used to diagnose ovarian cancer are:

• Physical examination (pelvic, abdominal, general)
• Tumor markers – CA125 (cancer antigen 125) is the most frequently investigated marker as it is a protein in the blood which can be elevated in the presence of ovarian cancer. Ca125 is found to be high in 90% of individuals with advanced disease and in 50% of those with Stage 1 disease. There is generally a positive correlation between Ca125 levels and disease extent and tumor burden. In some studies, it has also been reported that Ca125 levels can be prognostic (predicting disease and treatment outcomes). ACOG (American College of Obstetricians and Gynecologists) recommends referring patients with an adnexal (ovarian) mass whose blood CA125 level is above 200 IU/ml in the premenopausal period and above 35 IU/ml in the postmenopausal period to a Gynecological Oncologist for definitive diagnosis and appropriate management. 
• Imaging methods (including transabdominal/transvaginal ultrasound and advanced imaging tests)
• Endoscopic examinations (colonoscopy, gastroscopy)
• Breast examination
• Endometrial biopsy
• Cytological examination
• Percutaneous (external) biopsy techniques
• Laparoscopy
• Laparotomy.

On the other hand, many different problems (especially in young women) can mimic or be confused with ovarian cancer. Despite examination, ultrasound, tumor markers and advanced imaging tests, it is still sometimes not possible to distinguish between ovarian cancer and a benign disease without performing a laparotomy (or laparoscopy). Some conditions that should be considered in the differential diagnosis of ovarian cancer (which can be confused with ovarian cancer) are:

• Benign ovarian tumors (e.g., cystadenoma, teratoma)
• Functional ovarian cysts (e.g., corpus hemorrhagicum cyst, follicle cyst)
• Endometriosis and chocolate cysts
• Ovarian torsion
• Tubo-ovarian abscess
• Pedunculated (subserous) fibroids
• Pelvic (located in the lower abdomen) kidney
• Colon cancer
• Colon diverticulum
• Endometrial (uterine) cancer
• Metastasis of other cancers (stomach, colon, pancreas, breast etc.) to the ovary.

The TNM staging system recommended by AJCC (American Joint Committee on Cancer) and FIGO (the International Federation of Gynecology & Obstetrics) is used for staging of ovarian cancer (size of T-primary tumor and its relationship with neighboring structures and organs; spread to N-lymph nodes; M-distant metastasis). Current "pathological stages" of ovarian cancer (pTNM) are:

• Stage 1 – The tumor is limited to one or both ovaries, there is no regional (pelvic or para-aortic) lymph node involvement and distant metastases, but tumor cells can be found on the ovarian surface and peritoneal washing fluid (T1-N0-M0). Stage 1 has three substages: Stage 1A, Stage 1B, Stage 1C
• Stage 2 – Pelvic (adjacent organs or pelvic peritoneum) spread. There is no spread to the lymph nodes and outside of the pelvis (T2-N0-M0). Stage 2 has two substages: Stage 2A, Stage 2B
• Stage 3 – Peritoneal spread outside the pelvis or regional (pelvic and/or paraaortic) lymph node involvement (T1/2-N1-M0 or T3-N0/1-M0). This stage has three substages: Stage 3A, Stage 3B, Stage 3C
• Stage 4 – There is metastasis other than peritoneal spread (any T-any N-M1). Stage 4 has two substages: Stage 4A, Stage 4B.

Almost 80% of invasive epithelial ovarian cancer cases are diagnosed as advanced stage (Stage 3-4) disease due to the absence or scarcity of warning symptoms in the early stage. On the other hand, 80% of the cases in the "borderline" subgroup are diagnosed in Stage 1.

TREATMENT & PROGNOSIS

Ovarian cancer treatment usually consists of a combination of surgery and chemotherapy. The standard approach is surgical removal of visible tumor tissue and potential areas of tumor spread followed by systemic (intravenous) chemotherapy. Other treatment modalities are targeted (smart) drug therapy, immunotherapy, hormone therapy and rarely radiotherapy.

Clinical, surgical and pathological data, as well as various biomarkers (biomarker testing: genomic/molecular/mutational profiling or testing) are used to guide treatment. Germline (innate and found in all cells) or somatic (only found in tumor cells and acquired) BRCA mutation (and/or HRD positivity) is a good marker for response to PARP inhibitor group targeted drugs. Therefore, germline BRCA mutation should be investigated in all ovarian cancer patients. If no germline mutation is detected, a somatic BRCA mutation search should be done. Tumor mutational burden (TMB) refers to the total number of tumor mutations and determines the number of acquired somatic mutations in the tumor. Tumors with TMB-H (high tumor mutation burden) are more likely to benefit from cancer immunotherapy. Other biomarkers used for immunotherapy are MSI/MMR and PD-L1.

Treatment in Stage 1 Ovarian Cancer

Initial treatment is “staging surgery”. According to the substages, the post-surgical approach varies according to the Grade and what the substage is. If it is Grade 1 in Stage 1A/1B, only close monitoring is needed without additional treatment. If it is Grade 2, close monitoring or 3-6 cycles of chemotherapy (paclitaxel/docetaxel + carboplatin/cisplatin) can be applied. If it is Grade 3 or Stage 1C, 3-6 cycles (6 cycles in “high-grade serous” type cancer) chemotherapy is administered.

Treatment in Stage 2-4 Ovarian Cancer

Cytoreductive/debulking surgery (and incorporating HIPEC with surgery in appropriate cases) is followed by 6 cycles of chemotherapy. The VEGF inhibitor “Bevacizumab (Altuzan®)” can be given concomitantly (or following chemotherapy). Altuzan® alone or in combination with Olaparib (Lynparza®) can be sustained for up to 1 year (“maintenance” therapy).

Those who are in stage 3/4 and whose general condition is not suitable for primary surgery can be initially given 3-4 cures of chemotherapy and then (interval) surgery. Subsequently, 3 more cycles of chemotherapy are given.

Treatment in Recurrent Ovarian Cancer

Surgical treatment (+/-HIPEC) should be considered initially, if the general condition of the patient, location and extent of the disease are appropriate. With or without surgery, most patients will receive chemotherapy again. If the cancer recurred more than 6 months after the last course of chemotherapy (platinum-sensitive disease), the chemotherapy Palitaxel + Carboplatin that was initially given is usually re-administered. In other cases, different chemotherapy agents are considered. In relapsed disease, targeted (smart) drugs (including use for "maintenance" therapy) of the PARP inhibitor group, such as Bevacizumab (Altuzan®) and Olaparib (Lynparza®), Niraparib (Zejula®) or Rucaparib (Rubraca®) can be administered.

Types of Ovarian Cancer Surgery

Surgery is the main component of ovarian cancer treatment and plays a vital role for long-term survival. Unlike many other solid tumors, in ovarian cancer surgical treatment is unique as it gives very good results in all stages of the disease and in relapses.

Ovarian cancer surgery can be defined in different ways depending on their purpose and scope:

• Staging surgery (including fertility/organ-sparing surgery)
• Re-staging surgery: for patients who have undergone understating surgery or who have ovarian cancer incidentally detected in their pathology reports
• Radical (cytoreductive) surgery (CRS)
• Second-look surgery: “Surgical second look” done 4-6 weeks post adjuvant chemotherapy which is given after the completion of primary surgery
• Palliative surgery: surgery to relieve symptoms.

Staging surgery

Before attempting to remove and staging the tumor, a detailed intra-abdominal review (detailed surgical exploration) must be done to reveal disease extent and resectability. Thus:

• Checking for ascites (fluid accumulation in the abdomen)
• Investigate primary tumor characteristics and capsule integrity
• Examination of the contralateral ovary and uterus for the presence of metastatic tumor
• A careful examination of the peritoneal surfaces and intra-abdominal organs from the culde-sac (the deepest point of the abdominal cavity) to the diaphragm (by eye and by hand)
• Evaluation of retroperitoneal lymph nodes

In a patient who was operated for a limited ovarian mass (localized disease), a rapid pathological evaluation called "frozen section" examination can be applied to confirm ovarian cancer diagnosis. In invasive type of epithelial ovarian cancer, the accuracy rate of frozen is around 98%.

However, the chance of success in “borderline” epithelial tumors and non-epithelial cancers is low (78%). Frozen is not needed where there is obvious peritoneal (peritoneal) invasion.

Procedures during surgical staging of early ovarian cancer include:

• Peritoneal cytology – taking a sample if there is ascites, otherwise doing multiple cytological washings from the peritoneum
• Peritoneal biopsies – If there are suspicious areas in the peritoneum take sample, if not, take random peritoneal biopsies
• TAH-BSO – Removal of the uterus, ovaries and fallopian tubes
• Omentectomy – Removal of the intra-abdominal fatty tissue between the stomach and the colon
• Appendectomy – Applicable in mucinous tumors
• Retroperitoneal lymph node dissection (RPLND) – Removal of lymph nodes around major vessels such as the pelvic veins, aorta and vena cava.

Sentinel lymph node biopsy (SLNB), which is frequently used method in breast cancer and some other tumors instead of standard lymphatic dissection in ovarian cancer staging surgery, though its efficacy has not been proven yet (today it is an experimental and research topic).

A fertility/organ-preserving (conservative) approach is used in some ovarian tumor surgeries in women of childbearing age who have not yet had children or who want to preserve their fertility. Provided that the uterus and one ovary are preserved via "staging surgery". While this approach is usually the case for "borderline" epithelial tumors and "malignant" germ cells or stromal tumors, it is sometimes possible in selected patients with invasive epithelial ovarian cancer. The following criteria are sought for a fertility-sparing surgical approach:

• Consent of self and family with strong fertility desire
• Acceptance of close oncological follow-up and further (after giving birth) complementary surgery
• No negative fertility history (e.g., no repeated unsuccessful IVF attempts, etc.)
• Age <40 and/or good ovarian reserve
• Does not have dysgenetic gonads
• Unilateral tumor that has not protruded beyond the ovary (Stage 1A).

In early-stage tumors where the ovaries cannot be preserved (bilateral), alternative fertility preservation options such as ovarian tissue freezing can also be considered. It should be noted that the pregnancy rate after ovarian tissue freezing is not as high as in embryo and oocyte freezing processes.

Radical (Cytoreductive/Debulking) Surgery

In advanced stage disease, in addition to the standard "staging surgery" procedures performed in patients with early-stage disease, removal of tumor spread peritoneal areas and organs (peritonectomy and multi-visceral organ resection) to reduce the tumor burden. As mentioned earlier, this procedure is called “cytoreductive/debulking surgery (CRS)” and it is very crucial to do it at the maximum level to increase survival rate. Optimal/maximal cytoreductive surgical procedures:

• Peritonectomy: anterior parietal, paracolic, pelvic, diaphragmatic, bursa omentalis, hepato-duodenal ligament
• Colon resection (with or without colostomy)
• Small bowel resections (with or without jejunostomy/ileostomy)
• Liver resections: metastasectomy, segmentectomy, lobectomy (right/left)
• Cholecystectomy (removal of the gallbladder)
• Splenectomy (removal of the spleen)
• Distal pancreatectomy (removal of the pancreatic tail section)
• Partial gastrectomy (partial stomach removal)
• Urinary system resection
• Adrenal gland resection
• Abdominal wall resection
• Diaphragm full-thickness resection
• Resection of pleural (lung membrane) disease.

Traditionally, a scoring system called the Peritoneal Cancer Index (PCI) is used to assess the disease severity of extensive disease. Here, in each of the 13 regions in the peritoneal cavity, the size of the largest tumor nodule is measured and scores ranging from 0-3 are given for each region (“0” if no visible tumor is present; “1” if the largest tumor nodule is less than 0.5 cm; “2” if tumors measure between 0.5 cm and 5 cm; and “3” for lesions larger than 5 cm. The total score is noted as PCI (total maximum score 13x3 = 39). Surgery performed in cases with PCI>20 is difficult, risky and with very limited benefits. Recently, other than PCI scoring systems (e.g. Peritoneal Surface Disease Severity Score-PSDSS)  have been used.

"Surgery First" or "Chemotherapy First"?

In cases with good general condition and no extra-abdominal disease, treatment is usually started with "upfront surgery" (staging or cytoreductive). In the following group of patients, we prefer to start with neoadjuvant chemotherapy instead of "primary surgery":

• Lung, bone or brain metastases
• Diffuse pleural involvement or cytology positive pleural fluid
• Multiple parenchymal liver metastases
• Radiological “peritoneal cancer index (PCI)” >20
• Clinically and radiologically fixed/unresectable disease
• Estimated operation time >8 hours
• ECOG performance ≥3

Adding HIPEC to Surgery

Although not a standard approach, regional chemotherapy in the form of "intra-abdominal heated chemotherapy" (HIPEC-Hyperthermic Intraperitoneal Chemotherapy) can be incorporated with surgery, especially in Stage 3 or recurrent disease. Therefore, a patient’s medical/surgical performance must be suitable, and the post-surgical disease burden should be "minimal residual disease" (diameter of the largest visible tumor remnant ≤2.5 mm) or "microscopic" (no visible residual tumor).

The procedure is generally performed by circulating various chemotherapy drugs in the abdomen for 30-120 minutes in a closed environment at an average temperature of 42°C, with 2-4 liters of fluid, over 2 inlet and 2 outlet cannulas.

The ideal timing for HIPEC is controversial. There are those who argue that it would be more appropriate to apply frontline (in the first diagnosis), interval (surgery after 3-4 chemotherapy), consolidation (during the second look of the surgery after the initial treatment is completed) or relapse.

Although HIPEC has certain complications and risks (15-20% serious complications and 1-5% mortality), it can provide an additional survival advantage of approximately 12 months in selected cases.

Who Should Perform the Surgery?

The following 3 factors, which are also related to each other, have proven to be very important in ovarian cancer surgery. These are the amount of residual disease after surgery, the level and volume of expertise of the surgeon and health care standards of the hospital where the surgery is taking place. When regarding residual disease amount:

• Maximal/complete cytoreduction (no visible residue): Provides excellent survival outcomes
• Optimal cytoreduction (minimal residue = greatest residue ≤2.5 mm): Provides good survival outcomes
• Optimal cytoreduction (largest residue ≤5 mm): Provides moderate survival outcomes
• Suboptimal cytoreduction (largest residue >5 mm): Associated with poor survival outcomes.

Many studies have shown that; doing the first surgery of both early and advanced stage ovarian cancer patients by an experienced and high-volume “Gynecological Oncologist” increases survival. However, unfortunately, women with ovarian cancer receive substandard and suboptimal care even in Europe and America. Studies published in Norway and the USA have revealed that only less than 50% of patients are operated in appropriate centers and by appropriate surgeons which negatively affected survival rate. Ovarian cancer is a “peritoneal surface cancer” that can affect not only genital organs but also many intra-abdominal organs due to its biological behavior and nature, therefore, it is a disease that requires specific surgical expertise. When ovarian cancer surgery is conducted by experienced and high-volume Gynecologic Oncologic Surgeons who are specialized in this field:

• Shorter operating time
• Less complication rate
• Higer rate of early detection and correction of a possible complication
• Less re-operation rates
• Less need for intensive care and the duration of stay in the intensive care unit
• 70% less surgery-related death rates
• Less tumor scattering and spreading during surgery
• More optimal surgery rates
• Less recurrence
• Longer survival time
• More chances of long-term survival.

It is important to inquire and research the surgeon who will conduct your ovarian cancer surgery for; area of expertise, professional experience, having sufficient notion of "oncological surgery", having cancer-specific work experince, volume of surgery (how many ovarian cancer surgeries performed per year), having the competence to manage problems that can arise during and after surgery and working with a hospital that have the appropriate infrastructure for the surgery. Prof Yusuf Yıldırım,MD has a unique position in ovarian cancer surgery with his gynecological oncology specialization as well as his general surgical oncology proficency. He has more than 20 years of experience in the field and is one of the highest volume surgeons in Turkey with thousands of ovarian cancer surgery cases. He also pioneered regional hot chemotherapy (HIPEC) practices, conducted international multicenter researchs on ovarian cancer, made innovations and gave subspecialty trainings. He performs surgeries in a high standard JCI (Joint Commission International) accredited hospital.

Treatment Success and Prognosis (outcome)

The prognosis of ovarian cancer varies depending on the patient, disease and many factors associated with treatment. It should be noted that the biology of the tumor, the mechanism of counteracting cancer and the response to treatment may differ in each patient and long-term survival can sometimes be achieved even in Stage 4 disease. In fact, although it is rare spontaneous regression of the tumor is also possible. Therefore, it is important for patients to participate in relevant treatment processes without despair and to keep their morale-motivation high, regardless of disease stage. The main prognostic factors in ovarian cancer are:

• Stage (disease extent) – Stage is an important prognostic factor in invasive epithelial ovarian cancers, with 5-year survival rates according to stages being around 90%, 75%, 45% and 15% in Stage 1/2/3/4, respectively.
• Optimality of surgery and amount of post-surgical residue – Extensive residual disease after surgery (suboptimal cytoreduction) is associated with poor prognosis. In cases where the first surgery is performed by experienced gynecological oncologists, optimal surgery rates and thus, long-term survival chances are higher.
• Tumor type and grade – “High grade” and “clear-cell histology” are negative indicators.
• Genomic/molecular profile of the tumor (biomarker testing results) – Tumor mutation profile (e.g., TP53 mutation and other mutations) can provide insight into treatment response and prognosis.
• CA125 level – Although the relationship of preoperative Ca125 level with prognosis is controversial, the lack of expected CA125 reduction after surgery and during chemotherapy seems to be associated with an adverse outcome.
• Age and performance status – The prognosis is worse in patients over 65 years of age and with a low overall quality of life score and physical performance.
• Conditions of care and level of psycho-social support – Treatment outcomes are better in patients with good care conditions and high psycho-social support.

You can visit our current website “oncosurgery.com.tr” for further information about ovarian cancer and its surgery.