Ovarian cancer is a gynecological cancer that originates from the surface of the ovaries. The ovaries are two small intra-abdominal organs that, during reproductive age, cyclically produce the egg cell or ova. Over the years, the ovary gradually decreases its activity until you get to a state of quiescence that determines the menopause.

STAFF

At the IEO ovarian cancer is treated by a multidisciplinary team consisting of specialists in:

• Gynecologic Cancer Surgery
• Gynecologic Cancer Medical Treatments
• Unit of Preventive Gynecology
• Innovative Therapeutic Strategies in Ovarian Cancer Unit
• Peritoneal Cancer Surgery Unit
• New Drugs and Early Drug Development for Innovative Therapies
• Department of Pathology and Laboratory Medicine
• Department of Medical Imaging and Radiation Sciences

Ovarian cancer originates from the surface of the organ and can be benign or malignant.

Benign ovarian cancer does not cause metastases, while the malignant ones can metastasise to other parts of the body. Malignant ovarian cancers are mainly divided into cancer and stromal tumours; epithelial carcinomas account for 90% of malignant ovarian cancers. It has recently been shown that epithelial ovarian carcinoma is not a single ovarian tumor but combines different diseases with different biological behaviour. A specific consideration is deserved for borderline ovarian cancers, for which conservative surgery is always indicated.

Despite the relatively low incidence of ovarian cancer, it is carries the burden of high mortality. Ovarian cancer affects all ages with greater frequency between 50 and 65 years.

About 5% of women diagnosed with ovarian cancer present a genetic mutation (BRCA1, BRCA2, Lynch syndrome) of hereditary/family nature, which increases the risk of this and other types of cancer.

Risk factors for ovarian cancers

Epidemiological studies have identified the following risk factors for ovarian cancer:

• Nulliparity
• First pregnancy after age of 35
• Hormone therapy
• Early menarche
• Late menopause
• Persistent inflammation of the pelvis (pelvic inflammatory disease)
• Ovarian stimulation for in vitrofertilisation (especially for "borderline" cancers)
• Breast cancer diagnosed at a young age
• Endometriosis (1)
• BRCA1, BRCA2
• Lynch syndrome type II.

Protecting factors for ovarian cancers

• 25 years or less at first pregnancy
• High number of pregnancies
• Use of oral contraceptives
• Breastfeeding (2).

There are no known pre-cancerous lesions of ovarian cancer. For this reason, there is no preventive screening. However, certain factors have demonstrated a reduction or an increase in the risk. In particular, women who took the oestrogen-progestin pill for contraception for more than 15 years have half the risk of developing ovarian cancer; ovarian cancer risk decreases by 20% after only 5 years of taking the contraceptive pill. Furthermore, the protective effect remains after 30 years from the suspension of the pill, although it tends to decrease with time. The protective effect seems to be due to inhibition of ovarian function while taking the contraceptive.

Finally, prophylactic oophorectomy, namely bilateral removal of the healthy ovaries and fallopian tubes, can reduce the risk of ovarian cancer by about 90-95%, as well as breast cancer, especially if endocrine-responsive, when performed in pre-menopausal aged women with BRCA1/BRCA2 genetic mutation. The risk of ovarian cancer does not vanish because there is still a 2-4% risk of developing peritoneal primary tumours.

It is recommended to perform the surgery in patients with genetic ovarian cancer risk after completion of reproductive activity or if they are over 35 years old. According to the most recent data, a significant percentage of ovarian cancers seems to originate from the cells of the distal part of the fallopian tubes, so a single salpingectomy should reduce the risk of ovarian tumor. It has not yet been shown that this procedure can substitute prophylactic oophorectomy in women with a genetic ovarian cancer risk.

NOTE

(1) Endometriosis is a disease characterised by the cells lining the uterus (endometrium) that forms outside of this organ. It can be found mainly in the pelvis (ovaries, bowel or bladder) and more rarely in other organs (skin, lungs), where the cells continue to be stimulated by sex hormones and periodically undergo proliferation and exfoliation, resulting in bleeding. In recent years, the association between endometrial clear cell ovarian cancer and endometriosis has been demonstrated. The transformation of endometriosis into cancer is a rare event. Neoplastic degeneration occurs in 0.4-1% of cases and typically occurs in the third to fourth decade of life. In 80% of cases the ovary is involved, but the neoplastic process may affect any other part of endometrium. It is important that women with endometriosis undergo periodic inspections, particularly above the age of 35.

(2) Other protective or risk factors are related to eating habits.

a) According to the National Cancer Institute being overweight/obesity increases the risk of ovarian cancer by 80% in the age between 50 and 70.

b) Low fat diet reduces the risk of ovarian cancer in general, according to the study Women's Health Initiative Dietary Modification. After 4 years, women who reduce fat intake show a 40% lower risk of developing ovarian cancer.

c) Use of tea. A study conducted by the University of Washington on 2,000 women revealed that women who drink at least one cup of green tea every day have a 54% lower risk of ovarian cancer. A study by the National Institute of Environmental Medicine in Stockholm showed that a cup of black tea a day reduced the risk by 50%.

Classification of ovarian cancers

Ovarian cancers can be classified into the following categories according to the cells they are derived from.

Epithelial cancers

Epithelial cancers derive from epithelial cells lining the ovary. They represent about 90% of malignant ovarian cancers. They can be divided into two types - type 1, low-grade serous cancers, mucinous, endometrial cancers and clear cell cancers, and type 2, high-grade serous cancers that represent the most common ovarian cancer, often diagnosed at an advanced stage.

Germ cell cancers

These represent about 5% of ovarian cancers and arise from the cells from which the ova derive. Eighty percent of cases occur before the age of 30. They include teratomas, dysgerminomas, endodermal sinus tumours and choriocarcinomas.

Stromal or sex cord cancers

These are rare, originate from the connective structures, and produce oestrogen and progesterone. On average, they occur during the sixth decade of life and metastasise in the latter stages. The main ones are granulosa cancers, granulosa-theca cancers, and Sertoli-Leydig cancers.

Borderline cancers

These ovarian cancers have a low degree of malignancy, with little tendency to metastasise, and in the majority of cases, it is possible to totally remove only the lesion while preserving a large amount of ovarian tissue. They are often diagnosed at a young age and generally have a good prognosis, but may give rise to type 1 epithelial cancers. This type of ovarian cancer tends to recur, but young patients can still benefit from a conservative approach. As emerged from a study conducted at our institution, relapses grow by an average of 1 mm per month, allowing the patients to be followed up for long periods without any need for timely surgical intervention.

Primary peritoneal cancers

These types of ovarian cancer are rare, arise from serous cells lining the pelvis and abdomen, and can occur even in women who have undergone annexectomy.

Symptoms of ovarian cancer

The vast majority of women have non-specific symptoms of ovarian cancer, with large differences among individuals. The most common signs of ovarian cancer are abdominal discomfort or pain, bloating, indigestion, feeling of pressure, cramps, difficulty eating or feeling full quickly even after a light meal. Other signs of ovarian cancer are nausea, diarrhoea, constipation, increased urinary frequency and/or urgency, unexplained weight loss or gain, loss of appetite, and abnormal vaginal bleeding.

These ovarian cancer symptoms do not indicate the presence of ovarian cancer, but it is good practice to obtain in-depth investigations, particularly in the case of new-onset ovarian cancer symptoms - less than six months - that last for more than three months and occur more than 12 times per month. A gynaecological evaluation with TVS and CA125 assay is recommended if at least two signs of ovarian cancer with the above-described characteristics occur. Using these symptoms of ovarian cancer for screening purposes is neither sensitive nor specific, in particular for identifying the early stage disease.

It is important to know that...

• one out of ten cancers is family-based and can be prevented
• the contraceptive pill can prevent up to 60% of ovarian tumours
• yearly gynaecological examination is not useful for the purposes of early diagnosis of ovarian tumor, while the transvaginal ultrasound, despite being the best diagnostic tool of ovarian cancers, cannot reduce mortality
• ovarian cancer is a silent disease, but even the slightest nuanced symptoms can raise suspicion and hasten diagnosis
• the quality of the first surgery impacts on survival from ovarian cancer

Signs of ovarian cancer in symptomatic and asymptomatic patients

Cells that cause early metastases in other organs flake off the malignant ovarian tumour. The ovarian surface is in close contact with the abdominal structures, so the cells from the ovarian tumour spread into the abdominal cavity and give rise to metastatic implants when the ovarian cancer is still very small. In turn, these systems are so small that they do not cause symptoms of ovarian cancer. When symptoms of ovarian cancer appear the disease is already at an advanced stage. For this reason, in asymptomatic patients there is no chance of conducting any prevention screening and obtain early diagnosis in the case of ovarian cancer, which consequently has high mortality rates.

The diagnosis of ovarian cancer is achieved in most cases through a trans-vaginal ultrasound (TVS). The TVS is a minimally invasive test that evaluates the ovarian morphology very well and is much more accurate than clinical examination. TVS is indicated when there are symptoms of ovarian cancer. However, it cannot be used for the screening of asymptomatic women because the ovarian cancer originates as already metastatic and so the ultrasound diagnosis could never form an early diagnosis. In addition, a negative test does not exclude the possibility of the appearance of an already advanced ovarian cancer within a few months. As it is an operator-dependent examination, the quality of execution is an important factor. Despite all its limitations, TVS is the first diagnostic test in women with suspected ovarian cancer and in high-risk patients.

Other tests include the measurement of Ca125 and HE4 markers (1), where clinical examination or ultrasonography result in suspected ovarian cancer, and a careful clinical examination of the pelvis, with abdominal palpation and vaginal exploration. Often it is also necessary to use a rectovaginal exam in order to assess the pelvis more deeply. (2)

Note

(1) CA 125 (Cancer Antigen 125) is a glycoprotein produced by various organs such as the uterus, cervix, fallopian tubes and the lining cells in the organs of the respiratory tract and abdomen. When one of these tissues is damaged or inflamed, it is possible to find small amounts of CA125 in the blood. An increase of this marker in younger women is less likely to be related to a diagnosis of ovarian cancer because the marker may be increased in the event of pregnancy, menstruation, uterine fibromatosis, adenomyosis, endometriosis, pelvic inflammatory disease or liver disease. Less than half of ovarian cancers at an early stage induce an increase in plasma levels of CA125.

Another marker was recently found called HE4 (human epididymis Protein 4). It is more specific and more sensitive than CA125 in the diagnosis of ovarian cancer. Compared to CA125, HE4 may make it possible to identify 7 additional cases of cancer every 1000 patients investigated. The combined use of CA125 and HE4 is less sensitive but more specific, since it eliminates increases in CA125 levels due to diseases that are not ovarian.

(2) Although clinical evaluation has low sensitivity and through clinical examination no more than 45% of the tube-ovarian masses can be detected, abdomen evaluation, vaginal exploration and palpation of any enlarged lymph nodes (lymphadenopathy) are essential to appreciate the mobility and the eventual tendency to determine pain of the pelvic structures as well as the presence of pelvic masses and abdominal fluid (ascites).

Ovarian Cancer Center

Opened in September 2008, the Center’s specific aims are:

Patient Care

Diagnosis: ultrasound and radiology specialists are available to patients with ovarian cancer using the most modern diagnostic tools.

Surgery: a close collaboration between Gynaecological Surgeons, General Surgeons, Anaesthetists and Pathologists provides the best surgical treatment to patients with ovarian cancer. Different approaches are employed, tailoring the most appropriate surgery for each patient: from minimally-invasive fertility-sparing surgery for young patients with early ovarian cancer to the most aggressive surgical debulking for patients with advanced ovarian cancer. More than 450 patients are treated surgically for primary/recurrent ovarian cancer.

Chemotherapy: Gynaecological Oncologists offer the most innovative ovarian cancer treatments, also allowing patients to participate in both National and International Trials. More than 2500 chemotherapies are administered yearly to patients with ovarian cancer.

Supportive Therapy: psychological, nutritional support and palliative care are offered to all patients affected by ovarian cancer by dedicated physicians and nurses.

Research

Many collaborative trials and clinical/translational research projects are ongoing in order to improve the outcome of patients with ovarian cancer.

Education

ESGO fellowships for young Gynecologists and the ESAGON School (European School of Abdominal/Pelvic Surgery) are part of the Ovarian Cancer Center programme with the aim of training new generations of Gynaecological Oncologists and offering better care to patients with ovarian cancer.

Surgery

Surgery is essential in ovarian cancer management. Depending on the type and spread of the ovarian tumor, surgery can be performed through laparoscopy or traditional laparotomy, and may have purposes of diagnosis, staging, cytoreduction or debulking the ovarian cancer. When an operation for complete staging of the ovarian tumor has to be performed or for optimal debulking, a median longitudinal incision is carried out, starting at the pubis and stopping either at the umbilicus or proceeding higher up in order to explore the liver, diaphragm and spleen.

In the case of advanced ovarian cancer, the goal of surgery consists in removing all of the macroscopically visible cancer. If obtained, this result itself improves prognosis and promotes the effect of antineoplastic drugs. From data published in international literature, it is clear that patients who undergo optimal cytoreductive surgery (no visible ovarian cancer at the end of the intervention) have a significantly better prognosis compared to patients who undergo sub-optimal surgery (presence of residual ovarian cancer). To date, primary cytoreduction should be considered the standard treatment of ovarian tumor.

Minimally-invasive surgery

In cases in which the ovarian tumor seems to be limited to the ovary, patients can be referred for minimally-invasive surgery. At our institution, the majority of these surgical procedures is performed with the help of the Da Vinci robotic system. Robotic surgery provides patients affected by ovarian cancer, with all the now well-known and validated advantages of the conventional minimally-invasive approach, that also include less intra-operative blood loss and a shorter hospital stay, both associated with a better quality of life and cosmetic result, due to the presence of small cutaneous scars.

Early-stage ovarian cancer patients can benefit from the advantages of robotic surgery thanks to its unique versatility of application. The minimally-invasive approach can also be used in cases of ovarian cancer patients, who undergo laparotomy with incomplete staging. This approach allows an optimal view of the diaphragm and paracolic lodges.

Ovarian cancer staging is based on the surgically-performed balance of lesions in the abdomen and pelvis.

First line chemotherapy

Many patients with ovarian cancer need chemotherapy after surgery. In general, paclitaxel and platinum are the most frequently-used drugs. The majority of patients receiving chemotherapy for ovarian cancer have an excellent quality of life. Other drugs used for the therapy of ovarian cancer are liposomal doxorubicin, Topotecan, Gemcitabine, Etoposide, etc.

Ovarian cancer metastases

The most common sites of extra-peritoneal disease qualifying for stage FIGO IV are malignant pleural effusion in 33–53%, liver in 14– 26%, subcutaneous/abdominal wall in 10–41%, and extra-abdominal lymph nodes in 5–44%; brain metastases (0.3–2.2% ) and bone involvement (2%) are uncommon.

Life expectancy of FIGO IV patients with metastatic disease greatly depends on the residual tumor burden and the response to chemotherapy and, therefore, 5-year-survival rates vary between 8% and 39% for suboptimally and optimally debulked patients, respectively.

The first step in patients with stage FIGO IV with metastatic disease should be to assess whether the patient´s performance status and comorbidities allow state-of-the art treatment or only modified standard treatment (chemotherapy and radiotherapy) - or even makes the patient a candidate for best supportive care and palliative care for symptom relief “only”.