Section A
by Dr. S. Trompoukis, Gynecologist

Introduction

Ovarian cancer is the 6th most common form of cancer among women, with the highest incidence rates among European and North American populations. The median age of diagnosis is 63.

It is frequently asymptomatic until the cancer has spread extensively beyond the ovary. The vast majority of the cases are found at stage 3 or later. This is mostly due to the lack of definite symptoms at the early stages of the disease development process.

Caucasian women have the highest rate. Survival is dependent on the type of and stage of cancer and the care the patient receives. For this reason, every ovarian cancer patient should ideally obtain a referral to a gynecologic oncologist before she starts any treatment or has any surgery.

 

Etiology

The exact cause of ovarian cancer is unknown, although a number of possible risk factors are thought to be involved. Risk factors are related to two major categories: menstrual cycles and family history.

The ovary is subject to a repetitive hormonal stimulus during the reproductive years. Suppression of the ovarian function, as in pregnancy and puerperium, or breastfeeding, is associated with decreased incidence. The use of combined oral contraceptives is thought to be protective, as studies have shown that users have a 30-60% smaller chance.

The more cycles a woman has over her lifetime, the higher her risk of ovarian cancer. Thus starting her period at a younger age (early menarche), ending her period at a late age (late menopause), and not getting pregnant (nulliparity) are all risk factors.

The risk of ovarian cancer increases with age and most cases occur after the menopause. The median age of diagnosis is 63 and older women have worse prognosis. However, approximately 25% of cases are diagnosed between ages 35 and 54.

Women who take Hormone Replacement Therapy (HRT) have been shown to have a slightly increased risk of ovarian cancer. However, if HRT is stopped, after five years the risk is reduced to the same level as women who have never taken HRT.

Approximately 10% of cases are genetically related. Because of this, current guidelines suggest that all women with family history of ovarian cancer should undergo testing for BRCA1 and BRCA2 mutations. If a woman has two or more relatives who developed ovarian cancer or breast cancer, she may be at higher risk of developing the disease.

 

Symptoms

The signs and symptoms, when present, are very vague. These can include fatigue, clothes suddenly not fitting, leg swelling, changes in bowel habits, changes in bladder habits (urinary urgency or frequency), back pain and shortness of breath. The early symptoms of ovarian cancer are rarely characteristic and can be difficult to recognize. The woman will complain of an ache or discomfort in the lower abdomen.

However, three main symptoms are more frequent in women diagnosed with ovarian cancer:

  1. abdominal swelling and persistent symptoms of bloating
  2. persistent pelvic and/or abdominal pain
  3. difficulty eating and getting full quickly.

 

Histological types

There are several types of ovarian cancer. They include:

  • Epithelial ovarian cancer: affects the surface layers of the ovary and is the most common type, accounting for about 70% of all ovarian cancers. The most common types are:
    • Serous adenocarcinoma
    • mucinous adenocarcinoma
    • endometroid adenocarcinoma
    • adenosarcoma
    • clear cell adenocarcinoma
    • transitional cell carcinoma
    • undifferentiated cell carcinoma.
  • Borderline ovarian tumors: often, thorough surgical staging is curative, even at more advanced stages.
  • Germ cell tumors: arise from the reproductive cells of the ovary. These tumors include:
    • dysgerminoma
    • yolk sac tumors
    • embryonal carcinoma
    • teratomas
    • mixed germ cell tumors
    • nongestetional choriocarcinoma.
  • Stromal tumors: arise from the supporting tissues within the ovary itself. The commonest subtypes are: granulosa cell tumors, sertoli cell tumors, sex cord tumors.

 

Grading

Grading refers to the appearance of cells under the microscope.

  • Low grade (well differentiated): Although abnormal, cells appear to be slowly growing
  • Moderate grade: Cells look more abnormal than low-grade cells
  • High grade (poorly differentiated): Cells look very abnormal and are likely to be fast growing

The majority of fatal ovarian cancers are high grade serous carcinomas.

 

Diagnosis

The diagnosis in early stages occurs during a routine pelvic gynecological examination, by palpation of an asymptomatic mass in the ovaries. Less than 5% of ovarian cysts in pre-menopausal women is due to ovarian cancer. In menopause, the likelihood is higher.

Unfortunately ovarian cancer is usually diagnosed late because of its lack of symptoms and it commonly metastasizes quickly and widely. Approximately 75-85% of cases are diagnosed when the disease has spread outside the pelvis. Often vague symptoms eventually lead to a clinical diagnosis, or based on suspicion generated by physical exam, laboratory tests, and imaging. However, the final tissue diagnosis and staging requires a laparotomy.

The woman may have a blood test to look for a tumor marker called CA-125 in the blood, which is a useful marker that is often, but not always, elevated with ovarian cancer. If a postmenopausal woman has a mass and an elevated CA-125, she has an extremely high risk of having a cancer (specificity of 78%). However, in young women, CA-125 is not specific to ovarian cancer and may also be raised in many benign conditions.

Various types of imaging studies can be used to diagnose ovarian cancer. Ultrasound and Computed Tomography (CT) scans are the most common. These can often give pictures that show masses in the abdomen and pelvis, fluid in the belly (ascites), obstructions of the bowels or kidneys, or disease in the chest or liver. Positron Emission Tomography (PET) scans can be used, but are often not necessary. Pap smear tests cannot detect ovarian cancer. However, fluid from the abdomen (ascites) can be removed and the cytology may reveal malignant cells.

 

Staging

Staging is the process of classifying a tumor according to the extent to which it has spread in the body at the time of diagnosis. Once diagnosed with ovarian cancer, a woman should have further tests, which may include:

  • Chest x-ray: This test may reveal if the ovarian cancer has spread to the lungs or caused a build-up of fluid around the lungs.
  • Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) scan: These imaging techniques are used to look for signs of cancer elsewhere in the chest, abdomen and pelvis.
  • Abdominal fluid aspiration: If there is a build-up of fluid in the abdomen and it looks swollen, it could mean that cancer has spread. To find out, a thin needle is passed into the abdomen to take a sample of fluid to be tested for cancer cells.
  • Laparoscopy: This small operation may be performed if the Gynecologist wants to take a better look at the ovaries. A thin tube with a camera is inserted through a small cut in the lower abdomen in order to examine the ovaries. A small sample of tissue may be taken from the ovaries for testing (biopsy).

Staging helps doctors decide on the best kind of treatment. Complete staging is often based on surgical findings and includes hysterectomy, removal of the ovaries, tubes, pelvic and aortic lymph node biopsies or dissection, removal of the omentum and peritoneal biopsies.

Ovarian Cancer has four (4) stages:

  • Stage 1: The cancer is limited to one or both ovaries.
  • Stage 2: The cancer has spread from the ovary and into the pelvis or uterus.
  • Stage 3: The cancer has spread outside the pelvis, but limited to the abdomen, or lymph node involvement, but not including the inside of the liver
  • Stage 4: The cancer has spread to the liver or outside of the abdomen

The above is a simplified guide. Each stage is divided into further categories called A, B and C. Ovarian cancer staging is determined surgically, unless it is stage 4. The survival of patients is directly correlated with the tumor stage.

 

Treatment strategies for ovarian cancer

Ovarian cancer treatment most often consists of surgery and chemotherapy. The order is best determined by a tumor board which includes a gynecologic oncologist and a medical oncologist. Since a number of difficult decisions may be required, and the surgery itself may be difficult, it is essential that appropriate specialist referral is made. In order to decide the optimal treatment path, the following must be considered:

  • The stage, grade and histology of her cancer
  • Her general health
  • Whether fertility is an issue

The treatment will depend on the stage that cancer has reached. Ovarian cancer is often diagnosed at an advanced stage (3-4), meaning the cancer has spread beyond the pelvis or to the lymph nodes. Advanced cancer may not be curable. The goal of treatment is to put the tumor into remission, which means that either shrinks or disappears.

Even if there is no possibility of complete cure, surgery may be used to remove as much of the cancer as possible. Chemotherapy can reduce symptoms such as pain by shrinking the cancer, and this can help the woman feel better. Occasionally, radiotherapy may be used to shrink the tumor.

  • Surgery: In the majority of cases, surgery is to be carried out. The extent will depend on the estimated stage of the disease, which sometimes is not possible to confirm until the time of the surgery. Operation should be carried out through a vertical incision. The standard excision comprises uterus, both ovaries and tubes, the omentum and lymphadenectomy and random peritoneal biopsies. If the disease is not localized and the cancer has spread, the surgeon will try to remove as much of it as possible. This is known as debulking surgery. This won’t cure the cancer, but may ease some of the symptoms.
  • Chemotherapy: After surgery, there is still a risk that cancer cells remain. Cytotoxic drugs are given, to destroy these cells. The need for chemotherapy depends on the stage of the disease. In some cases, it can be given before surgery as it may help shrink the tumor and make it easier to remove. This is called neoadjuvant chemotherapy. Ovarian cancer can come back (relapse) after treatment. If this happens, the woman may have another course of chemotherapy. This is called second-line treatment.
  • Radiotherapy: Uses high energy x-rays. It works by targeting rapidly growing cancer cells. Radiotherapy is not often used to treat ovarian cancer, but occasionally may be recommended, under very specific circumstances.

 

Prognosis

The prognosis depends on the stage and remains poor, due to the lack of symptoms and late diagnosis. The 5 year survival rates are generally estimated as follows:

  • Stage 1: 79%
  • Stage 2: 59%
  • Stage 3: 29%
  • Stage 4: 11%

Many factors may affect patient’s prognosis, such as her general health the histological type of the cancer and the degree of response to treatment.

 

Screening & Prevention

The screening tests for ovarian cancer are the same as those routinely used to diagnose it: a blood test (for an elevated CA-125 level), and a transvaginal ultrasound.

There is no known way to truly prevent ovarian cancer. One would think that removal of the fallopian tubes and ovaries would prevent the disease but this is not always the case.

However, there are ways to significantly reduce the risk. If a woman takes birth control pills for more than 10 years, then the risk of ovarian cancer drops significantly. Some women may be candidates for prophylactic oophorectomy, especially if at higher risk for this disease (family history, genetic risk, BRCA mutation etc). This can be planned at the end of child bearing, or at age 35. Also, losing weight through exercise and having a balanced diet may lower the risk of ovarian cancer.

 

Section B
by Dr. M. Tsiatas, Medical Oncologist

Chemotherapy for Ovarian Cancer

Following surgery for ovarian cancer, reappearance of the cancer cells in the abdomen or elsewhere in the body is still possible. For very early cases of stage 1A or 1B, this is unusual. For all other cases, chemotherapy is mandatory and certainly improves the survival of these patients, decreasing the chance of dying from ovarian cancer

Among chemotherapy drugs, the most commonly used in the treatment of this cancer are taxanes (paclitaxel or docetaxel) and platinum agents (carboplatin or cisplatin). It has been demonstrated that platinum and taxane-containing chemotherapy improves the survival of women with ovarian cancer in comparison with other types of regimens. Therefore, the combination of a platinum drug (usually carboplatin) and a taxane (typically paclitaxel) is the most common chemotherapy regimen.

In the vast majority of patients chemotherapy drugs are given into the vein (IV). However, for women with optimally resected stage 3 disease, another way of treatment is through a combination of chemotherapy both into the vein and directly into the abdominal (peritoneal) cavity. This is called intraperitoneal (IP) chemotherapy (IV/IP treatment).

The treatment strategy after operation is based upon the stage and is outlined below:

  1. Stage 1: Most women with stage 1A or 1B ovarian cancers do well without chemotherapy, and follow-up is a standard approach. Women with aggressive (grade 3) stage 1A or 1B ovarian cancers and all women with stage 1C (cancer cells in the abdomen) ovarian cancer should receive the standard chemotherapy. Treatment usually starts within 2 to 6 weeks following surgery and is given every 3 weeks for a total of six cycles. 
  2. Stage 2: Most oncologists administer 6 cycles of intravenous chemotherapy with paclitaxel plus carboplatin. 
  3. Stage 3: All patients with stage 3 disease will need chemotherapy. The  chemotherapy can be given in different ways:
  • The most common method includes 6 cycles of paclitaxel plus carboplatin given every 3 weeks. Recently, some reports indicated that adding another drug, bevacizumab, to this regimen postpone relapse and may improve overall survival. Bevacizumab is given for 18 months every 3 weeks after the initial chemotherapy.
  • Another method, which is more toxic, includes six cycles of carboplatin on day 1 with paclitaxel on days 1, 8, and 15 every three weeks.
  • Finally, the last method includes six cycles of a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy. This treatment is given every three weeks and requires placement of an IP catheter. This method is associated with significant toxicity and many patients cannot tolerate it. The drugs used are platinum and paclitaxel.
  1. Stage 4: All women require chemotherapy. The chemotherapy is given to control cancer growth and carboplatin, paclitaxel are administered as long as it is tolerated and a benefit is documented.

 

Side effects of chemotherapy

Side effects that occur during chemotherapy are usually temporary and reversible. The most frequent are nausea, vomiting, temporary drop in blood counts, numbness of fingers and toes, hair loss, bone pains, allergy etc. The numbness may last for longer period.

Bevacizumab can cause side effects that include hypertension, nose bleeds, dizziness, headache, and delayed wound healing. Women with preexisting tumor involvement of the gastrointestinal tract or history of inflammatory bowel disease appear to be at a risk for bowel perforation. 

 

Special Considerations

Neoadjuvant chemotherapy

In certain cases, it is too risky to operate initially, because of the extensive nature of the cancer and the non-operable large tumors which may infiltrate other organs. In these instances, chemotherapy may be recommended as a first step in the treatment process. This is called neoadjuvant chemotherapy. Neoadjuvant chemotherapy can shrink the tumor, making the patient a better candidate for subsequent debulking surgery.

 

Surveillance after ovarian cancer treatment

Following treatment, a patient is considered to have a "complete response" based on certain criteria: Physical examination is normal, no evidence of cancer on imaging studies and the blood levels of the tumor marker CA-125 are normal. Even when all of these criteria are normal, microscopic residual cancer can still be present. These microscopic tumor cells may be responsible for cancer recurrence later on.

The guidelines from the U.S. National Comprehensive Cancer Network (NCCN) for an accepted follow-up of patients with ovarian cancer are:

  • Doctor visits with pelvic examination every 4 months for two years, then every 6 months for three years, then annually.
  • Periodic blood tests for CA-125.
  • Chest X-ray and pelvic CT scan are indicated for patients with any abnormalities on clinical examination, or blood test.

 

Signs of recurrence

The possibility of a tumor recurrence is highest in patients who had advanced-stage disease at diagnosis, particularly if the initial debulking surgery was not able to remove all visible tumor. Among the earliest evidence of recurrent ovarian cancer is a rising blood level of the tumor marker (CA-125). It is reasonable to mention that treatment based only on the rising levels of tumor markers, and without evidence of clinical or radiological recurrence is not justified.

 

Treatment of recurrent ovarian cancer

Patients with recurrence after the initial treatment are candidates for further chemotherapy (“second-line” chemotherapy). The choice of chemotherapy drugs for second-line treatment depends upon whether the patient is platinum-sensitive or platinum-resistant, and the degree of long term side-effects from previous chemotherapies. The possibility of second operation in case of recurrence exists, especially for small tumors which can be easily removed and the time interval since the last chemotherapy is longer than 6 to 12 months.

 

Platinum-sensitive ovarian cancer

Patients with a complete response, which lasted for at least six months, are considered to have “platinum-sensitive” cancer and re-treatment with platinum-based chemotherapy is usually recommended. The longer the time interval of the complete response, the higher chance of benefit with platinum rechallenge. Other drugs can be added to platinum such as taxanes, gemcitabine, pegylated doxorubicin, bevacizumab etc, with significant benefit. Trabectedin is another option.

 

Platinum-resistant ovarian cancer

Patients are resistant to platinum in certain cases, such as no response to first line treatment, or relapse in less than 6 months from the end of chemotherapy. For these women. a variety of agents may be considered, including pegylated liposomal doxorubicin, topotecan and weekly paclitaxel, with or without bevacizumab, as well as docetaxel, gemcitabine, vinorelbine etc.

 

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