Ovarian Cancer

The ovary is part of the female reproductive system. Women have two ovaries, located at both sides of the uterus. The ovaries are almond-shaped and each is about 1.5 inches in length. Ovary is the main source of human oestrogen and progesterone (female hormone). Ovary contains eggs, which are also known as germ cells. The female hormones allow the growth of breasts, changes in body shape and body hair, regulation of menstrual cycle and pregnancy. After menopause, the ovaries stop releasing eggs and the female hormones.

Ovarian cancer generally refers to malignant tumours that affect the female ovaries. There are different types of ovarian cancer. Although they are all collectively called “ovarian cancer”, in fact, their respective origin under microscope, treatment and prognosis are different.

Ovarian cancer ranks sixth among the top ten common cancers of women in Hong Kong, with about 400 new cases every year. Most ovarian cancers occur after menopause. The average age of diagnosis is 55 years old. 1 in 95 women might develop ovarian cancer. Ovarian cancer is difficult to detect in its early stage as the patient may not have obvious symptoms. Patients with early staged ovarian cancer may have mild abdominal discomfort only, which may be mistaken as a symptom of indigestion.

Risk factors of ovarian cancer include:

• Have never given birth
• History of miscarriage
• Menopause at an older age
• No breastfeeding before
• Having a family history of ovarian or breast cancer (especially first-degree relative: mother, sister, aunt)
• Excessive use of assisted reproductive therapies
• History of polycystic ovaries
• Overweight or obesity, taking too much fatty food
• History of breast cancer
• Had used hormonal replacement therapy over 5 years after menopause
• Getting older: Older adults are at a higher risk of having ovarian or fallopian tube cancer. Over half of the ovarian cancer patients are over 63 years old at diagnosis.
• Inherited BRCA1 or BRCA2 gene

Since ovaries are located deep inside the pelvic cavity, early symptoms of ovarian cancer are not obvious. Attention should be paid to the following symptoms:

• Bloating
• Pelvic or abdominal pain
• Changes in appetite, such as loss of appetite or easy fullness
• Frequent urination

Ovarian cancer patients may also experience the following symptoms:

• Fatigue
• Back pain
• Pain during sexual intercourse
• Constipation
• Irregular menstruation
• Weight loss

Symptoms of ovarian cancer are often mistaken for minor ailments such as epigastric pain or minor abdominal pain. If the symptoms have persisted for weeks and worsen, please consult a doctor and seek medical help.

Doctor will perform the following investigations to confirm the diagnosis.

1. Pelvic Examination

Your doctor will first examine the external genitalia, vagina and cervix to check for any abnormalities. Then, the doctor will put one hand over the abdomen and one hand in the vagina to check the uterus, rectum and pelvis for any abnormal mass.

2. Blood Test

You may have blood test for serum CA-125 which is a tumour marker or ovarian cancer. Ca-125 is usually raised in patients with ovarian cancer. Ca-125 may also be raised in other benign conditions, e.g. endometriosis, pelvic inflammatory disease or uterine fibroid.

Moreover, if ovarian germ cell tumour is suspected, your doctor may check for other tumour markers, such as human Chorionic Gonadotropin (hCG), α-fetoprotein (AFP) and lactate dehydrogenase (LDH).

3. Ultrasound

Your doctor may perform a transvaginal or abdominal ultrasound to detect any abnormalities or tumours in the ovaries and uterus.

4. CT/ MRI

CT or MRI scans can check for the size of the tumour, and any metastasis to other parts of the body.

5. Laparoscopy

Laparoscopy is carried out under general anaesthesia and you will not feel any pain. During laparoscopy, the surgeon makes one or more small incisions in the abdomen. These allow the surgeon to insert the laparoscope, small surgical tools, and a tube used to pump gas into the abdomen. This makes it easier for the surgeon to look around and operate. During the procedure, the surgeon will check for the tumour location, any spread to the peritoneum and decide if resection can be done completely. The surgeon may also take biopsy for histology during laparoscopy.

6. Tissue biopsy

Biopsies for ovarian or fallopian tube cancer are often done as part of the first surgery.

During operation, the surgeon will remove the ovaries and fallopian tubes then send for pathological diagnosis. This is called surgical staging. If the tumour cannot be resected and has spread to the peritoneum, your surgeon will take tissue biopsy from the peritoneum. If you have ascites (fluid in the abdomen), your doctor will also send the fluid for cytology.

Ovarian cancers are classified according to their cells of origin, including:

• Epithelial ovarian carcinoma
  • Epithelial ovarian cancer means the cancer started in the surface layer covering the ovary.
  • Epithelial ovarian cancer is the most common type of ovarian cancer. There are different types of epithelial ovarian cancers.
    • Adenocarcinoma
    • Serous
    • Mucinous
    • Endometrioid
    • Undifferentiated
• Germ cell tumours
  • Germ cell ovarian tumours begin in the ovarian cells that develop into eggs (germ cells).
  • They are rare and usually affect girls and young women.
• Sex-cord stromal tumours
  • Sex cord stromal tumours are rare tumours of the ovaries. They start in the stroma or the sex cords. The stroma and the sex cords are tissues that support the ovaries.
  • Sex cord stromal tumours account for around 7% of all types of ovarian cancers.

There are four stages in epithelial ovarian cancer (FIGO Staging).

• Stage I
  • The cancer is only in the ovaries or fallopian tubes.
  • Stage IA: The cancer is completely inside one ovary.
  • Stage IB: The cancer is completely inside both ovaries.
  • Stage IC: The cancer is in one or both ovaries or fallopian tubes, with any of the following:
    • Stage IC1: The cancer ruptures during surgery.
    • Stage IC2: The cancer ruptures before surgery or there is cancer on the surface of an ovary.
    • Stage IC3: There are cancer cells in the fluid from the peritoneal cavity taken during surgery.
• Stage II
  • The cancer has grown outside the ovaries and is growing within the pelvis.
• Stage III
  • The cancer has spread to the peritoneum outside the pelvis and/or to the lymph nodes in the retroperitoneum (lymph nodes along the major blood vessels, such as the aorta) behind the abdomen.
• Stage IV
  • The cancer has spread to other organs, e.g. liver, lungs, etc.

Early-stage ovarian cancer

If you are diagnosed to have ovarian cancer, your healthcare team will create a treatment plan for you. The team will consider the followings when deciding on the treatment:

• Cancer information: stage of the disease, grade and type of the cancer
• Your health status: any comorbidities, performance status, any concerns about sexual health or future pregnancy

Surgery

Surgery is an important treatment for ovarian cancer. The operation should be performed by gynaecologic oncologists who are specialised in treating gynaecologic cancers. The goals of the surgery are to confirm the diagnosis, provide an accurate stage of the disease and remove the tumour completely.

During surgery, the surgeon removes your ovaries, fallopian tubes, womb, cervix and the fatty tissue surrounding the female genital tract, called omentum. The pelvic area will also be examined thoroughly to check if the cancer has spread. The surgeon will take biopsies from different areas within the abdomen and pelvis, e.g. tissue below diaphragm and on liver surface, remove the abdominal and pelvic lymph nodes and do the peritoneal washing. Peritoneal washing is a procedure that the surgeon will put some sterile fluid inside your abdomen and remove it, like washing the abdomen, the fluid will be sent to laboratory for checking any cancer cells present.

If you have plan for pregnancy in the future and have early-stage cancer with involvement of only one ovary and one fallopian tube, you may discuss with your surgeon for the possibility of removing the  affected side of the ovary and fallopian tube only.

Complications after surgery:

All operations can cause minor or more severe complications. Most of these complications are short-term but some can be life threatening.

After operation, you may have pain over the lower abdomen and wound. Your doctor will prescribe analgesics to you to relieve the pain. You may have vaginal bleeding after operation. The bleeding usually changes from red to brown discharge and can last for a few weeks. Other complications include difficulty in emptying your bladder or bowel movements. Surgery can also cause more severe effects, including infection, bleeding, injury to other organs, or blood clots in the pelvis or legs (deep vein thrombosis).

If both ovaries are removed, the sex hormones can no longer be produced, resulting in early menopause. You may experience menopausal symptoms, including hot flushes, sweating, tiredness, dry skin and dry vagina, and feeling emotional.

Chemotherapy

Adjuvant chemotherapy is usually given following surgery if your cancer is:

• Stage IC or above
• At an earlier stage (1A or 1B) but is high grade.

The standard chemotherapies used for ovarian cancer in adjuvant/ neoadjuvant settings are

• Paclitaxel and carboplatin
• Route of administration: intravenous injection (IV)
• Given once every 3 weeks for total 6 cycles.
• Each cycle lasts for around 3-4 hours.

Side effects of chemotherapy:

• Risk of infection
• Low blood count
• Fatigue
• Nausea and vomiting
• Hair loss
• Loss of appetite
• Mouth sores
• Peripheral neuropathy
• Diarrhoea

Advanced stage ovarian cancer

Cytoreductive/ debulking surgery

The aim of the cytoreductive surgery or debulking surgery is to remove as much of the tumour as safely possible. Besides removing the female genital organs, the surgery may remove tissues from nearby organs, such as liver, bowel or spleen. The tissues will then be sent to laboratory to find out if the cancer has spread.

If the surgery can remove most or all the cancer, heated chemotherapy may be infused into the abdomen during the debulking surgery to kill any cancer cells in the peritoneum. This process is called Hyperthermic Intraperitoneal Chemotherapy (HIPEC). Traditional intravenous chemotherapy may not be effective in treating cancer cells that have spread to the peritoneum. HIPEC has the advantage of single administration, and all the peritoneal surfaces are exposed to heated chemotherapy. The chemotherapy needed to be heated as this higher temperature can improve its effectiveness in killing the cancer cells. 

If the tumour size is too big and has spread to the peritoneum, your doctor may prescribe 3 to 6 cycles of chemotherapy (neoadjuvant chemotherapy) to shrink the size of the tumour before operation.

Chemotherapy

Chemotherapy is recommended for all advanced stage ovarian cancer. Combination of platinum-based (carboplatin, cisplatin, oxaliplatin) and taxanes-based (paclitaxel, docetaxel, nab-paclitaxel) chemotherapies are mostly recommended. Paclitaxel-carboplatin is the preferred option for all stages. The chemotherapy is usually given once every 3 weeks, lasting for around 4 to 6 months.

Your doctor may add a targeted agent called bevacizumab on top of the chemotherapy. Bevacizumab is a targeted agent that stops blood vessel growth. Studies have shown that adding bevacizumab on top of chemotherapy would extend the progression-free survival (i.e. the length of time people with advanced ovarian cancer lived without their tumours growing or spreading compared with chemotherapy alone, 18.2 months vs. 12.0 months).

After chemotherapy, your doctor may consider giving maintenance therapy to reduce the chance of progression.

If the disease progresses unfortunately, your doctor will calculate the duration from the last chemotherapy to the time that the cancer progresses again. If it is over 6 months, you may be treated with platinum-based chemotherapy again. However, if less than 6 months (this is called platinum-refractory disease), other drug combinations may be used, including:

• pegylated liposomal doxorubicin
• topotecan
• trabectedin
• etoposide
• gemcitabine

Targeted therapy

Targeted therapy may be used together with chemotherapy or after chemotherapy as maintenance therapy in advanced ovarian cancer. There are two main types of targeted therapies: Anti-VEGF inhibitor (bevacizumab) and PARP inhibitors.

1. Anti-VEGF inhibitor (bevacizumab)

Bevacizumab is an antibody that binds vascular endothelial growth factor (VEGF) and prevents it from being active. VEGF promotes new blood vessels to form into the tumour and deliver nutrition to it. Anti-VEGF inhibitor will bind to VEGF and stop blood vessels to grow and can help starving the tumour. Studies have proven that combination of bevacizumab and chemotherapy can improve the progression-free survival in patients with stage III or stage IV ovarian cancer.

Administration: intravenously, given every 3 weeks

Common side effects: nausea, vomiting, diarrheoa, tiredness, headache, low cell counts, nosebleeds, high blood pressure, proteinuria

Severe side effects (rare): thromboembolic events (DVT, pulmonary embolism, heart attack, stroke), heart failure, bowel perforation, severe bleeding, kidney damage

2. PARP inhibitors (Olaparib, niraparib, rucaparib)

PARP is an enzyme that involves in repairing damaged DNA. By blocking this enzyme in cancer cells, the DNA inside the cancer cells will less likely be repaired, leading to cells death and slowing down tumour growth.

Olaparib, niraparib and rucaparib are PARP inhibitors that can be used for maintenance therapy for advanced ovarian cancer after first- or second-line platinum-based chemotherapy. The PARP inhibitors are more effective in patients with BRCA mutation or those without BRCA mutation but with homologous recombination deficiency (HRD).

Administration: oral medication

Common side effects: fatigue, diarrheoa, increased risk of infection, bleeding, headache, dizziness, taste change, changes in liver or renal function

Rare but severe side effects: myelodysplastic syndromes, acute myeloid leukaemia. Patients need to continue blood cell count monitoring even after stopping PARP inhibitors.

Immunotherapy

Immunotherapy is not commonly used in metastatic ovarian cancer. Immune checkpoint inhibitors can be used for treating metastatic ovarian cancer if the tumour has high microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR). However, these mutations are very rare in ovarian cancer. Examples of immune checkpoint inhibitors for ovarian cancer include pembrolizumab and dostarlimab.

There is no guarantee way to prevent  ovarian cancer. However, there are some lifestyle modifications that are associated with a lower chance of getting ovarian cancer:

1. Regular exercises: Maintaining regular exercises and working out 30 minutes a day, you can decrease risk up to 20%.
2. Diet control: Food rich in Vitamin D, like beans, eggs, nuts, and Vitamin A like carrots, leafy greens and sweet potatoes may reduce the chance of ovarian cancer.
3. Pregnancy and breast feeding: Women who have delivered a child, especially before the age of 30, and have breastfeeding have a lower risk of developing ovarian cancer.
4. Avoid smoking and drinking.
5. Family history of ovarian cancer or breast cancer: Patients with first-degree or second-degree relatives with ovarian cancer that harbour BRCA mutation should be tested for BRCA as the risk of cancer can be inherited. If you are found to have germline BRCA mutation, your doctor will recommend regular testing and imagings to screen for any ovarian or breast cancers.
6. Use of oral contraceptives: Studies showed that women who have taken oral contraceptives over 5 years have a 30 - 50% lower risk of developing ovarian cancer. However, oral contraceptives have other side effects. You have to consult your doctor before long-term use of oral contraceptives.

Hong Kong Cancer Registry, 2020,  Ovarian & Peritoneal Cancer

Smart Patient Website – Ovarian Cancer (ha.org.hk)

Women-Cancer-booklet-1s.pdf (cancer-fund.org) (Chinese version only)

American Society of Clinical Oncology (ASCO): Ovarian, Fallopian Tube, and Peritoneal Cancer

Cancer Research UK: Ovarian cancer

Canadian Cancer Society:  Ovarian cancer

Special thanks to Ms. Tai Yin Ling, Ms. CHIU Hoi Yin Hilary (Class M27), Ms. He Yixuan (Class M27), Ms Fung Mong Chi (Class M27), medical students of Li Ka Shing Faculty of Medicine, the University of Hong Kong, and Dr. Wendy Wing-Lok Chan, Department of Clinical Oncology, the University of Hong Kong for authoring and editing this article.