Ovarian cancer

What is ovarian cancer?

Ovarian cancer is a malignancy arising from the ovary. It is the leading cause of death from gynaecological cancer in the UK. Early symptoms may be subtle and presentation is often late.

The vast majority of ovarian cancers are classified as epithelial, as they arise from the epithelial surface of the ovary. Malignant ovarian tumours may be solid or cystic.

Types of ovarian cancer (classification)¹

There are many different types of ovarian cancer. The age group affected, management and prognosis vary widely between them. Classification varies across the literature but can be broadly broken down as follows.

Epithelial ovarian tumours

• The most common type, accounting for around 90% of all ovarian cancers.

• Arise from the epithelial surface of the ovary.

• Occur most commonly in women aged over 50 years.

• There are a number of subtypes of epithelial tumours. These include:
  

  • Serous. The most common subtype, accounting for more than half of epithelial tumours. Most occur in women between 40-60 years of age.

  • Endometrioid. Account for around 20% of epithelial tumours. Most common between ages 50-70 years. Around 5% of these are linked to endometriosis.

  • Clear cell tumours. 6% of epithelial tumours. Affect ages 40-80 years. Around half are associated with endometriosis.

  • Mucinous tumours. 10% of epithelial tumours. Most commonly affect ages 30-50 years.

  • Brenner (transitional cell) tumours. Rare.

  • Undifferentiated tumours. Do not fit into any of the above categories. 15% of epithelial tumours.

Germ cell tumours

• Derived from primitive germ cells of embryonic gonad.

• Account for 5-10% of all ovarian tumours.

• Most common in younger women under the age of 35 years.

• Often curable with high survival rates.

• Usually present as a rapidly enlarging abdominal mass, which causes considerable pain.

• They often rupture or undergo torsion.

• Dysgerminoma is the most common type and has an excellent prognosis for Stage I tumours.

• Types of germ cell tumours are:
  

  • Dysgerminoma.

  • Endodermal sinus tumours.

  • Teratoma.

  • Embryonal carcinoma.

  • Choriocarcinoma.

  • Sarcomas.

Sex cord-stromal tumours

• Derive from connective tissue cells.

• Fewer than 5% of all ovarian tumours.

• Include:
  

  • Fibroma.

  • Fibrosarcoma.

  • Sertoli-Leydig tumours.

  • Granulosa cell tumours.

Metastatic tumours
Ovarian secondary tumours may arise from the breast, gastrointestinal tract, haemopoietic system, uterus or cervix.

Malignant potential²

Tumours may be:

• Benign.

• Malignant.

• Borderline (tumours of low malignant potential) which do not fit into the category of benign or malignant and account for 10-15% of ovarian tumours. They are managed primarily by surgery and do not respond well to chemotherapy. Types are:

  • Borderline serous - the most common.

  • Borderline mucinous.

  • Borderline endometrioid.

How common is ovarian cancer? (Epidemiology)

Ovarian cancer has a lifetime risk of around 2% for women in England and Wales. It is the leading cause of death from gynaecological cancer.³ Ovarian cancer is most common in the postmenopausal age group.⁴

Cancer Research UK statistics show that in the UK:⁵

• There are around 7,500 new ovarian cancer cases in the UK every year - that's 21 every day.

• Ovarian cancer accounts for 4% of all new cancer cases in females and accounts for 2% of all new cancer cases in females and males combined.

• Incidence rates for ovarian cancer in the UK are highest in females aged 75 to 79.

• Almost 6 in 10 ovarian cancer cases are diagnosed at a late stage.

• Incidence rates for ovarian cancer have been projected to rise by 5% in the UK by 2040.

• Ovarian cancer is more common in White women than Asian or Black women.

Globally, around 200,000 women died of ovarian cancer in 2020, with developed nations having the highest disease burden and mortality.¹

Risk factors⁶

• Increasing age.

• Lifestyle. It has been estimated that 21% of ovarian cancer can be attributable to lifestyle. Factors which increase the risk include:
  

  • Smoking. It is estimated that 3% of cases may be caused by smoking.

  • Obesity. There is evidence of increased risk in postmenopausal women who are overweight.

  • Lack of exercise. There is some evidence that regular physical exercise protects against some forms of ovarian cancer.

  • Talcum powder use (pre-1975, after which regulation was introduced to prevent the contamination of talcum powder with asbestos).

  • Occupational exposure to asbestos.

• Hormonal factors:

  • History of infertility and use of fertility drugs - eg, clomifene.

  • Nulliparous women are more likely to develop an ovarian malignancy than women who have been pregnant three or more times.

  • Early menarche and late menopause.

  • Hormone replacement therapy (HRT): 4% of ovarian cancer cases in the UK are caused by postmenopausal hormones. Ovarian cancer risk is 37% higher in current or recent users of HRT, compared with never-users. This association may be limited to serous and endometrioid ovarian tumours.⁵

  • However, pre-diagnosis menopausal hormone therapy use for 5+ years has been shown to be a favourable prognostic factor for women with ovarian cancer.

• Genetic factors:

  • Family history of ovarian cancer. Women with a first-degree relative with ovarian cancer have 2.7-3.5 times the risk of developing the disease. However, only 3% of cases arise in women with a positive family history.

  • Presence of BRCA1 and 2 genes increases susceptibility. Presence of the BRCA1 gene increases risk by up to 65%, and BRCA2 by up to 35%. BRCA1 gene confers familial susceptibility for the breast-ovarian cancer syndrome.

• Medical history:

  • Women with a prior history of ovarian cancer, breast cancer or bowel cancer have an increased risk of ovarian cancer.

  • History of endometriosis confers a significant increased risk.⁷ Studies suggest a link between ovarian endometriosis and clear-cell ovarian cancer, possibly linked to mutation of the ARID1A gene.⁸

Protective factors

Any factor which prevents or inhibits ovulation appears to protect against ovarian cancer. Protective factors therefore include:⁶

• Having children.

• Breastfeeding.

• Early menopause.

• The oral contraceptive pill.

Screening for ovarian cancer

No screening method has been shown to affect mortality significantly. Screening may result in unnecessary surgery. A large trial in the USA in 2011 based on cancer antigen 125 (CA 125) levels and ultrasound scan confirmed there was no benefit to screening the general population.⁹

The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) was designed to look at the effect of screening. The results were reported in 2023.¹⁰

202,638 post-menopausal average risk women were included in the study: 50,640 women were randomised to multimodal screening (blood tests and ultrasound), 50,639 had ultrasound based screening and 101,359 were in the control group.

Many ovarian cancers were detected in women with no symptoms at an early stage. Unfortunately, this did not always mean there was a lower risk of death. Additionally, many women who had an abnormal screening test had unnecessary surgery, as they were found not to have ovarian cancer.

They concluded that screening using the CA125 blood test or ultrasound scan to test for ovarian cancer did not save lives. Additionally, it was associated with some harm. Therefore, an ovarian cancer screening programme for most women cannot be currently recommended.

Familial and genetic risk

NICE guidelines advise that women, trans men and non-binary people with female reproductive organs (ovaries, fallopian tubes and/or a uterus), who may have a pathogenic variant that increases the risk of developing ovarian cancer (familial ovarian cancer), should be referred for genetic counselling and testing if any of the following apply:¹¹

• They have a first-degree relative with a diagnosis of ovarian cancer.

• They have a maternal or paternal second-degree relative with a diagnosis of ovarian cancer (this includes people with an unaffected intervening blood relative).

• They are from an at‑risk population (Ashkenazi Jewish, Sephardi Jewish, Greenlander).

• They have been identified through cascade testing.

• They have a diagnosis of ovarian cancer and have not already had mainstream genetic testing.

Men, trans women and non-binary people born with male reproductive organs can pass the pathogenic variant on to their children, or may be at risk of developing other cancers. They should also be referred to genetic services if they fall into the categories above.

Scottish Intercollegiate Guidelines Network (SIGN) guidelines also advise that women with a family history that appears to increase their risk of developing ovarian cancer should be referred to a clinical genetics service for full assessment of risk. Any of the following criteria would signify an increased risk:¹²

• The woman is a known carrier of BRCA1, BRCA2, or any other known relevant cancer gene mutations.

• She has a first-degree or second-degree relative who carries a known relevant gene mutation.

• Two family members who are first-degree relatives of each other have ovarian cancer.

• A family member who has ovarian cancer at any age and is a first-degree relative of someone who developed breast cancer under the age of 50 years, or of two who developed it under the age of 60 years.

• Three or more family members with colon cancer; or two with colon cancer and one with stomach, ovarian, endometrial, small bowel or urinary tract cancer in two generations. (One must be diagnosed under the age of 50 years and they should be first-degree relatives of each other.)

• One family member with both breast and ovarian cancer.

These high-risk people should be offered genetic screening and counselling. They may also be offered referral for prophylactic salpingo-oophorectomy. NICE recommends only offering risk-reducing surgery to people who have completed their family, or are not planning to conceive naturally and have a total lifetime risk of ovarian cancer of 5% or over because they have a pathogenic variant associated with familial ovarian cancer, or a strong family history of ovarian cancer.¹¹The type of surgery offered depends on variant type, and the age of the person involved.

If a person is at risk of developing ovarian cancer and chooses to delay or not have risk-reducing surgery they can be referred to the familial ovarian cancer multidisciplinary team. They consider surveillance for those who are over 35 and have a BRCA1 pathogenic variant, aged over 40 who have a BRCA2 pathogenic variant, or are over 45 and have RAD51C, RAD51D, BRIP1 and PALB2 pathogenic variants. The surveillance the familial ovarian cancer multidisciplinary team provides includes:

• Serial 4‑monthly CA125 longitudinal testing.

• CA125 testing using a call and recall system.

• Annual review appointment

Genetics services assess the probability of having a pathogenic variant using a calculation method such as the Manchester scoring system, CanRisk (BOADICEA), BRCAPRO, or criteria based on specific clinical circumstances or a verified family history. The percentage risk calculated is used with the patient's age to give a threshold for testing eg, 2% or higher for a 30-49 year old with female reproductive organs, or 10% or higher for males, trans women and non-binary people aged over 50 years.¹¹

Symptoms of ovarian cancer (presentation)

Almost 60% of patients present with advanced (Stage III or IV) disease.⁵

• Onset of symptoms is insidious. Early symptoms are often vague, such as abdominal discomfort, abdominal distension or bloating, urinary frequency or dyspepsia. Constitutional symptoms include fatigue, weight loss, anorexia and depression.

• It most commonly presents with a pelvic or abdominal mass that may be associated with pain. Abdominal, pelvic or back pain is usually a late sign and seen only with early disease that is complicated by torsion, rupture, or infection.

• It may cause abnormal uterine bleeding.

• Often associated with ascites. One third of patients with ascites also have a pleural effusion.

• Ovarian cancers metastasise to pelvic and peri-aortic lymph nodes, as well as over the pelvic and abdominal peritoneum.

Differential diagnosis²

• Other causes for a mass:

  • Benign ovarian tumour or cyst.

  • Fibroids.

  • Primary peritoneal carcinoma.

  • Other pelvic malignancy (uterus, cervix, bladder, rectum).

  • Secondary carcinoma: breast, gastrointestinal tract, lymphomas and pelvic-organ tumours may all metastasise to ovary.

• Endometriosis.

• Other causes of ascites (eg, cirrhosis).

• Other causes of altered bowel habit or abdominal pain/bloating, such as:

  • Irritable bowel syndrome (IBS).

  • Constipation.

  • Coeliac disease.

  • Crohn's disease or ulcerative colitis.

  • Gastroenteritis.

  • Diverticular disease.

  • Pelvic inflammatory disease.

Investigations and referral^{3 13}

• Make an urgent referral to a gynaecological cancer service if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids).

• Carry out tests in primary care (serum CA 125, ultrasound - see below) if a woman (especially if 50 or over) reports having any of the following symptoms on a persistent or frequent basis - particularly more than 12 times per month:

  • Persistent abdominal distension ('bloating').

  • Feeling full (early satiety) and/or loss of appetite.

  • Pelvic or abdominal pain.

  • Increased urinary urgency and/or frequency.

• Consider carrying out tests in primary care if a woman reports unexplained weight loss, fatigue or changes in bowel habit.

• Advise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent.

• Carry out appropriate tests for ovarian cancer in any woman of 50 or over who has experienced symptoms within the previous 12 months that suggest IBS, because IBS rarely presents for the first time in women of this age.
  Measure serum CA 125 in primary care in women with symptoms or examination findings that suggest ovarian cancer (see above).

• If serum CA 125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.

• If the ultrasound suggests ovarian cancer, make an urgent referral to a gynaecological cancer service. The National Institute for Health and Care Excellence (NICE) has recommended that a person should receive a diagnosis or ruling out of cancer within 28 days of being referred urgently by their GP for suspected cancer.¹³

• For any woman who has normal serum CA 125 (less than 35 IU/ml), or CA 125 of 35 IU/ml or greater but a normal ultrasound:

  • Assess her carefully for other clinical causes of her symptoms and investigate if appropriate.

  • If no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent.

Investigations in secondary care

• CA 125, pelvic and abdominal ultrasound, if not already done in primary care.

• Consider CT scan of the pelvis and abdomen if CA 125, ultrasound and clinical status suggest malignancy, to establish the extent of disease (may also need CT scan of the thorax if clinically appropriate).

• CT or MRI scan can be used for pre-operative staging.¹ CT is the investigation of choice in the UK, although MRI may be useful for imaging other pelvic tumours, or if contrast-enhanced CT cannot be used.

• NICE and SIGN guidelines both advise using the Risk Malignancy Index 1 to assess the likelihood of malignancy, and if >250 (NICE) or >200 (SIGN), refer to a specialised multidisciplinary team. This score is calculated as ultrasound score x menopausal score (where 1 = pre-menopausal and 3 = postmenopausal) x CA 125 level in U/mL. The ultrasound score is the number of the following findings on scan: multilocular cyst, solid areas, bilateral lesions, ascites, intra-abdominal metastases. (0 = no abnormalities, 1 = one abnormality, 3 = two or more).

• In women under 40 years, exclude endodermal sinus tumours by arranging alpha-fetoprotein (AFP). Also check beta human chorionic gonadotrophin (beta-hCG) to identify women who may have dysgerminomas, embryonal carcinomas or choriocarcinomas.

• If cytotoxic therapy is to be offered, discuss risks and benefits of obtaining tissue confirmation first. This may be done at laparotomy, or via percutaneous image-guided biopsy

• Occasionally, chemotherapy may be offered without tissue confirmation.

Associated diseases

Three different familial syndromes of cancer have been identified:

• Site-specific: at risk of development of ovarian cancer only.

• Breast-ovarian: increased risk of either cancer alone or in combination. BRCA1 and BRCA2 susceptibility genes are responsible for at least 90% of hereditary breast-ovarian cancer and site-specific ovarian cancer cases.

• Nonpolyposis colon cancer families: increased risk of ovarian, endometrial and breast cancer.

Stages of ovarian cancer

The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging system remains the best indicator of prognosis and guides management strategy.¹

• Stage I ovarian cancer is limited to the ovaries:
  

  • Stage IA: tumour is limited to one ovary, the capsule is intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.

  • Stage IB: tumour is limited to both ovaries, capsules intact, no tumour on ovarian surface and no malignant cells in ascites or peritoneal washings.

  • Stage IC: tumour is limited to one or both ovaries with any of the following: capsule ruptured, tumour on ovarian surface, malignant cells in ascites or peritoneal washings.

• Stage II ovarian cancer is tumour involving one or both ovaries with pelvic extension and/or implants:
  

  • Stage IIA: extension and/or implants on the uterus and/or Fallopian tubes. No malignant cells in ascites or peritoneal washings.

  • Stage IIB: extension to and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.

  • Stage IIC: pelvic extension and/or implants (Stage IIA or Stage IIB) with malignant cells in ascites or peritoneal washings.

• Stage III ovarian cancer is tumour involving one or both ovaries with microscopically confirmed peritoneal implants outside the pelvis:
  

  • Superficial liver metastasis equals Stage III.

  • Stage IIIA: microscopic peritoneal metastasis beyond pelvis (no macroscopic tumour).

  • Stage IIIB: macroscopic peritoneal metastasis beyond pelvis less than 2 cm in greatest dimension.

  • Stage IIIC: peritoneal metastasis beyond pelvis greater than 2 cm in greatest dimension and/or regional lymph node metastasis.

• Stage IV ovarian cancer is tumour involving one or both ovaries with distant metastasis. Parenchymal liver metastasis equals Stage IV.

Management of ovarian cancer^{1 3 12}

If epithelial ovarian cancer is suspected on the basis of physical examination and imaging, an exploratory laparotomy is usually done for histological confirmation, staging and tumour debulking.

The standard comprehensive surgical staging approach consists of a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH and BSO) along with examination of all peritoneal surfaces, an infracolic omentectomy, biopsies of pelvic and para-aortic lymph nodes and clinically uninvolved areas and peritoneal washings.

Further management is then determined by the stage and histology of the tumour. Adjuvant therapy to surgery for epithelial ovarian cancer varies according to the stage of the disease but, in most cases, will consist of chemotherapy.

Response to chemotherapy is usually good; however, relapse is common and occurs in around 75%. Further regimes for relapse may prolong survival. Much of the evidence relates to the most common subtype of epithelial cancer, serous carcinoma; however, it is increasingly clear that the different types need different treatment strategies based on the differing molecular biology involved.¹⁴ Available guidelines apply mainly to epithelial cancers.

Because of late diagnosis and high risk of relapse, much of the appropriate management may be directed towards palliative care.

A clinical nurse specialist should be present when the diagnosis of ovarian cancer is given.

Surgery

• Standard treatment is surgery (staging and optimal debulking) followed by adjuvant chemotherapy in most cases. Even if optimal surgery is not possible, removing as much tumour as possible will provide significant palliation of symptoms.

• Borderline lesions may be treated with conservative surgery.

• In early disease, assessment of peritoneal cytology, hysterectomy, removal of ovaries and Fallopian tubes and infracolic omentectomy should be performed. Routine systematic lymphadenectomy in early-stage epithelial ovarian cancer is not recommended in the UK.

• Management of early ovarian cancer in young women who desire future childbearing may be more conservative, ie a unilateral salpingo-oophorectomy and staging but the long-term safety is uncertain. Treatment choice will depend on type of tumour and stage and be in partnership with the patient, who will need to be fully informed about prognosis.

• In advanced disease, debulking is recommended. Interval debulking is recommended if there is evidence of a response to chemotherapy as determined by CA 125 and imaging. There is evidence that complete clearance of all visible disease at the time of surgery is associated with a better prognosis.

• The value of surgery for relapse and palliation remains unclear.

Chemotherapy

• Adjuvant platinum-based chemotherapy improves survival in early (Stage I/IIa) epithelial ovarian cancers.¹⁵

• Chemotherapy is advised for all women with Stage II-IV disease following surgery. The standard regime is paclitaxel and carboplatin given intravenously every three weeks for six cycles. Possible alternatives to paclitaxel are pegylated liposomal doxorubicin (PLD) or gemcitabine.

• Intraperitoneal chemotherapy may be used as an alternative. Evidence suggests it is more effective but, as it is more difficult to deliver and associated with more risks, is not standard treatment, although it may be used in certain specialised centres.¹⁶ Optimal regimes are yet to be established.

• Biological therapies have been developed and continue to undergo trials as understanding of the molecular biology of the types of ovarian cancer has advanced. These targeted treatments include:
  

  • Bevacizumab. This is a monoclonal antibody against vascular epithelial growth factor (VEGF). This helps to prevent angiogenesis (the formation of new blood vessels), which is an important part of cancer growth. Trials suggest it improves progression-free survival and quality of life in women with recurrent disease, although it has a significant risk of adverse effects.¹⁷

  • Bevacizumab in combination with paclitaxel and carboplatin is not recommended by NICE for the first-line treatment of advanced ovarian cancer. Bevacizumab in combination with gemcitabine and carboplatin is also not recommended within its marketing authorisation (ie for the treatment of the first recurrence of platinum-sensitive advanced ovarian cancer that has not been previously treated with bevacizumab or other vascular endothelial growth factor (VEGF) inhibitors or VEGF receptor-targeted agents.¹⁸

  • Poly (ADP-ribose) polymerase (PARP) Inhibitors - eg, olaparib and niraparib.^{19 20} These are able to target cancer cells whilst sparing normal cells. They work by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. A Cochrane review concluded they improve progression-free survival in women with recurrent platinum-sensitive disease.²¹ Olaparib is also an option for maintenance treatment of BRCA mutation-positive, advanced (FIGO stages 3 and 4), high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to first-line platinum-based chemotherapy in adults.²²

• With targeted therapy undergoing further evaluation, relapses are most often treated with platinum-based combination chemotherapy. There is no evidence as yet for any maintenance chemotherapy to prevent or delay relapse. NICE guidelines recommend paclitaxel or PLD for recurrent disease but not alternatives gemcitabine, trabectedin or topotecan.²³ Gemcitabine is, however, recommended as an option by SIGN guidelines as part of a platinum-based combination. A Cochrane review found PLD to be no more effective in combination for overall survival but it possibly increased progression-free survival.²⁴

• There may in some cases be a role for hormonal therapies, where there is platinum-resistant recurrence, particular subtypes, or a wish to avoid chemotherapy. Options studied include tamoxifen, aromatase inhibitors and luteinising hormone-releasing hormone (LHRH) agonists. A Cochrane review found insufficient evidence to support the use of LHRH agonists in this situation.²⁵

Complications of ovarian cancer²

• Complications of the tumour: torsion, rupture, infection.

• Complications of treatment: bone marrow depression, infection, neurotoxicity, nephrotoxicity, ototoxicity.

• Complications of advanced disease: malnutrition, electrolyte imbalance, small and large bowel obstruction, infection, ascites, pleural effusion.

Prognosis⁵

• In females in the UK, ovarian cancer is the 6th most common cause of cancer death, with around 4,100 deaths annually in 2017-2019.

• Ovarian cancer accounts for 5% of all cancer deaths in females in the UK (2017-2019).

• Ovarian cancer accounts for 2% of all cancer deaths in females and males combined in the UK (2017-2019).

• Mortality rates for ovarian cancer in the UK are highest in females aged 85 to 89 (2017-2019).

• Since the early 1970s, ovarian cancer mortality rates have decreased by around a fifth (23%) in females in the UK.

• Over the last decade, ovarian cancer mortality rates have decreased by a sixth (17%) in females in the UK.

• Mortality rates for ovarian cancer are projected to fall by 15% in the UK between 2023 and 2040.