Ovarian cancer in primary care

Abstract

Ovarian cancer continues to be the leading cause of gynaecological cancer death in the UK. It has previously been described as the ‘silent killer’, as symptoms are typically absent or non-specific early in the disease leading to a later stage at diagnosis where fewer treatment options are available. Stage at presentation influences patient survival, and therefore, early detection within primary care is vital. Currently, there is no screening programme for ovarian cancer, and so diagnosis relies on investigation of symptomatic women presenting to healthcare professionals and an awareness of vague symptoms that could indicate ovarian cancer pathology. This article aims to provide an overview of ovarian cancer, including epidemiology, risk factors, signs and symptoms, and diagnosis within primary care. We will also briefly discuss current treatment strategies for ovarian cancer.

Clinical case scenario

A 62-year-old retired nurse, Janet, is booked in for a telephone appointment with you this afternoon to discuss her recent blood results. The previous consultation was with your colleague and the notes state:

‘Patient presents with 4-month history of early satiety, loss of appetite, persistent feeling of bloating and increased urinary frequency. No weight loss/dysphagia/change in bowel habit. No other relevant past medical history or family history. Examination unremarkable. Urinalysis normal’

From her notes you can see she had a normal full blood count, urea and electrolytes and liver function tests. Her CA125 is elevated at 85 U/ml.

How will you explain the result to Janet? After explaining the result Janet is keen to know what further investigations she might need and how this will be organised.

Epidemiology

Ovarian cancer is the leading cause of death from a gynecological cancer in the UK and is the sixth most common cancer in females in the UK. There are 7443 new cases of ovarian cancer in the UK each year – 20 every day (Cancer Research UK, 2018). Ovarian cancer more commonly affects women after the menopause, although it can occur at any age. The risk rises sharply after the age of 45. It is more common in white women than black or Asian women. The lifetime risk for women is currently 1 in 50 (Cancer Research UK, 2018) but the incidence is expected to rise by a further 15% by 2035, due to an ageing population (Smittenaar et al., 2016).

Stage at diagnosis strongly influences prognosis, with a notable decrease in survival in later stages. Five-year survival at stage one is 93%, reducing to 13.4% when a patient is diagnosed at stage four (Cancer Research UK, 2018). Unfortunately, over half of patients are diagnosed at stages three and four where fewer treatment options are available and the prognosis is worse.

There have been significant improvements in ovarian cancer survival over the last 40 years. However, the UK continues to have worse 1-year survival outcomes compared with similar developed nations (Arnold et al., 2019; Maringe et al., 2012).

Risk factors for ovarian cancer

Age

Risk of ovarian cancer increases with age, rising sharply after 45 years and peaks in females aged between 75 and 79 years. Over a quarter of new cases are in females over 75 years of age.

Family history

Certain genes are particularly linked with ovarian cancer including BRCA1 and BRCA2 (these also increase the risk of breast cancer). These genes account for approximately 10% of ovarian cancer cases (Centre for Disease Control and Prevention, 2020).

Having a first degree relative with ovarian cancer increases an individual’s risk by three times compared with that of an individual without a family history (Cancer Research UK, 2018). In addition, individuals with a family history of breast cancer (even in the absence of BRCA1 and BRCA2 mutations) have an increased risk of developing ovarian cancer. Individuals with a past medical history of cancer, in particular breast cancer at a young age or bowel cancer, have an increased risk of going on to develop ovarian cancer. This highlights the importance of taking a detailed family history and past medical history (especially of previous cancers) during the initial consultation.

Reproductive history

Nulliparity is associated with an increased risk whilst use of oral contraceptives and breastfeeding, which limit the number of times a woman ovulates, appear to reduce an individual’s risk of developing ovarian cancer. Studies have shown that nulliparous women have a 30–60% higher risk of developing ovarian cancer than parous women (Reid et al., 2017).

Pathophysiology

There are several different types of ovarian cancer. The most common is epithelial ovarian cancer (EOC), which includes fallopian tube and peritoneal cancer, and accounts for 90% of ovarian cancer diagnoses. The most common subtypes of EOC are: high grade serous (70%), high grade endometroid (11%), clear cell (11%), low grade serous (5%) and mucinous (3%). These subtypes have distinct clinical behaviours.

Rarer forms of ovarian cancer (which more commonly affect younger women) include;

Germ cell tumours: These tumours usually present in the first two decades of life. They have a significantly better prognosis than EOC and often present at an early stage. They are very chemo-sensitive and have a 5-year survival approaching 100% for early-stage disease and 75% for stages three and four.

Sex cord stromal tumours (for example, granulose cell tumours): These tumours are also more likely to present at an early stage and have a favourable prognosis compared with EOC. They can cause steroid hormone production, so can present with associated symptoms such as precocious puberty and abnormal vaginal bleeding.

Borderline ovarian tumours: These are another rare form of ovarian tumour that are slow growing and non-invasive and often diagnosed at an early stage. They are also more common in younger women. Rarely, borderline ovarian tumours can undergo malignant transformation.

Staging for ovarian cancer is via the International Federation of Gynaecology and Obstetrics staging system (FIGO staging) (Prat, 2014). Table 1 shows the four stages of ovarian cancer.

Table 1.

FIGO staging system (2014).

Stage one – tumour confined to ovaries	IA One ovary involved, capsule intact, no tumour on surface, negative washings
	IB Both ovaries involved but no spill
	IC1 Surgical spill
	IC2 Capsule rupture before surgery or tumour on ovarian surface
	IC3 Malignant cells in ascites or peritoneal washings
Stage two – tumour involves one or both ovaries with pelvic extension. Or primary peritoneal disease	IIA Extension to fallopian tubes and/or uterus
	IIB Extension to other pelvic intraperitoneal tissues
Stage three – spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes	IIIA1 Positive retroperitoneal lymph nodes
	IIIA2 Microscopic, extrapelvic peritoneal involvement +/− retroperitoneal lymph nodes
	IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤2 cm +/− retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen
	IIIC Macroscopic, extrapelvic, peritoneal metastasis >2 cm +/− positive retroperitoneal lymph nodes. Includes extension to capsule of liver/spleen
Stage four – Distant metastasis	IVA Pleural effusion
Stage four – Distant metastasis	IVB Hepatic and/or splenic parenchymal metastasis, metastasis to extra abdominal organs

Reproduced with permission, from Prat J, FIGO Committee on Gynecologic Oncology. FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum: abridged republication. Journal of Gynecologic Oncology, 2015; 26(2): 87–89, which is an abridged version of the staging classification published in the International Journal of Gynecology and Obstetrics in January 2014. Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. International Journal of Gynaecology and Obstetrics, 2014; 124(1): 1–5.

Diagnosis in primary care

Screening

Unfortunately, no screening programme exists within the UK and recent large scale screening trials have failed to demonstrate a reduction in long term mortality (Henderson et al., 2018; Jacobs et al., 2016; Menon et al., 2021). These trials in asymptomatic women included either CA 125 testing (fixed cut off or serial), or transvaginal ultrasound scan (USS) or both. None of these methods showed a statistically significant survival benefit at follow up. In addition, potential harms of screening must be considered, including unnecessary surgery with associated complications. Within the two large screening trials, screening led to unnecessary surgery in women without cancer and a false positive result in 1–3%, with major complications occurring in 3–15% of these individuals. As such screening is not currently recommended at a population level. Therefore, diagnosis relies on symptomatic women presenting to healthcare professionals. The main route to diagnosis is via primary care (Dilley et al., 2020) with approximately a quarter of patients presenting as an emergency direct to secondary care (Dilley et al., 2020; Swann et al., 2018).

Signs and symptoms

The difficulty for GPs is recognising the symptoms of ovarian cancer which can be vague and non-specific. The symptoms also overlap with other more common benign conditions, increasing the challenge for GPs. It is, therefore, important to take a full history (including gynaecological history), family history and social history. The common signs and symptoms are listed in Table 2.

Table 2.

Symptoms and signs of ovarian cancer.

Symptoms	Signs
Abdominal or pelvic pain	Ascites
Feeling full/early satiety	Palpable abdominal/pelvic mass
Bloating	Pleural effusion
Increased urinary frequency/urgency	Cachexia
Changes to bowel habit
Weight loss
Fatigue

Examination

Targeted examination in women with symptoms of possible ovarian cancer should include general assessment for signs of weight loss, pallor and jaundice. Assessment should also include examination for any palpable abdominal or pelvic masses or evidence of ascites. These warrant an immediate onward referral to a specialist via a 2-week wait (2WW) in England or urgent suspicion of cancer (USOC) in Scotland if they are not obviously fibroids (i.e., the presence of a bulky uterus). Many women may have no signs on examination, particularly in early-stage disease.

Investigations in primary care

The National Institute of for Health and Care Excellence (NICE) guidance recommends carrying out tests in primary care if a woman (especially if 50 years or over in age) reports having any of the following symptoms on a persistent or frequent basis:

Persistent abdominal distension

Feeling of ‘bloating’

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

Pelvic or abdominal pain

Increased urinary urgency and/or frequency

They also suggest considering carrying out tests in primary care if a woman reports unexplained weight loss, fatigue or changes in bowel habit. In particular, the guidance highlights the importance of testing women aged over 50 years who have new symptoms suggestive of irritable bowel syndrome (IBS) for ovarian cancer as it is unusual for IBS to present in women of this age for the first time (NICE, 2011).

The initial investigations recommended for primary care differ around the UK, and so local guidance should be sought. The Scottish cancer referral guidelines recommend dual testing which includes both CA125 and USS as initial first line investigations. In contrast, the rest of the UK follows NICE guidance which recommends sequential testing- CA125 followed by USS if the CA125 is abnormal as demonstrated in Fig. 1.

Figure 1.

Diagnostic pathway in primary care.

NICE recommends referral of patients with an elevated serum CA125 greater than or equal to 35 U/ml for further investigation with urgent USS. If the USS suggests ovarian cancer women should be referred urgently to gynaecology under the 2WW in England. In Scotland it is recommended that an elevated CA125 or abnormal USS should prompt onward referral to gynaecology.

If the USS is normal despite an elevated CA125 or if the original CA125 is normal it is important to assess for other clinical causes and investigate as appropriate. Effective safety netting should be used by the GP to advise the patient that should their symptoms persist or become more frequent they should revisit their GP who should investigate accordingly and refer on to secondary care as appropriate. It is important to recognise CA125 testing in isolation has the possibility of missing 20% of ovarian cancers particularly with early-stage disease.

CA125 is a serum tumour biomarker. It is elevated in around 80% of ovarian cancers (Funston et al., 2021). A recent large scale primary care cohort study demonstrated that in all age groups CA125 has a sensitivity of 78%, a positive predictive value of 10% and a negative predictive value of 99.8% for ovarian cancer when used in a primary care setting (Funston et al., 2020). The authors found 15% of women over the age of 50 years who had a CA125 greater than or equal to 35 U/ml tested in primary care had ovarian cancer, and interestingly, 20.4% were diagnosed with a non-ovarian cancer. It is, therefore, important to consider other malignancies in older patients with an elevated CA125 and normal scan. CA125 should not be measured during menstruation, as this can cause a falsely elevated reading (Lehtovirta et al., 1990). CA125 can be elevated in other conditions, including endometriosis, non-malignant gynaecological conditions, non-ovarian cancers, heart failure and liver cirrhosis.

Other investigations (usually undertaken in secondary care)

Definitive diagnosis in secondary care requires a computerised tomography (CT) chest-abdomen-pelvis and pathology from tissue biopsy. All non-mucinous subtype patients should be offered genetic testing for germline BRCA mutation, as this would have implications both on the patient, family members, as well as potential treatment options.

Management in secondary care

Multidisciplinary team input, including specialist gynaecology-oncology surgeons and medical oncologists is essential. Management depends on patient fitness, histological subtype and FIGO staging. Treatment often includes a combination of radical cytoreductive surgery (i.e. complete removal of all visible disease at the time of operation) and peri-operative platinum-based chemotherapy.

The strongest predictor of overall survival is complete surgical resection of all macroscopic disease (Vergote et al., 2018). Unfortunately, the risk of relapse (especially with advanced disease) remains high.

Patients with stage three and four ovarian cancers are usually considered for maintenance PARP (poly adenosine diphosphate ribose polymerase) inhibitors after the completion of primary therapies provided they have had a complete or partial response. The choice of therapy is dependent on the presence of absence of BRCA mutations – Olaparib in tumours with BRCA mutations, and Niraparib in those without (Gonzalez-Martin et al., 2019; Moore et al., 2018). Patients who have completed primary treatment are generally offered close follow-up in the medical oncology clinic with CA125 monitoring, although there is no proven survival benefit in starting chemotherapy for relapsed disease earlier based on asymptomatic CA125 rise (Rustin et al., 2010).

The management of relapsed disease depends on the time interval between relapse and the end of their first line platinum-based chemotherapy. Patients who relapse after a year following their most recent platinum-based chemotherapy may be rechallenged with a different platinum-based regimen. Prognosis for ‘platinum-sensitive’ relapsed disease can average up to a short number of years depending on response to further treatment. ‘Platinum-resistant’ relapse (i.e. less than 6 months since most recent platinum-based chemotherapy) have a poorer prognosis of approximately 12 months.

Complications and end of life care

There are several potential complications from advanced ovarian cancer. These include malignant ascites, subacute bowel obstruction, bladder obstruction and pleural effusion (Herrinton et al., 2007). Surgery or chemotherapy may be considered for individuals with subacute bowel obstruction. Other supportive measures include Nasogastric tube (NG) suctioning, subcutaneous antiemetics, steroids and parental nutrition. Acute kidney injury from obstructive uropathy may require stenting/nephrostomy. Malignant ascites often requires drainage for comfort.

In patients with advanced disease, it is important to support patients and their families with discussions around anticipatory care planning. Early discussions enable better coordinated, quality patient care (Ekberg et al., 2021). There are several resources to aid with these discussions including the REDMAP framework (SPICT Supportive and Palliative Care Indicators Tool., 2022) which is six-step guide to future care planning conversations with individuals whose health is deteriorating and their families and ReSPECT forms, which creates a summary of personalised recommendations for a patient’s clinical care in a future emergency (Resuscitation Council UK., 2022).

GPs can consider prescribing ‘just in case’ anticipatory medication for individuals within the final weeks and days of life to ensure they are available for the patient at the time they are needed both in and out of hours. Close working with community nursing colleagues (and palliative care dependent on symptom complexity) is vital. It is also important to update the patients’ records and ensure sharing of information with out-of-hours colleagues and secondary care through the Key Information Summary.

Clinical case scenario continued.

In the clinical case scenario the patient was found to have an elevated CA125 and symptoms which are possibly consistent with ovarian cancer. She should be referred urgently for a pelvic USS to investigate this further. The GP should explain to the patient CA125 is not a diagnostic blood test and can be elevated for many reasons. However, with her symptoms she should be investigated further for the possibility of ovarian cancer specifically.

Key points

Ovarian cancer is the leading gynaecological cause of cancer death in the UK

Ovarian cancer often presents at a later stage of disease where fewer treatment options are available

Family history, history of breast cancer and age are important risk factors

Symptoms are often vague, but include persistent/frequent bloating, early satiety, abdominal or pelvic pain, increased urinary frequency or urgency

Serum CA125 and USS are first line investigations in primary care

Palpable pelvic mass and/or ascites warrants immediate onward referral

Footnotes

ORCID iD

Dr Susanne Sarah Maxwell

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