Clinical Review - Ovarian cancer

How to investigate and manage ovarian cancer as a GP. By Miss Jane Borley and Miss Sadaf Ghaem-Maghami

Hysterosalpingogram showing ovarian cancer (Photograph: SPL)
Hysterosalpingogram showing ovarian cancer (Photograph: SPL)

Section 1. Epidemiology and aetiology

Ovarian cancer is the most lethal of the gynaecological malignancies, with approximately 6,500 women diagnosed annually in the UK. Most women will initially respond to therapy but ultimately relapse, contributing to about 4,400 deaths a year.1

Classification and staging
Ovarian cancer is currently classified by histology with three main categories: epithelial ovarian cancer (for example, containing subtypes serous, mucinous, endometroid and clear cell); germ cell tumours (dysgerminoma, immature teratoma, yolk sac tumour) or sex-cord stromal tumours (malignant granulosa cell tumour, Sertoli-Leydig cell tumours). Most malignant tumours are epithelial cell in origin, with serous carcinomas the most common.

Staging of ovarian cancer (see table below) is classified according to the International Federation of Gynaecological Oncologists (FIGO) guidelines2 with approximately 75% of women presenting with advanced stage 3C and 4 disease.

Risk factors
Family history is an important clinical risk factor, although only 10% of ovarian cancer cases occur in women with a positive family history.

Well-studied gene mutations include BRCA1 and BRCA2, which confer an approximate 30% lifetime risk of developing ovarian cancer up to the age of 60-70 years.3 Mismatch repair gene mutations, which account for hereditary non-polyposis colorectal cancer, also increase the risk of ovarian and endometrial carcinoma.

Risk of ovarian cancer increases with age, being most prevalent at 60-75 years. Factors known to decrease risk are associated with a decrease in ovulation, such as pregnancy and oral contraception use.

Section 2. Making the diagnosis

Historically, ovarian cancer was described as the 'silent killer', but this belief is incorrect and it is increasingly apparent that the disease is associated with common symptoms.

DH guidance recommends further investigation if a woman experiences any of these symptoms on an almost daily basis:

  • Persistent abdominal or pelvic pain.
  • Increased abdominal girth or persistent bloating (not bloating that comes and goes).
  • Difficulty eating and feeling full quickly.4

NICE guidance agrees with this and suggests that symptoms of increased urinary urgency and frequency which occur on a persistent or frequent basis, unexplained weight loss, fatigue or changes in bowel habit should also be investigated for suspected ovarian cancer.5

Additionally, a new diagnosis of irritable bowel syndrome (IBS) is rare in women aged over 50, therefore IBS symptoms should alert the clinician.

On clinical examination, the presence of a large pelvic or abdominal mass, ascites or lymphadenopathy suggests advanced disease and warrants urgent referral to secondary care. Smaller adnexal masses are more difficult to ascertain and reports suggest that only 45% of adnexal masses are detected by pelvic examination.6 Clinicians should therefore not be reassured by the clinical absence of a pelvic mass.

Initial investigations
NICE guidance recommends preliminary investigation of serum CA125 if a woman presents with any symptoms that suggest ovarian cancer.

Patients with a CA125 of ?35IU/ml should undergo an ultrasound scan (USS) of the pelvis and abdomen (including transvaginal USS). If the CA125 is within normal limits (<35IU/ml), NICE recommends careful assessment to exclude other clinical conditions.

It should be noted that CA125 is not highly sensitive or specific and only 50% of stage 1 ovarian cancers have an abnormally raised CA125. We suggest this approach may be less sensitive in detecting early stage disease and non- epithelial cell tumours, therefore if symptoms persist, further investigation by pelvic USS should be performed, despite a normal CA125 measurement.

Screening
Those women identified as high risk owing to a strong family history, known BRCA or other genetic mutations should be referred to a cancer genetic centre for diagnostics and counselling.

High-risk women may be offered screening as part of a research study (results of the UKFOCS study are awaited) and/or prophylactic bilateral salpingo-oophorectomy (BSO). Prophylactic BSO has been shown to decrease the risk of developing breast and gynaecological cancer in a cohort population with a hazard ratio of 0.25 (95% CI 0.08-0.74).7

There is currently no recommended screening programme for the detection of ovarian cancer in the UK in women without known genetic mutations or strong family history. Results from the recent UKCTOCs trial8 have been encouraging (see section 6).

Section 3. Managing the condition

Suspected ovarian cancer should be urgently referred to secondary care. Guidance recommends that those under 40 years of age should have alpha-fetoprotein (AFP), beta- human chorionic gonadotrophin (beta-HCG) and lactate dehydrogenase (LDH) determined, in addition to CA125, to exclude germ-cell tumours.

A risk of malignancy index (RMI) should be calculated to inform clinicians of the appropriate centre for management. The most widely used and recognised RMI combines presurgical features of CA125 level, menopausal status (M) (1 = premenopausal, 3 = postmenopausal) and ultrasound score (U).

Ovarian cancer: a CT scan will help to assess stage and extent of disease (Photograph: SPL)

The ultrasound score is calculated from the number of suspicious features found (multilocular cysts, solid areas, metastases, ascites and bilateral lesions). U = 0 in the absence of any of these, U = 1 for one feature and U = 3 for two or more features.

A score of >250 indicates a high risk of malignancy and referral to a tertiary centre is indicated. A CT scan of the abdomen and pelvis plus thorax (if clinically indicated) should then be performed to assess stage and extent of disease.

In tertiary units an MRI of the pelvis is also often performed, although this is not evidence-based and as such, NICE recommends against routine use. Tissue diagnosis is mandatory in all but exceptional circumstances by percutaneous image-guided or laparoscopic biopsy.

Stage 1 disease
Patients with stage 1 disease are recommended to undergo optimal surgical staging with a midline laparotomy (to allow assessment of the pelvis and abdomen), peritoneal washing, total abdominal hysterectomy, BSO, infracolic omentectomy and retroperitoneal lymph node sampling.

Generally, those who are confirmed to have grade 1, stage 1A or 1B epithelial ovarian cancer do not require adjuvant chemotherapy (as recommended by NICE guidelines).

Chemotherapy for grade 2 stage 1A or 1B is debatable and is decided on a case-by-case basis, depending on the histological subtype. Modified regimens of chemotherapy may be considered in this group of patients.

Those with grade 3 or stage 1C disease are offered standard adjuvant chemotherapy, which normally consists of six cycles of carboplatin.

Stage 2-4 disease
For patients presenting with stage 2-4 disease, standard treatment includes primary debulking surgery with adjuvant or neoadjuvant chemotherapy. NICE recommends a combination of paclitaxel with platinum-based compounds (carboplatin or cisplatin).

Combination chemotherapy is associated with significantly greater adverse effects, including neutropenia, allergic reactions and cardiovascular problems, so platinum-based agents may be used alone, depending on performance status, comorbidities and the patient's wishes.

Recent evidence has demonstrated a potential role for the vascular endothelial growth factor inhibitor bevacizumab, showing a significant but small improvement in progression-free survival and overall survival.9,10

In some cases, primary surgery may not be appropriate, for example, if the patient is not fit for surgery or if the disease appears too extensive.

The survival benefits of neoadjuvant versus adjuvant chemotherapy are not clear and further RCTs are planned to address this. Intraperitoneal chemotherapy is not currently recommended routinely but is being tested in a randomised trial in the UK (PETROC/OV21).

The primary aims of debulking surgery are to resect all visible macroscopic disease. There are clear survival benefits associated with minimal residual disease which have been replicated throughout the literature. To achieve optimal debulking, more extensive surgery is required, such as bowel resection, splenectomy and diaphragm and peritoneal stripping.

RMI Calculation
RMI = U x M x CA12

Section 4. Prognosis

The overall prognosis for epithelial ovarian cancer is poor. The current overall five-year survival rate is approximately 41%. This varies widely, depending on the stage at diagnosis, with five-year survival for stage 1 disease being 92%, versus 5.6% in stage 4 disease.10

Chemotherapy will be initially effective in most cases, but relapse and carboplatin chemotherapy resistance are thought to occur in more than 90% of patients with advanced disease.11 It is thus important for patients to be made aware of symptoms of recurrence, which are similar to the common symptoms at initial presentation.

Recurrence
In the past, it was thought that early identification of recurrence was important to prevent performance status deterioration and allow early secondand third-line chemotherapeutics.

However, recent evidence from an RCT demonstrated that for patients with relapse diagnosed by elevated CA125 levels, there was no improvement in overall survival compared with those who waited for clinical or symptomatic relapse (HR 0.98, 95% CI 0.80-1.20, p = 0.85).12

Currently, there is no clear evidence for the benefit of secondary surgery versus chemotherapy following recurrence. An RCT is currently in the process of addressing this further.

Psychosocial and psychosexual impact
The psychosocial and psychosexual impact of ovarian cancer on patients and their family is significant, and NICE and SIGN guidance highlights the importance of addressing these matters.

Patients and family members should be offered verbal and written information about all aspects of the disease, including its effects on sexuality and fertility. Support groups and structured emotional support for patients and their carers may also be available.

Section 5. Case study

A 64-year-old retired teacher presented to her GP with increasing abdominal swelling, poor appetite, indigestion and change in bowel habits. She was opening her bowels more frequently and had a feeling of incomplete emptying.

She was given advice about diet and prescribed omeprazole and hyoscine. Her symptoms improved slightly, but she continued to have difficulty opening her bowels. She also became short of breath over the next three months.

She saw her GP again and in view of the continuing bowel symptoms, was referred for colonoscopy. Her symptoms worsened over the following weeks, with severe dyspnoea and low exercise tolerance. The difficulty in breathing led her to attend the local A&E.

Complex pelvic mass
Chest X-ray showed a large pleural effusion. She was admitted and the pleural effusion was drained. A CT pneumocolon (virtual colonoscopy) was also carried out, which showed no colonic lesions. However, there was extensive ascites and a large complex pelvic mass, which was compressing the rectosigmoid, with loss of fat plane between the mass and the bowel.

The mass had solid and cystic areas and arose from the left ovary. There was evidence of peritoneal deposits, omental mass and bilateral pleural effusions and pleural nodules.

The ascites was drained. Cytological examination of cells from the ascites and the pleural effusion revealed the presence of high-grade adenocarcinoma. Her serum tumour markers were measured; CA125 was elevated at 364IU/ml.

The patient was informed that she was likely to have ovarian or primary peritoneal carcinoma and referred to the regional gynaecological cancer centre for further management. She was deemed fit for surgery.

Examination revealed bilateral pleural effusions, shifting dullness in the abdomen and presence of an epigastric fixed 12cm pelvic mass extending up to the abdomen.

Her imaging and cytology were reviewed in the multidisciplinary team meeting, where the findings were confirmed.

Debulking surgery
The patient had BSO, supraand infracolic omentectomy, excision of peritoneal nodules from the small and large bowel and peritoneal surfaces, and excision of the segment of rectosigmoid (with primary anastomosis) affected by tumour. Total macroscopic debulking of all peritoneal tumour was achieved.

Final histology showed grade 3 serous ovarian tumours involving both ovaries, sigmoid serosa and muscularis mucosa, omentum and peritoneal and bowel serosal deposits.

Following a course of chemotherapy, the patient remains disease-free three months after treatment.

Section 6. Evidence base

Clinical trials

  • Menon U, Gentry-Maharaj A, Hallett R et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncol 2009; 10(4): 327-40.

Initial results reported the multimodal screening group had a significantly (p <0.0001) improved specificity of 99.8% and a similar sensitivity of 89.4% compared with the USS group. Almost 50% of invasive malignancy detected was stage 1 and 2 (compared with 20-30% in the general population).

It is now widely accepted that ovarian cancer is not one disease but a collective term for invasive cancers originating from different tissues but presenting as ovarian or pelvic tumours.

Studies have determined distinct molecular subtypes within the same histological group which are also associated with clinical endpoints such as disease progression and survival.

Guidelines

Online

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    CPD IMPACT: EARN MORE CREDITS

    These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

    • Discuss this article at a clinical meeting highlighting potential pitfalls in ovarian cancer diagnosis.
    • Perform a case review of your patients with ovarian cancer, concentrating on how they were diagnosed.
    • Review the causes of raised CA125 and share this with your colleagues.

    References
    1. Office of National Statistics. 2007.

    2. Changes in definitions of clinical staging for carcinoma of the cervix and ovary: International Federation of Gynecology and Obstetrics. Am J Obstet Gynecol 1987; 156(1): 263-4.

    3. Ford D, Easton DF, Bishop DT et al. Lancet 1994; 343(8899): 692-5.

    4. DH. Key messages for ovarian cancer for health professionals, 2009. www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalas set/dh_110533.pdf)

    5. NICE. Ovarian cancer: the recognition and initial management of ovarian cancer. CG122. London, NICE, 2011.

    6. Myers ER, Bastian LA, Havrilesky LJ et al. Evid Rep Technol Assess 2006(130): 1-145.

    7. Kauff ND, Satagopan JM, Robson ME et al. N Engl J Med 2002; 346(21): 1609-15.

    8. Menon U, Gentry-Maharaj A, Hallett R et al. Lancet Oncol 2009; 10(4): 327-40.

    9. Perren TJ, Swart AM, Pfisterer J et al. N Engl J Med 2011; 365(26): 2484-96.

    10. Burger RA, Brady MF, Bookman MA et al. N Engl J Med 2011; 365(26): 2473-83.

    11. Agarwal R, Kaye SB. Nat Rev Cancer 2003; 3(7): 502-16.

    12. Rustin GJ, van der Burg ME, Griffin CL et al. Lancet 2010; 376(9747): 1155-63.

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