Ovarian cancer: recognition and initial management

This guideline covers detecting, diagnosing and treating women (18 years and older) who have, or are suspected of having, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer or borderline ovarian cancer. It aims to enable earlier detection of ovarian cancer and improve initial treatment.

# Introduction
Ovarian cancer is the leading cause of death from gynaecological cancer in the UK, and its incidence is rising. It is the fifth most common cancer in women, with a lifetime risk of about 2% in England and Wales.
The outcome for women with ovarian cancer is generally poor, with an overall 5-year survival rate of less than 35%. This is because most women who have ovarian cancer present with advanced disease. The stage of the disease is the most important factor affecting outcome. The woman's general health at the time of presentation is also important because it affects what treatments can be used. Most women have had symptoms for months before presentation, and there are often delays between presentation and specialist referral. There is a need for greater awareness of the disease and also for initial investigations in primary and secondary care that enable earlier referral and optimum treatment.
Despite the relatively poor overall survival rates for ovarian cancer, there has been a two-fold increase in survival over the last 30 years. This has coincided with the advent of effective chemotherapy, and the introduction of platinum-based agents in particular, as well as changes in surgical practice. More recently, there has been a significant shift towards greater specialisation in the delivery of care, resulting from the implementation of the Department of Health's cancer service guidance 'Improving outcomes in gynaecological cancers'. It is likely that some or all of these changes have contributed to the improved survival rates, emphasising the need to ensure that women with diagnosed ovarian cancer are treated in specialist centres that can provide comprehensive cancer care.
This guideline does not cover the entire care pathway for ovarian cancer. It focuses on areas where there is uncertainty or wide variation in clinical practice with regard to the detection, diagnosis and initial management of ovarian cancer. The guideline recommendations are applicable to women with epithelial ovarian cancer (the most common type of ovarian cancer), as well as women with fallopian tube carcinoma, primary peritoneal carcinoma or borderline ovarian cancer (see research recommendations for further details).
The guideline assumes that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.# Guidance
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.

# Detection in primary care
Recommendations in this section have been incorporated into the NICE guideline on suspected cancer.

## Awareness of symptoms and signs
Refer the woman urgently if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids).An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks. See also the NICE guideline on suspected cancer: recognition and referral.
Carry out tests in primary care (see section on asking the right question  first tests) 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 (women often refer to this as 'bloating')
feeling full (early satiety) and/or loss of appetite
pelvic or abdominal pain
increased urinary urgency and/or frequency.See also the NICE guideline on suspected cancer: recognition and referral.
Consider carrying out tests in primary care (see section on asking the right question  first tests) 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 (see section on asking the right question  first tests) in any woman of 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS), because IBS rarely presents for the first time in women of this age.See NICE's clinical guideline on irritable bowel syndrome in adults.

## Asking the right question  first tests
Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section on awareness of symptoms and signs).
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.
If the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation.An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks. See also the NICE guideline on suspected cancer: recognition and referral.
For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 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.

# Establishing the diagnosis in secondary care

## Tumour markers: which to use?
Measure serum CA125 in secondary care in all women with suspected ovarian cancer, if this has not already been done in primary care.
In women under 40 with suspected ovarian cancer, measure levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as serum CA125, to identify women who may not have epithelial ovarian cancer.

## Malignancy indices
Calculate a risk of malignancy index I (RMI I) score (after performing an ultrasound; see recommendation 1.2.3.1) and refer all women with an RMI I score of 250 or greater to a specialist multidisciplinary team.See the appendix for details of how to calculate an RMI I score.

## Imaging in the diagnostic pathway: which procedures?
Perform an ultrasound of the abdomen and pelvis as the first imaging test in secondary care for women with suspected ovarian cancer, if this has not already been done in primary care.
If the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a CT scan of the pelvis and abdomen to establish the extent of disease. Include the thorax if clinically indicated.
Do not use MRI routinely for assessing women with suspected ovarian cancer.

## Tissue diagnosis
Requirement for tissue diagnosis
If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not appropriate) in all but exceptional cases.
Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without a tissue diagnosis (histology or cytology) only:
in exceptional cases, after discussion at the multidisciplinary team and
after discussing with the woman the possible benefits and risks of starting chemotherapy without a tissue diagnosis.
Methods of tissue diagnosis other than laparotomy
If surgery has not been performed, use histology rather than cytology to obtain a tissue diagnosis. To obtain tissue for histology:
use percutaneous image-guided biopsy if this is feasible
consider laparoscopic biopsy if percutaneous image-guided biopsy is not feasible or has not produced an adequate sample.Use cytology if histology is not appropriate.

# Management of suspected early (stage I) ovarian cancer

## The role of systematic retroperitoneal lymphadenectomy
Perform retroperitoneal lymph node assessment as part of optimal surgical staging in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease).Lymph node assessment involves sampling of retroperitoneal lymphatic tissue from the para-aortic area and pelvic side walls if there is a palpable abnormality, or random sampling if there is no palpable abnormality. Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment (Winter-Roach et al. ).
Do not include systematic retroperitoneal lymphadenectomy (block dissection of lymph nodes from the pelvic side walls to the level of the renal veins) as part of standard surgical treatment in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease).

## Adjuvant systemic chemotherapy for stage I disease
Do not offer adjuvant chemotherapy to women who have had optimal surgical staging and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib).
Offer women with high-risk stage I disease (grade 3 or stage Ic) adjuvant chemotherapy consisting of 6 cycles of carboplatin.
Discuss the possible benefits and side effects of adjuvant chemotherapy with women who have had suboptimal surgical staging and appear to have stage I disease.Optimal surgical staging constitutes: midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum; and retroperitoneal lymph node assessment (Winter-Roach et al. ).

# Management of advanced (stage II to IV) ovarian cancer
For NICE technology appraisal guidance on first-line chemotherapy see the NICE topic page on ovarian cancer.

## Primary surgery
If performing surgery for women with ovarian cancer, whether before chemotherapy or after neoadjuvant chemotherapy, the objective should be complete resection of all macroscopic disease.

## Intraperitoneal chemotherapy
Do not offer intraperitoneal chemotherapy to women with ovarian cancer, except as part of a clinical trial.

## Second-line and subsequent treatment
For NICE technology appraisal guidance on second-line and subsequent treatment for ovarian cancer, including genomic biomarker-based therapy, see the NICE topic page on ovarian cancer.
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments.

# Support needs of women with newly diagnosed ovarian cancer
Offer all women with newly diagnosed ovarian cancer information about their disease, including psychosocial and psychosexual issues, that:
is available at the time they want it
includes the amount of detail that they want and are able to deal with
is in a suitable format, including written information.
Ensure that information is available about:
the stage of the disease, treatment options and prognosis
how to manage the side effects of both the disease and its treatments in order to maximise wellbeing
sexuality and sexual activity
fertility and hormone treatment
symptoms and signs of disease recurrence
genetics, including the chances of family members developing ovarian cancer
self-help strategies to optimise independence and coping
where to go for support, including support groups
how to deal with emotions such as sadness, depression, anxiety and a feeling of a lack of control over the outcome of the disease and treatment.# Research recommendations
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

# Relationship between duration of symptoms of ovarian cancer and stage at diagnosis
Further research should be undertaken on the relationship between the duration and frequency of symptoms in women with ovarian cancer before diagnosis, the stage of disease at diagnosis and subsequent survival.

## Why this is important
Most women presenting with ovarian cancer have advanced disease and have had symptoms for months. Greater awareness among both women and healthcare professionals might result in women presenting earlier with less advanced disease, leading to better outcomes. There is insufficient understanding of the factors that influence earlier diagnosis in women with ovarian cancer, especially the relationship between duration of symptoms and stage at diagnosis. Data demonstrating benefits from earlier presentation will justify investment in raising awareness among women and healthcare professionals. This is likely to be a population-based study that records both the duration and frequency of symptoms.

# Imaging in the diagnostic pathway for women with ovarian cancer
Large multicentre casecontrol studies should be conducted to compare the accuracy of CT versus MRI for staging and for predicting optimal cytoreduction in women with ovarian cancer.

## Why this is important
Currently most women with ovarian cancer will undergo a CT scan before surgery to assess the extent and resectability of disease. CT and MRI are complementary in their abilities to detect disease, but no adequate studies have been performed that compare their effectiveness in women with suspected ovarian cancer. No comparative studies have been undertaken evaluating surgical outcome. A prospective study in women undergoing primary surgery would be feasible.

# The value of primary surgery for women with advanced ovarian cancer
Research should be undertaken to determine the effectiveness of primary surgery for women with advanced ovarian cancer whose tumour cannot be fully excised.

## Why this is important
Most women with advanced ovarian cancer undergo surgery at some point. Previous studies have shown that surgery after the completion of chemotherapy has no therapeutic value. Studies are being performed to investigate whether the timing of surgery during primary chemotherapy influences outcome. No studies have evaluated whether primary surgery itself has any therapeutic value when compared with chemotherapy alone. The potential advantages of surgery have to be offset against the morbidity, occasional mortality and undoubted costs associated with it. This would be a prospective randomised clinical trial recruiting women who have biopsy-proven advanced ovarian cancer and who are fit enough to receive surgery and chemotherapy. Women would be randomised to either chemotherapy and surgery (conventional arm) or chemotherapy alone (experimental arm). Primary outcome measures would be survival at 1 and 5 years.# Appendix: Risk of malignancy index (RMI I)
RMI I combines 3 pre-surgical features: serum CA125 (CA125), menopausal status (M) and ultrasound score (U). The RMI is a product of the ultrasound scan score, the menopausal status and the serum CA125 level (IU/ml).
RMI = U x M x CA125
The ultrasound result is scored 1 point for each of the following characteristics: multilocular cysts, solid areas, metastases, ascites and bilateral lesions. U = 0 (for an ultrasound score of 0), U = 1 (for an ultrasound score of 1), U = 3 (for an ultrasound score of 2 to 5).
The menopausal status is scored as 1 = pre-menopausal and 3 = post-menopausal.
The classification of 'post-menopausal' is a woman who has had no period for more than 1 year or a woman over 50 who has had a hysterectomy.
Serum CA125 is measured in IU/ml and can vary between 0 and hundreds or even thousands of units.