Ovarian Cancer symptoms, diagnosis and treatment

A recent consensus statement reported the following symptoms to be frequent in ovarian cancer patients: persistent pelvic and abdominal pain; increased abdominal size/persistent bloating; loss of appetite and feeling full quickly.1 Other symptoms include urinary symptoms, change in bowel habits, extreme fatigue, back pain, postmenopausal bleeding and rectal bleeding.2 All these symptoms have positive predictive values (PPV) of less than 1% except for persistent abdominal distension which has the highest PPV of 2.5.2 Symptoms that are frequent, persistent and severe may help to pinpoint women with ovarian cancer.3 If ovarian cancer is suspected, Department of Health advice to health professionals is to request a serum CA125 assay and a pelvic ultrasound scan.4 While it is hoped that ‘earlier recognition and referral will translate into earlier stage at diagnosis’, no studies have yet proved this.4 The imprecision of symptoms, and indeed of serum CA125 levels and pelvic ultrasound, underline the need for more accurate diagnostic tests to detect disease at an earlier, more treatable, stage.5

Ovarian cancer is neither an asymptomatic disease nor a so-called ‘silent killer’. Symptoms do not only become apparent when the disease is advanced. Recent studies have demonstrated that patients with all stages of the disease have symptoms.2,6-7 However, the symptoms reported by patients to their primary carers are vague and easily confused with other conditions, especially abdominal and gastrointestinal disorders. A case-control study found that 95% of women (in general) presenting to primary care reported at least one symptom annually, and 72% reported symptoms occurring at least once per month.7 Raising awareness is one line of attack while another is the development of a symptom index.1,6,8-9 A key task is how the general practitioner, who sees on average one case of ovarian cancer every five years, can efficiently refer women with suspected ovarian cancer - half of whom are not being referred directly to gynaecological cancer clinics.6

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If ovarian cancer is suspected, an urgent referral should be made to a dedicated diagnostic centre.10 A risk of malignancy index (RMI) has been developed which combines the results of transvaginal ultrasound examination, menopausal status and blood levels of the ovarian cancer marker CA125 (measured in U/ml).11 Use of measures such as the RMI and clinical examination enables the gynaecologist to refer patients with likely ovarian cancer to a specialist gynaecological oncologist who should undertake surgery for suspected ovarian cancer.10,12

The primary procedure in a woman with suspected ovarian cancer is to obtain histological confirmation of the disease. This is generally undertaken at a laparotomy, whereby the disease can also be staged. The International Federation of Obstetricians and Gynaecologists (FIGO) staging system is shown in Table 6.113.

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Prophylactic oophorectomy has been shown to decrease the risk of BRCA-mutation-related gynaecological cancers and breast cancer in BRCA1 and BRCA2 mutation carriers.14-15 Prophylactic bilateral salpingo-oophorectomy, with or without hysterectomy, in women with Lynch syndrome (HNPCC) was found to be effective in preventing ovarian cancer.16 It is important that women have access to the appropriate specialists, as such a procedure can have extensive psychological consequences.17

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In younger patients, where fertility is an issue, the appropriate surgery is to diagnose and stage the disease while, importantly, retaining the woman's fertility. This is because, in many cases, the cancer will be a germ cell tumour or early ovarian cancer (Stage 1A), which are amenable to non-radical surgical interventions.18-21 In women who have completed their families, or are post-menopausal, it is recommended that the uterus, fallopian tubes and ovaries are removed and relevant biopsies performed.13

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Immediately following surgery, many women are given adjuvant chemotherapy, normally using a platinum compound. In women with no residual disease, the recent randomised controlled trial (RCT) ICON1, indicated that platinum-based chemotherapy does improve survival.22 Another RCT, ACTION, found that disease-free survival was improved in women receiving adjuvant chemotherapy.23 A meta-analysis of five trials of adjuvant chemotherapy compared with no further treatment in early ovarian cancer (including the two mentioned above) showed an improvement in both overall survival and disease-free survival (hazards ratios of 0.71,95% CIs 0.63 to 0.80; and 0.68, 95%CIs 0.59 to 0.79, respectively).24 A pre-planned combined analysis of the ICON1 and ACTION trials also came to the same conclusion. 25

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In a situation where there is very advanced disease, all of which cannot be excised by surgery, many surgeons perform ‘debulking’ surgery, endeavouring to leave behind as little tumour as possible. This is thought to improve the efficacy of adjuvant chemotherapy, but the evidence to support this is questionable. Two ongoing studies are addressing this important question, EORTC 55971, and CHORUS.26-27

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In more advanced disease, some studies have reported improved survival when paclitaxel is combined with a platinum agent.28-29 However, the largest study, ICON3, suggested that there was no difference in outcome with combination therapy.30 Debate continues with regard to these findings, and NICE recommends that women requiring chemotherapy should have a platinum agent administered, and the possible addition of paclitaxel should be discussed on an individual basis.31

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The role of routine surgery in relapsed disease is another area of controversy.32 Surgery can sometimes be helpful in the alleviation of symptoms, but whether its routine use is useful needs addressing through clinical trials. From retrospective studies, it appears that optimum debulking surgery at relapse results in lengthened survival.33

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In relapsed disease, the main determinant of continued survival and, indeed, response to further chemotherapy is the time interval from completion of the last therapy. Disease which develops within six months from the end of treatment is deemed resistant to that therapy, and further therapy will be individualised. Outside this time period, further responses to platinum can be anticipated, or to paclitaxel if it was not used previously. ICON4, a randomised controlled trial, revealed that in relapsed disease (occurring six months or more after cessation of treatment), the combination of carboplatin and paclitaxel afforded a better survival when compared to single agent carboplatin.34 This finding contradicts those of ICON3 but, of course, the disease processes at relapse may be different. A phase I trial of olaparib, a PARP inhibitor, found that it was well-tolerated and had a high response rate in BRCA1 or BRCA2 mutation carriers who were either platinum-sensitive or platinum-resistant.35

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