Managing ovarian cancer

According to the Singapore Cancer Registry, ovarian cancer was the fifth most frequent cancer among women in Singapore and accounted for 5.4 percent of all female cancers diagnosed between 2011 and 2015, with an increasing incidence rate through the last four decades.

Ovarian cancer incidence rises with age, but particularly sharply after the fourth decade of life. More than 90 percent of ovarian malignancies are derived from epithelial cells, with the remainder arising from other non-epithelial cell types viz. germ cell tumours and sex cord-stromal tumours.

Epithelial carcinoma of the ovaries, fallopian tubes, and peritoneum (EOC) is considered the same clinical entity due to similar clinical course and treatment. A growing body of evidence points to a common pathogenesis, with the tubal epithelium at the fimbriate end being the putative precursor site for the serous variant. The commonest histological subtypes of EOC in Singapore are high grade serous (35 percent), clear cell (20 percent), and endometrioid (17 percent). [Singapore Cancer Registry Report No. 8, https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/cancertrends_7312_web128e09a5c9d76bafab5aff000014cdee.pdf?sfvrsn=0, accessed August 9, 2018]

Diagnosing ovarian cancer

Primary care physicians (GPs) can be important partners in recognizing potentially relevant signs and symptoms of ovarian cancer and referring such patients to a gynaecologist for further evaluation. Symptoms of ovarian cancer may mimic or overlap with many other conditions, for instance, dyspepsia or malignancies of other abdominopelvic organs. Therefore, GPs coming across a female patient with seemingly non-specific abdominal complaints should maintain an appropriate level of suspicion for ovarian cancer as a differential diagnosis. When ovarian cancer patients present to the gynaecological oncologist at earlier (localized) stages, they are more likely to receive curative-intent treatment and survive longer than those who present at advanced stages.

Women with symptoms and signs which suggest ovarian cancer should be evaluated with pelvic examination and pelvic and abdominal imaging. Pelvic ultrasound is the imaging study of choice to detect the presence of adnexal mass(es). Computer tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis are the most commonly used modalities to assess disease extent in women with suspected intra-abdominal spread of ovarian cancer. Chest imaging (radiography or CT) is used to detect the presence of pleural effusion(s), pulmonary metastases, or supradiaphragmatic adenopathy.

Serum tumour markers are often part of the diagnostic work-up of adnexal or ovarian mass(es). A ratio of cancer antigen 125 (CA 125):carcinoembryonic antigen (CEA) of >25 suggests that primary ovarian cancer is more likely than metastasis from a gastrointestinal primary malignancy. Other markers such as alpha fetoprotein, beta chorionic gonadotrophin, lactate dehydrogenase, and inhibin may be elevated in non-epithelial ovarian cancers.

Ultimately, the definitive diagnosis of ovarian cancer is histopathological. Cyto-histopathological examination is performed following surgical removal of the primary tumour and/or biopsies of the peritoneum. Less commonly, diagnosis is achieved based upon tissue or fluid obtained via image-guided biopsy, abdominal paracentesis, or thoracentesis. Ancillary tests such as mammograms and gastrointestinal scopes may be helpful to exclude ovarian metastases from other malignancies.

Routine screening of average-risk women on a population basis for ovarian cancer is not recommended. There may be a role for screening limited to high-risk women who are carriers of hereditary breast and ovarian cancer syndrome and Lynch syndrome.

Diagnostic challenges

Advanced ovarian cancer typically presents with abdominal distension, nausea, appetite loss, or early satiety due to malignant ascites and omental metastases. Malignant pleural effusion(s) may manifest as dyspnoea. These symptoms may be mistaken for other conditions.

Historically, ovarian cancer was called “the silent killer” because it was thought to be relatively asymptomatic early in the disease course and present late. This has since been refuted by observations that most women with early ovarian cancer may have symptoms – usually abdominal symptoms which are often gastrointestinal or urinary – as opposed to gynaecologic in nature. Early diagnosis therefore relies on symptom recognition by patients and clinicians. The barriers to recognition of a symptom complex as ovarian cancer and early detection can be addressed through education and increasing awareness among women and their healthcare providers, and clinical research.

The goal of early detection is to improve prognosis by diagnosing the disease while it is confined to the ovary or when the disease volume is low, whereby treatment is potentially curative. Abdominal bloating or distension, anorexia, early satiety, urinary urgency or frequency, and abdominal or pelvic pain occur in many gastrointestinal disorders but are also common in women with ovarian cancer. GPs should suspect ovarian cancer when dealing with this constellation of symptoms, particularly if the symptoms persist despite symptomatic treatment and/or are more severe than expected. In this scenario, it is appropriate to perform pelvic examination and transvaginal ultrasound, and measure serum CA 125.

Women with a complex adnexal mass, ascites, evidence of metastatic EOC, and/or elevated serum CA 125 should be referred to a gynaecologist, preferably a gynaecological oncologist, for further management.

Treating ovarian cancer

The staging and initial management of EOC is surgical and should be performed by a gynaecological oncologist whenever possible. Optimal or complete surgical cytoreduction is associated with improved survival. Most women with resected EOC, including early-stage disease at increased risk of relapse, benefit from postoperative adjuvant chemotherapy to reduce recurrence and improve survival. Stage III or certain IV EOC patients who are not good candidates for primary debulking surgery due to the location and volume of disease involvement or medical comorbidities at diagnosis may be considered for neoadjuvant chemotherapy, with a view to interval debulking surgery. Hyperthermic intraperitoneal chemotherapy at the time of interval debulking surgery has recently generated much interest. [N Engl J Med 2018;378:230-240]

For patients requiring first-line chemotherapy, the standard intravenous regimen utilizes platinum and taxane agents. Patients with small volume (<1 cm) or no residual disease after surgery may be considered for intravenous and intraperitoneal chemotherapy. However, this treatment has not been adopted widely because of its greater toxicity and logistical constraints. In selected high-risk postoperative patients, bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, may be used concurrently with adjuvant chemotherapy followed by maintenance by itself.

Treatment challenges 

Despite optimal upfront surgery and front-line taxane-platinum chemotherapy, approximately 70 percent of patients with EOC will relapse in the first 3 years. The response rate and prognosis associated with the next line of chemotherapy depends greatly on the duration of time between the last dose of the preceding line of chemotherapy and the detection of relapse.

Traditional teaching dictates that the platinum-free interval directs choice of next treatment line. Extending the platinum-free interval with use of non-platinum therapy (eg, bevacizumab anti-angiogenetic therapy, taxanes, hormonal therapy) can possibly help improve patients’ chance of responding to platinum rechallenge in the future. Poly (ADP-ribose) polymerase (PARP) inhibitors were recently approved as maintenance therapy following response to platinum-based chemotherapy to treat platinum-sensitive relapse of EOC. In Singapore, the licensed indication of the only currently commercially available PARP inhibitor, olaparib, is restricted to patients harbouring a germline or tumour BRCA mutation.

Most patients with recurrent EOC are treated with chemotherapy. Surgery for recurrent EOC is controversial and should probably be reserved for carefully selected patients (eg, platinum-sensitive relapse, limited sites of disease).

Patients with platinum-resistant or refractory EOC have poor prognosis. Hence, treatments should aim to maximize quality of life while attempting to control disease, generally with sequential single-agent therapy.

Cancer immunotherapy is an emerging modality of treatment against cancer that involves or uses components of the immune system. It is under active clinical research in advanced EOC.

Side effect management

GPs may encounter patients with EOC who present with infective complications while on chemotherapy. Most times, these patients are not neutropenic from their chemotherapy, unless heavily pre-treated, and can be managed in the community if clinically stable. GPs can triage patients back to their primary treatment centre or discuss with the primary oncologist if unsure.

A possible side effect of taxane chemotherapy is peripheral neuropathy, which can occasionally be severe and/or long-lasting even after treatment cessation and may impair patients’ function and mobility. Oncologists can work with rehabilitation medicine physicians to help ameliorate such neuropathy.