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Analysing primary versus interval debulking for treating ovarian cancer

Each year in Ireland, more than 300 women are diagnosed with ovarian cancer. It has the highest mortality of all gynaecological malignancies, with a worldwide mortality of 125,000 each year.

The ovary is made up of many different cell types, all of which can have malignant potential. However, 90 per cent of ovarian cancers are epithelial in nature. Damage to the ovarian surface epithelium is thought to be involved in the aetiology of ovarian cancer. Therefore, there is an increased risk in women with multiple ovulations, including nulliparous women. Those with an early menarche and late menopause are also thought to be at an increased risk. Pregnancy and the use of the oral contraceptive pill are thought to be protective.

Genetic components

There are known genetic components to some ovarian cancers, however, only 10-15 per cent have an identifiable mutation. The lifetime risk of developing ovarian cancer, with the genetic condition hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is 12 per cent.

An inherited mutation in the BRCA1 and BRCA2 genes leads to an increased risk of developing ovarian and breast cancer. BRCA1 poses a higher risk of developing ovarian cancer than BRCA2. This risk is age-related; at 50 years of age, the risk of developing ovarian cancer with BRCA1 or BRCA2 is 21 per cent versus 2 per cent respectively, increasing to 46 per cent versus 12 per cent at age 70.1

Even if a patient is deemed at high risk of developing ovarian cancer, there is still no reliable method for early detection and no effective screening test. Performing yearly transvaginal pelvic ultrasounds and serum tumour markers (CA125) does not reduce mortality rates and does not allow for early detection.

Serum CA125 levels can be raised in non-gynaecological cancers and in benign conditions (eg, endometriosis) and is therefore not specific. It is elevated in 85 per cent of patients with advanced ovarian cancer but in only 50 per cent of those with the International Federation of Gynaecology and Obstetrics (FIGO) stage 1 disease.

What can be offered to those patients deemed at high risk, or those with a family history of ovarian cancer, is risk-reducing surgery. Typically, this involves a laparoscopic bilateral salpingo-oophorectomy (BSO). Additionally, given that many ovarian cancers are thought to arise from the Fallopian tube, it is now best practice to perform bilateral salpingectomy in any woman requesting tubal ligation as a form of contraception, as opposed to the previously performed Fallopian tube clipping.

Unfortunately, the vague nature of presenting symptoms in ovarian cancer can often lead to a delay in diagnosis. Seventy-five per cent of patients will present with advanced disease (FIGO stage 3 or 4). Typically, at presentation, patients have ascites, omental caking or a large abdominal mass noted on imaging.

The aim of surgical management in advanced-stage disease is a complete cytoreduction of all macroscopically-visible tumour deposits. Optimal debulking is defined as residual implants less than 1cm by the Gynaecologic Oncology Group, however there is a further survival advantage in patients with no visible residual disease.

Full surgical staging includes laparotomy, hysterectomy, BSO, omentectomy +/- appendicectomy, lymph node sampling, peritoneal biopsies, and pelvic washings.

Surgery should be performed by a gynaecological oncologist and patients should be referred to a tertiary unit to avail of this if there is no such service locally. Survival rates are higher when a gynaecological oncologist is involved.

If a comprehensive surgical staging is performed, up to 30 per cent of patients with apparently early epithelial ovarian cancer will be upstaged following surgery, depending on the histological grade and subtype. This allows for appropriate adjuvant treatment to be put in place.

Surgical debulking followed by adjuvant platinum-based chemotherapy has been long thought of as the gold standard in the treatment of advanced-stage ovarian cancer.

The replacement of cisplatin-based chemotherapy with carboplatin combinations has been one of the only major developments over the past 20 years. Recently, an alternative management of neoadjuvant chemotherapy (NACT) followed by interval debulking surgery is becoming more widely accepted. This has the potential to minimise the amount of surgical resection and radical procedures required, without reducing the efficacy of the surgery in reducing the residual disease to less than 1cm.

In these circumstances, the diagnosis of ovarian cancer would usually be confirmed following an ascitic tap or a CT-guided biopsy, with neoadjuvant chemotherapy commenced. A review of the patient’s imaging and tumour markers following three-to-four cycles of chemotherapy is performed to assess the response to treatment, followed by a surgical resection and further adjuvant chemotherapy. This approach has followed on from the recently-published, randomised trial of the European Organisation for Research and Treatment of Cancer — National Cancer Institute, Canada (EORTC-NCIC) of patients with advanced FIGO stage IIIc and IV ovarian cancer.2 The results of the trial demonstrated similar survival rates for patients randomised to NACT, followed by interval debulking versus those randomised to primary surgical debulking, followed by chemotherapy.

In the interval, debulking group post-operative complications were lower and it was associated with less early mortality. Surgical morbidity had a non-significant trend to be lower in the neoadjuvant arm, with fewer radical procedures needing to be performed. Regardless of treatment group, the reported median overall survival was about 30 months. The most important independent prognostic factor for overall survival was no residual tumour, but the timing of surgery did not seem to matter.

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Table 1: EORTC and CHORUS data 

Survival rates

Results from the Medical Research Council (MRC) Chemotherapy or Upfront Surgery in Ovarian Cancer Patients (CHORUS) trial3 mirrored these findings, in that median overall survival rates were comparable in patients receiving NACT followed by surgery, then chemotherapy versus those who had primary surgery followed by chemotherapy. Progression-free survival was also similar in the two arms. Optimal debulking was more likely to be achieved in the neoadjuvant treatment group. However, it should be noted that the median survival rates remained low in all patients.

Many patients in the study had large-volume disease and poor performance status, so there has been some criticism that it cannot be generalised to all patients with advanced ovarian cancer and only to those with a poor performance status.

There is currently no consensus on optimal management. In advanced stage III or IV ovarian cancer, the overall prognosis is poor, with a five-year survival rate of less than 30 per cent. Many patients will achieve remission, regardless of initial treatment, but ultimately 80-to-90 per cent of patients will relapse. The above-mentioned large clinical trials have concluded that NACT followed by interval debulking surgery is not inferior to primary debulking surgery followed by chemotherapy.

Delaying surgery with chemotherapy does not impact negatively on survival. This information is of particular benefit when deciding the best approach in patients with poor performance status at presentation and those with extensive tumour dissemination. It indicates that it is appropriate to consider the use of NACT in these cases or when it is thought to be difficult to achieve an optimal primary surgical cytoreduction.

Regardless of which management plan is adopted, a single, maximal surgical debulking attempt does make a difference in patients with advanced ovarian cancer.

Whether it is done with a primary surgery or at an interval between chemotherapy, it certainly plays a role in patients’ overall survival. For those patients who appear to be unresectable at initial diagnosis based on radiological imaging (CT or MRI) and in those who are unfit to undergo surgery at the outset, interval debulking does appear to be a valid alternative. Inherently, it is not logical to adopt a single approach in the management of such a complex and heterogeneous disease, where there remains no compelling evidence that one strategy is superior to the other.

Ultimately, treatments should be tailored to the patient and should take into consideration their age, medical comorbidities, resectability, histological type, stage and grade of tumour. It is evident that different histological types can affect the response to standard chemotherapy, with advanced mucinous and clear-cell cancers having a poorer response than serous carcinomas.

Future trials are needed to help us identify which patients will respond better to which treatments. In this emerging era of personalised medicine, a greater understanding of the molecular profile of each person and of ovarian cancer itself may help us identify personalised, targeted treatment options.

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Table 2: Both trials showed a reduction in morbidity for the neoadjuvant arms 

References

  1. King MC, Marks JH, Mandell JB, et al (2003). Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643-6.
  2. Vergote I, et al. N Engl J Med. 2010;363(10):943-953.
  3. Kehoe S, et al. J Clin Oncol. 2013;31(Suppl): Abstract 5500.

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