Description of the condition

Ovarian cancer is the seventh most common cancer in women. It is also the fourth most common cause of death due to cancer in women (Denny 2013; Ledermann 2013). The majority of these cancers occur in older and postmenopausal women. A woman's risk of developing ovarian cancer by the age of 65 years ranges from 0.4% in developing countries to 0.6% in developed countries (GLOBOCAN 2012). Epithelial ovarian cancer (EOC) is a disease in which malignant cells arise from the tissues covering the surface of the ovary. The exact cause of EOC remains unknown, but has been found to be associated with nulliparity (women who have not delivered fetuses greater than 24 weeks pregnancy), delayed childbearing, early menarche, late menopause, obesity, and BRCA1 and BRCA2 tumour suppressor gene mutations (inherited faulty genes in the family which increase the risk of both ovarian and breast cancer), and women of Ashkenazi Jewish descent who have a far higher incidence of the BRCA1 and BRCA2 genes (Denny 2013; Feig 2006; Ledermann 2013). Also, recent advances in molecular pathogenesis (the study and diagnosis of disease through examination of molecules within organs, tissues or body fluids) reveals that high‐grade serous ovarian cancer (the most common histological subtype of EOC) appears to develop from intra‐epithelial carcinoma (precancerous cells) in the fallopian tube. This precancerous condition is termed as 'serous tubal intra‐epithelial carcinoma' (STIC) and is often seen in women with BRCA1 and BRCA2 mutations. A bilateral salpingo‐oophorectomy (removal of tubes and ovaries) has shown to reduce the risk of developing EOC (Kurman 2013; Polcher 2015).

In the USA, the five‐year survival rate for ovarian cancer is 45% (Siegel 2011). In the UK, the age‐standardised relative survival rates for ovarian cancer are 72% at one year, falling to 43% at five years or more (Cancer Research UK 2012). Women with advanced EOC may be relatively asymptomatic, or may have only mild, vague symptoms when they present to the clinician. This results in poor survival rates for this group of women, since most women will relapse despite high initial response rates to chemotherapy (Jemal 2008). Other causes of poor survival include late presentation, tumour biology and suboptimal cytoreduction either due to disease distribution or limited surgical ability.

The International Federation of Gynecology and Obstetrics (FIGO) describes ovarian cancer staging as I to IV (see Appendix 1) (Society of Gynaecologic Oncology). Epithelial ovarian cancer spreads trans‐coelomically (across the abdominal cavity) by the spillage of tumour cells. It is also known to spread to pelvic and para‐aortic nodes (lymph nodes situated behind the womb and the upper abdomen) via retroperitoneal lymphatic channels (lymphatic channels situated behind the lining of the abdomen), especially in advanced EOC. It can spread to the liver and outside the peritoneal cavity to the chest and supraclavicular nodes (lymph nodes felt above the collar bone) via lymphatic channels through the diaphragm. Approximately two thirds of women with EOC present with FIGO stage III and IV (Makar 1995; Pettersson 1994; Twombly 2007).

The FIGO surgical stage predicts the five‐year survival rate for women with ovarian cancer. The survival rates are shown in Appendix 2 (Cancer Research UK 2011; Cancer Research UK 2012). Staging is carried out by midline laparotomy (opening the abdomen via a midline vertical cut) and systematic examination of all areas in the abdomen and pelvis. This normally involves obtaining peritoneal washings or ascites for cytology, total abdominal hysterectomy (removal of the womb), bilateral salpingo‐oophorectomy (removal of both ovaries and tubes), omentectomy (removal of the fatty apron covering the bowel), debulking of any visible disease (removal of any visible cancer), random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment (removal of lymph nodes situated within the pelvis and abdomen) (Cancer Research UK; Denny 2013).

A key indicator for survival in women with advanced EOC is the amount of residual disease remaining following primary debulking surgery (Griffiths 1975; Hoskins 1992; Hoskins 1994). The aim of primary debulking surgery is complete cytoreduction (removal of all visible cancer) or residual disease < 1 cm if complete cytoreduction not achievable. A meta‐analysis has demonstrated that patient survival is longer in the absence of residual disease in comparison to the presence of residual disease (whether it is < 1 cm or > 1 cm) (Shih 2010). A systematic review on optimal primary cytoreduction for advanced EOC showed that women with residual disease < 1 cm still do better than women with residual disease > 1 cm (Elattar 2011). To what extent this is due the direct effect of surgical intervention or underlying tumour biology affecting tumour resectability remains a matter of debate.

Women with early stage disease, FIGO stage IC (grade 3) and above, are recommended to have platinum‐based chemotherapy, either after surgery (adjuvant) or increasingly before surgery if disease is widespread (neoadjuvant chemotherapy) (Du Bois 2009; Feig 2006; Vergote 2010). A recent Cochrane review concluded that neoadjuvant chemotherapy (chemotherapy given prior to surgery in order to reduce the bulk of the disease) is a reasonable alternative to primary debulking surgery in patients with bulky advanced EOC that cannot be optimally reduced (Morrison 2012). However, most women (75%) with advanced EOC will relapse following surgery and chemotherapy, despite initial chemosensitivity with platinum‐based regimens. Eventually, sometime after several cycles of chemotherapy, most women who relapse will develop resistance to conventional chemotherapy drugs (Gonzalez‐Martin 2013).

Description of the intervention

Although women with advanced EOC initially respond well to cytoreductive surgery and platinum‐based, first‐line chemotherapy (initial response rate following platinum‐based chemotherapy is around 70%), the majority of women (70% to 80%) will relapse or progress within 12 to 24 months (Colombo 2014; Ledermann 2013; Sourbier 2012). In general, women with relapsed EOC are treated with chemotherapy. However, if complete cytoreduction can be achieved in these women (recurrent disease in single site or few sites with resectable disease), chemotherapy could be held in reserve for when surgery is no longer an option.

The response to chemotherapy and type of chemotherapeutic regimen used for women with relapse depends on the time interval between the initial platinum‐based chemotherapy and recurrence of disease (relapse‐free interval). If relapse occurs after 12 months of completion of initial platinum chemotherapy, the tumour is considered to be platinum‐sensitive, and if relapse occurs within six months after completion of initial chemotherapy, the tumour is considered to be platinum‐resistant. Patients presenting with disease between six to 12 months post completion of initial platinum combination are considered to be partially platinum‐sensitive (Banerjee 2011; Colombo 2014; Friedlander 2011; Pfisterer 2006).

Women with platinum‐sensitive or partially platinum‐sensitive disease are generally treated with carboplatin, alone or in combination with paclitaxel, liposomal doxorubicin or gemcitabine (Ledermann 2013). The Ovarian Cancer Study (OCEANS) assessed the role of bevacizumab (anti‐angiogenic drug) in the treatment of platinum‐sensitive recurrences. In this phase III double‐blind placebo‐controlled trial, chemotherapy (gemcitabine + carboplatin), with or without bevacizumab was used for recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer. The results demonstrated an improved median progression‐free survival (PFS) for patients receiving bevacizumab when compared to those receiving a placebo (Aghajanian 2012).

Women resistant to platinum chemotherapy are treated with non‐platinum drugs; the most commonly‐used drugs are liposomal doxorubicin, gemcitabine, taxanes and topotecan. These patients have low response rates and experience severe side effects. This can negatively influence quality of life (QoL). Eventually women develop resistance to any chemotherapeutic regimen (Ledermann 2013). It is therefore important to balance the benefits and toxicities of prolonged chemotherapy treatment in women with recurrent disease. New treatments that can be used to treat recurrence or prevent disease progression after first‐line chemotherapy or subsequent chemotherapy are important, especially those with a low toxicity profile (few side effects).

Luteinising hormone releasing hormone (LHRH) agonists have been used in both the treatment of advanced EOC (in addition to first‐line, platinum‐based chemotherapy) and also in relapsed disease. Some studies have shown objective remissions, whilst other studies (including phase II studies) have shown little or no benefit (Adelson 1993; Levine 2007; Lind 1992; Medl 1993; Miller 1992; Ron 1995). Most studies have shown a better side‐effect profile for LHRH agonists when compared to standard chemotherapeutic agents used in EOC (relapsed or progressive disease) (Emons 1990; Emons 1994). In addition, LHRH agonists have shown disease stabilisation and improved PFS when used in patients with relapsed EOC, without any major side effects (Lind 1992). Anecdotal reports on LHRH agonists use as consolidation therapy in advanced EOC and recurrent ovarian cancer showed long‐term complete clinical remission and longer (seven to 14 years) overall survival (OS) (Chudecka‐Glaz 2009). Despite several studies showing benefit, to date there has been no systematic review addressing the role of LHRH agonists versus other chemotherapeutic interventions in relapsed EOC.

How the intervention might work

Cramer 1983 hypothesised that elevated gonadotrophin hormonal levels (hormones produced by the pituitary gland) found in postmenopausal women can be a causative factor for developing ovarian cancer. Emons 1990 postulated that EOC can be gonadotrophin‐dependent. Adelson 1993 reported the presence of luteinising hormone (LH), follicle‐stimulating hormone (FSH) and gonadotrophin releasing hormone (GnRH) receptors on ovarian tumours, and manipulation of these hormones resulted in tumour response both in vivo and in vitro. Other studies found that human EOC cell lines express LHRH receptors and proliferation of these cells was decreased by treatment with both agonists and antagonist analogues of LHRH in vitro (Emons 1994; Emons 1996; Emons 2000). It is reported that specific LHRH binding sites can be found in at least 80% of EOC (Emons 1990; Emons 1994; Emons 1996; Emons 2000; Lind 1992), and this could be a target for hormonal therapy with LHRH agonists. In vivo, LHRH agonists cause suppression of LH and FSH levels, which in turn inhibit the growth of EOC (Dowsett 1988; Emons 2000). Hence LHRH analogues could be used in EOC treatment due to their anti‐proliferative effect. A number of phase I and phase II clinical trials have reported that suppression of endogenous LH and FSH secretion by administration of LHRH analogues induces objective remissions of 9% to 12% and disease stabilisation in 15% to 26% of patients with advanced resistant EOC, and with less side effects than chemotherapy (Emons 2000; Paskeviciute 2002).

Why it is important to do this review

In women with stage I or II EOC, around 20% to 25% will have relapse of disease following treatment, while most women (75%) with advanced EOC will relapse (Ushijima 2010). Treatment after relapse is usually palliative and there is a need to find treatments with low toxicity to improve QoL outcomes. There have been observational studies in the literature evaluating the role of LHRH agonists in patients with advanced EOC and some studies report a beneficial effect (Lind 1992; Rzepka‐Gorska 2003) in terms of overall and PFS. Hassan 2005 reported that a combination of goserelin and tamoxifen prolonged survival in women with relapsed and platinum‐resistant disease similar to that seen for single‐agent chemotherapy regimens. Hormonal therapy might be better than conventional chemotherapy due to its relative lack of toxicity, ease of administration and tolerability in the context of compromised bone marrow function, and suitable for women heavily pre‐treated with other chemotherapeutic agents and with platinum‐resistant disease. There have been a few randomised controlled trials (RCTs) addressing this important clinical question (Du Bois 2002; Emons 1996; Jager 1995). 

As far as we are aware, there has been no systematic review and meta‐analysis published addressing this clinical question. Due to the lack of consensus in the literature, there was a need to conduct a comprehensive systematic review on this subject.