Does giving chemotherapy before surgery improve survival or quality of life for women with advanced ovarian epithelial cancer?

What is the issue?
Epithelial ovarian cancer, arising from the surface layer of the ovaries or lining of the fallopian tubes, is the seventh most common cancer worldwide in women, and is the most common form of ovarian cancer (approximately 90% of ovarian cancers). Unfortunately, most women with ovarian cancer present at a late stage, when their disease has spread throughout the abdomen. This is because ovarian cancer often arises from the ends of the fallopian tubes, from where single cells can drop out into the abdominal cavity even when the primary tumour is microscopic. These cells circulate around the abdominal cavity in the lubricating peritoneal fluid, implant on other surfaces and grow over time until they cause symptoms. Even then symptoms, such as bloating and bowel disturbance (most commonly constipation), are non-specific and easily attributed to more common benign conditions. In Europe, just over a third of women diagnosed with ovarian cancer are alive five years after diagnosis.

Conventional treatment for ovarian cancer involves two modalities of treatment: surgery and chemotherapy. The intention of surgery is to stage the disease (assess where the cancer has spread to) and remove as much of the visible (macroscopic) cancer as possible (known as debulking or cytoreduction), preferably to the point where the surgical team is not able to see any visible residual disease in the abdominal cavity. However, since most women will have widespread disease, surgery alone is unlikely to cure the disease and most will also need chemotherapy. Chemotherapy for ovarian cancer uses platinum-based drugs to treat cells that cannot be removed by surgery (macroscopic disease) or are too small to be seen (microscopic disease). Traditionally chemotherapy was given after surgery. However, chemotherapy can be used before surgery (known as neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)) with the aim of shrinking the cancer and allowing women to get better prior to undertaking radical surgery.

What did we do?
We searched electronic databases on 11 February 2019. We included randomised controlled trials of NACT and IDS versus surgery followed by chemotherapy (primary debulking surgery (PDS) in women diagnosed with advanced stage epithelial ovarian cancer and pooled study outcome data where appropriate.

What did we find?
We found 1952 potential titles. From these we found five studies which met our inclusion criteria, including a total of 1713 women with advanced ovarian cancer. We were able to pool data from four studies. These studies compared women who were given chemotherapy prior to surgery (NACT) with women who underwent surgery first (PDS) prior to chemotherapy. We found little or no difference between the two treatments with respect to the time to death or the time to progression of the disease. We found that giving NACT probably reduces the risk of some complications of surgery, but these data were less well reported in the included studies and so we have low certainty about these results. The studies only enrolled women with stage IIIc/IV ovarian cancer i.e. those who had advanced disease; a large proportion of women in this review had very bulky tumours. We are currently awaiting results of two ongoing studies and one unpublished study that will hopefully contribute more evidence to guide clinical practice in this area in the future.

What does this mean?
Overall, the evidence was of moderate certainty. There is probably little or no difference in how long women with advanced epithelial ovarian cancer will survive, if they have chemotherapy or surgery first, where both treatments are planned. NACT may reduce some of the risks of surgery, and probably halves the risk of needing bowel removed and/or the bowel diverted through the abdominal wall via a stoma (a bag attached to the abdominal wall to collect bowel contents). NACT/IDS is an alternative to PDS followed by chemotherapy in women with bulky stage IIIc/IV disease. Individual decisions about which treatment to have first will depend on the individual woman's wishes, how well she is at the time of diagnosis, the risks of surgery and the burden and distribution of disease.

Authors' conclusions: 

The available moderate-certainty evidence suggests there is little or no difference in primary survival outcomes between PDS and NACT. NACT may reduce the risk of serious adverse events, especially those around the time of surgery, and the need for bowel resection and stoma formation. These data will inform women and clinicians and allow treatment to be tailored to the person, taking into account surgical resectability, age, histology, stage and performance status. Data from an unpublished study and ongoing studies are awaited.

Read the full abstract...
Background: 

Epithelial ovarian cancer presents at an advanced stage in the majority of women. These women require surgery and chemotherapy for optimal treatment. Conventional treatment has been to perform surgery first and then give chemotherapy. However, there may be advantages to using chemotherapy before surgery.

Objectives: 

To assess whether there is an advantage to treating women with advanced epithelial ovarian cancer with chemotherapy before debulking surgery (neoadjuvant chemotherapy (NACT)) compared with conventional treatment where chemotherapy follows debulking surgery (primary debulking surgery (PDS)).

Search strategy: 

We searched the following databases on 11 February 2019: CENTRAL, Embase via Ovid, MEDLINE (Silver Platter/Ovid), PDQ and MetaRegister. We also checked the reference lists of relevant papers that were identified to search for further studies. The main investigators of relevant trials were contacted for further information.

Selection criteria: 

Randomised controlled trials (RCTs) of women with advanced epithelial ovarian cancer (Federation of International Gynaecologists and Obstetricians (FIGO) stage III/IV) who were randomly allocated to treatment groups that compared platinum-based chemotherapy before cytoreductive surgery with platinum-based chemotherapy following cytoreductive surgery.

Data collection and analysis: 

Two review authors independently extracted data and assessed risk of bias in each included trial.

Main results: 

We found 1952 potential titles, with a most recent search date of February 2019, of which five RCTs of varying quality and size met the inclusion criteria. These studies assessed a total of 1713 women with stage IIIc/IV ovarian cancer randomised to NACT followed by interval debulking surgery (IDS) or PDS followed by chemotherapy. We pooled results of the three studies where data were available and found little or no difference with regard to overall survival (OS) (1521 women; hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.94 to 1.19, I2 = 0%; moderate-certainty evidence) or progression-free survival in four trials where we were able to pool data (1631 women; HR 1.02; 95% CI 0.92 to 1.13, I2 = 0%; moderate-certainty evidence).

Adverse events, surgical morbidity and quality of life (QoL) outcomes were poorly and incompletely reported across studies. There may be clinically meaningful differences in favour of NACT compared to PDS with regard to serious adverse effects (SAE grade 3+). These data suggest that NACT may reduce the risk of need for blood transfusion (risk ratio (RR) 0.80; 95% CI 0.64 to 0.99; four studies,1085 women; low-certainty evidence), venous thromboembolism (RR 0.28; 95% CI 0.09 to 0.90; four studies, 1490 women; low-certainty evidence), infection (RR 0.30; 95% CI 0.16 to 0.56; four studies, 1490 women; moderate-certainty evidence), compared to PDS. NACT probably reduces the need for stoma formation (RR 0.43, 95% CI 0.26 to 0.72; two studies, 581 women; moderate-certainty evidence) and bowel resection (RR 0.49, 95% CI 0.26 to 0.92; three studies, 1213 women; moderate-certainty evidence), as well as reducing postoperative mortality (RR 0.18; 95% CI 0.06 to 0.54:five studies, 1571 women; moderate-certainty evidence). QoL on the EORTC QLQ-C30 scale produced inconsistent and imprecise results in two studies (MD -1.34, 95% CI -2.36 to -0.32; participants = 307; very low-certainty evidence) and use of the QLQC-30 and QLQC-Ov28 in another study (MD 7.60, 95% CI 1.89 to 13.31; participants = 217; very low-certainty evidence) meant that little could be inferred.

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