Surgical cytoreduction is the most significant modifiable prognostic factor in EOC, with complete cytoreduction consistently associated with improved progression free and overall survival[9]. There is little published data regarding cytoreductive surgery in the UK and, this case series, represents only the third UK report of outcomes from cytoreductive surgery[10, 11]. Surveys of UK practice in this regard have suggested significant variation in surgical practice with some centres reporting never achieving complete cytoreduction in either the primary (12%) or interval surgical setting (21%) [7, 8]. The issue of variation in surgical practice is not unique to the UK [12]. Factors contributing to ovarian cancer outcomes in the UK are undoubtedly complex and multifactorial, however an apparently less radical surgical approach in the UK may contribute to lower survival when compared to countries where more radical surgery has been widely adopted [4]. Structural resources and surgical training or skills have been highlighted as barriers to improving rates of cytoreduction. We report the results from the adoption of a multidisciplinary approach to EOC surgery in an attempt to overcome some of these barriers.
Our study describes surgical outcomes from consecutive, prospectively registered patients with EOC in a single region in Scotland, excluding selection bias. We report a combined complete and optimal (<1cm) cytoreduction rate of 69.0%. These data compare favourably with two large, randomized-controlled trials in women with advanced EOC where resection rates varied significantly between centres [3, 13] yet remain lower than those reported by other centres both nationally and internationally [10, 11, 14]. The median PFS of 14.3 months is similar to those reported in other UK populations and several international trials [10, 15]. Despite a significant increase in the number of bowel resections (20.5% in group 1 vs. 42.7% in group 2) and an associated reduction in pelvic residual disease, a more aggressive surgical approach did not significantly improve rates of complete or optimal cytoreduction and no significant improvement in progression free survival was seen between the two groups. This finding is in keeping with data from other groups which have suggested that incorporation of upper abdominal surgery is required if rates of cytoreduction are to be significantly improved. Chi et al reported a significant increase in rates of complete cytoreduction associated with a change in the surgical paradigm to include upper abdominal procedures in surgery for EOC, achieving optimal resection rates of 80% with an associated improvement in both PFS and OS as a result [14]. Similarly, in a UK setting, the two previously published reports on cytoreductive surgery demonstrated high rates of maximal cytoreduction following incorporation of upper abdominal procedures. Fotopoulou et al report complete cytoreduction in 89% of patients [10]. Turnbull at et al reported complete cytoreduction in 54.1% and optimal in a further 34.1% of women giving a combined rate of 88.2% [11]. Although a small number of upper abdominal procedures were performed in this series, complex, cytoreductive upper abdominal surgery was not regularly incorporated into surgical practice in this cohort in which twenty-five patients had single site residual disease in the upper abdomen. With the incorporation of surgical procedures in the upper abdomen in this cohort we suggest that rates of cytoreduction could have increased to 79.0%.
Of note, while the operational changes introduced in our institution did not improve rates of complete or optimal cytoreduction, surgical outcomes were maintained while the number of patients undergoing primary surgery rather than interval debulking increased significantly. The EORTC 55971 and CHORUS trials both reported significantly lower rates of optimal cytoreduction in patients undergoing primary surgery [3,14]. In our population, a move towards more primary surgery did not result in a significant change in cytoreduction nor any increase in morbidity or mortality. Whilst these randomised trials demonstrated interval debulking to be non-inferior to primary surgery, the choice between these strategies remains controversial. A secondary analysis of the EORTC 55971 trial suggested that survival may be superior in selected patients undergoing primary surgery and data from retrospective studies have suggested that complete macroscopic resection at primary surgery may be associated with improved survival[16, 17]. This is currently being further examined in the TRUST trial, a randomized, controlled multicentre trial comparing radical upfront surgery to interval debulking surgery (clinicaltrials.gov, ID NCT02828618). In our study, primary surgery was associated with improved PFS compared to delayed surgery when examined across the entire study population. A significant improvement in PFS was also identified in group 1. No difference was identified in group 2, in which more patients underwent primary surgery, although follow up was noted to be significantly shorter in group 2 and thus this figure may subsequently change. Of course, the process of patient selection for primary surgery introduces some bias into this aspect of our analysis, however these results suggest that primary surgery should remain the preferred treatment option when possible.
A significant concern regarding the adoption of increasing radicality in EOC surgery relates to the potential for increased morbidity and mortality and the subsequent effect on quality of life. In our cohort, overall 30-day and 60-day mortality was low, 0.4% and 1.3%, respectively. This compares to the 3.2% 28-day mortality in similar settings in the CHORUS trial [13]. Similarly, our major morbidity rate of 10.3% was low and did not significantly change between the two groups (9.8% vs 10.7%) despite an increase in patients undergoing primary surgery. Centres with experience of more extensive surgery have reported major morbidity of around 20% [10, 14, 18]. Quality of life data for this cohort has not been collected, the SOCQER-2 study, a prospective study examining quality of life following surgery for EOC is currently recruiting (clinicaltrials.gov, ID NCT02559983) examining the impact of radical cytoreductive surgery.
We acknowledge that the assessment of residual disease following surgery is difficult and there remains significant risk of underestimation of residual disease status. Chi et al found a 43% discordance between surgeon’s assessment and postoperative CT assessment although this did not significantly affect median PFS [19]. By limiting this study to a single region some of the variability in the recording of residual disease status is reduced in comparison to studies investigating multiple sites.
In this study we attempted to introduce a collaborative system to overcome some of the barriers to maximal surgical effort identified in previous UK surveys. As a result, we have increased the radicality of surgery in the pelvis and mid abdomen and increased the number of patients undergoing primary surgery without significant increase in the associated surgical morbidity. Despite this, no significant improvement in residual disease status or consequently, PFS, was achieved (although the median follow up in group 2 of our study was somewhat short at 18 months). These findings support data from other authors indicating that upper abdominal surgery is required to achieve improvement in cytoreduction. These findings have enabled us to extend the surgical expertise in cases of advanced EOC to include support from colleagues in hepatobiliary surgery and we anticipate an associated improvement in cytoreduction as identified by other centres. While we recognise that alternative approaches have successfully been adopted in other centres we believe this approach represents a useful model for centres looking to co-ordinate institutional efforts to safely deliver maximal surgical effort in EOC.
Developing recognition of the cellular and molecular diversity of ovarian cancer may contribute to more refined selection of patients most likely to benefit most from such aggressive surgical management. In the meantime, the debate regarding primary surgery and neoadjuvant chemotherapy notwithstanding, if improvements in EOC are to be achieved in the UK, robust quality improvement strategies are required. Surgery with the aim of complete cytoreduction within healthcare models which support prolonged operating times and minimise morbidity must be established. When historic structural barriers such as institutional governance issues or surgical experience and training exist, collaborative multidisciplinary systems can be introduced with the aim of providing outcomes for UK patients equal to the best international results.