Maximal effort cytoreductive surgery for disseminated ovarian cancer in a UK setting:

challenges and possibilities.

ABSTRACT

Objective: To assess surgical morbidity and mortality of maximal effort cytoreductive

surgery for disseminated epithelial ovarian cancer (EOC) in a UK tertiary centre.

Methods / Materials: A monocentric prospective analysis of surgical morbidity & mortality

was performed for all consecutive EOC-patients who underwent extensive cytoreductive

surgery between 01/2013 and 12/2014. Surgical complexity was assessed by the Mayo-clinic

surgical complexity score (SCS). Only patients with high SCS≥5 were included in the

analysis.

Results: We evaluated 118 stage IIIC/IV patients, with a median age of 63 years (range: 19–

91); 47.5% had ascites and 29% a pleural effusion. Median duration of surgery was 247

minutes (range 100–540min). Median surgical complexity score was 10 (range: 5-15)

consisting of bowel resection (71%), stoma-formation (13.6%), diaphragmatic

stripping/resection (67%), liver/liver capsule resection (39%), splenectomy (20%), resection

stomach/lesser sac (26.3%), pleurectomy (17%), coeliac trunk/subdiaphragmatic

lymphadenectomy (8%). Total macroscopic tumor clearance rate was 89%. Major surgical

complication rate was 18.6% (n=22), with a 28-day and 3-months mortality of 1.7% and

3.4%, respectively. The anastomotic leak rate was 0.8%; fistula/bowel perforation 3.4%;

thromboembolism 3.4% and reoperation 4.2%. Median intensive-care-unit and hospital-stay

were 1.7 (range: 0-104) and 8 days (range: 4-118), respectively. Four patients (3.3%) failed

to receive chemotherapy within the first 8 postoperative weeks.

Conclusions: Maximal effort cytoreductive surgery for EOC is feasible within a UK setting

with acceptable morbidity, low intestinal stoma rates and without clinically relevant delays to

postoperative chemotherapy. Careful patient selection, and coordinated multi-disciplinary 1

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effort appear to be the key for good outcome. Future evaluations should include quality of life

analyses.

Short title: Extensive surgery in ovarian cancer in the UK

Key words: ovarian cancer, multivisceral, cytoreduction, morbidity, mortality, albumin

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INTRODUCTION

Epithelial ovarian cancer (EOC) is the 4th most common cancer in women and the most fatal

gynecological malignancy [1]. Surgery remains one of the main therapeutic modalities,

although controversy exists around the extent and limitations of cytoreductive procedures, the

optimum timing of surgery and the selection of ideal surgical candidates. These issues make

the management of this complex disease challenging, and have resulted in wide variations in

practice nationally and internationally [2-5]. Comparisons of EOC-patients’ mortality and

treatment in Europe within the EUROCARE 5 study have identified large survival differences

among the European countries, with a 5-year relative survival ranging from 31% in Ireland

and the United Kingdom (lowest) to 41% in Northern Europe (highest) and a European

average of 38%, across all stages [3]. Assuming that intrinsic tumor biology of EOC is not

worse in some countries than others, differences in survival are probably attributed to

variations in management, variability in healthcare and institutional resources and ultimately

perhaps the entire philosophy of the overall therapeutic approach, both systemic and surgical.

Barton et al from the Royal Marsden Institute in the UK, demonstrated this by showing,

through an anonymized questionnaire survey among UK consultant gynecological

oncologists, that the surgical goal of ovarian debulking surgery in many UK cancer centers is

not complete cytoreduction [6]. This was reflected in short operating times, and highly

variable rates of bowel surgery, upper abdominal resections and lymphadenectomies; all

surrogate markers of surgical endeavor. The authors concluded that this is likely to directly

contribute to the relatively poor outcomes in UK EOC-patients [6]. Opponents of maximal

effort cytoreductive surgery argue that increased surgical morbidity resulting in a negative

impact on quality of life as well as exhaustion of financial and institutional resources are

detrimental to patient care. Nevertheless, increasing evidence suggests that specialization and

expertise leads to higher tumor resection rates and hence potentially improved survival

without equivalent increase in complication rates or length of hospitalization [7].3

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The present work represents the evaluation of an attempt at maximization of surgical tumor

clearance in patients with peritoneal disseminated EOC within the UK system; these patients

underwent multi-visceral cytoreducion for total macroscopic tumor clearance. We evaluated

theatre and hospitalization times, surgical morbidity and mortality, delays in chemotherapy

and anaesthetic and peri-operative care issues.

MATERIALS AND METHODS

A retrospective evaluation of a prospectively gathered clinical database was performed to

assess the intraoperative tumor dissemination pattern, surgical outcome and morbidity as well

as the anaesthetic and peri-operative care for all consecutive patients who underwent

extensive cytoreductive surgical procedures for advanced primary or relapsed EOC in our

centre, between January 2013 and December 2014. Surgical complexity scores (SCS) were

calculated using the Mayo Clinic complexity scoring system [8]. Only patients with advanced

FIGO-stage IIIC/IV disease that underwent surgery with a SCS ≥5 were included [9]. Patients

with tumours of non-epithelial origin and those receiving surgery with palliative and not

cytoreductive aim, such as relief of bowel obstruction or perforation, were excluded. Under

current UK research governance arrangements this analysis of routinely captured clinical data

is classified as a service evaluation and is exempt from the requirement for research ethical

review.

All operations were performed through a midline laparotomy by a team of gynaecological

and, when necessary, hepatobiliary surgeons to achieve total macroscopic tumour clearance.

No systematic pelvic and para-aortic lymph node dissection was performed routinely in the

absence of bulky lymph nodes (defined as >1cm). Patients with large volume ascites and/or

pleural effusions, and those with major comorbidities and/or advanced age were routinely

admitted to the intensive care unit for post-operative care.4

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In every patient, the intra-operative tumour dissemination pattern was assessed prospectively

via a validated descriptive system (IMO: “Intraoperative Mapping of Ovarian Cancer” [10-

12]), specifically developed for ovarian neoplasms. Three “IMO-levels” divide the abdomen

into three spaces: lower (level-1), middle (level-2) and upper (level-3) abdomen (Table 1).

Nine “IMO-fields", three at each level, provide a sub-classification of the peritoneal cavity

that provides a more precise documentation of the tumor dissemination pattern.

Indications for surgery

The management of all patients and the indications for surgery were discussed within a

multidisciplinary team (MDT), consisting of five specialized gynaecological oncology

surgeons among medical and clinical oncologists, gynae-radiologists, gynae-pathologists, and

clinical nurse specialists. Patients with primary advanced EOC were considered for primary

debulking surgery unless they had unresectable parenchymal distant and/or extra-abdominal

metastases and/or had a poor performance status (Eastern Cooperative Oncology Group

[ECOG] performance status ≥3). Primarily one to two gynecological oncology surgeons

would perform the operations together with a hepatobiliary surgeon if needed.

Patients who were referred for consideration of interval debulking, having received

neoadjuvant chemotherapy in other centres, were deemed suitable for surgery as long as they

showed response to platinum or had stable disease according to RECIST criteria [13], and had

a good performance status. In cases with pleural effusions, the pleural cavity was evaluated

via the diaphragm, to ensure that no diffuse unresectable pleural carcinosis was present.

Patients with relapsed disease were considered for cytoreductive surgery if the recurrence

occurred in a platinum sensitive time frame, they did not have progressively re-accumulating

ascites or pleural effusions, did not have unresectable distant metastatic lesions and were fit

for surgery.

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Statistics

Statistical analysis was performed using SPSS statistical software, version 16.0 (SPSS Inc.,

233 S. Wacker Drive, Chicago, USA). Estimates of survival were calculated using the

Kaplan–Meier method. All parameters are expressed as median and range. The follow-up and

survival times were calculated starting on the day of surgery. All percentages given are in

relation to the entire cohort of patients (n=118).

RESULTS

We included 118 consecutive EOC-patients. Median age was 63 years (range:19-91).

Seventeen patients (14.4%) were ≥75 years old. Median body mass index was 25 kg/m2

(range:11-46). The majority of patients were stage IIIC (69.5%) and most were of high-grade

serous histology (89%). Almost half of the patients (n=56; 47.5%) had more than 500ml of

ascites. Nineteen patients (16.1%) had unilateral and 15 patients (12.7%) bilateral pleural

effusions pre-operatively. The timing and type of the surgery was as follows: 56.8% (n=67)

upfront/primary debulking; 22.9% (n=27) interval debulking; 18.6% (n=22) secondary

debulking and 1.7% (n=2) tertiary debulking. For patients who underwent interval debulking

surgery, the median number of neoadjuvant chemotherapy cycles was 3 (range:2-6). Detailed

patient and tumor-related characteristics, and ECOG-status [14], are presented in Table 2.

Tumor dissemination patterns and surgical procedures

The median number of IMO fields involved with tumor was 9 (range: 2-9); the majority of

patients (n=100; 84.7%) had tumor involvement in more than 7 IMO fields (see table 1).

In 105(89%) patients a complete macroscopic tumor resection was achieved. The most

common sites of residual disease were middle (10.2%) and upper abdomen (9.3%) compared

to only 1.7% residual disease in pelvis (table 2). The median complexity score was 10 (range:

5-15), with the majority of patients (n=86; 73%) undergoing surgery with a SCS ≥8. The 6

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median complexity score for patients at the initial presentation of their disease was 9.5 (range:

5-18), and at relapse 8 (range: 4-13). Median duration of surgery was 247 minutes

(range:100–540), with a duration of 4 hours or less in 44% of cases.

The surgical procedures that were performed outside of the “standard” total abdominal

hysterectomy, bilateral salpingo-oophorectomy and omentectomy are presented in detail in

Table 3. Hepatic surgery (39.0%) consisted of multiple debulking from liver capsule (n=43)

or minor resection (<3 segments, n=3). Sixty-five patients (55.1%) received one or more

primary bowel anastomosis, with 19 patients (16.1%) having >1 bowel anastomoses. The

most common type of anastomosis was end-to-end rectosigmoid anastomosis (n=45; 39%),

followed by side-to-side small to large bowel anastomosis (n=14; 11.9%). No protective

stoma were performed in such cases. Sixteen patients (13.6%) received a primary terminal

intestinal stoma: 2 (1.7%) received an ileostomy and 14 (11.8%) a colostomy. All stomas

were intended to be reversible. Median postoperative hospital stay for all patients was 8 days

(range: 4-118).

Surgical morbidity and mortality and ability to receive postoperative chemotherapy

The 28-day surgical mortality rate was 1.7% (n=2) for the patients at their initial presentation

of their disease and 0 for the relapsed patients. One patient died of fulminant sepsis with no

primary focus identified and one patient died from fulminant hepatic failure, both on the third

postoperative day. The patient with hepatic failure had not received any major segmental liver

resection and the CT after onset of symptoms showed no evidence of portal or hepatic vein

thrombosis or infarct, no biliary leak or haematoma/abscess. Two further patients died within

the first 3 months due to rapid and platinum refractory disease progression with liver and lung

metastases (3 months mortality 3.4%). The 3 months mortality of the relapsed patients alone

was 0.

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Twenty-two patients (18.6%) suffered at least one major surgical complication during the first

28 postoperative days (Table 3). If we divide them according to the stage of the disease; then

22% of the patients at their primary presentation experienced a major morbidity versus only

4% of the relapsed patients. The one patient with anastomotic leak of a rectosigmoid

anastomosis was managed conservatively and did not require reoperation. The patient who

developed a pelvic abscess was successfully treated with CT-guided drainage for 5 days and

did not require further operative intervention. None of the patients with persistent

lymphorrhoea needed re-operation; they were treated with serial abdominal drains and

octreotide, with the lymphorrhoea resolving in a median time of 3.2 weeks. Four patients

(3.4%) required re-operation for: aortoduodenal fistula (n=1) 21 days postoperatively;

postoperative hemorrhage (n=1) two days after interval debulking surgery, and bowel

perforation (n=2), unrelated to a bowel anastomosis, but rather as a consequence of extensive

peritoneal stripping. None of those patients who required re-operation died, and were

eventually discharged home. Readmission rate was 10% (n=12) for: spontaneously resolving

vaginal discharge (n=1); lymphorrhea/lymphocyst (n=3); diarrhea (n=1), pre-existing

hyponatraemia (n=1), fistula formation (n=1), infection/abscess/wound dehiscence (n = 3) and

social issues (n=2).

The majority of patients (n=105; 89%) commenced postoperative chemotherapy within the

intended time frame of eight weeks following surgery. Four patients (3.4%) were unable to

receive chemotherapy within this period due to death (n=2) or surgical morbidity (n=2). In 7

(6%) patients chemotherapy was not deemed necessary due to low grade histology or

complete removal of the tumor at relapse. Two patients (1.7%) refused chemotherapy. Median

time between surgery and first cycle of postoperative chemotherapy was 37 days (range: 13-

101).

ICU data8

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Seventy-three patients (61.8%) had a planned admission to the ICU for post-operative care

with a median ICU stay of 1.7 days (range:0.6-104). The median fluid balance at the

beginning of the first post-operative day was +2200 ml (range -300 ml to +6700 ml), although

this was difficult to measure accurately in patients with significant ascites. Median fresh

frozen plasma use was 0.27 units (range: 0-4 units) and was given intraoperatively and within

the first 48 hours post-operatively. Ten of the 73 patients required packed red cells in the first

24 hours post-operatively, receiving a median of median 2 units (range 1-4 units). The median

albumin level pre-operatively was 34.0g/L; range 9.0-40.5g/L. Following surgery, the median

albumin fell to 16 g/L (range 4.0-32.0g/L). Three patients required temporary total parenteral

nutrition (TPN) postoperatively. Forty patients received albumin supplementation in the

presence of large volume ascites or pleural effusion and post-operative albumin levels of

<20g/L.

Survival data

Four patients (3.4%) died within 3 months of surgery due to postsurgical organ failure (n=2)

or massive disease progression with liver and lung metastases (n=2). All patients were at the

initial presentation of their disease. Within a median follow up period of 7 months (range: 0-

23), 30 (25%) patients relapsed and 14 patients (11.9%) died. Even though the survival data

are still immature, median progression-free survival (PFS) was 15 months (95%CI: 11.94-

18.06), while the median overall survival (OS) had not been reached. If we distinct patients to

primary versus relapsed then median PFS was 14 months for primary patients (95%CI: 1.28-

11.49) and 18 months for relapsed patients.

Of the 75 patients who completed their postoperative chemotherapy within the follow-up

period, 27 (22.9%) relapsed, of which 16 (13.5%) occurred within a platinum resistant time

window of 6 months. Median CA125 levels after completion of postoperative chemotherapy

was 17 U/L (range: 3-569). 9

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DISCUSSION

This case series represents the first UK-based analysis following introduction of the NICE

(National Institute for Health and Care Excellence) guidance for ultraradical surgery in

advanced EOC [15], evaluating the surgical and anesthetic morbidity and mortality of

extensive cytoreductive procedures. We believe we have shown the feasibility of this

approach in the UK environment. We have demonstrated that when this type of surgery is

performed within a specialized setting with appropriate infrastructure and maximal

institutional effort, surgical morbidity and mortality appear acceptably low in the presence of

high multivisceral resections and total macroscopic clearance scores. Despite the high rate of

bowel resections, bowel-related morbidity such as anastomotic leak was low, with

comparably low rates of stoma formation. Importantly, only a small proportion of patients

failed to proceed to systemic adjuvant treatment within the intended time window. The

majority of the major morbidity incidents were identified early and managed successfully,

through proactive and intensified multidisciplinary postoperative care. The median hospital

stay of 8 days may seem long in the current fast track era. However, all patients included in

the present analysis had extensive tumor burden, experienced large fluid shifts exacerbated by

low albumin levels and underwent multivisceral resections. Also the median PFS of 15

months is perhaps lower than expected for a complete resection rate of more than 80 %,

however we have to consider the fact that in this analysis only high tumor burden patients

were included and as we know from large scale studies, initial disease burden remaines a

significant prognostic indicator despite R0 resection [31].

The results from this series are encouraging and correlate well with similar European and

American analyses in advanced EOC. Chi et al. describes a 22% major morbidity rate in 141

patients who underwent extensive upper abdominal surgical procedures, with a mortality rate

of 1.4% [16]. The Mayo clinic experience on extensive cytoreductive surgery showed also a 10

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20% major morbidity and 6% 3-months mortality rate [8]. Our results also correlate with the

experience of other authors regarding the relatively low bowel related morbidity [17-20].

without the necessity of high rates of a protective stoma. The Italian Gynaecological

Oncology Group describe an anastomotic leak rate of 1%, abscess formation rate of 1%,

postoperative hemorrhage of 0.5% and sepsis 2.7% [20]. Other authors report similar

anastomotic leak rates ranging between 1% and 3%; bowel fistula/perforation rates between

1% and 5.4% and sepsis 2.7% - 3.6% [17-21]. The reason that the leak rates appear lower than

the ones described for colorectal patients, is probably attributed to the fact that, as opposed to

rectal cancer patients, EOC-patients will rarely present with true tumor invasion into the

lumen of the rectum at short distance to the anal verge, so that after extraperitoneal dissection

and en bloc tumor resection the colorectal anastomosis is usually at least 7–10 cm from the

anal verge. This is known to be associated with a significantly lower anastomotic leak risk

compared to lower anastomoses required for rectal cancer patients and usually safe enough to

avoid the routine use of a protective ileostomy [19].

One of the arguments made against extensive cytoreductive surgery is the notion of increased

surgical morbidity and mortality in comparison to less radical surgery. The largest UK-based

analysis for debulking surgery in EOC, the recently published CHORUS trial [22], showed an

overall 28-day surgical mortality of 3% and 5.6% in the primary cytoreductive arm. This was

despite a much less radical approach where complete cytoreduction rate was 27%, a bowel

resection rate of 10%, less than 30% having undergone any other than the “standard”

procedures and 12% of patients not being stage IIIC/IV.

A further important consideration in the present analysis is the importance of adequate intra-

and early postoperative fluid management. In a similar fashion to other European experiences,

we have shown that fluid management is one of the greatest challenges in patients undergoing

extensive cytoreductive surgery. Although blood loss does not appear to represent a

significant problem [23-24], these patients require large volumes of fluid to correct pre-and 11

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peri-operative fluid deficits from intra-operative loss of ascites and pleural effusions as well

as insensible losses, and to compensate for cytokine release during peritonectomy [23].

Hypoalbuminemia is a predictor of increased morbidity and mortality in surgical or ICU

patients [25-26], and therefore albumin was usually replaced in these patients using human

albumin solution, even though no randomized trials exist to support this practice [27].

Barton et al emphasized, that this type of surgery has implications for the centralization of

surgical services and subspecialty training [6]. Although this may be provided in different

models of health care, provision is probably best achieved by greater centralization of surgery

to centers able to achieve high complete cytoreduction rates, and a system that supports the

longer operative times required by this approach [6,28].

This problem of limited resources and compromising of surgical care expands beyond the

borders of surgery for EOC. According to a major new Commission examining the state of

global cancer surgery, over 80% of the 15 million people diagnosed with cancer worldwide in

2015 will need surgery, but less than one-quarter of them will have access to proper, safe,

affordable surgical care when they need it [29-30]. New estimates suggest that less than 5% of

the patients in low-income countries and only roughly 22% of the patients in middle-income

countries can access even the even most basic cancer surgery. Despite this worldwide

shortfall in access to cancer surgery, the international community does not see surgical care as

an essential component of global cancer control, with surgical services being given low

priority within national cancer plans and being allocated few resources, due to the many

competing health priorities and substantial financial constraints [29-30]. These findings make

apparent that a rethinking needs to happen in terms of resource allocation, investment in

surgical training and the overall philosophy of cancer services, especially in an upcoming era

where increasingly more financial resources are allocated to novel systemic targeted agents

and where progress and “effort” of systemic treatment should ideally be in line and meet

surgical effort. 12

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A significant limitation of the present analysis is the lack of quality of life data, however a

newly upcoming prospective quality of life evaluation study, the SOCQER-2 study

(ClinicalTrials.gov Identifier: NCT02569983), will assess quality of life survey before and

after radical surgery for advanced EOC.

Despite the considerable logistical and financial challenges involved in conducting

randomized multicentre surgical trials, there has never been a more active and fruitful time for

this than the present time. Numerous international consortia are currently focusing on

answering many vital surgical questions such as the appropriate selection of patients, the

optimum timing of surgery, the optimal allocation of resources, as well as the systematic

evaluation of the postoperative quality of life, in order to finally establish and define surgical

treatment of advanced EOC.

Concluding, we show that maximal effort cytoreductive surgery for EOC is feasible within a

UK setting with acceptable morbidity, low intestinal stoma rates and without clinically

relevant delays to postoperative chemotherapy. Careful patient selection, and coordinated

multi-disciplinary effort appear to be the key for good outcome. Future evaluations should

include quality of life analyses.

Conflicts of interest

Professor Christina Fotopoulou is an associate editor for Archives of Gynecology and

Obstetrics. No other conflicts of interests to disclose.

Author Contribution

C Fotopoulou: Project development, Data collection, Manuscript writing

B Jones: Data collection, Manuscript editing

K Savvatis: Statistical data analysis

J Campbell: Manuscript writing13

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M Kyrgiou: Manuscript editing

A Farthing: Manuscript editing

S Brett: Manuscript writing

R Roux: Data collection, Manuscript editing

M Hall: Manuscript editing

G Rustin: Manuscript editing

H Gabra: Manuscript editing

L Jiao: Manuscript editing

R Stümpfle: Manuscript writing

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