Pre-operative serum albumin is associated with post-operative complication rate and overall survival in patients with epithelial ovarian cancer undergoing cytoreductive surgery

    Pre-operative serum albumin is associated with post-operative complication rate and overall survival in patients with epithelial ovarian cancer undergoing cytoreductive surgery Beyhan Ataseven, Andreas du Bois, Alexander Reinthaller, Alexander Traut, Florian Heitz, Stefanie Aust, Sonia Prader, Stephan Polterauer, Philipp Harter, Christoph Grimm PII: DOI: Reference:

S0090-8258(15)30067-6 doi: 10.1016/j.ygyno.2015.07.005 YGYNO 975981

To appear in:

Gynecologic Oncology

Received date: Revised date: Accepted date:

26 April 2015 1 July 2015 6 July 2015

Please cite this article as: Beyhan Ataseven, Andreas du Bois, Alexander Reinthaller, Alexander Traut, Florian Heitz, Stefanie Aust, Sonia Prader, Stephan Polterauer, Philipp Harter, Christoph Grimm, Pre-operative serum albumin is associated with post-operative complication rate and overall survival in patients with epithelial ovarian cancer undergoing cytoreductive surgery, Gynecologic Oncology (2015), doi: 10.1016/j.ygyno.2015.07.005

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Pre-operative serum albumin is associated with post-operative complication rate and overall survival in patients with epithelial ovarian cancer undergoing cytoreductive

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surgery

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Beyhan Ataseven1, Andreas du Bois1, Alexander Reinthaller2, Alexander Traut1, Florian Heitz1, Stefanie Aust2, Sonia Prader1, Stephan Polterauer2 , Philipp Harter1, Christoph Grimm

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Department of Gynecology and Gynecologic Oncology, Evangelische Huyssens-Stiftung,

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Kliniken Essen-Mitte, Essen, Germany 2

Department of Gynecology and Gynecologic Oncology, Comprehensive Cancer Center

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Vienna, Medical University of Vienna, Vienna, Austria

Beyhan Ataseven

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Corresponding author:

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Department of Gynecology and Gynecologic Oncology Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung,

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Henricistrasse 92

45136 Essen, Germany phone.: +4920117434521; fax: +4920117434200 Email address: [email protected] Indication: Clinical study Date of submission: 26.04.2015 Running titel: Low serum albumin in ovarian cancer Key words: low serum albumin, epithelial ovarian cancer, complication rate, mortality, overall survival

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Abstract Objective Hypoalbuminemia has been reported as a risk factor for post-operative complications and

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unfavorable survival in cancer patients. We aimed to evaluate the predictive value of

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preoperative serum albumin levels on post-operative complication rate and the impact on overall survival (OS) in patients with epithelial ovarian cancer (EOC) undergoing primary cytoreductive surgery.

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Methods

The present retrospective study included 604 consecutive patients with EOC who underwent

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primary cytoreductive surgery at two tertiary cancer centers specialized in gynecologic oncology. Hypoalbuminemia was defined as a pre-operative serum albumin level ≤35 g/L. Post-operative surgical complications were graded according to the Clavien-Dindo-

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Classification (CDC). Fisher-test was used to investigate the predictive value of

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hypoalbuminemia on the rate of severe post-operative complications. Survival analyses were calculated using log-rank test and Cox regression models.

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Results

The incidence of pre-operative hypoalbuminemia in the entire cohort was 16.4%.

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Hypoalbuminemia was a predictive factor for severe post-operative complications (CDC 3-5) (OR 3.65, CI95% 1.59-8.39), p=0.002). Furthermore, median overall survival time of patients with hypoalbuminemia was 24 months compared to 83 months in patients with normal albumin (p<0.001), respectively. Hypoalbuminemia was independently associated with shortened overall survival (HR 2.2 (95% CI 1.6-3.0); p<0.001) even after adjusting established prognostic factors such as age, tumor stage, performance status, and postoperative residual disease. Conclusion Pre-operative hypoalbuminemia can be used as both an independent predictive factor for severe post-operative complications and as prognostic parameter regarding overall survival

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in EOC patients. Therefore, albumin levels may be incorporated into future clinical trials as

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stratification factor.

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Introduction Cytoreductive surgery is one of the mainstays in the treatment of women with epithelial ovarian cancer (EOC). Surgical outcome significantly impacts patients’ survival [1-4].

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However, extensive surgery may be associated with considerable adverse events, and major

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post-operative morbidity has been reported to occur in 33% to 64% [5]. Several factors associated with peri-operative morbidity like age, performance status, surgical complexity, nutritional status and serum markers (e.g. prealbumin and albumin) have been described

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with heterogeneous results [6-9]. Many of these factors are difficult to standardize and classification is based on individual clinical judgement. A simple test based on objective

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values could help to better classify morbidity risks in a uniform, standardized way, independent of clinical and structural heterogeneity. Albumin is the most abundant plasma protein in humans, comprising for 50%–65% of the

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measured total serum protein [10]. It plays a key role in maintaining colloid osmotic pressure,

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as well as acting as a transport vehicle for intrinsic metabolites, drugs, and anti-oxidative agents [11]. Low serum albumin reflects inflammatory activity and has been reported as a

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risk factor of post-operative complications and survival in various cancer types [9, 12-15]. Furthermore, serum albumin level has been described to be a crucial parameter of

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malnutrition [16] and has also been reported to be an indicator of malnutrition in gynecologic patients [17]. Malnutrition at the time of cancer diagnosis occurs in about 20% of gynecologic cancer patients [18] with its highest prevalence in ovarian cancer (67%) [17]. Thus, the preoperative evaluation of ovarian cancer patients in regard to radical surgery with a significant risk for severe post-operative complications seems to be of particular importance. The present study focused on two major aims: the first aim was to evaluate the predictive role of pre-operative serum albumin levels on post-operative complications categorized by Clavien-Dindo-Classification (CDC). The second aim was to elucidate the prognostic association between pre-operative serum albumin levels and overall survival (OS) in patients with epithelial ovarian cancer undergoing primary cytoreductive surgery independent of peri-mortality.

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Patients and Methods We reviewed data on 604 consecutive patients with primary epithelial ovarian, primary peritoneal, and fallopian cancer (EOC) who underwent cytoreductive surgery at two

of

Vienna

(AKH),

Vienna-Austria).

Patients

treated

with

pre-operative

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University

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academic partner centers (Kliniken Essen-Mitte (KEM), Essen-Germany and Medical

chemotherapy and patients with borderline tumors or non-epithelial ovarian neoplasms were excluded. Pre-operative serum albumin was part of the routine pre-operative check-up in

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both centers and all patients with available serum albumin values were included. All patients gave informed consent for documentation of clinical data in the associated clinical tumor

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registries for clinical research and quality assurance. Surgery was performed by a dedicated surgical team specialized on gynecologic oncology. Surgical complexity scoring (SCS) system was based upon complexity and number of surgical procedures performed as

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reported previously [6]. Platinum-based chemotherapy was recommended stage adapted

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after surgery according to standard guidelines [19, 20]. We defined the cut-off for hypoalbuminemia as previously reported [21]. In clinical practice a

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value of serum albumin ≤35 g/L is generally considered as hypoalbuminemia. Serum albumin was assessed according to the bromocresol green technique [22] (Roche Diagnostics

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COBAS Integra Albumin Gen.2; Indianapolis, USA). Serum albumin concentrations between 35 and 52 g/L were considered as normal. For 309 patients treated at KEM post-operative complications were recorded and classified according to the Clavien-Dindo-Classification [23] including at least the period until patient’s discharge or post-operative death after surgery. The scoring grades complication in eight categories depending on severity (0: no complications, and 5: death; table 1-S-supplementary). We further categorized complications into mild (CDC 0-2) and severe (CDC 3-5), the latter representing those grades with serious clinical consequences. In patients who experienced more than one complication the highest CDC was noted.

Statistics

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Descriptive statistics such as mean, median, frequencies, and percentages were used to summarize the data: frequency (%) by categorical variables; median/range by ordinal variables and age; mean (standard deviation=SD) by metric variables. The relationship

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between complication and albumin was assessed by the Fisher-exact-test. For univariate

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and multivariate analyses, albumin levels were labeled as "hypoalbuminemia" and "normal albumin" to create a categorical variable. In order to evaluate independent risk factors for complication ("mild": CDC 0-2; "severe" CDC 3-5) binary logistic regression was used,

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incorporating all well-established parameters. The overall presence of interaction between risk factors and event was evaluated by the Wald test., To rule out a potential bias regarding

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prognostic value of hypoalbuminemia on OS patients, who died within 30 days after surgery, were excluded from this survival analysis to distinguish between those patients in whom albumin could have a prognostic value independent from peri-operative complications and

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those in whom albumin could predict complications with fatal outcome. However, a sensitivity

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analysis with all patients including those who died peri-operatively was also performed. Uniand multivariable survival analyses were performed using Kaplan-Meier and Cox proportional

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hazard models, respectively. Multiple logistic regression was conducted to analyse the association of variable with OS adjusting for potential confounding variables. Tests were two-

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sided at the 0.05 level. Statistical analysis was performed using SPSS version 20.0 (IBM Corporation, New York, USA).

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Results Patient’s characteristics A total of 604 consecutive patients with EOC were included in the present series. Three

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hundred and nine (51.2%), and 295 (48.8%) patients were enrolled from the Departments of

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Gynecology and Gynecological Oncology at the KEM and AKH, respectively. Patient’s characteristics are shown in table 1. Mean pre-operative serum albumin level was 41 g/L (SD 6 g/L). Low pre-operative serum albumin <35 g/L, was observed in 99 (16.4%) patients. Four

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hundred seventy-two (78.1%) patients had advanced disease (FIGO IIIB-IV). For the entire study group lymph node dissection was performed in 382 (63.2%) patients, of whom 217

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(56.8%) showed metastastic lymph node involvement. In 362 (59.9%) patients a complete tumor debulking without any macroscopic residual disease was achieved. Detailed information regarding peri- and post-operative status (e.g. surgical procedure) was available

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for 309 patients treated at KEM and is given in Table 2-S-supplementary.

Association of pre-operative albumin level and clinico-pathological parameters

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Significant differences between patients with hypoalbuminemia compared to patients with normal albumin levels were detected in terms of performance stage (ECOG >0: 21.2%

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versus 13.5%), ascites (ascites >500 mL: 58.6% versus 26.5%), and advanced FIGO-stage (FIGO IIIB-IV: 88.9% versus 76.0%; table 2). Hypoalbuminemia was associated with more advanced disease (stage or ascites volume) and poorer performance status. These associations between hypoalbuminemia and well known prognostic factors made it necessary to adjust univariate analyses and perform multivariate analyses. No differences with respect to albumin level were detected regarding patient’s age, grading and histology.

Association of pre-- serum albumin and post-operative complication (CDC) If all grades of complications were considered we could not detect a significant difference between patients with low as compared to normal albumin levels. (OR 2.40 [95% CI 0.5510.51], p=0.40, table 3). In the total cohort mild and severe complications had been observed

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in 74.8% (231/309) and 25.2% (78/309) of patients, respectively. Patients with hypoalbuminemia experienced severe complications in 52.0% of cases compared to 22.9% of patients with normal albumin (p=0.011). Moreover, patients with hypoalbuminemia were

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more likely to develop severe post-operative complications (CDC 3-5) than patients with

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normal albumin (OR 3.65, CI95% 1.59-8.39, p=0.002). Multivariate analysis was performed with adjustment of the following parameters: patient’s age, WHO performance status, serum albumin, blood loss, surgical complexity score, operative time, and FIGO stage (table 4).

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Hypoalbuminemia, poor performance status (ECOG>0), high surgical complexity score (SCS >10) and surgical time (>360 minutes) were independent significant factors associated with

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grade 3-5 complications. Patients with hypoalbuminemia were five times more likely to experience severe complication than patients with normal albumin (OR 5.24, 95%CI 1.9114.36, p=0.001). Ten patients died post-operatively due to i) multiorgan failure in five cases,

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ii) cerebral and respiratory failure in two cases, and iii) toxic shock syndrome in three cases.

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Mortality rate in the low and normal albumin group were 12.0% and 2.5%, respectively.

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Association of pre-operative serum albumin and overall survival After a median follow up of 31 months 201 (33.3%) patients had died. Median OS in the

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entire cohort was 58 months. In univariate analysis, patient’s age >65 years, low serum albumin, ECOG-status >0, higher FIGO-stage IIIB-IV, residual disease >0mm, grading (high grade), and serous histology were significantly associated with inferior OS (table 5). In multivariable analysis, patient’s age >65-years (HR 1.9; 95%CI: 1.4-2.6; p<0.001), hypoalbuminemia (HR 2.2; 95%CI: 1.6-3.0; p<0.001), ECOG-status (HR 2.5; 95%CI: 1.8-3.5; p<0.001), FIGO-stage IIIB-IV (HR 3.8; 95%CI: 2.2-6.7; p<0.001), and residual disease >0mm (HR 2.4; 95%CI: 1.7-3.4; p<0.001) remained independent and significant risk factors for poorer OS (table 5). Kaplan-Meier curves for OS broken down by pre-operative serum albumin are shown in figure 1. Median survival of patients with hypoalbuminemia was 24 months compared to 83 months in patients with normal albumin (p<0.001). The corresponding 5-year OS rate was 23% in the hypoalbuminemia group compared to 58% in

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the normal albumin group (p<0.001). Adjusting potential confounding factors (age >65 years, ECOG

>0,

residual disease

>0mm,

ascites

>500 ml,

and FIGO-stage IIIB-IV)

hypoalbuminemia remained independently associated with decreased OS in multivariable

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analysis (HR 1.8; 95%CI: 1.3-2.4.p<0.001). A sensitivity analysis with all patients including

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those who died peri-operatively showed that hypoalbuminemia remained an independent

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prognostic factor for OS with a hazard ratio of 2.1 (95%CI 1.5-2.8, p<0.001).

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Discussion In this retrospective study, which is to our knowledge the largest series published so far, we analyzed the predictive value of pre-operative serum albumin level on post-operative

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complications after primary cytoreductive surgery and survival of EOC patients. Overall, our

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results demonstrate that pre-operative hypoalbuminemia was an independent predictor not only for increased risk of post-operative complications, but also an independent adverse prognostic factor for OS.

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Hypoalbuminemia was the strongest prognostic parameter for major post-operative complications in our study. This observation is supported by Uppal et al. [9]. In their series

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with 2,110 patients with gynecologic malignancies the authors demonstrated that patients with hypoalbuminemia were six times more likely to experience severe complications and 10 times more likely to die within 30 days after operation. With respect to ovarian cancer

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patients Aletti et al. [21] and Obermair et al. [8] could evaluate the impact of

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hypoalbuminemia on complication rate in their studies. In patients with FIGO stage III-IV ovarian cancer endogenous patient factors like ASA score, tumor grade and albumin level (<

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3.5 g/dL) as well as complexity of surgery were independent predictors of 30-day major morbidity [21]. Obermair et al. [8] detected a significant increase of wound complications

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(64% vs 14%), septicemia (46% vs 8%) and anastomotic leakage (18% vs 0%) in patients with hypoalbuminemia who underwent low anterior en bloc resection as part of cytoreductive surgery in ovarian cancer. In our study hypoalbuminemia, poor performance status high surgical complexity score and surgical time >360 minutes were independent significant factors associated with grade 3-5 complications. This is in line with previous data reported by Chi et al. regarding major compilcations after the performance of extensive upper abdominal surgical procedures [24]. In their analysis ascites (>1625 mL) estimated blood loss (>1000mL), and surgical time (327 min) were independent parameters for grade 3-5 complications. The reason why pre-operative hypoalbuminemia is independently associated with increased risk for complications may be attributed to the fact that low serum albumin is a marker of malnutrition, cancer cachexia and chronic inflammatory activity and as such

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indicates post-operative complications and mortality [25]. This hypothesis is supported by Watanabe et al. [26] who demonstrated a correlation between rapid turnover protein levels and

inflammation-related

markers

in

ovarian

cancer

patients.

Furthermore,

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immunosuppression is associated with cancer cachexia [27] which again has been reported

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as a predictor for post-operative complications [7] and poor survival [12]. According to the ESPEN (European Society for Clinical Nutrition and Metabolism) criteria, low serum albumin is an established marker for malnutrition [28]. It is unclear whether low albumin serum levels

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only reflect malnutrition subsequently leading to a worse prognosis or directly influence patient’s prognosis independently of a patient’s body composition. Low serum albumin

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concentration was associated with a greater risk of malnutrition among gynecologic cancer patients [17]. We investigated, whether hypoalbuminemia was correlated with BMI (body mass index) as an indicator for malnutrition and could not reveal a significant correlation

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between hypoalbuminemia and BMI (Figure 1-S-supplementary). The ESPEN working group

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recommends pre-operative, parenteral [28], or enteral [16] nutritional support for 5-10 days in undernourished patients defined by at least one of the following criteria: weight loss >10-15%

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within 6 months; BMI <18 kg/m2; subjective global assessment grade C; serum albumin <30g/l. However, this raises the question whether an anti-inflammatory therapy, such as

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enteral immunonutrition, bears the potential to influence patients´ outcome sufficiently. Several clinical studies reported a beneficial impact of pre-operative nutrition to reduce surgical complications [29-34]. In ovarian cancer Geisler et al. [7] could demonstrate an improvement of serum prealbumin through pre-operative total parenteral nutrition. This was associated with an improvement of post-operative complications. Patients with pre-operative total parenteral nutrition, who successfully elevated their prealbumin despite beginning low, had equal complication rates as patients with high/normal prealbumin level. Of note, other randomized studies failed to show an additional benefit of pre-operative nutrition on complication rate, especially in well-nourished patients [35, 36]. Taken together, hypoalbuminemia is not only an indicator for malnutrition but also for a systemic inflammatory activity and thus useful as predictor post-operative morbidity and long term survival.

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In the present study hypoalbuminemia also revealed to be an independent negative prognostic factor for OS in EOC patients showing an absolute difference of 59 months of median survival between patients with low and normal albumin level. This has also been

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reported in various other cancers, e.g. breast [37], gastric [38], colorectal [39], endometrium

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[15], and ovarian [5, 12]. Asher et al. [12] assessed the median survival of EOC patients by pre-operative albumin level. Patients with albumin <25 g/L showed impaired median survival with 4.8 months compared to patients with albumin 25-35 g/L with 15.2 months and patients

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with albumin >35 g/L with 43.2 months.

The present study has some limitations. Firstly, as already mentioned, this is a retrospective

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study bearing potential risk for selection bias. Nevertheless, we analyzed patients´ survival outcome on hypoalbuminemia in the two institutions not only combined, but also independently and could demonstrate the impact of hypoalbuminemia in both collectives

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(data not shown). Secondly, the optimal cut-off value for pre-operative serum albumin still

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remains unclear. Previous study groups used a variety of different cut-off levels for low serum albumin or hypoalbuminemia and therefore the prevalence of hypoalbuminemia

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ranges from 18% to 70% (Table 3-S-supplementary). However, our results are in line with broad series published so far regarding the prognostic impact of hypoalbuminemia in

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different tumor types. Therefore, hypoalbuminemia in ovarian cancer seems be an independent parameter for patients’ selection who are at risk for relevant clinical postoperative complications and should better be treated with individual therapeutic concepts, e.g. neoadjuvant chemotherapy followed by interval debulking surgery. In conclusion, we could demonstrate that hypoalbuminemia is a risk factor for post-operative complications and OS in patients with EOC. The impact of preoperative nutrition in patients suffering from malnutrition and its influence on post-operative outcome as well as prognosis in patients with EOC undergoing cytoreductive surgery needs to be further elucidated. The identification of patients with a high risk of peri-operative mortality is an unresolved major problem in gynecologic oncology. One of the next multicenter AGO studies will also focus on

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this question - hopefully we could identify a pattern of pre-operative characteristics which will be helpful in the future.

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Conflict of interest

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The authors declare no conflict of interest.

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[33] Bozzetti F, Braga M, Gianotti L, Gavazzi C, Mariani L. Postoperative enteral versus parenteral nutrition in malnourished patients with gastrointestinal cancer: a randomised multicentre trial. Lancet. 2001;358:1487-92. [34] Bozzetti F, Gavazzi C, Miceli R, Rossi N, Mariani L, Cozzaglio L, et al. Perioperative total parenteral nutrition in malnourished, gastrointestinal cancer patients: a randomized, clinical trial. JPEN Journal of parenteral and enteral nutrition. 2000;24:7-14. [35] Hubner M, Cerantola Y, Grass F, Bertrand PC, Schafer M, Demartines N. Preoperative immunonutrition in patients at nutritional risk: results of a double-blinded randomized clinical trial. European journal of clinical nutrition. 2012;66:850-5. [36] Fujitani K, Tsujinaka T, Fujita J, Miyashiro I, Imamura H, Kimura Y, et al. Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer. The British journal of surgery. 2012;99:621-9. [37] Azab B, Kedia S, Shah N, Vonfrolio S, Lu W, Naboush A, et al. The value of the pretreatment albumin/globulin ratio in predicting the long-term survival in colorectal cancer. International journal of colorectal disease. 2013;28:1629-36. [38] Onate-Ocana LF, Aiello-Crocifoglio V, Gallardo-Rincon D, Herrera-Goepfert R, BromValladares R, Carrillo JF, et al. Serum albumin as a significant prognostic factor for patients with gastric carcinoma. Annals of surgical oncology. 2007;14:381-9. [39] Lai CC, You JF, Yeh CY, Chen JS, Tang R, Wang JY, et al. Low preoperative serum albumin in colon cancer: a risk factor for poor outcome. International journal of colorectal disease. 2011;26:473-81.

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List of tables and figures Table 1. Patient’s characteristics of women with epithelial ovarian cancer undergoing primary cytoreductive surgery.

PT

Table 2: Clinical and pathological characteristics stratified by preoperative serum albumin level

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Table 3: Numbers of postoperative complications classified according to Clavien-DindoClassification (CDC) broken down by pre-operative serum albumin levels (309 patients treated at KEM). Table 4 : Multivariate analysis of prognostic factors for high complication (CDC 3-5)

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Table 5 : Univariate and multivariate analysis of prognostic factors for overall survival (OS) excluding patients with death within 30 days after surgery.

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Figure 1. Overall survival in patients with epithelial ovarian cancer undergoing primary cytoreductive surgery broken-down by pre-operative serum albumin levels.

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Table 1. Patient’s characteristics of women with epithelial ovarian cancer undergoing primary cytoreductive surgery.

%

NU

515 89 25 282

PT

CE

AC

16.4 83.6

SC RI

604 60 (21-92) 41 (6) 99 505

85.3 14.7 46.7

294 118 192

48.7 19.5 31.8

132 472

21.9 78.1

362 230 12 165 217 222

59.9 38.1 2.0 27.3 35.9 36.8

60 518 26

9.9 85.8 4.3

432 172

71.5 28.5

61 (45-76) 255

42.2

201 403

33.3 66.7

MA

ED

All patients. Age – median (range) [yrs] Albumin (g/L) - mean (SD) Pts. with ≤35 g/L Pts with >35 g/L ECOG ECOG 0 ECOG >0 BMI (kg/m2) - mean unknown Ascites (mL) 0 <500 >500 FIGO-stage IA-IIIA IIIB-IV Residual disease 0 mm > 0 mm unknown pN-stage N0 N1 unknown Grade Low-grade High-grade unknown Histology Serous Others Outcome Median survival time -months Recurrence rate Status at last observation Dead alive

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Variable

BMI body mass index; ECOG (Eastern Cooperative Oncology Group) performance status; SD standard deviation; FIGO=International Federation of Gynecologists and Obstetricians,

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Table 2: Clinical and pathological characteristics stratified by preoperative serum

albumin level

%

n

%

386 218

63.9 36.1

59 40

515 89

85.3 14.7

294 118 192

48.7 19.5 31.8

132 472

21.9 78.1

60 518

9.9 85.8

26

4.3

n

%

59.6 40.4

327 218

64.8 36.1

78 21

78.8 21.2

437 68

86.5 13.5

22 19 58

22.2 19.2 58.6

272 99 134

53.9 19.6 26.5

11 88

11.1 88.9

121 384

24.0 76.0

8 89

8.1 89.9

52 429

10.3 85.0

2

2.0

24

4.8

NU

MA

ED

69.7 30.3

PT

69 30

Albumin >35 g/L

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n

CE

Age age ≤ 65-y age >65-y ECOG-stage 0 >0 Ascites (mL) 0 <500 >500 FIGO-stage I-IIIA IIIB-IV Grade Low-grade High-grade unknown Histology Serous Others

Albumin ≤35 g/L

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Total cohort

363 142

p-value

0.047 <0.001

0.005

0.353

0.660 71.9 28.1

432 172

71.5 28.5

FIGO=International Federation of Gynecologists and Obstetricians, ECOG (Eastern Cooperative Oncology Group) performance status

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0.329

ACCEPTED MANUSCRIPT Table 3: Numbers of postoperative complications classified according to Clavien-DindoClassification (CDC) broken down by pre-operative serum albumin levels (309 patients treated at KEM).

PT

total n % 51 16.5 30 9.7 150 48.5 7 2.3 35 11.3 20 6.5 6 1.9 10 3.2 309

MA

NU

SC RI

Albumin >35 g/L n % 49 17.3 26 9.2 144 50.7 6 2.1 29 10.2 17 6.0 6 2.1 7 2.5 284

ED PT CE

0 1 2 3a 3b 4a 4b 5 total

Albumin ≤ 35g/L n % 2 8.0 4 16.0 6 24.0 1 4.0 6 24.0 3 12.0 0 0 3 12.0 25

AC

CDC

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ACCEPTED MANUSCRIPT Table 4 : Multivariate analysis of prognostic factors for high complication (CDC 3-5) CDC 3-5 Multivariate p-value

1 1.46

0.77-2.79

1 5.24

1.91-14.36

1 3.73

1.03-13.45

1 0.52

0.19-1.46

0.215

0.39-5.85 1.18-16.15

0.56 0.028

0.69-2.60

0.39

ED

1 1.34 1 2.60

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0.247

0.001

0.045

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1 1.50 4.36

PT

Age Age ≤ 65-years Age >65-years Albumin (g/l) >35 ≤35 ECOG-status 0 >0 FIGO-stage I-IIIA IIIB-IV Surgical complexity score low (≤6) intermediate (7-9) high ≥10 Blood loss <500 ml >500 ml Duration of operation < 360 min > 360 min

95% CI

MA

OR

PT

Variable

1.30-5.19

0.007

AC

CE

FIGO=International Federation of Gynecologists and Obstetricians, ECOG (Eastern Cooperative Oncology Group) performance status

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ACCEPTED MANUSCRIPT Table 5 : Univariate and multivariate analysis of prognostic factors for overall survival (OS) excluding patients with death within 30 days after surgery.

Overall survival Univariate 95% CI

p-value

HR

1 2.1

1.6-2.8

<0.001

1 1.9

1.4-2.6

<0.001

1 3.0

2.2-4.0

<0.001

1 2.2

1.6-3.0

<0.001

1 2.5

1.8-3.4

<0.001 <0.001

1 2.5

1.8-3.5

<0.001 <0.001

1 5.3

3.2-8.9

<0.001 <0.001

1 3.8

2.2-6.7

<0.001 <0.001

1 4.4 3.9

3.2-6.0 2.0-7.5

<0.001 <0.001 0.001

1 2.4 3.0

1.7-3.4 1.5-5.8

<0.001 0.001 0.540

1 3.1 2.0

1.7-5.8 0.8-5.0

<0.001 0.129

1 1.1 1.6

0.6-2.1 0.6-4.3

0.760 0.308

0.4-0.8

0.002

1 1.0

0.7-1.4

0.977

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MA

ED

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1 0.6

95% CI

p-value

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HR

CE

Age Age ≤ 65-years Age >65-years Albumin (g/L) >35 ≤35 ECOG-status 0 >0 FIGO-stage I-IIIA IIIB-IV Residual disease 0 mm >0 mm unknown Grade Low-grade High-grade unknown Histology Serous Others

Multivariate

PT

Variable

AC

HR (95% CI) = Hazard Ratio (95% Confidence Interval), FIGO=International Federation of Gynecologists and Obstetricians, ECOG (Eastern Cooperative Oncology Group) performance status

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CE

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SC RI

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Fig. 1

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Highlights Pre-operative serum albumin is associated with post-operative complication

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rate and overall survival in patients with epithelial ovarian cancer undergoing

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cytoreductive surgery

1. Hypoalbuminemia is risk factor for severe postoperative complications. 2. Hypoalbuminemia is a risk factor for impaired overall survival.

AC

CE

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3. Albumin levels should be incorporated in pre-operative workup