Peri-operative blood management of Jehovah’s Witnesses undergoing cytoreductive surgery for advanced ovarian cancer

Abstract

Background

The aim of this study was to evaluate the efficacy and feasibility of a peri-operative bloodless medicine and surgery (BMS) protocol in reducing severe post-operative anaemia (haemoglobin [Hb] <7 g/dL) in Jehovah’s Witnesses undergoing cytoreductive surgery for advanced epithelial ovarian cancer.

Materials and methods

This was a single-institution retrospective study enrolling Jehovah’s Witnesses who underwent elective bloodless surgery for advanced epithelial ovarian cancer between October 2017 and April 2020. All patients followed a standardised bloodless medicine and surgery protocol based on ferric carboxymaltose and erythropoietin if indicated.

Results

Twenty-five patients with a mean age of 61.7 years (range, 35–80) were enrolled. Pre-operatively, ten patients (40%) were mildly anaemic (mean Hb of 10.2 g/dL [range, 9.2–11.4]) and received ferric carboxymaltose. Only four (16%) patients had severe anaemia after surgery (mean Hb of 6.1 g/dL [range, 4.1–6.9]) and received ferric carboxymaltose and erythropoietin. Compared to patients with a post-operative Hb ≥7 g/dL, those with Hb <7 g/dL had higher mean body mass index (25.8±1.8 vs 30.7±1.8 kg/m²; p<0.001), mean baseline CA125 (236.1±184.5 vs 783.7±273.5 IU/mL; p<0.001), median surgical complexity score (2 vs 10; p<0.001), and rate of post-operative complications (14.3 vs 100%; p<0.001). Moreover, these patients had a longer mean operating time (3.4±0.6 vs 5.5±0.4 h; p<0.001), duration of stay in hospital (5.5±0.7 vs 24.0±9.8 days; p<0.001), and time to adjuvant chemotherapy (27.2±2.6 vs 65.3±13.4 days; p<0.001).

Discussion

The use of a multidisciplinary bloodless medicine and surgery protocol is safe and effective in reducing the rate of severe post-operative anaemia and improving surgical and oncological outcomes of Jehovah’s Witnesses with advanced epithelial ovarian cancer. Further large-scale, prospective studies are required to confirm these data.

INTRODUCTION

Residual tumour after surgery, either after primary debulking surgery or interval debulking surgery, is one of the most important prognostic factors in patients with advanced epithelial ovarian cancer (AEOC)^1,2. Since this malignancy is often widespread, an aggressive surgical strategy, including radical pelvic surgery, bowel resection and removal of upper abdominal lesions (e.g., diaphragmatic, splenic, and hepatic lesions) is frequently required^3,4. The effort to achieve no residual disease carries an increased risk of peri-operative morbidities, including severe bleeding and post-operative anaemia^5–9. Approximately 5–10% of AEOC patients experience severe intra-operative bleeding during cytoreductive surgery, while the prevalence of post-operative anaemia reaches up to 90% with a blood transfusion rate of 30–60% ^10–15.

Many authors have identified anaemia as an independent prognostic factor for adverse outcomes in the peri-operative period^16,17. The current standard of care for patients with severe peri-operative anaemia (haemoglobin [Hb] <7 g/dL) is blood transfusion¹⁸. However, there are a number of situations in which patients may refuse blood transfusions, even in life-threatening scenarios, with the most well-known involving the expanding religious group of Jehovah’s Witnesses, with over eight million members worldwide. To our knowledge, currently, there is no standardised bloodless medicine and surgery (BMS) protocol for Jehovah’s Witnesses undergoing major elective surgery.

Several studies in the fields of gynaecological, abdominal and orthopaedic surgery suggested that the peri-operative use of intravenous iron is safe and may rapidly increase Hb levels, resulting in lower transfusion rates and fewer post-operative complications^19–22. Among different intravenous iron preparations, ferric carboxymaltose (FCM) is an innovative dextran-free iron complex that has shown faster and higher efficacy in replenishing depleted Hb concentrations and iron levels. In a meta-analysis, Moore et al. reported a mean Hb increase from baseline of about 1–1.5 g/dL by week 1, 2 g/dL by week 2, and 3 g/dL by week 6 with a plateau until week 12 following FCM treatment²³. Moreover, erythropoiesis-stimulating agents (ESA) have been shown to reduce the need for blood transfusions in surgical patients, especially when combined with intravenous iron^24–26.

In this scenario, the aim of the present study was to assess the efficacy and feasibility of FCM and erythropoietin (EPO) in reducing severe post-operative anaemia in Jehovah’s Witnesses undergoing surgery for AEOC.

MATERIALS AND METHODS

This retrospective study was approved by the appropriate Ethics Committee of Policlinico Umberto I Hospital of Rome (protocol number: 0724/2020). Written informed consent was obtained from all the study participants.

From October 2017 to April 2020, data from Jehovah’s Witnesses undergoing elective surgery for AEOC at the Department of Maternal and Child Health and Urological Sciences of Sapienza University (Rome) were collected. All bloodless operations were performed by experienced, skilled surgeons at a tertiary care referral centre. The exclusion criteria were as follows: emergency surgery, early-disease (FIGO stage IA–IIIA), incomplete medical records, recurrent disease, concomitant neoplasms, pregnancy, chronic inflammatory diseases and infections. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy plus interval debulking surgery were included. Demographic, oncological and surgical data were collected. The surgical complexity was evaluated according to the score system described by Aletti et al.²⁷. The Clavien-Dindo classification system was used to describe grade I–IV post-operative complications²⁸. According to the World Health Organization (WHO), anaemia was defined as serum Hb levels <12 g/dL and was classified as mild (11.0–11.9 g/dL), moderate (7.0–10.9 g/dL), and severe (<7 g/dL). We provided a multidisciplinary peri-operative BMS algorithm for Jehovah’s Witnesses undergoing elective bloodless major surgery, which is described in detail in Figures 1 and 2. Data on post-operative anaemia and peri-operative morbidity were recorded. All patients gave written informed consent attesting to their intention to decline some or all blood components (packed red blood cells, cryoprecipitate, albumin, whole blood) and intra-operative blood salvage.

Figure 1.

Pre-operative bloodless medicine and surgery (BMS) algorithm

B12: vitamin B12; CBC: complete blood count; CKD: chronic kidney disease; CRP: C-reactive protein; EPO: erythropoietin; FCM: ferric carboxymaltose; Hb: haemoglobin; IDWA: iron deficiency without anaemia; IV: intravenous; NS: normal saline; SC: subcutaneous; TSAT: transferrin saturation.

Figure 2.

Post-operative bloodless medicine and surgery (BMS) algorithm

CBC: complete blood count; CKD: chronic kidney disease; EPO: erythropoietin; FCM: ferric carboxymaltose; Hb: haemoglobin; IV: intravenous; NS: normal saline; SC: subcutaneous; TSAT: transferrin saturation.

The incidence rates were analysed using Fisher’s exact test. Normality testing was performed to determine whether data were sampled from a Gaussian distribution. The chi-square test was used to evaluate associations between two categorical variables. The t-test and Mann-Whitney U test were used to compare continuous parametric and non-parametric variables, respectively. Statistical software SPSS version 25.0 was used for all the analyses. A p value <0.05 was considered statistically significant.

RESULTS

Twenty-five Jehovah’s Witnesses fulfilling the inclusion criteria were enrolled in the study. Table I shows the patients’ baseline demographic and clinical data. Briefly, the mean age at the time of surgery was 61.7 years (range, 35–80) and the mean body mass index was 26.6 kg/m² (range, 22.0–32.8). All patients had advanced disease: according to the FIGO staging system 11 had stage IIIB (44%) and 14 had stage IIIC (56%). The vast majority of cases had serous histology (88%) and were G3 tumours (92%). Fifteen of the 25 (60%) patients underwent primary debulking surgery, whereas 10 (40%) were submitted to platinum-based neoadjuvant chemotherapy (40% complete response; 60% partial response) and subsequent interval debulking surgery. The pre-operative median American Society of Anesthiologists score and Eastern Cooperative Oncology Group status were 2 and 1, respectively. The mean CA125 value at diagnosis was 323.69 IU/mL (range, 50.0–1,157.3).

Table I.

Demographic, clinical and treatment characteristics

Variable	Total (n = 25)
Age (years); mean (range)	61.7 (35–80)
ASA score; median (range)	2 (1–3)
ECOG status; median (range)	1 (0–2)
BMI (kg/m 2 ); mean (range)	26.6 (22–32.8)
Stage; n (%)
IIIB	11 (44%)
IIIC	14 (56%)
Histology; n (%)
Serous	22 (88%)
Endometrioid	2 (8%)
Mucinous	1 (4%)
Grade; n (%)
3	23 (92%)
2	2 (8%)
CA125 at diagnosis (IU/mL); mean (range)	323.7.0 (50.0–1157.3)
Type of surgery; n (%)
PDS	15 (60%)
IDS	10 (40%)
Additional procedures; n (%)
Large bowel resection	12 (48%)
Small bowel resection	8 (32%)
Bladder resection	8 (32%)
Diaphragmatic resection	6 (24%)
Colostomy	3 (12%)
Ileostomy	2 (8%)
Splenectomy	1 (4%)

ASA: American Society of Anesthesiologists; BMI: body mass index; ECOG: Eastern Cooperative Oncology Group; IDS: interval debulking surgery; PDS: primary debulking surgery.

In the pre-hospitalisation period, the mean Hb level was 11.3 g/dL (range, 9.2–13.2). Ten (40%) patients were mildly anaemic (mean Hb of 10.2 g/dL; range, 9.2–11.4) and thus received FCM, for 20 days on average (range, 15–35) before surgery. The mean Hb increase reported by the time of surgery was 2.3 g/dL (range, 1.5–2.8). The mean pre-operative Hb and haematocrit levels were 12.7 g/dL (range, 10.7–14.0) and 38% (range, 30–43.2), respectively. None of the patients received EPO in the pre-operative period.

All patients underwent total hysterectomy with bilateral salpingo-oophorectomy and omentectomy. Additional procedures included large bowel resection (12/25 patients; 48%), small bowel resection (8/25; 32%), bladder resection (8/25; 32%), diaphragmatic resection (6/25; 24%), colostomy (3/25; 12%), ileostomy (2/25; 8%), and splenectomy (1/25; 4%). Optimal cytoreduction (residual tumour = 0 cm) was achieved in 22 patients (88%), whereas a residual tumour >1 cm was reported in three patients (12%). The mean estimated blood loss was 600 mL (range, 200–1,500). Post-operative outcomes are presented in Table II. The mean post-operative Hb and haematocrit levels were 9.7 g/dL (range, 4.1–12.7) and 28.8% (range, 13.2–39.7), respectively. Twenty (80%) patients were anaemic after surgery and were given intravenous FCM treatment. Among them, four patients (16%) had severe post-operative anaemia with a mean Hb of 6.1 g/dL (range, 4.1–6.9) and also received EPO 40,000 IU subcutaneously weekly. The mean Hb value at discharge was 10.7 g/dL (range, 8.4–13.1). No adverse events were reported during peri-operative FCM administration. The four patients (16%) with Hb<7 g/dL experienced early post-operative complications. In detail, all four required admission to the Intensive Care Unit for cardiovascular support and had pleural effusions. Moreover, one of them underwent an emergency re-operation for bowel perforation and suffered a deep wound dehiscence treated with vacuum-assisted closure therapy. For comparison, among patients with post-operative Hb levels ≥7 g/dL, pleural effusion, Intensive Care Unit admission and wound dehiscence occurred in 14.3%, 9.5%, and 4.8% of patients, respectively. Compared to the cohort of patients with post-operative Hb ≥7 g/dL, those with Hb <7 g/dL had a higher median surgical complexity score (2 [range, 2–5] vs 10 [range, 8–11]; p<0.001) and postoperative overall complications (14.3 vs 100%; p<0.001) and a longer mean operating time (3.4±0.6 vs 5.5±0.4 h; p<0.001), duration of stay in hospital (5.5±0.7 vs 24.0±9.8 days; p<0.001), and time to adjuvant chemotherapy (27.2±2.6 vs 65.3±13.4 days; p<0.001). No significant differences regarding the clinical characteristics between the two groups were observed, except for the mean body mass index (25.8±1.8 vs 30.7±1.8 kg/m²; p<0.001) and the median CA125 at diagnosis (236.1±184.5 vs 783.7±273.5 IU/mL; p<0.001) (Table III).

Table II.

Postoperative outcomes

Variable	Total (n = 25)
Hb (g/dL); mean (range)
Pre-hospitalisation	11.3 (9.2–13.2)
Pre-operative	12.7 (10.7–14.0)
Post-operative	9.7 (4.1–12.7)
Ht (%); mean (range)
Pre-operative	38.0 (30.0–43.2)
Post-operative	28.8 (13.2–39.7)
EBL (mL); mean (range)	600 (200–1500)
RT (cm); n (%)
0	22 (88)
≥1	3 (12)
SCS; median (range)	4 (2–11)
Operating time (hours); mean (range)	3.7 (2.5–6.0)
Hospital stay (days); mean (range)	8.5 (4.0–38.0)
Post-operative complications; n (%)
Pleural effusion	7 (28%)
ICU admission	6 (24%)
Wound dehiscence	2 (8%)
Re-operation	1 (4%)
Time to adjuvant CT (days); mean (range)	33.3 (24.0–85.0)

CT: chemotherapy ; EBL: estimated blood loss; ICU: intensive care unit; Hb: haemoglobin; Ht: haematocrit; ICU: Intensive Care Unit; RT: residual tumour; SCS: surgical complexity score.

Table III.

Differences between patients with postoperative Hb <7 g/dL and Hb ≥7 g/dL

	Hb <7 g/dL (n = 4)	Hb ≥7 g/dL (n = 21)	P
Age (years); mean ± SD	63.8 ± 12.1	61.3 ± 11.1	0.697
BMI (kg/m 2 ); mean ± SD	30.7 ± 1.8	25.8 ± 1.8	<0.001
CA125 at diagnosis (IU/mL); mean ± SD	783.7 ± 273.5	236.1 ± 184.5	<0.001
Albumin pre-op (g/L); mean ± SD	42.0 ± 4.1	43.2 ± 3.2	0.524
Operating time (hours); mean ± SD	5.5 ± 0.4	3.4 ± 0.6	<0.001
Hospital stay (days); mean ± SD	24.0±9.8	5.5±0.7	<0.001
Time to CT (days); mean ± SD	65.3 ± 13.4	27.2 ± 2.6	<0.001
SCS
1	0%	57.1%
2	0%	42.9%	<0.001
3	100%	9.5%
Pleural effusion; %	100%	14.3%	0.019
ICU admission	100%	9.5%	0.019
Wound dehiscence	25%*	4.8%	0.019
Reoperation	25%*	0%	0.019

^*Occurred in the same patient. Bold indicates statistical significance.

BMI: body mass index; CT: chemotherapy; Hb: haemoglobin; ICU: Intensive Care Unit; SCS: surgical complexity score; SD: standard deviation.

DISCUSSION

To our knowledge, this is the first study addressing the population of Jehovah’s Witnesses undergoing bloodless surgery for AEOC and the management of peri-operative anaemia.

Facing the decision of a patient to decline blood transfusion, even when life-saving, is probably one of the biggest and most frustrating clinical challenges. Peri-operative anaemia has been identified as a predictor of adverse surgical outcomes. In 2002, Carson et al. retrospectively studied surgical patients refusing blood transfusions for religious reasons and reported mortality and morbidity rates of 34.4% and 57.7%, respectively, in patients with post-operative Hb levels of 4–5 g/dL compared to 0% and 9.4%, respectively, in those with Hb levels of 7–8 g/dL²⁹. Pre-operative anaemia is common, affecting 30–60% of all patients undergoing major elective surgery, and is one of the major risk factors for blood transfusions³⁰. On the other hand, post-operative anaemia is present in up to 90% of patients^10–12. In 2004, the European Cancer Anaemia Survey (ECAS), which was conducted across 24 European countries and enrolled more than 13,600 patients, found that gynaecologic malignancies accounted for 11.6% of all cases of cancer-related anaemia, with a prevalence of 48.1% anaemic women at enrolment, of whom only 42.7% ever received treatment for their anaemia³¹. In a prospective review investigating the prognostic impact of pre-operative Hb levels in patients with ovarian cancer, Obermair et al. reported overall survival rates of 38.5% and 52.3% in patients with Hb levels <12 g/dL and ≥12 g/dL, respectively (p=0.008)³².

Although the current standard of care for severely anaemic patients (Hb <7 g/dL) is blood transfusion, in our study none of the patients accepted blood transfusions, even in the case of life-threatening anaemia. The paradigm of BMS for Jehovah’s Witnesses is becoming increasingly acknowledged among physicians and the early recognition and treatment of pre-operative anaemia could be the key³³. There is growing evidence supporting the efficacy and safety of peri-operative intravenous iron treatment as an alternative to allogenic blood transfusion. Indeed, intravenous iron is inexpensive, readily available (up to 1,000 mg can be administered with a single short-term infusion) and can allow up to a five-fold erythropoietic response to significant blood-loss anaemia^20,23,34,35. Furthermore, four meta-analyses evaluated the synergistic effect of combined iron therapy and ESA and all recorded similar findings^36–39. The most recent one by Mhaskar et al.³⁸ reported that, compared to ESA alone, ESA treatment combined with iron was significantly associated with a higher haematopoietic response (relative risk [RR], 1.17; 95% confidence interval [95% CI], 1.09 to 1.26) and a lower need for blood transfusions (RR, 0.74; 95% CI, 0.60 to 0.92) without increasing the risk of thromboembolism (RR, 0.95; 95% CI, 0.54 to 1.65). However, the use of ESA should be evaluated carefully, since these agents have been associated with a higher risk of thromboembolic events (generally easily manageable with prophylaxis), and their impact on survival and cancer progression/recurrence is still controversial⁴⁰. The American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) recently stated that the use of ESA should be limited to patients undergoing palliative chemotherapy with anaemia not amenable to proper management with blood transfusions⁴¹.

Promising results with the peri-operative use of FCM to reduce the need for blood transfusions have already been achieved in other surgical specialties, such as colorectal cancer surgery^42,43, gastrointestinal cancer surgery⁴⁴, major abdominal surgery^20,22, and orthopaedic surgery^45,46. To our knowledge, there is no standardised protocol available in gynaecologic oncology for Jehovah’s Witnesses. On this background, we report our single-institution experience with the use of a multidisciplinary peri-operative algorithm based on FCM and EPO in female Jehovah’s Witnesses undergoing cytoreductive surgery for AEOC. A key step was to identify all anaemic patients, even those with mild anaemia, at least 1 month before surgery, so that they could receive adequate counselling and treatment to obtain, possibly, the optimal Hb value of 12 g/dL (or at least 10 g/dL at the surgeon’s discretion) before undergoing surgery. Indeed, the importance of preoperative anaemia as a recognisable and preventable major surgical risk is underappreciated. Of note, it must be pointed out that the use of pre-operative intravenous iron. requiring on average 3 weeks to achieve maximum benefit, was part of the normal pre-hospitalisation timing and did not delay the surgical treatment in any way.

Following this protocol, we found that only 16% of patients became severely anaemic (Hb <7 g/dL) after surgery, which is far lower than the 30–60% reported in literature^10–15. Based on our experience, these results suggest that the introduction of a multidisciplinary BMS played a significant role in reducing the transfusion rate and improving surgical and oncological outcomes in AEOC patients treated at our centre. Our data confirm that low post-operative Hb levels (especially <7 g/dL), correlated with high body mass index and CA125 at diagnosis, along with worse surgical and oncological outcomes, such as longer operating time, higher surgical complexity score, prolonged hospital stay, post-operative complications (Intensive Care Unit admission, pleural effusion, bowel perforation, re-operation, wound dehiscence), and delayed initiation of chemotherapy.

The limitations of this study are related to its retrospective nature, the absence of a control group and the relatively small cohort of patients enrolled, which prevented reasonable adjustments from being made for variables other than Hb concentration, such as body mass index, operating time, and adverse events.

Ultimately, blood transfusions are one of the most overused healthcare measures and clinicians should learn to employ them more judiciously, considering both their risks and elevated costs. The use of a protocol for BMS could play a crucial role as part of the peri-operative enhanced recovery after surgery (ERAS) management in gynaecological oncology surgery.

CONCLUSIONS

Since the current standard of care for patients with Hb levels <7 g/dL is blood transfusion, the care of AEOC patients undergoing cytoreductive bloodless surgery poses a unique clinical challenge. In this study the application of a peri-operative BMS algorithm based on FCM and EPO reduced the rate of severe post-operative anaemia and improved surgical and oncological outcomes, while reducing transfusion-related risks and costs. Notably, this protocol could not only represent standard gynaecological oncology practice for female Jehovah’s Witnesses but could also be adapted and applied to all patients undergoing elective major surgeries as an effective alternative treatment to blood transfusions. Large-scale and prospective studies are required to confirm these data.