Ann Surg Oncol DOI 10.1245/s10434-015-4477-4
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
The Impact of Perioperative Red Blood Cell Transfusions on Long-Term Outcomes after Hepatectomy for Colorectal Liver Metastases Julie Hallet1,2, Melanie Tsang1,2, Eva S. W. Cheng1, Rogeh Habashi1, Iryna Kulyk1, Sherif S. Hanna1,2, Natalie G. Coburn1,2, Yulia Lin3,4, Calvin H. L. Law1,2, and Paul J. Karanicolas1,2 1
Division of General Surgery, Sunnybrook Health Sciences Centre – Odette Cancer Centre, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; 3Division of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
2
ABSTRACT Background. Red blood cell transfusions (RBCTs) are associated with cancer recurrence following resection of colorectal cancer. Their impact after colorectal liver metastases (CRLM) resection remains debated. We sought to explore the association between perioperative RBCT and oncologic outcomes following resection of CRLM. Methods. We reviewed patients undergoing partial hepatectomy for CRLM from 2003 to 2012 at a single institution. Date of death was abstracted from a validated population-based cancer registry. Primary outcome was overall survival (OS). Secondary outcome was recurrencefree survival (RFS). Survivals were estimated using Kaplan–Meier methods and compared with log-rank test based on transfusion status. Cox regression analysis examined the association of RBCT with OS and RFS, while adjusting for age, preoperative chemotherapy, Clinical Risk Score, and period of treatment (2003–2007 vs. 2008– 2012). Results. Among 483 patients, 27.5 % received RBCT. Ninety-day postoperative mortality was 4.8 %. At median
Part of this work has been accepted for poster presentation at the 67th Annual Cancer Symposium of the Society for Surgical Oncology in Houston, TX, and has been presented as a poster at the Gastrointestinal Cancer Symposium of the American Society for Clinical Oncology in San Francisco, CA. Ó Society of Surgical Oncology 2015 First Received: 11 December 2014 J. Hallet e-mail: [email protected]
follow-up of 33 (interquartile range 20.1–54.8) months, 5year OS was inferior in transfused patients (45.9 vs. 61.0 %; p \ 0.0001). Five-year RFS was decreased with RBCT (15.5 vs. 31.6 %; p \ 0.0001). The difference persisted when considering only 90-day survivors for 5-year OS (53.1 vs. 61.9 %, p = 0.023) and RFS (15.6 vs. 31.6 %; p \ 0.0001). After adjustment for prognostic factors, RBCT was independently associated with decreased OS (hazard ratio 2.24; 95 % confidence interval 1.60–3.15) and RFS (hazard ratio 1.71; 95 % confidence interval 1.28– 2.28). Conclusions. Perioperative RBCT is independently associated with decreased OS and RFS following hepatectomy for CRLM. Interventions to minimize and rationalize the use of RBCT for hepatectomy are warranted to mitigate this detrimental effect on long-term outcomes.
Significant advances have been made during the past decade for the treatment of colorectal liver metastases (CRLM) in both surgical and oncologic perioperative management. Improvements in surgical technique and perioperative care have led to diminished mortality that has reached 0–5 % in high-volume centres.1 Meanwhile, the introduction of perioperative chemotherapy regimens, as well as better patient selection and optimization tools have yielded improved long-term recurrence and survival outcomes.2–4 However, intraoperative blood loss remains a significant concern during hepatectomy, resulting in rates of red blood cell transfusions (RBCT) ranging from 17 to 40 %.5–8 In addition to infection-transmission and haemolytic reactions, RBCTs also carry risks of increased morbidity
J. Hallet et al.
after a variety of surgical procedures, including hepatectomy.9–11 Transfusion related immunomodulation (TRIM) is believed to suppress immunity in the perioperative period, thereby creating a fertile ground for infectious complications that significantly impact patients’ postoperative progresses and recovery.12,13 Because postoperative immunosuppression is known to promote replication of micrometastases, RBCTs administered around the time of surgery while patients are already subjected to surgical stress also may compromise long-term oncologic outcomes.14 Indeed, patients with colorectal cancer receiving perioperative RBCTs experience increased cancer recurrence and decreased survival following primary tumor resection.15 However, data regarding the impact of RBCTs on oncologic outcomes in the surgical treatment of CRLM is limited by small sample size or dated cohorts.10,16–18 In this study, we sought to examine the impact of perioperative RBCTs on recurrence and survival following hepatectomy for CRLM, in the contemporary era of liver resections. METHODS We conducted a retrospective cohort study using the Odette Cancer Centre prospective liver resection database, complemented by provincial cancer registry survival data. The Sunnybrook Health Sciences Centre Research Ethics Board approved this study. Selection of Participants Patients undergoing liver resection at a single tertiary care hepatobiliary surgery academic centre (Sunnybrook Health Sciences Centre—Odette Cancer Centre) were identified in the institutional liver resection database, from 2003 to 2012. Adult patients (C18 years old) operated for CRLM were included. Outcomes and Data Collection The primary outcome was overall survival (OS) computed from the date of liver resection to the date of death. Secondary outcome was recurrence-free survival (RFS) calculated from the date of liver resection to the date of recurrence. Recurrence was defined as intrahepatic or extrahepatic biopsy-proven recurrent adenocarcinoma or a lesion deemed suspicious on cross-sectional imaging. Perioperative RBCT was defined as transfusion of one or more units of allogeneic RBC during or 30 days following surgery. The database was queried for data regarding baseline demographics, clinical characteristics, including use of perioperative chemotherapy, and postoperative course
characteristics, including recurrence. Anemia was defined as preoperative haemoglobin \130 g/L according to the World Health Organization definition.19 Clinical risk score (CRS) was computed for each patient based on nodal status of the primary tumor, number of liver lesions, size of the largest liver lesion, CEA level [ 200 pg/L, and diseasefree interval \12 months.20 Two time periods of treatment were considered: 2003–2007 and 2008–2012. Date of death was obtained from the Ontario Cancer Registry (OCR), a provincial administrative database of Ontario residents diagnosed with cancer since 1964, receiving hospital discharge records, pathology reports, death certificates, and reports from regional cancer centres in the province of Ontario.21 Liver resections at our institution are performed aiming for low central venous pressure. According to institutional guidelines, RBCTs are administered for hemoglobin (Hb) level \ 70 g/L or in case of symptoms in the nonbleeding patient, and to maintain Hb between 70 and 80 g/L in the bleeding patient. All blood products are provided by the Canadian Blood Services, and 280-mL leukoreduced RBCT units were used during the study period. After hepatectomy for CRLM, patients are initially followed every 3–6 months clinically and radiologically with crosssectional imaging of the chest, abdomen, and pelvis for 3 years and every 12 months for 5 years thereafter. Statistical Analysis Descriptive analysis was first performed to describe the characteristics of transfused patients and compare them to those of not transfused patients. Categorical data were reported as absolute numbers (n) and proportion (%) and continuous data mean with standard deviation (SD) or median with interquartile range (IQR). Comparative analysis based on transfusion status was initially undertaken using Student’s t test, Fisher exact test, Mann–Whitney U test, or Pearson v2, as appropriate. The Kaplan–Meier method was used to estimate survival outcomes.22 OS was computed using date of death from the OCR as of August 8th, 2014. End of follow-up for OS analysis was defined as date of death or August 8th, 2014. For RFS, date of first evidence of recurrence was used, and date of last follow-up was considered as date of recurrence, date of death, or date of last clinical encounter. Difference in OS and RFS based on transfusion status were examined with the log-rank test.22 A sensitivity analysis was conducted to examine OS and RFS in patients alive 90 days after surgery. OS and RFS were further compared based on the number of RBCT received between patients receiving no transfusion, 1–2, 3–4, and 5 U or more. The association of relevant variables, including RBCT, with OS and RFS was examined using proportional Cox regression
Oncologic Impact of Transfusions TABLE 1 Characteristics of patients undergoing hepatectomy for colorectal liver metastases Transfused patients (n = 133)
Not transfused patients (n = 350)
p Value
Age (year)—mean (SD)
61.9 (11.1)
63.4 (11.7)
0.224
Male gender—n (%)
68 (51.1)
231 (66.0)
0.002
Preoperative anemia—n (%)a
71 (53.4)
116 (33.1)
\0.001
0
15(11.3)
38 (10.9)
1
35 (26.3)
86 (24.6)
2
38 (28.6)
129 (36.9)
3
39 (29.3)
79 (22.6)
4
4 (3.0)
17 (4.9)
Clinical risk score—n (%)
2 (1.5)
1 (0.3)
Preoperative chemotherapy—n (%) Major liver resection—n (%)b
5
100 (75.2) 93 (69.9)
232 (66.3) 215 (61.4)
0.228
0.062 0.090
Estimated blood loss (L)—mean (SD)
1.9 (1.7)
0.9 (0.7)
\0.001
Operative time (h)—mean (SD)
5.3 (1.7)
4.4 (1.6)
\0.001
Perioperative fresh-frozen plasma transfusion—n (%)
24 (18.0)
2 (0.6)
\0.001
Perioperative platelets transfusion—n (%)
17 (12.8)
2 (0.6)
\0.001
Resection margin status—n (%) R0
117 (88.0)
318 (90.9)
R1
9 (6.8)
12 (3.4)
R2
1 (0.8)
3 (0.9)
96 (72.2)
235 (67.1)
Time period 2008–2012—n (%) a
Anemia: Hb B 130 g/L
b
Major liver resection: C4 liver segments resected
analysis. Variables identified as significantly associated with RBCT on univariate analysis (p \ 0.05) were included in the regression model. In case of colinearity, the variable most relevant to the study question was included in the regression model. In addition, age at surgery, preoperative chemotherapy, time period of treatment, and CRS were included in the model a priori as they represent highly clinically relevant variables. Results were reported as hazard ratios (HR) with 95 % confidence interval (95 % CI). Statistical significance was set at p \ 0.05. All analyses were conducted with SPSS 21.0 (IBM Corp., Amon, NY). RESULTS Among 851 liver resections during the study period, 483 were performed for CRLM. RBCT was needed for 133 (27.5 %) patients. Most of those patients received RBCT intraoperatively (76.7 %), with RCT administered exclusively intraoperatively in 48.1 %, exclusively postoperatively in 23.3 %, and both intra- and postoperatively in 28.6 %. Preoperative and operative characteristics of included patients are presented in Table 1. Patients with preoperative anemia (p \ 0.001) were more commonly transfused. Median estimated blood loss was 1 L higher (p \ 0.001) and
0.458
0.170
operating time 0.9 h longer (p \ 0.001) in transfused compared with nontransfused patients. No significant difference was observed in extent of resection (p = 0.090), clinical risk score (p = 0.228), use of preoperative chemotherapy (p = 0.062), or time period (p = 0.170). Overall, 23 (4.8 %) patients died within 90 days of liver resection. Ninety-day mortality was more frequent among transfused patients (15.6 vs. 1.4 %; p \ 0.001). At a median follow-up of 33 (interquartile range [IQR]: 20.1–54.8) months, transfused patients experienced significantly inferior 3- and 5-year OS than their nontransfused counterparts (p \ 0.0001), with respectively 57.3 % (95 % CI 52.8–61.8 %) compared with 74.4 % (95 % CI 71.4– 76.6 %), and 45.9 % (95 % CI 40.7–51.1 %) compared with 61.0 % (95 % CI 57.8–62.2 %; Fig. 1a). When excluding 90-day deaths, the significant difference in OS persisted (p = 0.023), with 66.3 % (95 % CI 61.6–71.0 %) compared with 75.5 % (95 % CI 72.9–78.1 %) at 3 years, and 53.1 % (95 % CI 47.4–58.8 %) compared with 61.9 % (95 % CI 58.7–65.1 %) at 5 years (Fig. 1b). With regards to RFS, median follow-up was 11.7 (IQR 3.6–28.5) months. Three-year and 5-year RFS was significantly lower with RBCT (p \ 0.0001), with 20.3. % (95 % CI 15.8–24.8 %) compared with 38.9 % (95 % CI 35.6–42.2 %), and 15.5 % (95 % CI 11.3–19.7 %) compared
J. Hallet et al.
A
B Not transfused Transfused
1.0
0.8
0.8
0.6
0.6
Survival
Survival
1.0
0.4
0.4
0.2
0.2
0.0
0.0 0
12
24
36
48
60
Not transfused Transfused
0
12
Time (months) Number at risk Not transfused Transfused
350 133
329 105
248 70
24
36
48
60
174 55
122 27
Time (months) 174 54
122 29
83 16
Log rank : p < 0.0001
Number at risk Not transfused Transfused
345 115
329 105
248 71
82 16
Log rank: p = 0.023
FIG. 1 Overall survival of patients with liver resection for colorectal liver metastases, according to RBC transfusion status
with 31.6 % (95 % CI 28.3–34.9 %), respectively (Fig. 2a). In sensitivity analysis of patients who survived a minimum of 90 days following liver resection, RFS remained inferior for transfused patients with 20.4 % (95 % CI 15.9–24.9 %) compared with 38.9 % (95 % CI 35.6–42.2 %) at 3 years, and 15.6 % (95 % CI 11.4–19.8 %) compared with 31.6 % (95 % CI 28.3–34.9 %) at 5 years (Fig. 2b). When looking at survival curves according to the number of RBC units received, a significant difference in both OS and RFS was identified based on the amount of transfused RBC, with a dose–response relationship (Fig. 3). Early deaths occurred more frequently in the group of patients receiving five units or more of RBC, with 1-year OS of 87.9 % (95 % CI 83.9–91.9 %) with 1 to 2 units, 84.2 % (95 % CI 78.3–90.1 %) for 3–4 units, and 53.6 % (95 % CI 44.2–63.0 %) for five units or more. Factors associated with OS in Cox regression analysis are presented in Table 2. Due to the high correlation between estimated blood loss, operating time, and RBCT, only RBCT was included in the model. Perioperative RBCT was independently associated with diminished OS (HR 2.24; 95 % CI 1.60–3.15), when accounting for characteristics of transfused patients as well as CRS, preoperative chemotherapy, and time period. Other factors independently associated with OS were CRS and time period of liver resection. Results of the Cox regression analysis for RFS are detailed in Table 2. Perioperative RBCT was independently associated with lower RFS (HR 1.71; 95 % CI 1.28–2.28). Receipt of preoperative chemotherapy and higher CRS also were independently associated with decreased RFS.
DISCUSSION In this cohort of patients undergoing hepatectomy for colorectal liver metastases, we examined the impact of RBCTs on long-term oncologic outcomes. When adjusting for factors associated with higher risk of RBCT and for clinicopathological prognostic factors, OS and RFS were significantly inferior for patients receiving RBCTs. The issue of the detrimental impact of transfusions on cancer recurrence was initially raised in 1981, as a response to the publication of improved cadaveric renal graft survival among transfused patients.13,23 Soon after, evidence of TRIM was also observed in Crohn’s disease, with decreased recurrence of acute inflammatory episodes in patients receiving perioperative RBCTs.24 With regards to cancer, it is believed that micrometastases’ cells elude immune surveillance as a result of TRIM, thereby leading to increased recurrence. Indeed, animal models have confirmed tumor-growth promotion of cancer cells by blood transfusions.25,26 This phenomenon also could be potentiated by immunosuppression related to acute perioperative surgical stress state promoting cancer cells’ replication.14 However, the exact mechanism underlying TRIM remains unclear.27 Reduction in natural killer cell function, diminished T cell function, increased number of suppressor T cells, and impaired macrophages’ and monocytes’ functions have been outlined as possible sources of immunomodulation.12 The age of transfused blood also has been implicated in immune effects of transfusions, through a higher number of
Oncologic Impact of Transfusions
A
B Not transfused Transfused
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0 0
12
24
36
48
Not transfused Transfused
1.0
Survival
Survival
1.0
60
0
12
24
Time (months) Number at risk Not transfused Transfused
311 123
168 44
100 22
36
48
60
65 14
49 11
Time (months) 65 14
49 11
34 8
Number at risk Not transfused Transfused
308 111
168 44
100 22
34 8
Log rank: p < 0.0001
Log rank: p < 0.0001
FIG. 2 Recurrence free survival of patients with liver resection for colorectal liver metastases, according to RBC transfusion status
B
1.0
1.0
0.8
0.8
0.6
0.6
Survival
Survival
A
0.4 No transfusion 1 to 2 RBC units 3 to 4 RBC units 5 or more RBC units
0.2
0.4 No transfusion 1 to 2 RBC units 3 to 4 RBC units 5 or more RBC units
0.2
0.0
0.0 0
12
24
36
48
60
0
12
Time (months) Log rank: p < 0.0001
24
36
48
60
Time (months) Log rank: p < 0.0001
FIG. 3 Survival of patients with liver resection for colorectal liver metastases, according to the number of RBCT units received
inflammatory cytokines and other bioactive molecules generated by prolonged storage.28,29 Our findings regarding CRLM are consistent with a recent meta-analysis pooling data from 26 studies, including more than 12,000 patients that have confirmed the association of RBCTs with worse recurrence profiles following surgery for primary tumor in colorectal cancer.15 This issue is even more relevant in colorectal liver metastases giving the bleeding risk of hepatectomy and the frequent use of RBCTs in 17– 40 % of cases.5–8 Some previous studies have observed
worse outcomes in CRLM survival with RBCT on univariate analysis,16,18 whereas others did not.10,28 No study has yet identified a significant association on multivariate analysis.16,18,28 These studies relied on small sample sizes ranging from 55 to 239 patients, and noncontemporary cohorts dating back to 1976. The only large experience included 1351 patients but was conducted in a prior era in liver resection when techniques and perioperative care were different (1986– 2001).4,18 The difference they observed in survival lost significance on multivariate analysis adjusting for prognostic
J. Hallet et al. TABLE 2 Factors associated with overall and recurrence-free survival after liver resection for colorectal liver metastases (Cox regression) Overall survival
Recurrence free survival
Hazard ratio
95 % confidence interval
Age (year)
1.01
1.00–1.03
Male gender
1.32
0.94–1.87
Preoperative anemia
0.95
0.68–1.33
p Value
Hazard ratio
95 % confidence interval
p Value
0.05
1.00
0.99–1.01
0.565
0.113
1.14
0.85–1.53
0.376
0.759
1.02
0.76–1.37
0.876
Preoperative chemotherapy
1.29
1.90–1.85
0.160
1.68
1.05–2.67
0.028
Clinical risk scorea
1.29
1.11–1.49
0.001
1.28
1.12–1.46
\0.0001
Time period: 2008–2012b
0.46
0.33–0.63
\0.001
1.16
0.87–1.55
0.307
Perioperative RBC transfusion
2.24
1.60–3.15
\0.001
1.71
1.28–2.28
\0.0001
RBC red blood cells a
Ordinal variable—score from 0 to 5 out of 5
b
Reference category is time period: 2003–2007
factors (HR 1.1; 95 % CI 0.9–1.3), leading the authors to attribute worse outcomes to perioperative mortality and other tumor-related factors.18 Of note, this multivariate analysis considered all blood transfusions in the transfusion variable, including fresh-frozen plasma and platelets, even though use of those products resulted in similar survival curves as the nontransfused group.18 The current study is the largest contemporary analysis of RBCTs for CRLM surgery, with 483 patients from 2003 to 2012. We observed median OS (55.7 months) and RFS (18.5 months) consistent with the contemporary oncologic results obtained with hepatectomy for CRLM.4,29,30 Baseline cancer recurrence risk and use of neoadjuvant systemic treatment strategies are known to be associated with recurrence and survival in CRLM and were therefore included in the multivariate analysis.30,31 In addition, we included time period of treatment in the regression model in order to control for potential changes in management over time. In the resulting detailed Cox regression, RBCTs remained strongly and independently associated with both OS (HR 2.24; 95 % CI 1.6– 3.15) and RFS (HR 1.71; 95 % CI 1.28–2.28). Finally, an initial steeper slope can be observed in the survival curves of transfused patients due to more frequent postoperative mortality. When excluding 90-day postoperative mortality for sensitivity analyses, significant differences in OS and RFS persisted, thereby addressing the survival bias that can ensue from the potential higher requirement for RBCTs in complex resections faring worse in the early postoperative course as evidenced by higher 90-day mortality in the transfused group. The survival analysis according to the number of RBC units received also revealed that patients receiving a large amount of RBCT (five units or more) died early in the postoperative course, within the first year, which could be related to perioperative complications from more challenging and complex procedures. Patients administered fewer units still experienced decreased OS and RFS, with a dose–response relationship
observed even at 1 unit transfused, but suffered more delayed death that could be related to disease recurrence. These findings outline the need for comprehensive initiatives to minimize the use of RBCTs during and after hepatectomy. Outcomes of CRLM have significantly improved in the past decades.10,30,32 Reducing the use of RBCTs could further contribute to this improvement, but this question has yet to be addressed. In the meantime, many RBCTs may safely be avoided by using restrictive transfusion strategies.33–36 Indeed, the implementation of multidisciplinary blood conservation programs based on education sessions, transfusion consultation services, and mandated documentation of transfusion indication have been successfully implemented and diminished RBCT by 50 % in colorectal, orthopaedic, and cardiac surgery.36,37 Strengths of this study include the large sample size, contemporary timing, detailed survival data, and cautious multivariate analysis. We acknowledge the limitations inherent to the retrospective design of this study, including potential information bias and unknown confounders. However, we accounted for known prognostic confounders using Cox regression models. Survival data used in this study was abstracted from a validated population-based provincial cancer registry, with date of last follow-up defined as August 8, 2014 in patients without a date of death in the registry. We recognize that this censoring criterion does not account for patients who may have moved to another jurisdiction. However, the OCR survival data has previously been compared to individually obtained data, which revealed only one disagreement on vital status among more than 700 patients and 95 % agreement on the date of death (±1 month)38. Thus, it provides a more reliable dataset than what can be obtained with single-centre follow-ups, offering a unique assessment of the impact of RBCT on overall survival following liver resection for CRLM.
Oncologic Impact of Transfusions
CONCLUSIONS In this study, RBCT was independently associated with decreased OS and RFS following hepatectomy for CRLM, when adjusting for clinicopathological prognostic factors. Strategies to reduce the use of RBCT for liver resection are warranted to mitigate their detrimental effect on long-term outcomes following surgery for CRLM. ACKNOWLEDGMENT The authors thank Ms. Jessica Truong for her assistance with data collection. No funding was received for this work.
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patients undergoing resection for colorectal cancer. Am J Surg. 2012;204(6):944–51. 38. Hall S, Schulze K, Groome P, Mackillop W, Holowaty E. Using cancer registry data for survival studies: the example of the Ontario Cancer Registry. J Clin Epidemiol. 2006;59(1): 67–76.
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
The Impact of Perioperative Red Blood Cell Transfusions on Long-Term Outcomes after Hepatectomy for Colorectal Liver Metastases Julie Hallet1,2, Melanie Tsang1,2, Eva S. W. Cheng1, Rogeh Habashi1, Iryna Kulyk1, Sherif S. Hanna1,2, Natalie G. Coburn1,2, Yulia Lin3,4, Calvin H. L. Law1,2, and Paul J. Karanicolas1,2 1
Division of General Surgery, Sunnybrook Health Sciences Centre – Odette Cancer Centre, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada; 3Division of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
2
ABSTRACT Background. Red blood cell transfusions (RBCTs) are associated with cancer recurrence following resection of colorectal cancer. Their impact after colorectal liver metastases (CRLM) resection remains debated. We sought to explore the association between perioperative RBCT and oncologic outcomes following resection of CRLM. Methods. We reviewed patients undergoing partial hepatectomy for CRLM from 2003 to 2012 at a single institution. Date of death was abstracted from a validated population-based cancer registry. Primary outcome was overall survival (OS). Secondary outcome was recurrencefree survival (RFS). Survivals were estimated using Kaplan–Meier methods and compared with log-rank test based on transfusion status. Cox regression analysis examined the association of RBCT with OS and RFS, while adjusting for age, preoperative chemotherapy, Clinical Risk Score, and period of treatment (2003–2007 vs. 2008– 2012). Results. Among 483 patients, 27.5 % received RBCT. Ninety-day postoperative mortality was 4.8 %. At median
Part of this work has been accepted for poster presentation at the 67th Annual Cancer Symposium of the Society for Surgical Oncology in Houston, TX, and has been presented as a poster at the Gastrointestinal Cancer Symposium of the American Society for Clinical Oncology in San Francisco, CA. Ó Society of Surgical Oncology 2015 First Received: 11 December 2014 J. Hallet e-mail: [email protected]
follow-up of 33 (interquartile range 20.1–54.8) months, 5year OS was inferior in transfused patients (45.9 vs. 61.0 %; p \ 0.0001). Five-year RFS was decreased with RBCT (15.5 vs. 31.6 %; p \ 0.0001). The difference persisted when considering only 90-day survivors for 5-year OS (53.1 vs. 61.9 %, p = 0.023) and RFS (15.6 vs. 31.6 %; p \ 0.0001). After adjustment for prognostic factors, RBCT was independently associated with decreased OS (hazard ratio 2.24; 95 % confidence interval 1.60–3.15) and RFS (hazard ratio 1.71; 95 % confidence interval 1.28– 2.28). Conclusions. Perioperative RBCT is independently associated with decreased OS and RFS following hepatectomy for CRLM. Interventions to minimize and rationalize the use of RBCT for hepatectomy are warranted to mitigate this detrimental effect on long-term outcomes.
Significant advances have been made during the past decade for the treatment of colorectal liver metastases (CRLM) in both surgical and oncologic perioperative management. Improvements in surgical technique and perioperative care have led to diminished mortality that has reached 0–5 % in high-volume centres.1 Meanwhile, the introduction of perioperative chemotherapy regimens, as well as better patient selection and optimization tools have yielded improved long-term recurrence and survival outcomes.2–4 However, intraoperative blood loss remains a significant concern during hepatectomy, resulting in rates of red blood cell transfusions (RBCT) ranging from 17 to 40 %.5–8 In addition to infection-transmission and haemolytic reactions, RBCTs also carry risks of increased morbidity
J. Hallet et al.
after a variety of surgical procedures, including hepatectomy.9–11 Transfusion related immunomodulation (TRIM) is believed to suppress immunity in the perioperative period, thereby creating a fertile ground for infectious complications that significantly impact patients’ postoperative progresses and recovery.12,13 Because postoperative immunosuppression is known to promote replication of micrometastases, RBCTs administered around the time of surgery while patients are already subjected to surgical stress also may compromise long-term oncologic outcomes.14 Indeed, patients with colorectal cancer receiving perioperative RBCTs experience increased cancer recurrence and decreased survival following primary tumor resection.15 However, data regarding the impact of RBCTs on oncologic outcomes in the surgical treatment of CRLM is limited by small sample size or dated cohorts.10,16–18 In this study, we sought to examine the impact of perioperative RBCTs on recurrence and survival following hepatectomy for CRLM, in the contemporary era of liver resections. METHODS We conducted a retrospective cohort study using the Odette Cancer Centre prospective liver resection database, complemented by provincial cancer registry survival data. The Sunnybrook Health Sciences Centre Research Ethics Board approved this study. Selection of Participants Patients undergoing liver resection at a single tertiary care hepatobiliary surgery academic centre (Sunnybrook Health Sciences Centre—Odette Cancer Centre) were identified in the institutional liver resection database, from 2003 to 2012. Adult patients (C18 years old) operated for CRLM were included. Outcomes and Data Collection The primary outcome was overall survival (OS) computed from the date of liver resection to the date of death. Secondary outcome was recurrence-free survival (RFS) calculated from the date of liver resection to the date of recurrence. Recurrence was defined as intrahepatic or extrahepatic biopsy-proven recurrent adenocarcinoma or a lesion deemed suspicious on cross-sectional imaging. Perioperative RBCT was defined as transfusion of one or more units of allogeneic RBC during or 30 days following surgery. The database was queried for data regarding baseline demographics, clinical characteristics, including use of perioperative chemotherapy, and postoperative course
characteristics, including recurrence. Anemia was defined as preoperative haemoglobin \130 g/L according to the World Health Organization definition.19 Clinical risk score (CRS) was computed for each patient based on nodal status of the primary tumor, number of liver lesions, size of the largest liver lesion, CEA level [ 200 pg/L, and diseasefree interval \12 months.20 Two time periods of treatment were considered: 2003–2007 and 2008–2012. Date of death was obtained from the Ontario Cancer Registry (OCR), a provincial administrative database of Ontario residents diagnosed with cancer since 1964, receiving hospital discharge records, pathology reports, death certificates, and reports from regional cancer centres in the province of Ontario.21 Liver resections at our institution are performed aiming for low central venous pressure. According to institutional guidelines, RBCTs are administered for hemoglobin (Hb) level \ 70 g/L or in case of symptoms in the nonbleeding patient, and to maintain Hb between 70 and 80 g/L in the bleeding patient. All blood products are provided by the Canadian Blood Services, and 280-mL leukoreduced RBCT units were used during the study period. After hepatectomy for CRLM, patients are initially followed every 3–6 months clinically and radiologically with crosssectional imaging of the chest, abdomen, and pelvis for 3 years and every 12 months for 5 years thereafter. Statistical Analysis Descriptive analysis was first performed to describe the characteristics of transfused patients and compare them to those of not transfused patients. Categorical data were reported as absolute numbers (n) and proportion (%) and continuous data mean with standard deviation (SD) or median with interquartile range (IQR). Comparative analysis based on transfusion status was initially undertaken using Student’s t test, Fisher exact test, Mann–Whitney U test, or Pearson v2, as appropriate. The Kaplan–Meier method was used to estimate survival outcomes.22 OS was computed using date of death from the OCR as of August 8th, 2014. End of follow-up for OS analysis was defined as date of death or August 8th, 2014. For RFS, date of first evidence of recurrence was used, and date of last follow-up was considered as date of recurrence, date of death, or date of last clinical encounter. Difference in OS and RFS based on transfusion status were examined with the log-rank test.22 A sensitivity analysis was conducted to examine OS and RFS in patients alive 90 days after surgery. OS and RFS were further compared based on the number of RBCT received between patients receiving no transfusion, 1–2, 3–4, and 5 U or more. The association of relevant variables, including RBCT, with OS and RFS was examined using proportional Cox regression
Oncologic Impact of Transfusions TABLE 1 Characteristics of patients undergoing hepatectomy for colorectal liver metastases Transfused patients (n = 133)
Not transfused patients (n = 350)
p Value
Age (year)—mean (SD)
61.9 (11.1)
63.4 (11.7)
0.224
Male gender—n (%)
68 (51.1)
231 (66.0)
0.002
Preoperative anemia—n (%)a
71 (53.4)
116 (33.1)
\0.001
0
15(11.3)
38 (10.9)
1
35 (26.3)
86 (24.6)
2
38 (28.6)
129 (36.9)
3
39 (29.3)
79 (22.6)
4
4 (3.0)
17 (4.9)
Clinical risk score—n (%)
2 (1.5)
1 (0.3)
Preoperative chemotherapy—n (%) Major liver resection—n (%)b
5
100 (75.2) 93 (69.9)
232 (66.3) 215 (61.4)
0.228
0.062 0.090
Estimated blood loss (L)—mean (SD)
1.9 (1.7)
0.9 (0.7)
\0.001
Operative time (h)—mean (SD)
5.3 (1.7)
4.4 (1.6)
\0.001
Perioperative fresh-frozen plasma transfusion—n (%)
24 (18.0)
2 (0.6)
\0.001
Perioperative platelets transfusion—n (%)
17 (12.8)
2 (0.6)
\0.001
Resection margin status—n (%) R0
117 (88.0)
318 (90.9)
R1
9 (6.8)
12 (3.4)
R2
1 (0.8)
3 (0.9)
96 (72.2)
235 (67.1)
Time period 2008–2012—n (%) a
Anemia: Hb B 130 g/L
b
Major liver resection: C4 liver segments resected
analysis. Variables identified as significantly associated with RBCT on univariate analysis (p \ 0.05) were included in the regression model. In case of colinearity, the variable most relevant to the study question was included in the regression model. In addition, age at surgery, preoperative chemotherapy, time period of treatment, and CRS were included in the model a priori as they represent highly clinically relevant variables. Results were reported as hazard ratios (HR) with 95 % confidence interval (95 % CI). Statistical significance was set at p \ 0.05. All analyses were conducted with SPSS 21.0 (IBM Corp., Amon, NY). RESULTS Among 851 liver resections during the study period, 483 were performed for CRLM. RBCT was needed for 133 (27.5 %) patients. Most of those patients received RBCT intraoperatively (76.7 %), with RCT administered exclusively intraoperatively in 48.1 %, exclusively postoperatively in 23.3 %, and both intra- and postoperatively in 28.6 %. Preoperative and operative characteristics of included patients are presented in Table 1. Patients with preoperative anemia (p \ 0.001) were more commonly transfused. Median estimated blood loss was 1 L higher (p \ 0.001) and
0.458
0.170
operating time 0.9 h longer (p \ 0.001) in transfused compared with nontransfused patients. No significant difference was observed in extent of resection (p = 0.090), clinical risk score (p = 0.228), use of preoperative chemotherapy (p = 0.062), or time period (p = 0.170). Overall, 23 (4.8 %) patients died within 90 days of liver resection. Ninety-day mortality was more frequent among transfused patients (15.6 vs. 1.4 %; p \ 0.001). At a median follow-up of 33 (interquartile range [IQR]: 20.1–54.8) months, transfused patients experienced significantly inferior 3- and 5-year OS than their nontransfused counterparts (p \ 0.0001), with respectively 57.3 % (95 % CI 52.8–61.8 %) compared with 74.4 % (95 % CI 71.4– 76.6 %), and 45.9 % (95 % CI 40.7–51.1 %) compared with 61.0 % (95 % CI 57.8–62.2 %; Fig. 1a). When excluding 90-day deaths, the significant difference in OS persisted (p = 0.023), with 66.3 % (95 % CI 61.6–71.0 %) compared with 75.5 % (95 % CI 72.9–78.1 %) at 3 years, and 53.1 % (95 % CI 47.4–58.8 %) compared with 61.9 % (95 % CI 58.7–65.1 %) at 5 years (Fig. 1b). With regards to RFS, median follow-up was 11.7 (IQR 3.6–28.5) months. Three-year and 5-year RFS was significantly lower with RBCT (p \ 0.0001), with 20.3. % (95 % CI 15.8–24.8 %) compared with 38.9 % (95 % CI 35.6–42.2 %), and 15.5 % (95 % CI 11.3–19.7 %) compared
J. Hallet et al.
A
B Not transfused Transfused
1.0
0.8
0.8
0.6
0.6
Survival
Survival
1.0
0.4
0.4
0.2
0.2
0.0
0.0 0
12
24
36
48
60
Not transfused Transfused
0
12
Time (months) Number at risk Not transfused Transfused
350 133
329 105
248 70
24
36
48
60
174 55
122 27
Time (months) 174 54
122 29
83 16
Log rank : p < 0.0001
Number at risk Not transfused Transfused
345 115
329 105
248 71
82 16
Log rank: p = 0.023
FIG. 1 Overall survival of patients with liver resection for colorectal liver metastases, according to RBC transfusion status
with 31.6 % (95 % CI 28.3–34.9 %), respectively (Fig. 2a). In sensitivity analysis of patients who survived a minimum of 90 days following liver resection, RFS remained inferior for transfused patients with 20.4 % (95 % CI 15.9–24.9 %) compared with 38.9 % (95 % CI 35.6–42.2 %) at 3 years, and 15.6 % (95 % CI 11.4–19.8 %) compared with 31.6 % (95 % CI 28.3–34.9 %) at 5 years (Fig. 2b). When looking at survival curves according to the number of RBC units received, a significant difference in both OS and RFS was identified based on the amount of transfused RBC, with a dose–response relationship (Fig. 3). Early deaths occurred more frequently in the group of patients receiving five units or more of RBC, with 1-year OS of 87.9 % (95 % CI 83.9–91.9 %) with 1 to 2 units, 84.2 % (95 % CI 78.3–90.1 %) for 3–4 units, and 53.6 % (95 % CI 44.2–63.0 %) for five units or more. Factors associated with OS in Cox regression analysis are presented in Table 2. Due to the high correlation between estimated blood loss, operating time, and RBCT, only RBCT was included in the model. Perioperative RBCT was independently associated with diminished OS (HR 2.24; 95 % CI 1.60–3.15), when accounting for characteristics of transfused patients as well as CRS, preoperative chemotherapy, and time period. Other factors independently associated with OS were CRS and time period of liver resection. Results of the Cox regression analysis for RFS are detailed in Table 2. Perioperative RBCT was independently associated with lower RFS (HR 1.71; 95 % CI 1.28–2.28). Receipt of preoperative chemotherapy and higher CRS also were independently associated with decreased RFS.
DISCUSSION In this cohort of patients undergoing hepatectomy for colorectal liver metastases, we examined the impact of RBCTs on long-term oncologic outcomes. When adjusting for factors associated with higher risk of RBCT and for clinicopathological prognostic factors, OS and RFS were significantly inferior for patients receiving RBCTs. The issue of the detrimental impact of transfusions on cancer recurrence was initially raised in 1981, as a response to the publication of improved cadaveric renal graft survival among transfused patients.13,23 Soon after, evidence of TRIM was also observed in Crohn’s disease, with decreased recurrence of acute inflammatory episodes in patients receiving perioperative RBCTs.24 With regards to cancer, it is believed that micrometastases’ cells elude immune surveillance as a result of TRIM, thereby leading to increased recurrence. Indeed, animal models have confirmed tumor-growth promotion of cancer cells by blood transfusions.25,26 This phenomenon also could be potentiated by immunosuppression related to acute perioperative surgical stress state promoting cancer cells’ replication.14 However, the exact mechanism underlying TRIM remains unclear.27 Reduction in natural killer cell function, diminished T cell function, increased number of suppressor T cells, and impaired macrophages’ and monocytes’ functions have been outlined as possible sources of immunomodulation.12 The age of transfused blood also has been implicated in immune effects of transfusions, through a higher number of
Oncologic Impact of Transfusions
A
B Not transfused Transfused
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0.0
0.0 0
12
24
36
48
Not transfused Transfused
1.0
Survival
Survival
1.0
60
0
12
24
Time (months) Number at risk Not transfused Transfused
311 123
168 44
100 22
36
48
60
65 14
49 11
Time (months) 65 14
49 11
34 8
Number at risk Not transfused Transfused
308 111
168 44
100 22
34 8
Log rank: p < 0.0001
Log rank: p < 0.0001
FIG. 2 Recurrence free survival of patients with liver resection for colorectal liver metastases, according to RBC transfusion status
B
1.0
1.0
0.8
0.8
0.6
0.6
Survival
Survival
A
0.4 No transfusion 1 to 2 RBC units 3 to 4 RBC units 5 or more RBC units
0.2
0.4 No transfusion 1 to 2 RBC units 3 to 4 RBC units 5 or more RBC units
0.2
0.0
0.0 0
12
24
36
48
60
0
12
Time (months) Log rank: p < 0.0001
24
36
48
60
Time (months) Log rank: p < 0.0001
FIG. 3 Survival of patients with liver resection for colorectal liver metastases, according to the number of RBCT units received
inflammatory cytokines and other bioactive molecules generated by prolonged storage.28,29 Our findings regarding CRLM are consistent with a recent meta-analysis pooling data from 26 studies, including more than 12,000 patients that have confirmed the association of RBCTs with worse recurrence profiles following surgery for primary tumor in colorectal cancer.15 This issue is even more relevant in colorectal liver metastases giving the bleeding risk of hepatectomy and the frequent use of RBCTs in 17– 40 % of cases.5–8 Some previous studies have observed
worse outcomes in CRLM survival with RBCT on univariate analysis,16,18 whereas others did not.10,28 No study has yet identified a significant association on multivariate analysis.16,18,28 These studies relied on small sample sizes ranging from 55 to 239 patients, and noncontemporary cohorts dating back to 1976. The only large experience included 1351 patients but was conducted in a prior era in liver resection when techniques and perioperative care were different (1986– 2001).4,18 The difference they observed in survival lost significance on multivariate analysis adjusting for prognostic
J. Hallet et al. TABLE 2 Factors associated with overall and recurrence-free survival after liver resection for colorectal liver metastases (Cox regression) Overall survival
Recurrence free survival
Hazard ratio
95 % confidence interval
Age (year)
1.01
1.00–1.03
Male gender
1.32
0.94–1.87
Preoperative anemia
0.95
0.68–1.33
p Value
Hazard ratio
95 % confidence interval
p Value
0.05
1.00
0.99–1.01
0.565
0.113
1.14
0.85–1.53
0.376
0.759
1.02
0.76–1.37
0.876
Preoperative chemotherapy
1.29
1.90–1.85
0.160
1.68
1.05–2.67
0.028
Clinical risk scorea
1.29
1.11–1.49
0.001
1.28
1.12–1.46
\0.0001
Time period: 2008–2012b
0.46
0.33–0.63
\0.001
1.16
0.87–1.55
0.307
Perioperative RBC transfusion
2.24
1.60–3.15
\0.001
1.71
1.28–2.28
\0.0001
RBC red blood cells a
Ordinal variable—score from 0 to 5 out of 5
b
Reference category is time period: 2003–2007
factors (HR 1.1; 95 % CI 0.9–1.3), leading the authors to attribute worse outcomes to perioperative mortality and other tumor-related factors.18 Of note, this multivariate analysis considered all blood transfusions in the transfusion variable, including fresh-frozen plasma and platelets, even though use of those products resulted in similar survival curves as the nontransfused group.18 The current study is the largest contemporary analysis of RBCTs for CRLM surgery, with 483 patients from 2003 to 2012. We observed median OS (55.7 months) and RFS (18.5 months) consistent with the contemporary oncologic results obtained with hepatectomy for CRLM.4,29,30 Baseline cancer recurrence risk and use of neoadjuvant systemic treatment strategies are known to be associated with recurrence and survival in CRLM and were therefore included in the multivariate analysis.30,31 In addition, we included time period of treatment in the regression model in order to control for potential changes in management over time. In the resulting detailed Cox regression, RBCTs remained strongly and independently associated with both OS (HR 2.24; 95 % CI 1.6– 3.15) and RFS (HR 1.71; 95 % CI 1.28–2.28). Finally, an initial steeper slope can be observed in the survival curves of transfused patients due to more frequent postoperative mortality. When excluding 90-day postoperative mortality for sensitivity analyses, significant differences in OS and RFS persisted, thereby addressing the survival bias that can ensue from the potential higher requirement for RBCTs in complex resections faring worse in the early postoperative course as evidenced by higher 90-day mortality in the transfused group. The survival analysis according to the number of RBC units received also revealed that patients receiving a large amount of RBCT (five units or more) died early in the postoperative course, within the first year, which could be related to perioperative complications from more challenging and complex procedures. Patients administered fewer units still experienced decreased OS and RFS, with a dose–response relationship
observed even at 1 unit transfused, but suffered more delayed death that could be related to disease recurrence. These findings outline the need for comprehensive initiatives to minimize the use of RBCTs during and after hepatectomy. Outcomes of CRLM have significantly improved in the past decades.10,30,32 Reducing the use of RBCTs could further contribute to this improvement, but this question has yet to be addressed. In the meantime, many RBCTs may safely be avoided by using restrictive transfusion strategies.33–36 Indeed, the implementation of multidisciplinary blood conservation programs based on education sessions, transfusion consultation services, and mandated documentation of transfusion indication have been successfully implemented and diminished RBCT by 50 % in colorectal, orthopaedic, and cardiac surgery.36,37 Strengths of this study include the large sample size, contemporary timing, detailed survival data, and cautious multivariate analysis. We acknowledge the limitations inherent to the retrospective design of this study, including potential information bias and unknown confounders. However, we accounted for known prognostic confounders using Cox regression models. Survival data used in this study was abstracted from a validated population-based provincial cancer registry, with date of last follow-up defined as August 8, 2014 in patients without a date of death in the registry. We recognize that this censoring criterion does not account for patients who may have moved to another jurisdiction. However, the OCR survival data has previously been compared to individually obtained data, which revealed only one disagreement on vital status among more than 700 patients and 95 % agreement on the date of death (±1 month)38. Thus, it provides a more reliable dataset than what can be obtained with single-centre follow-ups, offering a unique assessment of the impact of RBCT on overall survival following liver resection for CRLM.
Oncologic Impact of Transfusions
CONCLUSIONS In this study, RBCT was independently associated with decreased OS and RFS following hepatectomy for CRLM, when adjusting for clinicopathological prognostic factors. Strategies to reduce the use of RBCT for liver resection are warranted to mitigate their detrimental effect on long-term outcomes following surgery for CRLM. ACKNOWLEDGMENT The authors thank Ms. Jessica Truong for her assistance with data collection. No funding was received for this work.
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