T R A N S F U S I O N C O M P L I C AT I O N S Allogeneic versus autologous blood transfusion and survival after radical prostatectomy Heather J. Chalfin,1 Steven M. Frank,2 Zhaoyong Feng,1 Bruce J. Trock,1 Charles G. Drake,1,3 Alan W. Partin,1 Elizabeth Humphreys,1 Paul M. Ness,4 Byong C. Jeong,1 Seung B. Lee,1 and Misop Han1
BACKGROUND: Potential adverse effects of blood transfusion (BT) remain controversial, especially for clinical outcomes after curative cancer surgery. Some postulate that immune modulation after allogeneic BT predisposes to recurrence and death, but autologous superiority is not established. This study assessed whether BT is associated with long-term prostate cancer recurrence and survival with a large singleinstitutional radical prostatectomy (RP) database. STUDY DESIGN AND METHODS: Between 1994 and 2012, a total of 11,680 patients had RP with available outcome and transfusion data. A total of 7443 (64%) had complete covariate data. Clinical variables associated with biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) were identified with Cox proportional hazards models for three groups: no BT (reference, 27.7%, n = 2061), autologous BT only (68.8%, n = 5124), and any allogeneic BT (with or without autologous, 3.5%, n = 258). RESULTS: Median (range) follow-up was 6 (1-18) years. Kaplan-Meier analysis showed significantly decreased OS (but not BRFS or PCSS) in the allogeneic group versus autologous and no BT groups (p = 0.006). With univariate analysis, any allogeneic BT had a hazard ratio (HR) of 2.29 (range, 1.52-3.46; p < 0.0001) for OS, whereas autologous BT was not significant (HR, 1.04 [range, 0.82-1.32], p = 0.752). In multivariable models, neither autologous nor allogeneic BT was independently associated with BRFS, CSS, or OS, and a dose response was not observed for allogeneic units and BRFS. CONCLUSION: Although allogeneic but not autologous BT was associated with decreased long-term OS, after adjustment for confounding clinical variables, BT was not independently associated with OS, BRFS, or CSS regardless of transfusion type. Notably, no association was observed between allogeneic BT and cancer recurrence. Observed differences in OS may reflect confounding.
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B
lood transfusion (BT) is among the most common hospital procedures, with an estimated 15 million units transfused annually in the United States alone.1 Ideally, indications for BT should be optimized to prevent overuse of a costly resource with potential harms. Accumulating data support a restrictive transfusion strategy with a low hemoglobin threshold (7-8 g/dL) to achieve this goal.2-4 While improved screening has significantly curtailed transmission of viral pathogens, noninfectious hazards of BT are less well understood. Immunosuppression has been observed both clinically and in the laboratory, with prolonged renal allograft survival in patients receiving pretransplant allogeneic BTs.5 Also, nonanemic patients with little operative blood loss who receive BT have a greater risk of perioperative death than their
ABBREVIATIONS: BCR = biochemical recurrence; BRFS = biochemical recurrence-free survival; BT(s) = blood transfusion(s); CCI = Charlson comorbidity index; CSS = cancer-specific survival; HR = hazard ratio; OS = overall survival; PSA = prostate-specific antigen; RP = radical prostatectomy. From the 1Department of Urology, 2Department of Anesthesiology, 3Department of Immunology, and 4Department of Pathology, James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Address reprint requests to: Heather J. Chalfin, MD, 600 N. Wolfe Street/Marburg 146, Baltimore, MD 21287-2101; e-mail: [email protected]. Funded by Johns Hopkins Prostate Cancer SPORE (P50CA058236). IRB: 1043052. Abstract presented May 6, 2013, at the annual American Urological Association national meeting. Received for publication October 12, 2013; revision received January 6, 2014, and accepted January 11, 2014. doi: 10.1111/trf.12611 © 2014 AABB TRANSFUSION 2014;54:2168-2174.
BLOOD TRANSFUSION AND SURVIVAL AFTER PROSTATECTOMY
nontransfused counterparts.4,6 The most provocative findings associate increased rates of cancer recurrence and mortality with perioperative BT in colorectal, esophageal, liver, breast, renal, and lung cancer patients.7-11 This observation, which may result from an immunosuppressive effect of allogeneic BT, is regarded as controversial and has been disputed.8,10,11 An alternative explanation for worse outcomes in transfused patients is simple confounding, as patient comorbidities, disease burden, and perioperative complications underlie the decision to transfuse.8,12 Radical prostatectomy (RP) patients comprise a unique population well suited to clarify the relationship of BT with cancer recurrence and mortality. RP is generally recommended for men with long life expectancy and limited comorbidities.13 Modern improvements in surgical technique have largely eliminated life-threatening hemorrhage, but need for BT in these patients persists, prompting some men to donate autologous blood preoperatively. In fact, some have reported absence of an association between autologous or allogeneic BT and prostate cancer recurrence.14-16 Investigations of the association between BT and survival after RP in small series have yielded conflicting results.16-18 The serum prostatespecific antigen (PSA) test facilitates early detection of cancer recurrence, but to capture both cancer-specific and overall mortality outcomes, long-term follow-up is essential due to the protracted clinical course of prostate cancer. We investigated whether perioperative BT (autologous vs. allogeneic) impacts recurrence, as well as cancer-specific survival (CSS) and overall survival (OS) after RP using a large tertiary referral center RP database.
MATERIALS AND METHODS Study population A retrospective cohort analysis included 18,099 patients who underwent RP (either open radical retropubic approach or laparoscopic approach with or without robotic assistance) for clinically localized prostate cancer between 1994 and 2012 at a single tertiary referral center. Of these, 11,680 had available outcome and transfusion data, and 7443 met complete inclusion criteria of available clinicopathologic variables and Charlson comorbidity index (CCI). Gleason grade and pathologic stage were determined for each surgical specimen in a standardized fashion by a single group of urologic pathologists. BT data were obtained from the Pathology Data Systems of Johns Hopkins Medical Institutions. The cohort was divided into three patient groups: 1) no BT (reference, n = 2061, 27.7%); 2) autologous BT only (n = 5124, 68.8%); and 3) any allogeneic BT (with or without autologous, n = 258, 3.5%). Characteristics of these subgroups are compared in Table 1. Universal leukoreduction began in the year 2000 and was complete by 2001.19
Mortality status and cause of death information were updated using medical records after RP. Death was considered to be attributable to prostate cancer if prostate cancer was listed as the underlying cause of death or the patient had hormone-refractory metastatic disease at the time of death. Cause of death information was also sourced from the Centers for Disease Control and Prevention’s National Death Index.
Statistical analysis Comparisons of demographic and clinical factors between progression, prostate cancer death, and/or overall death statuses were based on chi-square or Fisher’s exact test. The t test or Wilcoxon rank sum test were used for continuous variables. Survival time was determined from the date of surgery until the progression or death endpoint or censoring. A multivariable Cox proportional hazards model was used to evaluate the association between transfusion type and biochemical recurrencefree survival (BRFS; PSA ≥ 0.2), CSS, and OS, while adjusting for potential confounding factors. Confounding factors were systematically identified as variables whose introduction into the multivariable model caused the hazard ratio (HR) for transfusion to change by at least 10%. Our objective was to quantify the impact (if any) of transfusion on recurrence and survival, rather than to create a prediction model. Therefore, given the small numbers of deaths in the no transfusion and allogeneic transfusion groups, parsimony dictated that the final model be limited to the transfusion variable and identified confounding factors. Additionally a subgroup analysis was performed to identify specific subsets of men in which transfusion may be associated with BRFS, CSS, or OS. In a final analysis, the number of units of transfused blood was considered to determine whether a dose–response relationship existed between number of units transfused and survival. All analyses of CSS were performed as competing risk models with any noncancer death as the competing event. The level of significance was set at 0.05 in all analyses. All statistical analyses were a priori performed using computer software (SAS, Version 9.3, SAS Institute, Cary, NC).
RESULTS Median (range) follow-up was 6 (1-18) years. Those who received any BT were significantly older (p = 0.0002); were less likely to have had recent RP (p < 0.0001); had higher preoperative PSA (p < 0.0001); had worse pathologic stage (p = 0.014); and were more likely to experience progression (p = 0.0003), die of prostate cancer (p = 0.004), or die of any cause (p < 0.0001). Body mass index, RP Gleason score, and CCI were not significantly different for transfused and nontransfused men (Table 1). Volume 54, September 2014 TRANSFUSION
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TABLE 1. Demographic and clinical characteristics of study cohort by transfusion type
Characteristic Age Number Mean (SD) Median (range) BMI (categorical)† Underweight and normal (30) RP year Number Mean (SD) Median (range) Preoperative PSA (categorical)† 0-2.5 2.6-4.0 4.1-10.0 >10.0 RP Gleason† ≤6 7 8-10 Pathologic stage† OC EPE/FCP SVI LN+ CCI† 0 1 >1 Progression† No Yes Prostate cancer death† No Yes Overall death† No Yes
Overall (n = 11,680)
No transfusion (n = 5204)
Autologous only transfusion (n = 5878)
Any allogeneic transfusion (n = 598)
p value*
7443 57.5 (6.5) 58 (33-77)
2061 57.3 (6.3) 57 (37-77)
5124 57.5 (6.5) 58 (33-75)
258 59.0 (6.4) 59 (42-73)
0.0002
2060 (27.7) 4161 (55.9) 1222 (16.4)
554 (26.9) 1157 (56.1) 350 (17.0)
1434 (28.0) 2865 (55.9) 825 (16.1)
72 (27.9) 139 (53.9) 47 (18.2)
0.720
7443 2000.2 (3.3) 2000 (1994-2007)
2061 2002.3 (2.8) 2003 (1994-2007)
5124 1999.4 (3.1) 1999 (1994-2007)
258 2000.0 (3.2) 2000 (1994-2007)
BACKGROUND: Potential adverse effects of blood transfusion (BT) remain controversial, especially for clinical outcomes after curative cancer surgery. Some postulate that immune modulation after allogeneic BT predisposes to recurrence and death, but autologous superiority is not established. This study assessed whether BT is associated with long-term prostate cancer recurrence and survival with a large singleinstitutional radical prostatectomy (RP) database. STUDY DESIGN AND METHODS: Between 1994 and 2012, a total of 11,680 patients had RP with available outcome and transfusion data. A total of 7443 (64%) had complete covariate data. Clinical variables associated with biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) were identified with Cox proportional hazards models for three groups: no BT (reference, 27.7%, n = 2061), autologous BT only (68.8%, n = 5124), and any allogeneic BT (with or without autologous, 3.5%, n = 258). RESULTS: Median (range) follow-up was 6 (1-18) years. Kaplan-Meier analysis showed significantly decreased OS (but not BRFS or PCSS) in the allogeneic group versus autologous and no BT groups (p = 0.006). With univariate analysis, any allogeneic BT had a hazard ratio (HR) of 2.29 (range, 1.52-3.46; p < 0.0001) for OS, whereas autologous BT was not significant (HR, 1.04 [range, 0.82-1.32], p = 0.752). In multivariable models, neither autologous nor allogeneic BT was independently associated with BRFS, CSS, or OS, and a dose response was not observed for allogeneic units and BRFS. CONCLUSION: Although allogeneic but not autologous BT was associated with decreased long-term OS, after adjustment for confounding clinical variables, BT was not independently associated with OS, BRFS, or CSS regardless of transfusion type. Notably, no association was observed between allogeneic BT and cancer recurrence. Observed differences in OS may reflect confounding.
2168
TRANSFUSION Volume 54, September 2014
B
lood transfusion (BT) is among the most common hospital procedures, with an estimated 15 million units transfused annually in the United States alone.1 Ideally, indications for BT should be optimized to prevent overuse of a costly resource with potential harms. Accumulating data support a restrictive transfusion strategy with a low hemoglobin threshold (7-8 g/dL) to achieve this goal.2-4 While improved screening has significantly curtailed transmission of viral pathogens, noninfectious hazards of BT are less well understood. Immunosuppression has been observed both clinically and in the laboratory, with prolonged renal allograft survival in patients receiving pretransplant allogeneic BTs.5 Also, nonanemic patients with little operative blood loss who receive BT have a greater risk of perioperative death than their
ABBREVIATIONS: BCR = biochemical recurrence; BRFS = biochemical recurrence-free survival; BT(s) = blood transfusion(s); CCI = Charlson comorbidity index; CSS = cancer-specific survival; HR = hazard ratio; OS = overall survival; PSA = prostate-specific antigen; RP = radical prostatectomy. From the 1Department of Urology, 2Department of Anesthesiology, 3Department of Immunology, and 4Department of Pathology, James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, Maryland. Address reprint requests to: Heather J. Chalfin, MD, 600 N. Wolfe Street/Marburg 146, Baltimore, MD 21287-2101; e-mail: [email protected]. Funded by Johns Hopkins Prostate Cancer SPORE (P50CA058236). IRB: 1043052. Abstract presented May 6, 2013, at the annual American Urological Association national meeting. Received for publication October 12, 2013; revision received January 6, 2014, and accepted January 11, 2014. doi: 10.1111/trf.12611 © 2014 AABB TRANSFUSION 2014;54:2168-2174.
BLOOD TRANSFUSION AND SURVIVAL AFTER PROSTATECTOMY
nontransfused counterparts.4,6 The most provocative findings associate increased rates of cancer recurrence and mortality with perioperative BT in colorectal, esophageal, liver, breast, renal, and lung cancer patients.7-11 This observation, which may result from an immunosuppressive effect of allogeneic BT, is regarded as controversial and has been disputed.8,10,11 An alternative explanation for worse outcomes in transfused patients is simple confounding, as patient comorbidities, disease burden, and perioperative complications underlie the decision to transfuse.8,12 Radical prostatectomy (RP) patients comprise a unique population well suited to clarify the relationship of BT with cancer recurrence and mortality. RP is generally recommended for men with long life expectancy and limited comorbidities.13 Modern improvements in surgical technique have largely eliminated life-threatening hemorrhage, but need for BT in these patients persists, prompting some men to donate autologous blood preoperatively. In fact, some have reported absence of an association between autologous or allogeneic BT and prostate cancer recurrence.14-16 Investigations of the association between BT and survival after RP in small series have yielded conflicting results.16-18 The serum prostatespecific antigen (PSA) test facilitates early detection of cancer recurrence, but to capture both cancer-specific and overall mortality outcomes, long-term follow-up is essential due to the protracted clinical course of prostate cancer. We investigated whether perioperative BT (autologous vs. allogeneic) impacts recurrence, as well as cancer-specific survival (CSS) and overall survival (OS) after RP using a large tertiary referral center RP database.
MATERIALS AND METHODS Study population A retrospective cohort analysis included 18,099 patients who underwent RP (either open radical retropubic approach or laparoscopic approach with or without robotic assistance) for clinically localized prostate cancer between 1994 and 2012 at a single tertiary referral center. Of these, 11,680 had available outcome and transfusion data, and 7443 met complete inclusion criteria of available clinicopathologic variables and Charlson comorbidity index (CCI). Gleason grade and pathologic stage were determined for each surgical specimen in a standardized fashion by a single group of urologic pathologists. BT data were obtained from the Pathology Data Systems of Johns Hopkins Medical Institutions. The cohort was divided into three patient groups: 1) no BT (reference, n = 2061, 27.7%); 2) autologous BT only (n = 5124, 68.8%); and 3) any allogeneic BT (with or without autologous, n = 258, 3.5%). Characteristics of these subgroups are compared in Table 1. Universal leukoreduction began in the year 2000 and was complete by 2001.19
Mortality status and cause of death information were updated using medical records after RP. Death was considered to be attributable to prostate cancer if prostate cancer was listed as the underlying cause of death or the patient had hormone-refractory metastatic disease at the time of death. Cause of death information was also sourced from the Centers for Disease Control and Prevention’s National Death Index.
Statistical analysis Comparisons of demographic and clinical factors between progression, prostate cancer death, and/or overall death statuses were based on chi-square or Fisher’s exact test. The t test or Wilcoxon rank sum test were used for continuous variables. Survival time was determined from the date of surgery until the progression or death endpoint or censoring. A multivariable Cox proportional hazards model was used to evaluate the association between transfusion type and biochemical recurrencefree survival (BRFS; PSA ≥ 0.2), CSS, and OS, while adjusting for potential confounding factors. Confounding factors were systematically identified as variables whose introduction into the multivariable model caused the hazard ratio (HR) for transfusion to change by at least 10%. Our objective was to quantify the impact (if any) of transfusion on recurrence and survival, rather than to create a prediction model. Therefore, given the small numbers of deaths in the no transfusion and allogeneic transfusion groups, parsimony dictated that the final model be limited to the transfusion variable and identified confounding factors. Additionally a subgroup analysis was performed to identify specific subsets of men in which transfusion may be associated with BRFS, CSS, or OS. In a final analysis, the number of units of transfused blood was considered to determine whether a dose–response relationship existed between number of units transfused and survival. All analyses of CSS were performed as competing risk models with any noncancer death as the competing event. The level of significance was set at 0.05 in all analyses. All statistical analyses were a priori performed using computer software (SAS, Version 9.3, SAS Institute, Cary, NC).
RESULTS Median (range) follow-up was 6 (1-18) years. Those who received any BT were significantly older (p = 0.0002); were less likely to have had recent RP (p < 0.0001); had higher preoperative PSA (p < 0.0001); had worse pathologic stage (p = 0.014); and were more likely to experience progression (p = 0.0003), die of prostate cancer (p = 0.004), or die of any cause (p < 0.0001). Body mass index, RP Gleason score, and CCI were not significantly different for transfused and nontransfused men (Table 1). Volume 54, September 2014 TRANSFUSION
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TABLE 1. Demographic and clinical characteristics of study cohort by transfusion type
Characteristic Age Number Mean (SD) Median (range) BMI (categorical)† Underweight and normal (30) RP year Number Mean (SD) Median (range) Preoperative PSA (categorical)† 0-2.5 2.6-4.0 4.1-10.0 >10.0 RP Gleason† ≤6 7 8-10 Pathologic stage† OC EPE/FCP SVI LN+ CCI† 0 1 >1 Progression† No Yes Prostate cancer death† No Yes Overall death† No Yes
Overall (n = 11,680)
No transfusion (n = 5204)
Autologous only transfusion (n = 5878)
Any allogeneic transfusion (n = 598)
p value*
7443 57.5 (6.5) 58 (33-77)
2061 57.3 (6.3) 57 (37-77)
5124 57.5 (6.5) 58 (33-75)
258 59.0 (6.4) 59 (42-73)
0.0002
2060 (27.7) 4161 (55.9) 1222 (16.4)
554 (26.9) 1157 (56.1) 350 (17.0)
1434 (28.0) 2865 (55.9) 825 (16.1)
72 (27.9) 139 (53.9) 47 (18.2)
0.720
7443 2000.2 (3.3) 2000 (1994-2007)
2061 2002.3 (2.8) 2003 (1994-2007)
5124 1999.4 (3.1) 1999 (1994-2007)
258 2000.0 (3.2) 2000 (1994-2007)
