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ADULT UROLOGY

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INFLUENCE OF BLOOD TRANSFUSIONS DURING RADICALRETROPUBIC PROSTATECTOMY ON DISEASE OUTCOME

ROGER PAUL, ROLAND SCHMID, RAYMONDE BUSCH, HEINER VAN RANDENBORGH,MICHAEL ALSCHIBAJA, STEFAN SCHÖLER, AND RUDOLF HARTUNG

ABSTRACTbjectives. Blood transfusion in patients with malignant neoplasms may alter the disease outcome becausef a theoretical immunomodulatory effect. This effect may reduce prostate-specific antigen (PSA)-free andisease-specific survival in patients with prostate cancer after radical prostatectomy. However, the results inublished studies have been contradictory, and this effect has not yet been determined.ethods. We evaluated 1412 patients after radical prostatectomy from 1984 to 2003 in a retrospective

nalysis, with a special focus on the rate and type of blood transfusions, specifically heterologous versusutologous blood. Univariate analysis and Cox regression analysis were performed to evaluate the impact oflood transfusions on disease outcome.esults. The overall transfusion rate was 56.7%. The rate dropped from 88.9% in 1988 to 9.1% in 2002.SA recurrence (greater than 0.5 ng/mL) was noted in 11.0% in patients without and in 26.0% with bloodransfusions, which was not statistically significant on Kaplan-Meier analysis. Again, no difference was notedhen patients were stratified according to the type (autologous versus heterologous) or the amount (2 U or

ess versus more than 2 U) of blood transfusion. Evaluating overall survival, again no differences were found.he established Cox regression model also proved that blood transfusions had no impact on diseaseutcome.onclusions. Our retrospective analysis did not detect any effect of blood transfusions in patients withrostate cancer after radical prostatectomy. If a negative adverse effect occurs, this effect must be minimal.owever, the infectious risk and the costs of blood transfusions should be reason enough to reduce blood

oss and the transfusion rate further in patients with prostate cancer. UROLOGY 67: 137–141, 2006. © 2006lsevier Inc.

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n 1981, the nephrologist Clarence C. Gantt hy-pothesized that blood transfusions may influ-

nce the immune system.1 This effect may alter theisease outcome of neoplasms in that patients withlood transfusions may demonstrate a poorer prog-osis compared with patients without blood trans-usions. One major complication of radical retro-ubic prostatectomy is blood loss and the risk oflood transfusions. Several reports have evaluatedhe effect of blood transfusions in patients withrostate cancer; however, their results have not

rom the Department of Urology and Institute of Medical Statis-ics and Epidemiology, Technischen Universität München, Klini-um rechts der Isar, Munich, GermanyReprint requests: Roger Paul, M.D., Department of Urology,

echnische Universität München, Klinikum rechts der Isar, Is-aninger Strasse 22, Munich 81675, Germany. E-mail: R.Paul@

rz.tu-muenchen.deSubmitted: April 21, 2005, accepted (with revisions): July 12,

o005

2006 ELSEVIER INC.LL RIGHTS RESERVED

een conclusive. Some reports have demonstratednegative influence of blood transfusions2 and

thers have demonstrated no such effect.3 We triedo evaluate this hypothetic influence in our largeohort of patients with prostate carcinoma.

MATERIAL AND METHODS

We evaluated, in a retrospective analysis, 1412 patients whoad undergone radical retropubic prostatectomy from 1984 to003 at our institution for localized prostate cancer. Radicalrostatectomy was performed by 15 surgeons during this pe-iod, with one surgeon (R.H.) performing 718 (50.8%).

For all patients, the medical records were reviewed regard-ng preoperative screening parameters, histologic findings,nd blood transfusions done during and after radical retropu-ic prostatectomy. Recent follow-up data were obtained, withpecial focus on postoperative PSA values, local recurrence,nd survival. We analyzed three groups of patients. Patientsithout blood transfusions, patients with heterologous blood

ransfusions, and patients with autologous blood transfusions

nly. The heterologous blood transfusion and autologous

0090-4295/06/$32.00doi:10.1016/j.urology.2005.07.020 137

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lood transfusion only groups were also analyzed together.e investigated the influence of blood transfusions on PSA-

ree survival—defined as an elevated serum PSA level greaterhan the cutoff value of 0.5 ng/mL. We also considered localecurrence-free survival, defined as either histologicallyroven local recurrence or, in the case of suspicion of localecurrence and local radiotherapy, if decreasing PSA valuesfter radiotherapy were noted. Metastasis-free survival wasetermined if bone or visceral metastasis was detected by bonecan or computed tomography. Disease-specific and overallurvival were also calculated.

Statistical analysis was done using the Statistical Package forocial Sciences, version 11.5, software to test for differences inhe subgroups using the chi-square test for categorical param-ters and the Mann-Whitney U test for continuous variables.aplan-Meier analysis and log-rank test were used to evaluate

or disease outcome. The statistical power was calculated forhe sample size at 95% for a 10% difference at 120 monthsNumbers Cruncher Statistical System-Power Analysis andample Size statistical software, release October 2003,aysville, Utah). A Cox regression model was established forultivariate analysis of disease outcome. Statistical signifi-

ance was accepted at 5% (P � 0.05).

RESULTS

ATIENT COHORT

Altogether 1412 patients with radical prostatec-omy from 1984 to 2003 were included in our ret-ospective analysis. The patient characteristics areummarized in Table I. Of the 1412 patients, 80156.7%) received intraoperative and/or perioperativelood transfusions. Of the 141 (10.0%) patients whoeceived autologous blood transfusions, 45 (3.2%)eceived autologous blood only. A total of 756 pa-ients (53.5%) received heterologous blood transfu-ions, including 96 patients (6.8%) who receivedoth autologous and heterologous transfusions (Fig.A). We also stratified our patients according tohe amount of erythrocyte concentrates periopera-ively, because patients requiring massive transfu-ion (three or more concentrates) may have a moreompromised immune system than patients with aower transfusion (two or fewer concentrates) re-uirement. Of 1294 patients, 392 (30.3%) receivedhree or more erythrocyte concentrates and 90269.7%) received two or less. A dramatic change inhe transfusion rate was seen over time, rangingrom 88.9% in 1988 to 9.1% in 2003 (Fig. 1B),emonstrating improvement in the surgical tech-

TABLE I. Patiearameter Total wo/B

ge (yr) 64.7 64.1ollow-up time (mo) 58.2 35.5edian PSA (ng/mL) 9.0 8.0rgan-confined disease (%) 63.3 69.6

EY: wo/B � without blood transfusions; w/B � with blood transfusions; w/aB � wtatistically significant differences between patients with and without transfusions e

ique over time. The actual transfusion rate t

38

ropped for a single experienced surgeon (R.H.)or nerve-sparing radical prostatectomy to only.3% in 2003. The mean follow-up time was 58.2onths (median 50.5). A significant difference was

ound in the follow-up time of patients with heter-logous or autologous blood transfusions (73.8onths) and patients without blood transfusions

35.5 months) owing to the high transfusion raten the early cases.

SA-FREE SURVIVAL

PSA recurrence was defined as PSA progressionreater than 0.5 ng/mL. We did not use a lower PSAutoff because of the lack of sensitivity of early PSAssays. A postoperative PSA value was available for294 (91.6%) of 1412 patients. Of these, 21616.7%) demonstrated PSA progression to greater

IGURE 1. Blood transfusions in patients with radicalrostatectomy demonstrating (A) distribution of ratend type of blood transfusion for all patients (n � 1412)nd (B) dramatic change in rate of blood transfusionver time for single surgeon (R.H.). w/aB � with autol-gous blood transfusions; wo/B � without blood trans-usions; w/hB � with heterologous blood transfusions.

characteristicsw/B w/aB w/hB P Value

65.3 62.1 65.4 0.000373.8 61.6 74.5 �0.000110.1 6.3 10.3 �0.000158.5 72.1 57.7 �0.0001

ologous blood transfusions; w/hB � with heterologous blood transfusions.ed by chi-square and Mann-Whitney U tests.

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han 0.5 ng/mL. Of the 528 patients without blood

UROLOGY 67 (1), 2006

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ransfusions and 766 with heterologous or autolo-ous blood transfusions, 58 (11.0%) and 15820.6%) experienced PSA progression, respec-ively. Kaplan-Meier analysis and log-rank testingf patients with and without blood transfusionsFig. 2A) demonstrated no difference in PSA-free

IGURE 2. PSA-free survival in patients after radicalrostatectomy demonstrating (A) no difference for pa-ients with and without blood transfusions and (B) nonfluence by amount of blood transfused (two or lessersus three or more units) and (C) type of blood trans-usion. wo/B � without blood transfusions; w/aB � withutologous blood transfusions; w/hB � with heterolo-ous blood transfusions.

urvival (P � 0.53), owing to the difference in fol- f

ROLOGY 67 (1), 2006

ow-up time (Table I). We also tried to correlateSA-free survival with the amount of blood trans-

used. For patients with two or less and three orore erythrocyte concentrates perioperatively, we

lso could not detect a statistically significant dif-erence (log-rank test, P � 0.53; Fig. 2B). Finally,e stratified our patients according to those withoutlood transfusion, with autologous blood transfu-ions, and with heterologous blood transfusions.gain, we did not detect any statistically significantifferences (log-rank test, P � 0.37; Fig. 2C).For patients with and without blood transfu-

ions, we performed several subgroup analyses toorrect for differences resulting from the greaterransfusion rate in the early series. Consideringrgan-confined prostate cancer only (Stage pT2br less), no difference was found in Kaplan-Meiernalysis (log-rank test, P � 0.36). The same resultas found for prostate carcinoma with capsularenetration (Stage pT3a, P � 0.82) and locally ad-anced disease (Stage pT3b or worse, P � 0.27).onsidering the data for different surgeons, we

ound a difference regarding the rate of bloodransfusions, but not for PSA-free survival betweenatients with and without blood transfusions for aingle surgeon. All other subgroup analyses strati-ed by grade, PSA range, and age did not reveal anyifferences (data not shown).

OCAL RECURRENCE-FREE SURVIVAL

Local recurrence was defined as either histolog-cally proven local recurrence or, in the case ofuspicion of local recurrence and local radiother-py, if dropping PSA values after radiotherapy wereoted. Local recurrence developed in 37 (2.9%) of294 patients. Of the patients with blood transfu-ions, 3.8% experienced local recurrence and 1.5%f patients without blood transfusions did so. Thisifference did not reach statistical significance byaplan-Meier analysis and log-rank test (P �.50). Analyses stratified according to the amountf blood transfusions (log-rank test, P � 0.39) andype of transfusion (log-rank test, P � 0.76) alsoemonstrated no difference (data not shown).

ETASTASIS-FREE SURVIVAL

We investigated metastasis-free survival in ouratient cohort. Of the 1294 patients, 53 (4.1%)emonstrated confirmed metastases during the fol-ow-up period. In accordance with the above find-ngs, no statistically significant difference wasound by Kaplan-Meier analysis or log-rank test foratients with and without blood transfusions (P �.76) or according to the amount or type of trans-

usion.

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VERALL SURVIVAL

Survival data were available for 1303 patients. Ofhe 1303 patients, 129 (9.9%) died during the fol-ow-up period; 13.2% of patients with and 5.1% ofatients without blood transfusions died. Kaplan-eier analysis (Fig. 3) and the log-rank test proved

hat this difference was not statistically significantP � 0.99). The difference can be explained by theifferences in the follow-up time for these tworoups. No difference was found when the dataere stratified according to the amount (log-rank

est, P � 0.41) or type of transfusion (log-rank test,� 0.33). Regarding tumor-specific survival, 1297atients had data available for analysis, and 362.8%) had died of prostate cancer. As with overallurvival, no difference was found according to typer amount of transfusion (data not shown).

OX REGRESSION ANALYSIS FOR PSA RECURRENCE

We established a Cox regression model with pre-perative and perioperative parameters to estab-ish a multivariate analysis of risk factors for PSAecurrence. In addition to blood transfusion, wenvestigated digital rectal examination findings,ransrectal ultrasound results, PSA value at diag-osis, age, use of neoadjuvant hormonal ther-py, surgeon, type of operation (nerve sparingersus non-nerve sparing), tumor stage, N stage,orld Health Organization grade, and surgicalargin status. In our patient cohort, we identified

nly two independent prognostic parameters, tu-or stage and World Health Organization grade.erioperative blood transfusion was not an inde-endent prognostic parameter of PSA recurrence.he use of blood transfusions also did not showny prognostic power for our model of local recur-

IGURE 3. Overall survival of patients after radicalrostatectomy for those with (w/B) and without (wo/B)lood transfusions.

ence, metastasis, or survival (data not shown). g

40

COMMENT

Several published reports have raised concernsbout a negative prognostic impact of blood trans-usions on a variety of cancers, including lungancer,4,5 gastrointestinal cancer,6,7 head-and-neckancer,8 and breast cancer.9 The question ishether these effects are related to the morbidity of

dvanced tumor stages7 and the infectious risk ofeterologous blood transfusion or whether a dele-erious immunomodulatory effect is present as haseen proposed.10 The results have been contradic-ory, with some reports emphasizing the long-termnfluence on survival of blood transfusion in pa-ients with cancer according to data from multivar-ate analyses.5,8 Other studies have not been able toemonstrate an independent influence of bloodransfusion in their patient cohort.4 The influencef blood transfusion may be related to the amountf transfusion8 or the type of transfusion, if heter-logous blood has been used.6We were interested in the influence of blood

ransfusions on disease outcome in patients withrostate cancer after radical prostatectomy becauselood loss and transfusion requirement in radicalrostatectomy can still be regarded as significant, al-hough the rate of blood transfusions has droppedramatically with time. At our institution, we ob-erved a blood transfusion rate of 86.8% from 1984 to990 and only 9.1% in 2003, about the rate reportedn published studies.11 This reduction in the rate oflood transfusions for radical prostatectomy can bexplained by the marked improvement in surgicalechnique with time and a more conservative ap-roach regarding the indication for blood transfu-ions. The transfusion rate for a single experiencedurgeon at our institution for nerve-sparing radicalrostatectomy was only 6.3% recently. Providing au-ologous blood transfusion for all patients scheduledor radical prostatectomy no longer seems to be use-ul.11 However, different techniques have been sug-ested to reduce blood loss during radical prostatec-omy12,13 and may be mandatory if the prognosis ofatients could be improved.Whether an influence of blood transfusion on

he prognosis of patients undergoing radical pros-atectomy is still unclear. A possible negative influ-nce of blood transfusion in patients with prostateancer has been suggested in different studies.14–16

Davies et al.16 demonstrated the adverse outcomef patients undergoing transurethral resection ofhe prostate and radiotherapy for prostate cancer.atients with blood transfusions had a 5-year sur-ival rate of only 17% compared with 66% for pa-ients without blood transfusions. The Cox regres-ion model demonstrated that blood transfusionas an independent prognostic parameter, sug-

esting a negative immunomodulatory effect in

UROLOGY 67 (1), 2006

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rostate cancer. Heal et al.14 reported an increasedisk of tumor recurrence and prostate cancer-specificeath rate after radical prostatectomy in patients withlood transfusions.However, most of the published reports address-

ng this problem could not answer this questionecause their patient cohort was too small15 or wasnhomogeneous.14 One retrospective study17 fromhe Mayo Clinic from 1994, with a large cohort ofatients (n � 1785), reported no difference in dis-ase outcome for patients with and without bloodransfusions. However, that study had significantifferences compared with our analysis. The pa-ients from the Mayo Clinic were treated in there-PSA era (1966 to 1987), and our patient cohortnderwent treatment between 1984 and 2003. Theransfusion rate at the Mayo Clinic was 75.9%, butn our series it had decreased to 56.7%. Therefore,e believe that a small adverse prognostic effect oflood transfusions may have been missed in theeport by Velagapudi et al.17 However, even in ourore recent and more homogeneous patient co-ort, we could not detect any differences. A moreecent study by Oefelein et al.18 reported in 1995hat a blood loss of more than 2000 mL duringadical prostatectomy, but not the blood transfu-ion, had a negative impact on PSA-free survival.owever, only 251 patients were included in their

nalysis. It is obvious that blood loss and bloodransfusion correlate; therefore, the study by Oefe-ein et al.18 and our results suggest that in patientsith more advanced tumors, the blood transfusion

ate will be greater. This hypothesis may explainhy small-size and older studies described a sur-ival disadvantage for patients who received bloodransfusions.

CONCLUSIONS

Our analysis did not detect any influence of bloodransfusion on disease outcome in patients with pros-ate cancer after radical prostatectomy, regardlessf the type of blood transfusions—autologous oreterologous—or the amount of blood transfused,r tumor stage. If a negative influence of bloodransfusions by an immunomodulatory effect ex-sts, this effect must be minimal.10,19 Although weould not find an adverse disease outcome, the in-ectious potential of blood transfusions and theosts should be reason enough for additional ef-orts to reduce the blood loss and transfusion rate

n patients with prostate cancer. n

ROLOGY 67 (1), 2006

REFERENCES1. Gantt CL: Red blood cells for cancer patients. Lancet

242: 363, 1981.2. Landers DF, Hill GE, Wong KC, et al: Blood transfusion-

nduced immunomodulation. Anesth Analg 82: 187–204, 1996.3. Eickhoff JH, Gote H, and Baeck J: Peri-operative blood

ransfusion in relation to tumor recurrence and death afterurgery for prostatic cancer. Br J Urol 68: 608–611, 1991.

4. Ghosh S, Ahmed K, Hopkinson DN, et al: Pulmonarydenocarcinoma is associated with poor long-term survivalfter surgical resection: effect of allogeneic blood transfusion.ancer 101: 2058–2066, 2004.

5. Nosotti M, Rebulla P, Riccardi D, et al: Correlation be-ween perioperative blood transfusion and prognosis of pa-ients subjected to surgery for stage I lung cancer. Chest 124:02–107, 2003.

6. Motoyama S, Okuyama M, Kitamura M, et al: Use ofutologous instead of allogeneic blood transfusion duringsophagectomy prolongs disease-free survival among patientsith recurrent esophageal cancer. J Surg Oncol 87: 26–31,004.

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8. Taniguchi Y, and Okura M: Prognostic significance oferioperative blood transfusion in oral cavity squamous cellarcinoma. Head Neck 25: 931–936, 2003.

9. Tartter PI, Burrows L, Papatestas AE, et al: Periopera-ive blood transfusion has prognostic significance for breastancer. Surgery 97: 225–230, 1985.

10. Vamvakas EC, and Blajchman MA: Deleterious clinicalffects of transfusion-associated immunomodulation: fact orction? Blood 97: 1180–1195, 2003.11. Nuttall GA, Cragun MD, Hill DL, et al: Radical retropu-

ic prostatectomy and blood transfusion. Mayo Clin Proc 77:301–1305, 2002.12. Davis M, Sofer M, Gomez-Marin O, et al: The use of cell

alvage during radical retropubic prostatectomy: does it influ-nce cancer recurrence? BJU Int 91: 474–476, 2003.

13. Boldt J, Weber A, Mailer K, et al: Acute normovolaemicaemodilution vs controlled hypotension for reducing the usef allogeneic blood in patients undergoing radical prostatec-omy. Br J Anaesth 82: 170–174, 1999.

14. Heal JM, Chuang C, and Blumberg N: Perioperativelood transfusions and prostate cancer recurrence and sur-ival. Am J Surg 156: 374–380, 1988.

15. Ness PM, Walsh PC, Zahurak M, et al: Prostate cancerecurrence in radical surgery patients receiving autologous oromologous blood. Transfusion 32: 31–36, 1992.16. Davies AH, Ramarakha P, Cranston D, et al: Effect of

lood transfusion on survival after radiotherapy as treatmentor carcinoma of the prostate. Ann R Coll Surg Engl 73: 116–18, 1991.17. Velagapudi SR, Frydenberg ME, Osterling JE, et al: Ho-ologous blood transfusion in patients with prostate cancer:o effect on tumor progression or survival. Urology 43: 821–27, 1994.18. Oefelein MG, Colangelo LA, Redemaker AW, et al: In-

raoperative blood and prognosis in prostate cancer patientsndergoing radical retropubic prostatectomy. J Urol 154:42–447, 1995.19. Blajchman MA: Immunomodulatory effects of alloge-

eic blood transfusions: clinical manifestations and mecha-

isms. Vox Sang 74S2: 315–319, 1998.

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