Does Perioperative Blood Transfusion Affect Survival in Patients With Cervical Cancer Treated With Radical Hysterectomy? BRADLEY J. MONK, MD, KRISHNANSU TEWARI, MD, GISELA GAMBOA-VUJICIC, ROBERT A. BURGER, MD, ALBERTO MANETTA, MD, AND MICHAEL L. BERMAN, MD Objective: To determine if blood transfusions during or after radical hysterectomy adversely affect survival in patients with invasive cervical carcinoma. Methods: Two hundred eighty-three women with stage IA2-IIA cervical cancer were treated with radical hysterectomy and pelvic lymphadenectomy from 1980-1989. Thirteen were lost to follow-up, and five others received adjuvant chemotherapy. Among the remaining 265 patients, 131 were given blood transfusions during surgery or within 30 days, whereas 134 were not. The clinical and pathologic characteristics of these two groups were reviewed and analyzed statistically. Results: Transfused and nontransfused patients did not differ with respect to mean age (45.0 versus 43.4 years, respectively), stage, grade, cell type, depth of invasion, or prevalence of nodal metastasis. Transfused patients more frequently received adjuvant pelvic irradiation than did nontransfused (47 versus 33%, respectively, ~ P < .05). After a mean follow-up of 51 months (range 13--125), 19 women (14%) in each group were diagnosed as having recurrent disease, predominantly in the pelvis. Using life-table analysis, the calculated 5-year survival was 86% for transfused and 84% for nontransfused patients, a nonsignificant difference. Disease-free survival was also similar. In the study population, grade, depth of invasion, and nodal status predicted survival. When patients were stratified according to age, cell type, stage, depth of invasion, nodal involvement, and use of adjuvant radiation, blood transfusion still did not adversely influence survival. Using the Cox proportional hazards model, only nodal status was an independent predictor of death. Conclusion: Perioperative blood transfusion does not impact overall survival or time to recurrence after radical hysterectomy. (Obstet Gynecol 1995;85:343--8) From the Division of GynecologicOncology, Department of Obstetrics and Gynecology, University of California Irvine Medical Center, Orange, California. The authors wish to thank Tom Kurosaki, MS, for assistance in statistical analysis, CharlesNguyen and Hassan Borazjanifor assistance in data collection, and Amber Aubert of the U.C.I. Cancer Registry.
VOL. 85, NO. 3, MARCH 1995
Since the initial reports linking blood transfusion to improved cadaveric renal transplant survival, more than 400 publications, including several randomized, controlled studies, have demonstrated a beneficial immunosuppressive effect of pretransplant blood transfusion on graft survival. 1 Based on these data, Gantt hypothesized that patients with malignant neoplasms who receive perioperative blood transfusions might be at increased risk for tumor recurrence (Gantt CL. Red blood cells for cancer patients [letter]. Lancet 1981;ii: 363). The mechanism of transfusion-induced immunosuppression is thought to be multifactorial, including an increase in the number and activity of suppressor T lymphocytes, a decrease in natural killer-cell activity, an impairment of lymphocyte blastogenesis, and a stimulation of anti-idiotype antibody production. 2 The cellular components of transfused blood are largely responsible for the immunomodulatory effects of transfusion, particularly in renal transplantation; however, other components, including plasma protein fractions, may also impair immune fl,u'lction. 3 The nonspecific immunosuppressive effect of blood transfusion provides a theoretical basis for the hypothesis that transfusion associated with cancer surgery might adversely affect prognosis. Unfortunately, studies2'4 investigating this hypothesis have usually been retrospective and have not controlled for prognostic variables such as tumor volume, which makes their interpretation difficult. Nevertheless, many such studies, 2-7 particularly those involving patients with softtissue sarcomas, colorectal cancers, and lung cancers, have consistently reported that perioperative blood transfusion is associated with a worsened prognosis. Relatively few clinical data exist that address the impact of blood transfusion on survival among women with cervical cancer. One such study s of 126 patients with stage IB cervical carcinoma treated with radical
0029-7844/95/$9.50 343 0029-7844(94)00398-W
hysterectomy and pelvic lymphadenectomy and found to have negative nodes and clear margins, reported four times as many recurrences with perioperative transfusion than without (14.7 versus 3.4%). Unfortunately, the statistical methods used (Soper JT, Berchuck A, ClarkePearson DL. The clinical significance of blood transfusion at the time of radical hysterectomy [letter]. Obstet Gynecol 1990;6:110-3), the unique subset of stage IB patients studied, and the lack of confirmation by other investigators 9'1° call into question the validity of these data. To better define the prognostic significance of perioperative blood transfusion associated with radical hysterectomy and pelvic lymphadenectomy, we reviewed our 10-year experience with 283 unselected stage I and IIA cervical carcinoma patients using lifetable and multivariate analysis.
Materials and Methods From January 1980 through December 1989, 364 patients with International Federation of Gynecology and Obstetrics stage IA2, IB, and IIA cervical carcinoma were treated at the University of California Irvine Medical Center and Long Beach Memorial Medical Center. Two hundred eighty-three (78%) underwent Wertheim or Meigs radical hysterectomy with bilateral pelvic lymph node dissection as primary therapy. 11 Patients felt to be at high risk for pelvic recurrence because of deep (outer one-third) cervical stromal invasion, parametrial extension (including involved margins), or lymph node metastasis received adjuvant postoperative external beam irradiation as previously described) 2 Transfusions of packed red blood cells were administered if the hematocrit was 24% or less or, in the presence of persistent symptomatology or hemodynamic compromise, if the hematocrit was 30% or less. All transfused patients received allogeneic blood. Surveillance for recurrent disease usually consisted of physical examinations and Papanicolaou smears every 3 months for 2 years and semiannually thereafter. All recurrences were proven pathologically or radiographically, and salvage therapy was instituted when appropriate. Follow-up information was obtained from the tumor registries, office records, telephone contact with patients, and information from referring physicians. Statistics were compiled and analyzed using the SAS software program (Version 6; SAS Institute, Inc., Cary, NC). Survival curves were calculated using the KaplanMeier method. The statistical method used to determine a significant difference in the comparison of survival curves was the log-rank test. Chi-square analysis was used to compare proportions. Patients who died of
344 Monk et al
Hysterectomy and Transfusion
Table 1. Histopathologic and Clinical Variables* N Mean age (y) Stage IA2 IB IIA Histology Squamous Other Grade Well-differentiated Moderately differentiated Poorly differentiated Depth of invasion (mm) 0-5 6-10 >-11 Nodal metastasis Absent Present
5 (3.8%) 115 (87.8%) 11 (8.4%)
10 (7.5%) 116 (86.6%) 8 (6.0%)
83 (63.4%) 48 (36.6%)
80 (59.7%) 54 (40.3%)
23 (17.6%) 69 (52.7%) 39 (29.8%)
27 (20.2%) 64 (47.8%) 43 (32.1%)
48 (36.6%) 41 (31.3%) 42 (32.1%)
66 (49.3%) 39 (29.1%) 29 (21.6%)
106 (80.9%) 25 (19.1%)
111 (82.8%) 23 (17.2%)
*None of the differencesbetween the two groups were statistically significant.
causes other than cervical cancer were censored at the time of death during life-table analysis. Using the Cox proportional hazards method, a multivariate analysis was performed to independently control for transfusion status, adjuvant irradiation, depth of tumor invasion, nodal metastasis, and tumor grade. P ~ .05 was considered significant for all tests.
Results Two hundred sixty-five of the 283 patients were followed for a mean of 51 months (range 13-125). Eighteen patients were excluded; these included 13 women who received their postoperative care elsewhere and were lost to follow-up and five who received adjuvant cytotoxic chemotherapy. The mean age of the 265 patients in the study was 44.2 years (standard deviation [SD] 13.1, range 19-80). One hundred thirty-one women underwent perioperative blood transfusion(s) within 30 days of surgery, whereas 134 received no blood or blood products. The mean ages for the transfused and the nontransfused groups were 45.0 (SD 13.4, range 19-80) and 43.4 years (SD 12.7, range 19-80), respectively. The two groups did not differ with respect to mean age, stage, cell type, grade, depth of invasion, nodal involvement, length of follow-up, and frequency or site of recurrence (Tables 1 and 2). However, the mean estimated surgical blood loss was greater among transfused patients (1321 mL, SD 780, range 250-5000) compared with those not transfused (644 mL, SD 309, range 100-2000). Although the transfused and non-
Obstetrics & Gynecology
Table 2. Clinical Characteristics*
N 131 134 Estimated blood 1321 644 loss (mL) No. of units transfused 0 134 1-2 83 (63.4%) 3-11 48 (36.6%) Average months of 51.2 49.9 follow-up (SD 26.9, range 13-119) (SD 26.3, range 16-125) Adjuvant pelvic irradiation Yes 61 (46.6%) 44 (32.8%) No 70 (53.4%) 90 (67.2%) Recurrence Yes 19 (14.5%) 19 (14.2%) No 112 (85.5%) 115 (85.8%) Site of recurrence Pelvis 12 (63.2%) 12 (63.2%) Distant 6 (31.6%) 3 (15.8%) Both 1 (5.3%) 4 (21.1%) Status Alive 112 (85.5%) 118 (88.1%) Dead 19 (14.5%) 16 (11.9%) Cause of death Cancer 12 (63.2%) 12 (75.0%) Other 7 (36.8%) 4 (25.0%) SD = standard deviation. *Except for differencesin blood loss and adjuvant radiation, there were no statistically significant differences between the two groups.
transfused g r o u p s o n l y differed with respect to the a m o u n t of intraoperative blood loss, w h e n the g r o u p s were a n a l y z e d as a whole, there were m o r e patients w i t h a n i n d i c a t i o n for a d j u v a n t r a d i o t h e r a p y in the t r a n s f u s e d g r o u p than a m o n g n o n t r a n s f u s e d patients (47 versus 33%, ~ P < .05). Thus, m o r e patients w h o received b l o o d t r a n s f u s i o n s had a single i n d i c a t i o n for r a d i a t i o n (ie, n o d a l metastasis or d e e p l y i n v a s i v e tumors). This w o u l d account for the increase i n the n u m b e r of irradiated patients in this g r o u p c o m p a r e d with the n o n t r a n s f u s e d patients w h o f r e q u e n t l y had m u l t i p l e indications (ie, n o d a l metastasis a n d d e e p l y i n v a s i v e tumors) for radiotherapy. U s i n g life-table analysis, the calculated 5-year survival rate was 86% for t r a n s f u s e d a n d 84% for n o n t r a n s fused patients (Table 3). Five-year disease-free s u r v i v a l was also similar (85 a n d 82%, respectively, P = .96). U n i v a r i a t e analysis d e m o n s t r a t e d grade, d e p t h of invasion, a n d n o d a l status to predict survival, whereas the n u m b e r of u n i t s transfused, age, histologic cell type, a n d stage did n o t (Table 3). W h e n patients were stratified according to age, cell type, grade, d e p t h of invasion, n o d a l i n v o l v e m e n t , a n d use of a d j u v a n t radiation,
VOL. 85, NO. 3, MARCH 1995
Table 3. Life-Table Analysis According to Clinical and Histopathologic Variables
Calculated 5-year survival Transfusion Yes No Units transfused 1-2 3-11 Age (y) ~35 >35 Histology Squamous Other Grade I and II III Depth of invasion (mm) 0-10 ~11 Nodal metastasis Present Absent
blood t r a n s f u s i o n still did n o t adversely influence survival (Table 4). U s i n g the Cox p r o p o r t i o n a l h a z a r d s model, o n l y n o d a l status w a s a n i n d e p e n d e n t predictor of recurrence a n d death.
Table 4. Life-Table Analysis According to Clinical and Histopathologie Variables Stratified According to Transfusion
Calculated 5-year survival
Age (y) ---35 >35 Histology Squamous Other Grade I and II III Depth of invasion (ram) 0-10 ---11 Nodal metastasis Present Absent Adjuvant radiation No Yes
Monk et al
0.9 1 0.8 ~ H
Figure 1. Life-tableanalysis of pa-
tients with stage IA2, IB, and IIA cervical carcinomatreated with radical hysterectomyand pelvic lymphadenectomy, showing no difference in overallsurvivalbetween 131 transfused and 134nontransfusedpatients.
60 80 Time (Months)
Discussion The etiologic agent for cervical cancer is believed to be the h u m a n papillomavirus (HPV) because approximately 90% of all cervical cancers harbor HPV DNA. 13 Although type-specific HPV D N A can confer biologic heterogeneity to the cancers it induces, 14 the variability in the progression of this disease a m o n g individuals is poorly understood, and a variety of factors influence prognosis. Histopathologic factors alone have been relatively insensitive in predicting the clinical outcome a m o n g patients treated with radical hysterectomy and pelvic lymphadenectomy.l 1,12 Some of the differences in clinical outcome m a y be explained by alterations in host i m m u n e function rather than by histopathologic changes or intrinsic differences in tumor biology. For example, impairment of cell-mediated immunity in patients with cervical cancer has been associated with advanced stages of disease 15"16 and rapid disease progression. 17 Because blood transfusions impair host i m m u n e function, it is reasonable to infer that perioperative transfusion-related i m m u n o s u p p r e s s i o n could adversely affect the risk of recurrence a m o n g patients with stage I and IIA cervical cancer treated with radical hysterectomy. However, in the current series, no such impact on outcome could be detected, supporting the observations of other investigators (Soper JT, et al. Obstet Gynecol 1990;6:110-3). 9 A type II statistical error
346 M o n k et al
Hysterectomy and Transfusion
could explain the inability to demonstrate a negative influence on survival after aUogeneic transfusion. However, with the number of subjects in the current report and an alpha level of 0.05, one could expect only a 10% likelihood of missing a difference in survival distribution using a one-tailed test, even if the ratio of the survival estimates of the two study groups was as high as 1.5. If the ratio of the median survivals were smaller, the power would also decrease and a larger study would be necessary to detect a difference in survival. Despite this argument, the remarkably similar survival curves (Figure 1) of the two groups studied strongly support an absence of an adverse impact of transfusion on the survival of these women. The i m m u n o s u p p r e s s i v e effects of perioperative blood transfusion m a y be clinically significant in only certain types of cancers, providing a possible explanation for the lack of prognostic significance of perioperative transfusion a m o n g w o m e n with cervical cancer and a marked effect with other cancer types. For example, the c o m m o n route of metastatic spread of cervical malignancies via the lymphatics might help avoid an adverse effect of transfusion seen with soft-tissue sarcomas, colorectal cancers, and lung cancers, which commonly spread hematogenously. Thus, immunosuppression after allogeneic transfusion m a y allow blood-borne tumor cells (which would otherwise be destroyed by host defenses) to form metastatic foci, whereas cervical cancer cells embolizing to l y m p h nodes during intraop-
Obstetrics & Gynecology
erative m a n i p u l a t i o n to t h e ~ r n o r m a y b e r e l a t i v e l y unaffected b y t r a n s i e n t c h a n g e s in i m m u n e function. This is consistent w i t h m a n y of the r e t r o s p e c t i v e s t u d ies 2-7 that d e m o n s t r a t e a n e g a t i v e i m p a c t on s u r v i v a l after t r a n s f u s i o n s associated w i t h o p e r a t i o n s for m a n y solid t u m o r s . Recently, Busch et aP 8 r e p o r t e d the first p r o s p e c t i v e m u l t i - i n s t i t u t i o n a l s t u d y i n v e s t i g a t i n g the p r o g n o s t i c significance of p e r i o p e r a t i v e b l o o d t r a n s f u s i o n in a solid tumor. F o u r h u n d r e d s e v e n t y - f i v e p a t i e n t s w i t h colorectal cancer u n d e r g o i n g p o t e n t i a l l y c u r a t i v e resection w e r e r a n d o m i z e d to receive a u t o l o g o u s v e r s u s allogeneic p e r i o p e r a t i v e b l o o d t r a n s f u s i o n w h e n clinically indicated. There w a s no significant difference in 4-year, cancer-specific s u r v i v a l rates b e t w e e n the allogeneic t r a n s f u s i o n g r o u p a n d the a u t o l o g o u s transfusion g r o u p . N e v e r t h e l e s s , p a t i e n t s w h o r e c e i v e d a n y b l o o d transfusions, either aUogeneic or a u t o l o g o u s , h a d a 2.1 (P = .01) a n d 1.8 (P -- .04) relative risk of recurrence, respectively, c o m p a r e d w i t h p a t i e n t s w h o d i d n o t r e q u i r e b l o o d transfusion. The m o s t likely e x p l a n a t i o n for this f i n d i n g is a n a b s e n c e of a c a u s a l relationship between blood transfusion and prognosis in p a t i e n t s w i t h colorectal cancer a n d p e r h a p s o t h e r solid t u m o r s as well. A l t e r n a t i v e l y , a u t o l o g o u s b l o o d m i g h t i n d u c e the s a m e i m m u n o s u p p r e s s i v e effects as allogeneic b l o o d , a n o b s e r v a t i o n n o t s u b s t a n t i a t e d in a n i m a l testing. In t u m o r - b e a r i n g a n i m a l s in w h i c h allogeneic t r a n s f u s i o n s h a d an a d v e r s e effect on d i s e a s e o u t c o m e , the s a m e effect c o u l d n o t b e r e p r o d u c e d w i t h the a d m i n i s t r a t i o n of s y n g e n e i c b l o o d . 19 The f i n d i n g s of o t h e r r e t r o s p e c t i v e s t u d i e s 2-8 in w h i c h b l o o d t r a n s f u s i o n w a s s h o w n to b e a d e t e r m i n a n t of r e l a t i v e l y p o o r p r o g n o s i s m a y be d u e to c o n f o u n d i n g variables, such as p a t i e n t selection, r a t h e r t h a n transfusion-associated i m m u n o m o d u l a t i o n . It is conceivable that the w o r s e clinical o u t c o m e r e p o r t e d in t r a n s f u s e d p a t i e n t s m i g h t n o t b e a result of b l o o d t r a n s f u s i o n itself, b u t r a t h e r the result of c i r c u m s t a n c e s that necessitate transfusion. F o r e x a m p l e , p a t i e n t s w i t h m o r e a d v a n c e d lesions m a y r e q u i r e t r a n s f u s i o n m o r e often than those w i t h s m a l l e r lesions b e c a u s e larger t u m o r s a r e m o r e likely to b e a s s o c i a t e d w i t h t u m o r - a s s o c i a t e d a n e m i a (ie, intestinal b l e e d i n g f r o m a large colon cancer) a n d r e q u i r e larger o p e r a t i o n s w i t h c o n c o m i t a n t increases in i n t r a o p e r a t i v e b l o o d loss. In a d d i t i o n , o b e s i t y h a s b e e n s h o w n to be associated w i t h i n c r e a s e d b l o o d loss 2°'21 a n d a h i g h e r t r a n s f u s i o n rate 21 d u r i n g r a d i c a l hysterect o m y for stage ! a n d IIA cervical cancer. It is i n t e r e s t i n g that obese p a t i e n t s w h o m o r e f r e q u e n t l y r e q u i r e p e r i o p e r a t i v e t r a n s f u s i o n s e e m to b e at no i n c r e a s e d risk of recurrence c o m p a r e d w i t h p a t i e n t s of n o r m a l w e i g h t w h o are not t r a n s f u s e d , s u p p o r t i n g o u r f i n d i n g that b l o o d t r a n s f u s i o n associated w i t h r a d i c a l h y s t e r e c t o m y
VOL. 85, NO. 3, MARCH 1995
d o e s n o t affect clinical o u t c o m e a m o n g p a t i e n t s w i t h cervical carcinoma. 2°'21
References 1. Opetlz G. Current relevance of the transfusion effect in renal transplantation. Transplant Proc 1985;70:357-60. 2. Wu I-IS, Little AG. Perioperative blood transfusions and cancer recurrence. J Clin Oncol 1988;6:1348-54. 3. Marsh J, Donnan PT, Hamer-Hodges DW. Association between transfusion with plasma and the recurrence of colorectal carcinoma. Br J Surg 1990;77:62,%6. 4. Francis DMA. Relationship between blood transfusion and tumor behavior. Br J Surg 1991;78:1420-8. 5. Rosenberg SA, Seipp CA, White DE, Wesley R. Perioperative blood transfusions are associated with increased rates of recurrence and decreased survival in patients with high-grade soft-tissue sarcomas of the extremities. J Clin Oncol 1985;3:698-709. 6. Beynon J, Davies PW BJ, Billings PJ, et al. Perioperative blood transfusion increases the risk of recurrence in colorectal cancer. Dis Colon Rectum 1989;29:975-9. 7. Tartter PI, Burrows L, Kirschner P. Perioperative blood transfusion adversely affects prognosis after resection of stage I (subset NO) non-oat cell lung cancer. J Thorac Cardiovasc Surg 1984;88:659-62. 8. Eisenkop SM, Spirtos NM, Montag TW, Moossazadeh J, Warren P, Hendrickson M. The clinical significance of blood transfusion at the time of radical hysterectomy. Obstet Gynecol 1990;6:110-3. 9. Dalrymple JC, Monaghan JM. Blood transfusion and disease free survival in cervical cancer. J Obstet Gynaecol (Bristol) 1988;8: 356-9. 10. Blumberg N, Agarwal MM, Chuang C. A possible association between survival time and transfusion in cervical cancer. Yale J Biol Med 1988;61:493-500. 11. DiSaia PJ, Creasman WT. Invasive cervical cancer. In: DiSaia PJ, Creasman WT, eds. Clinical gynecologic oncology. 4th ed. St. Louis: CV Mosby, 1993:58-125. 12. Monk BJ, Cha DS, Walker JL, et al. Extent of disease as an indication for pelvic radiation following radical hysterectomy and bilateral pelvic lymph node dissection in the treatment of stage IB and IIA cervical carcinoma. Gynecol Oncol 1994;54:4-9. 13. Monk BJ, Cook N, Ahn C, Vasilev SA, Berman ML, Wilczynski SP. A comparison of the polymerase chain reaction and southern blot analysis in detecting and typing human papillomavirus deoxyribonudeic acid in tumors of the lower female genital tract. Diagn Molec Pathol 1994 (In press). 14. Walker J, Bloss JD, Liao SY, Berman M, Bergen S, Wilczynski SP. Human papillomavirus genotype as a prognostic indicator in carcinoma of the uterine cervix. Obstet Gynecol 1989;74:781-5. 15. Nalick RH, DiSaia PJ, Rea TH, Morrow M. Immunocompetence and prognosis in patients with gynaecologic cancer. Gynecol Oncol 1974;2:81-5. 16. Balaram P, Radhakrishna P, Padmanahhan TK, Abraham T, Hareendran NK, Nair MK. Immune function in malignant cervical neoplasia: A multiparameter analysis. Gynecol Onco11988;31:40923. 17. Maiman M, Fruchter RG, Guy L, Cuthill S, Levine P, Serur E. Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 1993;71:402-6. 18. Busch ORC, Hop WCJ, Hoynck van Papendrecht MAW, Marquet RL, Jeekel J. Blood transfusions and prognosis in colorectal cancer. N Engl J Med 1993;328:1372-6. 19. Singh SSK, Marquet RL, deBruin RWF, Westbroek DL, Jeekel I. Promotion of tumor growth by blood transfusions. Transplant Proc 1987;19:1473-4. 20. Levrant SG, Fruchter RG, Maiman M. Radical hysterectomy for
Monk et al
Hysterectomy and Transfusion
cervical cancer: Morbidity and survival in relation to weight and age. Gynecol Oncol 1992;45:317-22. 21. Soisson AP, Soper JT, Berchuck A, Dodge R, Clark-Pearson D. Radical hysterectomy in obese women. Obstet Gynecol 1992;80: 940-3. Address reprint requests to: Bradley J. Monk, M D Department of Obstetrics and Gynecology 101 The City Drive P.O. Box 14091 Orange, CA 92613-1491
Received July 25, 1994. Received in revised form November 3, 1994. Accepted November I4, 1994.
Copyright © 1995 by The American College of Obstetricians and Gynecologists.
WOMEN IN THE
May 4-5, 1995 The University of Toronto is sponsoring a course on the perimenopausal years, to be held at the C r o w n e Plaza in Toronto. This course has been a p p r o v e d for 14 cognate hours (Formal Learning) by The American College of Obstetricians and Gynecologists. For further information, contact Continuing Medical Education, University of Toronto, 150 College Street, R o o m 121, Toronto, Ontario M5S 1A8, Canada; (416) 978-2719.
Monk et al
Hysterectomy and Transfusion
Obstetrics & Gynecology