Blood Transfusion and Other Risk Factors for Recurrence of Cancer of the Head and Neck Kim Richard
Jones, MD, PhD, Mark Christian Weissler, MD
\s=b\ To determine whether perioperative blood transfusion affected the recurrence rate of squamous cell cancer of the head and neck, we performed a retrospective study of all patients with stage III and IV disease treated surgically at the University of North Carolina, Chapel Hill, between 1983 and 1986. Those who recurred were compared with those who did not in regard to 16 prognostic variables, including whether or not they had received a perioperative blood transfusion. Analyzing each variable separately, five were significantly related to recurrence. These were
(1) surgical margin status, (2) stage, (3) presence of pathologically positive nodes, (4) blood transfusion status, and (5) type of treatment. However, because several of these variables were clearly interrelated, the same data were subjected to a multivariate regression analysis specifically designed to identify significant prognostic variables independent of their association with other variables. By this analysis, only margin status and the presence or absence
of
a
blood transfusion
were
statisti-
cally significant predictors of recurrence. (Arch Otolaryngol Head Neck Surg. 1990;116:304-309)
immunosuppressive effects of The blood transfusion have been known for several
years, but only re¬ cently the effect of transfusion on the morbidity and mortality of cancer pa¬ tients undergoing surgical resection
Accepted for publication October 19, 1989. From the Department of Surgery, Division of Otolaryngology/Head and Neck Surgery, University of North Carolina, Chapel Hill. Read before the annual meeting of the American Society for Head and Neck Surgery, San Francisco, Calif, April 5, 1989. Reprint requests to University of North Carolina, Division of Otolaryngology/Head and Neck Surgery, CB 7070, Burnett-Womack Bldg, Chapel Hill, NC 27514-7070 (Dr Jones).
has been considered. Burrows and Tartter1 first reported in 1982 that in¬ traoperative transfusion was associ¬ ated with adverse effects on both the recurrence and survival rates of pa¬ tients when adenocarcinoma of the co¬ lon, and since then, numerous retro¬ spective studies have confirmed and extended these findings in regard to colorectal cancer.2"5 However, some question exists as to whether this ef¬ fect is seen in all types of cancer. For example, although similar findings have been reported for lung cancer,6 transfusion does not seem to have an effect on the recurrence rate of breast cancer57 or renal cell cancer.8 Since the resection of large head and neck tumors frequently requires intra¬ operative or postoperative blood trans¬ fusions, we were interested in whether transfusion might have an influence on the recurrence rate in head and neck cancer. This question has recently been addressed by Johnson et al,9 who reported that transfusion correlated positively with recurrence in patients with stage III squamous cell carci¬ noma (SCC) of the head and neck. However, this study failed to control for a number of variables that also af¬ fect either recurrence rate or the im¬ mune status of the patient, such as the presence of positive margins,10·" dura¬ tion of surgery and anesthesia,12·13 amount of blood loss,12 and nutritional status.14 We were thus interested in extending the findings of Johnson et al9 to include these other variables and to determine the extent to which they in¬ teracted with transfusion to affect the recurrence rate of patients with SCC of the head and neck.
SUBJECTS AND METHODS
Subjects The records of all patients seen at North Carolina Memorial Hospital, Chapel Hill, between 1983 and 1986 for tumors of the head and neck were reviewed (N 437). To be eligible for this study, several criteria had to be met. First, only those patients with histologically proved SCC of the aerodigestive tract were included. This encom¬ passed tumors of the paranasal sinuses, but not the esophagus or salivary glands. Sec¬ ond, patients must not have had any prior treatment of their tumor (ie, irradiation or chemotherapy) before being operated on for cure. This excluded patients with recur¬ rences, although in some cases, a decision had to be made as to whether a tumor rep¬ resented a recurrence or a new primary tu¬ mor. If there was any question, the patient was not considered for further analysis. Third, only stage III or IV tumors were in¬ cluded, since patients with stage I or II tu¬ mors rarely, if ever, required a transfusion. Finally, any patient who died within 6 months of their surgery of a cause unre¬ lated to their cancer was excluded. A total of 94 patients met all criteria; of these 94, 1 was unavailable for follow-up, and 1 was excluded because of an unclear recurrence status at the time of death. The remaining 92 patients form the basis of this study. Minimum follow-up time was 2 years or until death. Eighty-seven percent (80/92) of the patients received postoperative radi¬ ation therapy, while 11% (10/92) received surgery alone and 2% (2/92) received a combination of postoperative radiation therapy and chemotherapy. =
Staging
Staging was based on the American Joint Committee on Cancer staging system of 1983. Since this is a clinical staging system, all patients were staged based on their ini¬ tial clinical presentation as documented in
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the chart notes. The stage was not changed if surgery revealed the presence of previ¬ ously unsuspected positive nodes, or if pos¬ itive nodes were absent in a patient origi¬ nally thought to be node positive.
Pathologic Findings The original pathology reports were re¬ viewed for all patients. Information ob¬ tained included the histologie grade of the tumor (1, well differentiated; 3, moderately differentiated; and 5, poorly differentiated), the total number of positive nodes (if ap¬ propriate), and the status of the surgical margins. The margins were scored as posi¬ tive if
a
clear focus of carcinoma
was
present at the cut edge. They were scored as close if carcinoma was within 3 mm of the margin, or if carcinoma in situ or severe dysplasia was present at the margin.
Operative Variables and Transfusion Several variables relating to the patients' health status and surgical procedure were obtained. These included a preoperative hematocrit reading, a preoperative albu¬ min level (to obtain some measure of the patient's nutritional status), the duration of surgery, amount of surgical blood loss, and a discharge hematocrit. Patients were categorized as being transfused if they re¬ ceived blood products at any time from 2 weeks before surgery to 2 weeks afterward. In fact, however, the range of transfusion times in our patients was only from 2 days preoperatively to 5 days postoperatively, with greater than 90% of patients receiving their blood during the operation itself or immediately thereafter. Only 2 patients re¬ ceived blood products other than packed red blood cells, and both of these patients also received large amounts of red blood cells. The possible effect of blood products other than red blood cells was thus not explored.
Statistical Analysis The initial univariate analysis of each variable was performed using the 2 test. Because this test cannot detect the effect of possible interactions between variables, however, further analysis was done using the Cox proportional hazards model for nonparametric, multivariate regression.15 This model was designed to identify impor¬ tant prognostic variables independent of their possible correlation with other vari¬ ables and, hence, was particularly appro¬ priate and necessary for this study, because blood transfusion and other presumptive risk factors could covary with stage, margin status, and so forth, and be identified erro¬ neously as significant. The model also con¬ trols for varying lengths of follow-up by differentially weighting each observation depending on the follow-up interval.
Table 1.—Sixteen Variables That Were Examined in Their Effects on
Table 3.—-Variables That Did Not Have a Significant Effect on Recurrence Rate*
Recurrence
Recur¬
Clinical
Age Sex Site of lesion Size of primary Clinical node status
Variables
Age,
20
34
28
18
12
Pathologic Histologie grade of tumor Pathologic node status Surgical margins Laboratory Preoperative hematocrit reading Discharge hematocrit reading Preoperative albumin level Treatment type
T4 T3 T2-T1 Clinical node status NO
a
(48) (50) 9 (38) 16 (43) 1
13 22
12
1-5
Stage
Blood loss 0-0.5 0.5-1.0
Transfusion status
Pathologic Pathologic node
17 35
Pathologic Histologie grade of
32
positive positive node_20 Surgical margins 1
Positive Close
8
10 34
Negative
9 tumor 5
1
(20)
Moderately
(24) 30 (60) 10
differentiated
25
20 (45)
19
16
Poorly differentiated
(73) 8 (44) 10 (23)
22
(45)
Laboratory Preoperative hematocrit reading
Treatment 9 1 (10) Surgery alone 43 37 (46) Surgery and radiation Surgery, radiation, and chemotherapy 0 2(100) £ .05 by the 2 test. NED indicates no evidence
0.40
30
5(42) (50) 20 (40)
31
20
7
15
Discharge hematocrit reading 0.40 Preoperative albumin
17
30
20
40
17
15
(39) (55) (40)
level, g/L
RESULTS
Forty (43% ) of the 92 patients oper¬
ated on for stage III or IV SCC of the head and neck had recurred at the time of this study. Thirty-three (36%) of these recurred regionally at either the primary site or in the neck, and 7 (8% ) evidenced metastatic disease as their first sign of recurrence. For statistical purposes, both types of recurrences were combined into a single category.
(29) (47) 10 (47) 10
20
Well differentiated
status
nodes
25
>1.0
(64) 10(22)
30
4(25) (44) 9(64)
27
>10
(33) 25(54) 15
Surgical Received transfusion No transfusion
(35) (44) 12 (52) 5 (50) 12
Duration of surgery, h 5.1-10
21
23
Surgical
(%)
Clinical 31
(62) (41) 7(35)
10 33
N2 N3
rence
No.
(45) (40)
11
RecurNo. NED
(54) (44) 13 (38)
14
Pharynx Larynx Size of primary
Table 2.—Variables That Had Significant Effect on Recurrence Rate*
IV
(%)
7
Sex Male Female Site of lesion Oral cavity Paranasal sinuses
Transfusion status
:
25
rence
y
6 also shown an effect of transfusion on cancer recurrence rates. Perhaps the most extensively studied has been colorectal cancer, on which more than 12 studies have been done. Briefly, most of these have shown significantly higher recurrence rates among transfused patients,1"51617 but several have shown no effect.1820 These conflicting results are difficult to explain, since studies that have to for ascancer. For example, transfusions than those whoseattempted cancer of control colorectal variables as have re¬ has been shown to as possible did not and that survival many decreased blood transfusion and negative" number of units positive" a function of the ported affect patients with gastric adverselyresults. The data for othercancer,21 neo¬ types ofsoft-tissue transfused. sarcoma,22 and as somewhat are also at variance A number of previous have plasmsstudies mentioned above, squamous cell in general have less well also shown an effectand of transfusion on been butcon¬ has no effect in patients cancer,9 than some better trolledPerhaps studies theof the cancer recurrence rates. with cell carcinoma8·23 or breast renal studied been colcarcinoma.5·7 Studies of lung cancer most extensively has orectal cancer, on which more than 12 have been both positive6 and nega¬ studies have been done. Briefly, most of tive.24 The mechanism of how blood trans¬ these have shown significantly higher fusion affects tumor viability is still recurrence rates among transfused patients,1"51617 but several have shown unclear, although the weight of exper¬ imental evidence suggests that some no effect.1820 These conflicting results are difficult to explain, since studies type of immunosuppression is in¬ that have attempted to control for as volved. This immunosuppression has variables have been well described in the transplant as re¬ possible many ported positive" and negative19 results. literature, and clinically seems to de¬ The data for other types of neo¬ pend on the presence of leukocytes in plasms are also somewhat at variance the transfused blood. For example, and in general have been less well con¬ several studies have shown that frozen trolled than some of the better studies blood, washed and depleted of white
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blood cells and platelets, does not in¬ crease renal graft survival as well as whole blood.25·26 Conversely, transfu¬ sion of leukocytes alone does improve graft viability.27 The beneficial effects of packed red blood cells, often used clinically in transplant protocols, are easily explained by its significant con¬ tamination by white blood cells, gen¬ erally estimated to be about 106 cells per unit. Another question that remains to be answered is the mechanism of the im¬ munosuppression itself. Thus far, transfusion has been shown to cause a quantitative or qualitative defect in the functioning of at least three cell populations involved in the immune response. One of the most extensively studied has been that of the lympho¬ cytes, which are involved in antigen recognition, phagocytosis, and modu¬ lation of the immune response via their helper and suppressor subpopu¬ lations. In studies of human patients, Fischer et al28 have reported an in¬ crease in suppressor T-cell activity and a concomitant decrease in lymphocyte responsiveness following transfusion. Lenhard et al29 noted similar effects and found that the increase in suppres¬ sor T-cell activity lasted at least 12 weeks following transfusion. Other investigators have focused on the effect of blood transfusion on the activity of natural killer cells, since these cells have been postulated to have a major role in tumor control.30 Ford et al31 showed that natural killer cell activity in human subjects falls almost immediately following trans¬ fusion, and Gascon et al32 showed that this decrease is significantly related to the amount of blood transfused. Gas¬ con et al32 also showed in a single patient followed up serially that the natural killer cell activity took 3 months from the time of last transfu¬ sion to return to normal. Finally, the monocyte-macrophage system has also been studied, prima¬ rily because of its role in production of
prostaglandin E, a potent immunosup-
pressant. Lenhard et al33 have demon¬ strated that
serum
levels of pros¬
taglandin E increase in patients re¬ ceiving blood transfusions and that the effect is dose dependent. Data obtained from the same patients indicated that
the increased levels are due both to an increase in the number of monocytes and to an increased production of prostaglandin E by the monocytes them¬ selves. A similar study was done in animals by Waymack et al,34 who looked at the levels of prostaglandin E, prostaglandin F2, and thromboxane in transfused rats. All were significantly elevated in rats who received a trans¬ fusion of allogeneic blood, but not in those who received syngeneic blood. However, levels of leukotriene,),, an
immunostimulant,
were
unchanged.
The interaction of blood transfusion with other factors that influence re¬ currence rate was also of interest. In our study, we found that the major predictive variables of recurrence were blood transfusion and status of the surgical margins. Lymph node in¬ volvement and clinical stage were im¬ portant in the univariate analysis, but muitivariate analysis showed that their effects were mainly due to their association with the two main vari¬ ables. The importance of positive margins in head and neck cancer has been a matter of some debate. An oft-quoted study is that of Bauer et al,35 who reviewed the results of 111 hemilaryngectomies and found that while a pos¬ itive margin increased the number of recurrences threefold, more than 80% of patients with a positive margin still did not recur despite no further ther¬ apy. This result suggested to Bauer et al35 that the presence of a positive margin is relatively unimportant in relation to recurrence. Unfortunately, however, such favorable results have not been reported for other sites in the head and neck. Looser et al10 found a recurrence rate of 71% for SCC of the oral cavity and pharynx when margins were close or involved, compared with 32% when margins were negative. Zieske et al11 reported a similar recur¬ rence rate of 77% with positive mar¬ gins and 45% with negative margins in a study of 315 patients with stage III and IV SCC of the head and neck. The recurrence rate of our study was 66% with positive margins and 26% with negative margins. The results of the muitivariate analysis suggest that margin status is in fact one of the most important factors affecting recurrence
rate. Of course, this may vary by site of the tumor, but we did not have suffi¬ cient data to address this question.
The
finding that pathologic nodal as robust a predictive
status is not
variable as blood transfusion and mar¬ gin status was somewhat of a surprise. Since, to our knowledge, a true muiti¬ variate analysis of risk factors for re¬ currence of head and neck cancer has not been done previously, it is difficult to compare our results with other stud¬ ies that have used univariate analysis. In fact, looking at nodal status in iso¬ lation, in our study we found a recur¬ rence rate of 60% in those patients with at least one positive node, and only 24% in those patients with no nodal disease. This is similar to the oft-quoted figure that having a single positive node decreases one's survival by 50% .36 However, when blood trans¬ fusion, margin status, and nodal status were placed in a muitivariate regres¬ sion model, the results were clear: blood transfusion and margin status were stronger predictive variables than nodal status, and if the predictive power of the first two was first factored into the model, the effect of adding nodal status did not provide a statisti¬
cally significant improvement. One possible explanation for these results might be, as Johnson et al36 have pointed out, that it is not the
presence of metastatic SCC in
that is
a
node
important, but rather whether
extracapsular spread is present. Extracapsular spread was not examined in our study, and if it was, the extent of nodal disease
might have assumed
greater importance.
The prognostic importance of tumor size and histologie grade was also found to be negligible in our patient population. This was not entirely un¬ expected, since size of the primary has previously been shown not to correlate with prognosis in studies of oral cavity SCC37 and SCC of the larynx and hypopharynx.38 Also, several studies have shown no effect of histologie grade on recurrence or survival.39·40 More interesting was our finding that the effect of clinical stage on recur¬ rence could be explained by the associ¬ ation of margin status and stage. Since one of the purposes of the American Joint Committee on Cancer staging
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system currently in use is to be able to predict the clinical course of various levels of disease, it is not surprising
that several studies have shown dif¬ ferences in survival with regard to clinical stage.40·41 However, none of these studies controlled for the possi¬ ble confounding effects of factors not incorporated into the staging system. Johnson et al36 made this same point with respect to extracapsular spread; that is, that stage IV tumors have a much higher incidence of extracapsu¬ lar spread than stage III tumors, and it is this difference, rather than the stag¬ ing characteristics of primary tumor size and degree of nodal involvement, that may explain the poorer clinical
of patients with stage IV dis¬ In our study, the difference in margin status between stage IV and stage III disease was enough by itself to explain the differences in recurrence rates. This was shown by both the 2 and multiple-regression statistical methods. course ease.
CONCLUSIONS
The most important finding of this study was the marked effect that the presence of a perioperative blood transfusion had on the likelihood of recurrence of SCC of the head and neck. While this could still be due to some hitherto unidentified patient variable that is related to blood trans-
fusion,
we
demonstrated that it
was
not due to the association of transfu¬ sion with any of the 15 other possible
prognostic variables that we identi¬ fied. We also found that margin status is particularly important in relation to prognosis and that the effects of nodal status, stage, and so forth, can be explained to a greater or lesser degree by their association with blood trans¬ fusion and margin status. Julian Rosenman, MD, PhD, and Joel Tepper, MD, Department of Radiation Oncology, Univer¬ sity of North Carolina, Chapel Hill, provided ad¬ vice, encouragement, and use of their computer facilities, and Gary Koch, PhD, and Gail Tudor, MS, of the University of North Carolina Biomet¬ rics Consulting Center helped with the statistical
analysis.
References 1. Burrows L, Tartter P. Effect of blood transfusions on colonic malignancy recurrence rate. Lancet. 1982;2:662-664. 2. Blumberg N, Agarwal MM, Chuang C. Relation between recurrence of cancer of the colon and blood transfusion. Br Med J. 1985;290:1037-1039. 3. Foster RS, Costanza MC, Foster JC, Wanner MC, Foster CB. Adverse relationship between blood transfusions and survival after colectomy for colon cancer. Cancer. 1985;55:1195-1201. 4. Parrott NR, Lennard TWJ, Taylor RMR, Proud G, Shenton BK, Johnston IDA. Effect of perioperative blood transfusion on recurrence of colorectal cancer. Br J Surg. 1986;73:970-973. 5. Voogt PJ, Van de Velde CJH, Brand A, et al. Perioperative blood transfusion and cancer prognosis: different effects of blood transfusion on prognosis of colon and breast cancer patients. Cancer. 1987;59:836-843. 6. Hyman NH, Foster RS, DeMeules JE, Costanza MC. Blood transfusions and survival after lung cancer resection. Am J Surg. 1985;149:502\x=req-\ 507. 7. Foster RS, Foster JC, Costanza MC. Blood transfusions and survival after surgery for breast cancer. Arch Surg. 1984;119:1138-1140. 8. Manyonda IT, Shaw DE, Foulkes A, Osborn DE. Renal cell carcinoma: blood transfusion and survival. Br Med J. 1986;293:537-538. 9. Johnson JT, Taylor FH, Thearle PB. Blood transfusion and outcome in stage III head and neck carcinoma. Arch Otolaryngol Head Neck
Surg. 1987;113:307-310. 10. Looser KG, Shah JP, Strong EW. The significance of "positive" margins in surgically resected epidermoid carcinomas. Head Neck Surg. 1978;1:107-111. 11. Zieske LA, Johnson JT, Myers EN, Thearle PB. Squamous cell carcinoma with positive margins. Arch Otolaryngol Head Neck Surg. 1986; 112:863-866. 12. Jubert AV, Lee ET, Hersh EM, McBride CM. Effects of surgery, anesthesia and intraoperative blood loss on immunocompetence. J Surg Res.
1973;15:399-403. 13. Slade MS, Simmons RL, Yunis E, Greenberg LJ Immunodepression after major surgery in normal patients. Surgery. 1975;78:363-372. 14. Linn BS, Robinson DS, Klimas NG. Effects
of age and nutritional status on surgical outcomes in head and neck cancer. Ann Surg. 1988;207:267\x=req-\ 273. 15. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-220.
16. Arnoux R, Corman J, Peloquin A, Smeesters C, St Louis G. Adverse effect of blood transfusions on patient survival after resection of rectal cancer. Can J Surg. 1988;31:121-126. 17. Creasy TS, Veitch PS, Bell PR. A relationship between perioperative blood transfusion and recurrence of carcinoma of the sigmoid colon following potentially curative surgery. Ann R Coll
Surg Engl. 1987;69:100-103. 18. Ota D, Alvarez L, Lichtiger B, Giacco G, Guinee V. Perioperative blood transfusion in patients with colon carcinoma. Transfusion. 1985;25:392-394. 19. Nathanson SD, Tilley BC, Schultz L, Smith RF. Perioperative allogeneic blood transfusions. Arch Surg. 1985;120:734-738. 20. Weiden PL, Bean MA, Schultz P. Perioperative blood transfusion does not increase the risk of colorectal cancer recurrence. Cancer. 1987; 60:870-874. 21. Kaneda M, Horimi M, Ninomiya S, et al. Adverse effect of blood transfusions on survival of patients with gastric cancer. Transfusion.
1987;27:375-377.
22. Rosenberg SA, Siepp CA, White DE, Wesley R. Perioperative blood transfusions are asso-
ciated with increased rates of recurrence and decreased survival in patients with high-grade softtissue sarcoma of the extremities. J Clin Oncol.
1985;3:698-709. 23. Moffat LEF, Sunderland GT, Lamont D. Blood transfusion and survival following nephrectomy for carcinoma of kidney. Br J Urol. 1987;60:316-319. 24. Pastorini U, Valente M, Cataldo I, Leguaglie C, Ravasi G. Perioperative blood transfusion and prognosis of resected stage Ia lung cancer. Eur J Cancer Clin Oncol. 1986;11:1375-1378. 25. Opelz G, Terasaki PI. Poor kidney trans-
plant survival
in recipients with frozen blood transfusions or no transfusions. Lancet. 1974; 2:696-698. 26. Persijn GG, Cohen B, Landsberger Q, van Rood JJ. Retrospective and prospective studies on the effect of blood transfusions in renal transplantation in the Netherlands. Transplantation.
1979;28:396-401. 27. Okazaki H, Takahashi H, Miura K, Ishisaki M, Taguchi Y. Significant reduction of sensitiza-
improved allograft outcome with donorspecific buffy coat transfusion. Transplantation. tion and
1984;37:523-525. 28. Fischer E, Lenhard V, Seifert P, Kluge A,
pression of cellular immunity in man. Hum Immunol. 1980;3:187-194. 29. Lenhard V, Maassen G, Grosse-Wilde H, Wernert P, Opelz G. Effect of blood transfusions on immunoregulatory mononuclear cells in prospective transplant recipients. Transplant Proc. 1983;15:1011-1015.
30. Heberman RB. Natural killer cells and their
possible roles in host resistance against tumor. Transplant Proc. 1984;16:476-478. 31. Ford CD, Warnick CT, Sheets S, Quist R,
Stevens LE. Blood transfusions lower natural killer cell activity. Transplant Proc. 1987;19:1456\x=req-\ 1457. 32. Gascon P, Zoumbos N, Young N. Immunologic abnormalities in patients receiving multiple blood transfusions. Ann Intern Med. 1984;100:173\x=req-\ 181. 33. Lenhard V, Gemsa D, Opelz G. Transfusioninduced release of prostaglandin E2 and its role in the activation of T suppressor cells. Transplant
Proc. 1985;17:2380-2382. 34. Waymack JP, Gallon L, Barcelli U, Trocki 0, Alexander JW. Effect of blood transfusions on immune function, III: alterations in macrophage arachidonic acid metabolism. Arch Surg.
1987;122:56-60. 35. Bauer WC, Lesinski SG, Ogura JH. The significance of positive margins in hemilaryngectomy specimens. Laryngoscope. 1975;85:1-13. 36. Johnson JT, Barnes EL, Myers EN, Schramm VL, Borochovitz D, Sigler BA. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol. 1981;107:725-729. 37. Moore C, Flynn MB, Greenberg RA. Evaluation of size in prognosis of oral cancer. Cancer. 1986;58:158-162. 38. Sessions DG. Surgical pathology of cancer of the larynx and hypopharynx. Laryngoscope. 1976;86:814-839. 39. Vikram B, Strong EW, Shah JP, Spiro RH. Failure at the primary site following multimod-
ality treatment in advanced head and neck cancer. Head Neck Surg. 1984;6:720-723. 40. Shah JP, Cendon RA, Farr HW, Strong EW. Carcinoma of the oral cavity: factors affecting treatment failure at the primary site and neck. Am J Surg. 1976;132:504-507. 41. Decker JW, Price JC, Goldstein JC. Advanced laryngeal cancer: relevance of pathologic stage to survival and therapy. Arch Otolaryngol Head Neck Surg. 1986;112:1163-1167.
Johannsen R. Blood-transfusion-induced sup-
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Jones, MD, PhD, Mark Christian Weissler, MD
\s=b\ To determine whether perioperative blood transfusion affected the recurrence rate of squamous cell cancer of the head and neck, we performed a retrospective study of all patients with stage III and IV disease treated surgically at the University of North Carolina, Chapel Hill, between 1983 and 1986. Those who recurred were compared with those who did not in regard to 16 prognostic variables, including whether or not they had received a perioperative blood transfusion. Analyzing each variable separately, five were significantly related to recurrence. These were
(1) surgical margin status, (2) stage, (3) presence of pathologically positive nodes, (4) blood transfusion status, and (5) type of treatment. However, because several of these variables were clearly interrelated, the same data were subjected to a multivariate regression analysis specifically designed to identify significant prognostic variables independent of their association with other variables. By this analysis, only margin status and the presence or absence
of
a
blood transfusion
were
statisti-
cally significant predictors of recurrence. (Arch Otolaryngol Head Neck Surg. 1990;116:304-309)
immunosuppressive effects of The blood transfusion have been known for several
years, but only re¬ cently the effect of transfusion on the morbidity and mortality of cancer pa¬ tients undergoing surgical resection
Accepted for publication October 19, 1989. From the Department of Surgery, Division of Otolaryngology/Head and Neck Surgery, University of North Carolina, Chapel Hill. Read before the annual meeting of the American Society for Head and Neck Surgery, San Francisco, Calif, April 5, 1989. Reprint requests to University of North Carolina, Division of Otolaryngology/Head and Neck Surgery, CB 7070, Burnett-Womack Bldg, Chapel Hill, NC 27514-7070 (Dr Jones).
has been considered. Burrows and Tartter1 first reported in 1982 that in¬ traoperative transfusion was associ¬ ated with adverse effects on both the recurrence and survival rates of pa¬ tients when adenocarcinoma of the co¬ lon, and since then, numerous retro¬ spective studies have confirmed and extended these findings in regard to colorectal cancer.2"5 However, some question exists as to whether this ef¬ fect is seen in all types of cancer. For example, although similar findings have been reported for lung cancer,6 transfusion does not seem to have an effect on the recurrence rate of breast cancer57 or renal cell cancer.8 Since the resection of large head and neck tumors frequently requires intra¬ operative or postoperative blood trans¬ fusions, we were interested in whether transfusion might have an influence on the recurrence rate in head and neck cancer. This question has recently been addressed by Johnson et al,9 who reported that transfusion correlated positively with recurrence in patients with stage III squamous cell carci¬ noma (SCC) of the head and neck. However, this study failed to control for a number of variables that also af¬ fect either recurrence rate or the im¬ mune status of the patient, such as the presence of positive margins,10·" dura¬ tion of surgery and anesthesia,12·13 amount of blood loss,12 and nutritional status.14 We were thus interested in extending the findings of Johnson et al9 to include these other variables and to determine the extent to which they in¬ teracted with transfusion to affect the recurrence rate of patients with SCC of the head and neck.
SUBJECTS AND METHODS
Subjects The records of all patients seen at North Carolina Memorial Hospital, Chapel Hill, between 1983 and 1986 for tumors of the head and neck were reviewed (N 437). To be eligible for this study, several criteria had to be met. First, only those patients with histologically proved SCC of the aerodigestive tract were included. This encom¬ passed tumors of the paranasal sinuses, but not the esophagus or salivary glands. Sec¬ ond, patients must not have had any prior treatment of their tumor (ie, irradiation or chemotherapy) before being operated on for cure. This excluded patients with recur¬ rences, although in some cases, a decision had to be made as to whether a tumor rep¬ resented a recurrence or a new primary tu¬ mor. If there was any question, the patient was not considered for further analysis. Third, only stage III or IV tumors were in¬ cluded, since patients with stage I or II tu¬ mors rarely, if ever, required a transfusion. Finally, any patient who died within 6 months of their surgery of a cause unre¬ lated to their cancer was excluded. A total of 94 patients met all criteria; of these 94, 1 was unavailable for follow-up, and 1 was excluded because of an unclear recurrence status at the time of death. The remaining 92 patients form the basis of this study. Minimum follow-up time was 2 years or until death. Eighty-seven percent (80/92) of the patients received postoperative radi¬ ation therapy, while 11% (10/92) received surgery alone and 2% (2/92) received a combination of postoperative radiation therapy and chemotherapy. =
Staging
Staging was based on the American Joint Committee on Cancer staging system of 1983. Since this is a clinical staging system, all patients were staged based on their ini¬ tial clinical presentation as documented in
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the chart notes. The stage was not changed if surgery revealed the presence of previ¬ ously unsuspected positive nodes, or if pos¬ itive nodes were absent in a patient origi¬ nally thought to be node positive.
Pathologic Findings The original pathology reports were re¬ viewed for all patients. Information ob¬ tained included the histologie grade of the tumor (1, well differentiated; 3, moderately differentiated; and 5, poorly differentiated), the total number of positive nodes (if ap¬ propriate), and the status of the surgical margins. The margins were scored as posi¬ tive if
a
clear focus of carcinoma
was
present at the cut edge. They were scored as close if carcinoma was within 3 mm of the margin, or if carcinoma in situ or severe dysplasia was present at the margin.
Operative Variables and Transfusion Several variables relating to the patients' health status and surgical procedure were obtained. These included a preoperative hematocrit reading, a preoperative albu¬ min level (to obtain some measure of the patient's nutritional status), the duration of surgery, amount of surgical blood loss, and a discharge hematocrit. Patients were categorized as being transfused if they re¬ ceived blood products at any time from 2 weeks before surgery to 2 weeks afterward. In fact, however, the range of transfusion times in our patients was only from 2 days preoperatively to 5 days postoperatively, with greater than 90% of patients receiving their blood during the operation itself or immediately thereafter. Only 2 patients re¬ ceived blood products other than packed red blood cells, and both of these patients also received large amounts of red blood cells. The possible effect of blood products other than red blood cells was thus not explored.
Statistical Analysis The initial univariate analysis of each variable was performed using the 2 test. Because this test cannot detect the effect of possible interactions between variables, however, further analysis was done using the Cox proportional hazards model for nonparametric, multivariate regression.15 This model was designed to identify impor¬ tant prognostic variables independent of their possible correlation with other vari¬ ables and, hence, was particularly appro¬ priate and necessary for this study, because blood transfusion and other presumptive risk factors could covary with stage, margin status, and so forth, and be identified erro¬ neously as significant. The model also con¬ trols for varying lengths of follow-up by differentially weighting each observation depending on the follow-up interval.
Table 1.—Sixteen Variables That Were Examined in Their Effects on
Table 3.—-Variables That Did Not Have a Significant Effect on Recurrence Rate*
Recurrence
Recur¬
Clinical
Age Sex Site of lesion Size of primary Clinical node status
Variables
Age,
20
34
28
18
12
Pathologic Histologie grade of tumor Pathologic node status Surgical margins Laboratory Preoperative hematocrit reading Discharge hematocrit reading Preoperative albumin level Treatment type
T4 T3 T2-T1 Clinical node status NO
a
(48) (50) 9 (38) 16 (43) 1
13 22
12
1-5
Stage
Blood loss 0-0.5 0.5-1.0
Transfusion status
Pathologic Pathologic node
17 35
Pathologic Histologie grade of
32
positive positive node_20 Surgical margins 1
Positive Close
8
10 34
Negative
9 tumor 5
1
(20)
Moderately
(24) 30 (60) 10
differentiated
25
20 (45)
19
16
Poorly differentiated
(73) 8 (44) 10 (23)
22
(45)
Laboratory Preoperative hematocrit reading
Treatment 9 1 (10) Surgery alone 43 37 (46) Surgery and radiation Surgery, radiation, and chemotherapy 0 2(100) £ .05 by the 2 test. NED indicates no evidence
0.40
30
5(42) (50) 20 (40)
31
20
7
15
Discharge hematocrit reading 0.40 Preoperative albumin
17
30
20
40
17
15
(39) (55) (40)
level, g/L
RESULTS
Forty (43% ) of the 92 patients oper¬
ated on for stage III or IV SCC of the head and neck had recurred at the time of this study. Thirty-three (36%) of these recurred regionally at either the primary site or in the neck, and 7 (8% ) evidenced metastatic disease as their first sign of recurrence. For statistical purposes, both types of recurrences were combined into a single category.
(29) (47) 10 (47) 10
20
Well differentiated
status
nodes
25
>1.0
(64) 10(22)
30
4(25) (44) 9(64)
27
>10
(33) 25(54) 15
Surgical Received transfusion No transfusion
(35) (44) 12 (52) 5 (50) 12
Duration of surgery, h 5.1-10
21
23
Surgical
(%)
Clinical 31
(62) (41) 7(35)
10 33
N2 N3
rence
No.
(45) (40)
11
RecurNo. NED
(54) (44) 13 (38)
14
Pharynx Larynx Size of primary
Table 2.—Variables That Had Significant Effect on Recurrence Rate*
IV
(%)
7
Sex Male Female Site of lesion Oral cavity Paranasal sinuses
Transfusion status
:
25
rence
y
6 also shown an effect of transfusion on cancer recurrence rates. Perhaps the most extensively studied has been colorectal cancer, on which more than 12 studies have been done. Briefly, most of these have shown significantly higher recurrence rates among transfused patients,1"51617 but several have shown no effect.1820 These conflicting results are difficult to explain, since studies that have to for ascancer. For example, transfusions than those whoseattempted cancer of control colorectal variables as have re¬ has been shown to as possible did not and that survival many decreased blood transfusion and negative" number of units positive" a function of the ported affect patients with gastric adverselyresults. The data for othercancer,21 neo¬ types ofsoft-tissue transfused. sarcoma,22 and as somewhat are also at variance A number of previous have plasmsstudies mentioned above, squamous cell in general have less well also shown an effectand of transfusion on been butcon¬ has no effect in patients cancer,9 than some better trolledPerhaps studies theof the cancer recurrence rates. with cell carcinoma8·23 or breast renal studied been colcarcinoma.5·7 Studies of lung cancer most extensively has orectal cancer, on which more than 12 have been both positive6 and nega¬ studies have been done. Briefly, most of tive.24 The mechanism of how blood trans¬ these have shown significantly higher fusion affects tumor viability is still recurrence rates among transfused patients,1"51617 but several have shown unclear, although the weight of exper¬ imental evidence suggests that some no effect.1820 These conflicting results are difficult to explain, since studies type of immunosuppression is in¬ that have attempted to control for as volved. This immunosuppression has variables have been well described in the transplant as re¬ possible many ported positive" and negative19 results. literature, and clinically seems to de¬ The data for other types of neo¬ pend on the presence of leukocytes in plasms are also somewhat at variance the transfused blood. For example, and in general have been less well con¬ several studies have shown that frozen trolled than some of the better studies blood, washed and depleted of white
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blood cells and platelets, does not in¬ crease renal graft survival as well as whole blood.25·26 Conversely, transfu¬ sion of leukocytes alone does improve graft viability.27 The beneficial effects of packed red blood cells, often used clinically in transplant protocols, are easily explained by its significant con¬ tamination by white blood cells, gen¬ erally estimated to be about 106 cells per unit. Another question that remains to be answered is the mechanism of the im¬ munosuppression itself. Thus far, transfusion has been shown to cause a quantitative or qualitative defect in the functioning of at least three cell populations involved in the immune response. One of the most extensively studied has been that of the lympho¬ cytes, which are involved in antigen recognition, phagocytosis, and modu¬ lation of the immune response via their helper and suppressor subpopu¬ lations. In studies of human patients, Fischer et al28 have reported an in¬ crease in suppressor T-cell activity and a concomitant decrease in lymphocyte responsiveness following transfusion. Lenhard et al29 noted similar effects and found that the increase in suppres¬ sor T-cell activity lasted at least 12 weeks following transfusion. Other investigators have focused on the effect of blood transfusion on the activity of natural killer cells, since these cells have been postulated to have a major role in tumor control.30 Ford et al31 showed that natural killer cell activity in human subjects falls almost immediately following trans¬ fusion, and Gascon et al32 showed that this decrease is significantly related to the amount of blood transfused. Gas¬ con et al32 also showed in a single patient followed up serially that the natural killer cell activity took 3 months from the time of last transfu¬ sion to return to normal. Finally, the monocyte-macrophage system has also been studied, prima¬ rily because of its role in production of
prostaglandin E, a potent immunosup-
pressant. Lenhard et al33 have demon¬ strated that
serum
levels of pros¬
taglandin E increase in patients re¬ ceiving blood transfusions and that the effect is dose dependent. Data obtained from the same patients indicated that
the increased levels are due both to an increase in the number of monocytes and to an increased production of prostaglandin E by the monocytes them¬ selves. A similar study was done in animals by Waymack et al,34 who looked at the levels of prostaglandin E, prostaglandin F2, and thromboxane in transfused rats. All were significantly elevated in rats who received a trans¬ fusion of allogeneic blood, but not in those who received syngeneic blood. However, levels of leukotriene,),, an
immunostimulant,
were
unchanged.
The interaction of blood transfusion with other factors that influence re¬ currence rate was also of interest. In our study, we found that the major predictive variables of recurrence were blood transfusion and status of the surgical margins. Lymph node in¬ volvement and clinical stage were im¬ portant in the univariate analysis, but muitivariate analysis showed that their effects were mainly due to their association with the two main vari¬ ables. The importance of positive margins in head and neck cancer has been a matter of some debate. An oft-quoted study is that of Bauer et al,35 who reviewed the results of 111 hemilaryngectomies and found that while a pos¬ itive margin increased the number of recurrences threefold, more than 80% of patients with a positive margin still did not recur despite no further ther¬ apy. This result suggested to Bauer et al35 that the presence of a positive margin is relatively unimportant in relation to recurrence. Unfortunately, however, such favorable results have not been reported for other sites in the head and neck. Looser et al10 found a recurrence rate of 71% for SCC of the oral cavity and pharynx when margins were close or involved, compared with 32% when margins were negative. Zieske et al11 reported a similar recur¬ rence rate of 77% with positive mar¬ gins and 45% with negative margins in a study of 315 patients with stage III and IV SCC of the head and neck. The recurrence rate of our study was 66% with positive margins and 26% with negative margins. The results of the muitivariate analysis suggest that margin status is in fact one of the most important factors affecting recurrence
rate. Of course, this may vary by site of the tumor, but we did not have suffi¬ cient data to address this question.
The
finding that pathologic nodal as robust a predictive
status is not
variable as blood transfusion and mar¬ gin status was somewhat of a surprise. Since, to our knowledge, a true muiti¬ variate analysis of risk factors for re¬ currence of head and neck cancer has not been done previously, it is difficult to compare our results with other stud¬ ies that have used univariate analysis. In fact, looking at nodal status in iso¬ lation, in our study we found a recur¬ rence rate of 60% in those patients with at least one positive node, and only 24% in those patients with no nodal disease. This is similar to the oft-quoted figure that having a single positive node decreases one's survival by 50% .36 However, when blood trans¬ fusion, margin status, and nodal status were placed in a muitivariate regres¬ sion model, the results were clear: blood transfusion and margin status were stronger predictive variables than nodal status, and if the predictive power of the first two was first factored into the model, the effect of adding nodal status did not provide a statisti¬
cally significant improvement. One possible explanation for these results might be, as Johnson et al36 have pointed out, that it is not the
presence of metastatic SCC in
that is
a
node
important, but rather whether
extracapsular spread is present. Extracapsular spread was not examined in our study, and if it was, the extent of nodal disease
might have assumed
greater importance.
The prognostic importance of tumor size and histologie grade was also found to be negligible in our patient population. This was not entirely un¬ expected, since size of the primary has previously been shown not to correlate with prognosis in studies of oral cavity SCC37 and SCC of the larynx and hypopharynx.38 Also, several studies have shown no effect of histologie grade on recurrence or survival.39·40 More interesting was our finding that the effect of clinical stage on recur¬ rence could be explained by the associ¬ ation of margin status and stage. Since one of the purposes of the American Joint Committee on Cancer staging
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system currently in use is to be able to predict the clinical course of various levels of disease, it is not surprising
that several studies have shown dif¬ ferences in survival with regard to clinical stage.40·41 However, none of these studies controlled for the possi¬ ble confounding effects of factors not incorporated into the staging system. Johnson et al36 made this same point with respect to extracapsular spread; that is, that stage IV tumors have a much higher incidence of extracapsu¬ lar spread than stage III tumors, and it is this difference, rather than the stag¬ ing characteristics of primary tumor size and degree of nodal involvement, that may explain the poorer clinical
of patients with stage IV dis¬ In our study, the difference in margin status between stage IV and stage III disease was enough by itself to explain the differences in recurrence rates. This was shown by both the 2 and multiple-regression statistical methods. course ease.
CONCLUSIONS
The most important finding of this study was the marked effect that the presence of a perioperative blood transfusion had on the likelihood of recurrence of SCC of the head and neck. While this could still be due to some hitherto unidentified patient variable that is related to blood trans-
fusion,
we
demonstrated that it
was
not due to the association of transfu¬ sion with any of the 15 other possible
prognostic variables that we identi¬ fied. We also found that margin status is particularly important in relation to prognosis and that the effects of nodal status, stage, and so forth, can be explained to a greater or lesser degree by their association with blood trans¬ fusion and margin status. Julian Rosenman, MD, PhD, and Joel Tepper, MD, Department of Radiation Oncology, Univer¬ sity of North Carolina, Chapel Hill, provided ad¬ vice, encouragement, and use of their computer facilities, and Gary Koch, PhD, and Gail Tudor, MS, of the University of North Carolina Biomet¬ rics Consulting Center helped with the statistical
analysis.
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