Leucocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer

Letters to the Editor

Leucocyte-depleted or buffy-coat-depleted blood in surgery for colorectal

cancer

SIR-Houbiers and co-workers (Aug 27, p 573) conclude that perioperative blood transfusion is independently associated with postoperative bacterial infections in a dosedependent fashion, and that this effect of blood transfusion was not prevented by the use of leucocyte-depleted blood. There is much evidence that blood transfusion causes immunosuppression with respect to both cell-mediated and These immunity macrophage migration. immunosuppressive effects, in many instances, are properly mediated by leucocytes. In another prospective study’ the use of leucocyte-depleted blood abolished the immunosuppressive effects of blood transfusion as indicated

by postoperative infection, The effect of perioperative blood transfusion on outcome after resection for colorectal cancer has not been properly assessed in the many published retrospective studies. Chung et aF have reviewed all studies published between 1982 and 1990 with the statistical method of Mantel-Haenszel-Peto. This analysis represents 5236 patients and supports the hypothesis that perioperative blood transfusion is associated with an increased risk of recurrence of colorectal cancer and death. Therefore one new study with an opposite result does not answer Gantt’s question.3 More studies are needed. The major difficulty in Houbiers and co-workers’ study is the multicentre design and the exceptionally high frequency of postoperative infections and deaths. The study population included 697 patients from sixteen participating hospitals. Were the patients evenly distributed between centres? This question is crucial because the infection rate for transfused patients was 39% versus 24% for non-transfused. In patients who received more than three units of blood the infection rate was 45%. Furthermore, 31 % of these patients died from their infections, and 9% died from blood loss. All these figures are unacceptably high in a study population undergoing elective colorectal surgery and are not in accord with those of other studies.1,4 Houbiers and co-workers found a substantial difference in infection rates between the participating hospitals. They thought that this variation could be attributed to differences such as patient population and diagnostic efforts, but do not discuss the most obvious reason which is the surgeon-specific effect. Infection rates are well known to be surgeon specific’ and in Houbiers’ study with sixteen centres, surgeon effect is probably the dominating factor. This theory is also supported by the fact that size and location of the tumour were independent risk factors. How many surgeons took part, and were they of consultant, senior registrar, or other educational level? Our investigation’ of one type of bedside leucocytedepletion in patients transfused with whole blood showed a decrease in wound infection from 23% to less than 2%, which was the same as in non-transfused patients.’ There were no infection-related deaths. In addition, patients transfused with leucocyte-depleted blood had a median hospital stay of 6.2 days less than patients transfused with unfiltered blood. Houbiers and co-workers used various filters that are unlikely to show the same degree of leucocyte

was the level of removal consistently quality controlled? Another difficulty is that only 334 patients received the transfusion to which they were randomised, and consequently 10% of the leucocyte-depleted group were withdrawn. Therefore the validity of the results of treatment in this group is cast into doubt.

depletion:

Lone S Jerisen University Department of Surgical Gastroenterology, Aarhus Municipal Hospital, 8000 Aarhus, Denmark

1

2

Jensen LS, Andersen AJ, Christiansen PM, et al. Postoperative infection and natural killer cell function following blood transfusion in patients undergoing colorectal surgery. Br J Surg 1992; 79: 513-16. Chung M, Steinmetz OK, Gordon PH. Perioperative blood transfusion after resection for colorectal carcinoma. 80: 427-32. Gantt CL. Red blood cells for cancer patients. Lancet 1981; ii: 363. Tartter PI. Blood transfusion and infectious complications following colorectal cancer surgery. Br J Surg 1988; 76: 789-92. Collier C, Miller P, Borst M. Community hospital surgeon-specific infection rates. Infect Control 1987; 8: 249-54. and

outcome

Br J Surg 1993;

3 4

5

SIR-Houbiers and colleagues’ basic assumption was that leucocytes have a causal role in blood transfusion-associated immunosuppression; therefore, a reduction in number of transfused leucocytes should be followed by reduced immunosuppression, which is shown by decreased postoperative infection and tumour recurrence rates. This assumption is the main drawback in this study design and, we believe, led to inappropriate conclusions. There is much evidence that not only leucocytes but also erythrocytes and plasma products can alter the immune potential.’-3 In addition, no reports have shown a threshold for the number of transfused leucocytes per unit of blood, below which they are no longer immunosuppressive. In Houbiers’ study, however, with each unit of leucocytedepleted blood large amounts of allogeneic erythrocytes and an average of 0.2X106 (SD 0.3X106) allogeneic leucocytes were transfused, making the so-called non-immunosuppressive blood transfusion wholly speculative. With respect to these workers’ intention "to prove the causal relation between blood transfusion and poor prognosis in cancer", their study is not designed to address this issue, especially since the mechanism of tumour growth modulation induced by blood transfusion is unknown and therefore also the probable components of blood units influencing cancer. This study only can answer the question "do patients benefit from a considerable reduction of transfused allogeneic leucocytes?". Every multicentre trial has intrinsic difficulties with standardisation of important factors that will probably influence the variable tested. However, the large number of patients already randomised but excluded thereafter (237 patients, 21-4% of the whole study population) is surprising. Additionally, the 8% of patients receiving blood products who had not been randomised to do so indicates difficulty in controlling variables. This impression is also corroborated by the statement that surgical procedures and antibiotic prophylaxis, important variables influencing tumour recurrence and postoperative infections, were not defined by 1429

the

study protocol but done "according to the usual procedures of the 16 participating hospitals". Furthermore, Houbiers and colleagues provide no clear definition for indications for blood and plasma transfusion or exact criteria for assuming infectious complications, especially since the main course for infectious complications in colorectal

surgery-the anastomotic insufficiency reported for participating hospitals.

rate-was

not

W B Ross

Houbier and co-workers’ results are in accordance with our finding4 that allogeneic blood transfusion is an important risk factor for postoperative infections, independent of the lower number of leucocytes transfused. Interpreting the postoperative infection rate as the expression of transfusionassociated immunosuppression in accordance with the basic assumption, the use of a leucocyte-filter did not induce much difference in the achieved immunosuppressive potential of the two blood products. The absence of a difference in survival between the randomised study groups is thus not surprising. However, the blood transfusion effect was seen for patients who had received blood transfusions of either blood product in a significantly reduced overall rate and in disease-free data (relative risk 1-34, (p<0-001) p=009) for patients with more than three units transfused. Houbiers and colleagues account for the absence of a transfusion effect for cancer recurrence risk by a higher noncancer death rate. However, an alternative explanation might be the fact that deaths without evidence of cancer recurrence were censored in this analysis (which might have underestimated the real recurrence rate) since the number of necropsies done was not given. It is generally believed that overall survival analysis is the most relevant variable in oncological studies. By contrast with Houbiers and colleagues’ conclusions, results showing the influence of allogeneic and our autologous blood transfusions on tumour recurrencelead us to recommend that further clinical studies are done. M M Heiss, W Mempel, K-W Jauch, F W Schildberg Ludwig-Maximilians-University, Klinikum Grosshadern, Department of Surgery Transfusion Center, III Medical Department, 81377 Munich, Germany

and

PA, Descamps B. Improved renal allograft survival after blood transfusion; a non-specific erythrocyte-mediated immunoregulatory process. Lancet 1979; i: 20-22. 2 Shau H, Golub SH. Modulation of natural killer-mediated lysis by red blood cells. Cell Immunol 1988; 116: 60. 3 Marsh J, Konnan PT, Hamer-Hodges DW. Association between transfusion with plasma and the recurrence of colorectal carcinoma. 1

Keown

4

Br J Surg 1990; 77: 623-26. Heiss MM, Mempel W, Jauch KW,

et al. Beneficial effect of infectious complications after colorectal cancer surgery. Lancet 1993; 342: 1328-33. Heiss MM, Mempel W, Delanoff Chr, et al. Blood transfusion modulated tumor recurrence—first results of a randomized study of autologous vs allogeneic blood transfusion in colorectal cancer surgery. J Clin Oncol 1994; 9: 1859-67.

autologous blood transfusion

5

on

SIR-Houbiers and co-workers randomised controlled trial clearly indicates that patients undergoing surgery for colorectal cancer who receive perioperative blood transfusion have a poor outlook compared with non-transfused patients. They conclude that the results provide no support for the theory that blood transfusion promotes cancer recurrence. They also suggest that, because of this, blood transfusion may be associated with non-cancer deaths. From the methods section it is not clear what steps were actually taken in this

large study

to

systematically diagnose

recurrent

It is my experience that patients with colorectal cancer often enter a terminal phase with symptoms of weight loss, lethargy, and so on. These patients may not be investigated further and indeed may not have met the endpoint criteria as described by Houbiers et al. Secondly, if this cancer.

1430

suggests that transfused patients have non-cancer problems, then these should have been identified by assessment of anaesthetic risk factors preoperatively. I am not therefore convinced that Gantt’s question has now been answered by this study. Perhaps the authors have more data to substantiate their hypothesis?

St

George Hospital, Belgrave Street, Kogarah

NSW 2217. Australia

Authors’ reply

SIR-Our report contains two types of analysis. The first analysis gives the result of the randomised controlled trial by comparing the endpoints between the two transfusion regimens (leucocyte-depleted blood versus packed cells without buffy coat, whereas the second analysis (observational) compares transfused with non-transfused patients, which is similar to comparisons in retrospective studies. We agree that blood transfusions have various immunomodulating effects. The fact that Jensen and Heiss propose different blood components responsible for this effect shows that we have examined a relevant question: do patients benefit from a rigorous reduction of transfused allogeneic leucocytes? Such leucocyte-depleted blood, for example, lacks the beneficial effect on allograft survival and suppressive effects on natural killer cells. There is a clear negative answer on analysis of all 871 eligible patients, the 697 curatively operated patients, and various subpopulations of the 446 transfused patients. We anticipated the obvious difficulties with a multicentre trial design and stratified the randomisation procedure per hospital. We thereby precluded the influence of differences between hospitals in, for example, transfusion policy, protocol violations, and diagnosis and treatment of infection and cancer, on the overall comparison. Jensen’s doubt about the validity of the results is based on the assumption of application of various types of filters and of 10% protocol violation in the leucocyte-depletion group. The first misunderstanding is caused by two trade names for the same filter. All blood banks used this filter, whose effectiveness was validated and subject to continuous quality control. Secondly, transfusion of the other-as-randomised type of blood occurred in both trial groups (10% and 6%) and mainly affected the multitransfused patients. Exclusion of these patients who had received the other type of blood with a (after additional exclusion of prerandomisation history of blood transfusion, 334 of the 446 transfused patients remain), or allocation of these patients into the other trial group also showed no differences between the leucocyte-depleted and buffy-coat-depleted transfusion regimens. second The observational analysis lacks the methodological power of the randomisation and might select patients with bad outlook and high risk of infection into the group of transfused patients. Nevertheless, blood transfusion was not associated with cancer recurrence and, apart from the subgroup of multitransfused patients, was not associated with survival. The difficulty with the recognition of cancer recurrence, which Ross raises, is substantial, but is equally present in all patient populations. That the perioperative transfusion status

patients

is correlated with the likelihood of diagnosing cancer recurrence is doubtful. Furthermore, we considered possible effects of differences in recurrence risks between hospitals. These differences were not significant and a Cox’s regression analysis stratified by hospital also showed no increased recurrence risk for transfused patients.

The results of treatment with respect to (infectious) complications have not been as bad as Jensen’s interpretation of data suggests. It is only in the subgroup of multitransfused patients who had died without evidence of cancer recurrence (n=32) that, mainly shortly after surgery, 31% (n=10, 5% of the 198 patients transfused with >3 units) died from infection and 9% (n=3, 1-5%) died because of blood loss. As

explain and in accordance with Jensen and Heiss, we consistently showed-also after correction for other risk factors and for differences between hospitals-only blood transfusion and tumour location to be an independent risk factor of infection. One of the reasons for the high overall percentage of infections is the inclusion of urinary and respiratory tract infections (16% and 9%, respectively). The we

percentage of wound infections/abscesses we recorded is in the same order as that shown by Jensen and Heiss (9-5%, 8-1%, and 6-7%, respectively). Whether survival or cancer recurrence is the most valid index for measurement of cancer prognosis, we detected no beneficial effect of leucocyte depletion; nor did we show an association between blood transfusion and outlook in the overall study population. The observed correlation between transfusion of greater than 3 units with survival is restricted to a patient subpopulation that is rather prone to selection for risk factors or bad outlook. The lack of an association between blood transfusion and cancer prognosis in our large prospective study is in agreement with most retrospective studies’ and the conclusion of a recent meta-analysis,2 and provides no evidence for the cause-and-effect relation that Gantt postulated. J G A Houbiers, L M G van de C J H van de Velde, A Brand

Watering,

and Blood Bank, P0 Box 9600, 2300 RC Leiden, Netherlands

Department of Immunohaematology

PJ M

Verwey,

University Hospital Leiden,

1 Francis DMA. Relationship between blood transfusion and tumour behaviour. Br J Surg 1991; 78: 1420-428. 2 Vamvakas EC, Moore SB. Perioperative blood transfusion and colorectal cancer recurrence: a qualitative statistical overview and meta-analysis. Transfusion 1993; 33: 754-65.

Local

recurrence

after colorectal surgery

SiR-Adam and colleagues (Sept 10, p 707) report the relation between involvement of the circumferential tumour margin and local recurrence of rectal cancer. They show that the circumferential margin was involved in 25% of biopsy specimens that surgeons thought were potentially curative, compared with 6-5% of specimens in a previous study.’ In part, this difference can be explained by variations in laboratory technique of examining the specimens. However, it is far more likely that this difference is attributable to failure to excise the mesorectum completely with the tumour. Adam and colleagues’ paper reports the poor outcome after 190 procedures done by 23 different surgeons. It is hardly surprising that incomplete excision of carcinoma results in local recurrence. Surely this makes a compelling case for the treatment of these patients by

Dimethylsulphoxide-induced serum hyperosmolality after cryopreserved stem-cell graft SIR-Haemopoietic stem cells used for marrow transplantation are commonly cryopreserved in 10% v/v dimethylsulphoxide (DMSO) which is a 1-4 molar solution of DMSO. This solution is very hypertonic with a total tonicity of about 1700 mosmol/L, more than fivefold that of human plasma. There is little information on the human toxicity of intravenous DMSO, as highlighted in a previous case report.’ We describe a case with pre-existing central diabetes insipidus and symptomatic plasma hyperosmolarity after infusion of haemopoietic stem cells cryopreserved in DMSO. A 16-year-old boy was treated for second relapse of a malignant intracranial germ-cell tumour with chemotherapy and peripheral blood stem-cell rescue. Hypothalamic infiltration by tumour had caused pituitary failure and central diabetes insipidus requiring full hormone replacement. He maintained fluid balance on intranasal desmopressin 5 µg twice daily. Anorexia was the principal symptom of relapse, the patient weighing only 27 kg. Stem cells harvested after priming chemotherapy and granulocyte colony-stimulating factor were cryopreserved in 700 mL 10% v/v DMSO and reinfused rapidly two days after highdose cyclophosphamide. One hour after the infusion (35 mmol DMSO per kg) he was extremely unwell with severe headache, confusion, and abdominal pain. Physical examination revealed sunken eyes and poor tissue turgor. Measurement of plasma osmolality and electrolytes confirmed severe hyperosmolality (396 mosmol/L) with a positive osmolal gap (50 mosmol/L) and hypernatraemia (sodium 170 mmol/L) (figure). He was vigorously rehydrated with 3 LJm2 half-normal saline and clinically returned to normal the following day. Four weeks later a second cryopreserved stem-cell graft was infused in 187 mL 10% v/v DMSO (8 mmoL DMSO per kg). Care was taken to ensure adequate hydration with hypotonic fluids. He remained clinically well. No significant hypernatraemia occurred; plasma osmolality increased to 340 mosmol/L with an osmolal gap of 48 mosmol/L. In both instances measured serum osmolalities up to ten hours after DMSO infusion grossly exceeded the osmolality expected from serum electrolytes and DMSO load. This strongly argues against the widely assumed rapid distribution attributed to DMSO and would explain significant transient fluid shifts. A linear relation between serum DMSO and serum osmolarity has been shown by Runckel and Swanson.2

specialist surgeons? C G Marks Royal Surrey County Hospital, Guildford, Surrey GU2 5XX, 1

2

-

UK

-J

V

J

Time to stem-cell

LV

graft (h)

Cawthorn SJ, Parums DV, Gibbs NM, et al. Extent of mesorectal spread and involvement of lateral resection margin as prognostic

Figure: Increased osmolality after infusion cryopreserved with DMSO

factors after surgery for rectal cancer. Lancet 1990; 335: 1055-59. Heald RJ. The Holy Plane of rectal suyrgery. J R Soc Med 1988; 81: 503-08.

Calculated osmolality was approximated by doubling values for serum sodium since glucose and urea concentrations remained constant

of stem-cell

graft

throughout. 1431