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1 K. Pavenski, MD FRCPC Transfusion Medicine Resident, McMaster University TMR Journal Club June 20, 2007 Risk of Cancer After Blood Transfusion From Donors.

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Presentation on theme: "1 K. Pavenski, MD FRCPC Transfusion Medicine Resident, McMaster University TMR Journal Club June 20, 2007 Risk of Cancer After Blood Transfusion From Donors."— Presentation transcript:

1 1 K. Pavenski, MD FRCPC Transfusion Medicine Resident, McMaster University TMR Journal Club June 20, 2007 Risk of Cancer After Blood Transfusion From Donors with Subclinical Cancer: A Retrospective Cohort Study

2 2 Introduction Can blood transfusion transmit cancer? YES Postulated mechanism Immune modulation Transmission of factors causally related to cancer development (ex. Oncogenic virus) Engraftment of malignant cells of donor origin Cohorts and case control studies Blomberg 1993 (case control; based on age and sex stratified analyses, odds ratio (OR) 1.74, 95% confidence interval (CI) 1.24 to 2.44 for lymphoma and skin cancer) Brandt et al 1996 (cohort; age and sex adjusted RR for Non-Hodgkin lymphoma (NHL) 1.74, 95% CI 1.24 to 2.44) Cerhan et al 2001 (cohort; age-adjusted RR for NHL 1.6, 95% CI 1.2 to 2.1)

3 3 Introduction Can blood transfusion transmit cancer? Yes Proof of principle – Cancer can be transmitted by solid organ or tissue transplant, hematopoietic stem cell transplant (HSCT) and from mother to fetus (AABB News Sept/Oct 2006) – Caveats: immunosuppression, HLA similarity, prolonged exposure, tissue damage at exposure site, etc. – Blood, HSCT and solid organ or tissue transplant can transmit oncogenic viruses (ex. HHV-8) – Needles or surgical instruments can transmit cancer cells – Cancer cells can survive in human graft recipients – Long-term donor microchimerism after blood transfusion has been demonstrated (Reed 2007)

4 4 Introduction Can blood transfusion transmit cancer? NO Case control studies (all deal with NHL) Adami et al 1997 (odds ratio 0.93, 95% CI, 0.71 to 1.23) Chow & Holly 2002 (odds ratio 1.0, 95% CI 0.84 to 1.2) Maguire-Boston et al 1999 (odds ratio 0.84, 95% CI 0.50 to 1.41) Zhang et al 2004 (odds ratio 1.0, 95% CI 0.7 to 1.3)

5 5 Introduction Can blood transfusion transmit cancer? NO Proof of principle Unsuccessful attempts at transmission of cancer to human research subjects by blood transfusion (Thiersch 1945, Lanman et al 1950) or sternal marrow route (Thiersch 1946) Intentional transfusion of blood from patients with CML to patients with AML and acute infection (Schiffer et al 1983) In rare cases malignant granulocytes persisted but recipients did not develop CML Accidental transfusion of blood from cancerous donors does not result in cancer in recipient (Vargas et al 1999 (case, CML), Greenwald 1976 (cohort, leukemia and lymphoma)) Cancer recurrence is no more likely in patients who received intra-op salvaged autologous blood versus allogeneic blood (Stoffel 2006)

6 6 Methods Design: Retrospective cohort study Goal of the study: To investigate the possible risk of cancer transmission through blood transfusion

7 7 Methods Databases: – SCANDAT All computerized registers of blood donations and transfusions maintained by blood banks and transfusion medicine clinics in Sweden from 1968-2002 and Denmark from 1982-2002 Donor and recipient variables: DOB, sex, type, number and dates of donations/transfusions Each transfused blood unit can be traced to its donor – National population and health registers of Denmark and Sweden Included national registers of migration, death, cancer and in- hospital care

8 8 Methods Recipients – All individuals with no history of cancer and who received at least 1 unit of WB, RBC, platelets, or plasma between 1968 and 2002 – All transfusions during the first 30 days after the first recorded blood transfusion were considered Donors – All donors that have contributed to the above transfusions – Precancerous blood donors - donors who have been diagnosed with malignancy (excluding non-melanoma skin cancer) within 5 years of a blood donation

9 9 Methods Definitions: Exposed – recipients of blood from precancerous donors Unexposed (controls) – recipients of blood exclusively from donors NOT diagnosed with cancer within 5 years of donation

10 10 Methods Follow-up – Started 6 months after the first recorded transfusion Recipients who developed cancer, died or emigrated within first 6 months were excluded from analysis To exclude recipients with incipient cancer – Ended on the date of first cancer diagnosis, death, emigration, or December 31, 2002 Censored all recipients who after the initial 30-day exposure period received a transfusion originating from a precancerous donor, unknown donor or a donor with less than 5 years of follow-up

11 11 Results

12 12 Table 1

13 13 Results Relative risk of cancer after transfusion with blood from a precancerous donor was assessed as incidence rate ratios estimated from Poisson regression models Potential confounding factors: – sex, age ( 70), area of residence at the time of first transfusion, ABO blood group, number of transfusions during the first 30 days after first transfusion (1-2, 3-4, 5-9, or >10 transfusions), calendar period (1968-79, 1980-89, or 1990-2002) and number of years since first transfusion (<1, 1, 2, 3-4, 5-9, 10-19, or 20-34 years) – Attained age, calendar period, and time since first transfusion were treated as time-dependent covariates allowing individuals to move between categories with time Subanalyses stratified by recipient age and sex, calendar period of transfusion, number of units administered and component type

14 14 Results All recipients Contributed 3 200 800 person-years of follow-up 29 651 primary cancers were diagnosed Exposed 12 012 (3%) of recipients Contributed 90 928 person-years of follow-up 978 cancers were recorded

15 15 Table 2

16 16 Results Overall, there was no excess of cancer among recipients who had received one or more blood products from a precancerous blood donor compared with recipients who had received blood only from non-cancerous donors Adjusted relative risk (RR) 1.00, 95% confidence interval (CI) 0.94-1.07 The relative risk was not substantially affected by sex, age, calendar period, or number of transfusions

17 17 Results Analyses stratified by sex and follow-up revealed a significantly increased cancer risk among exposed male recipients in the period between 5-9 years after the first transfusion Adjusted RR 1.19, 1.03-1.38 This was not true for women or any other follow-up period Spurious result?

18 18 Results Sensitivity analyses No obvious pattern observed when definition of precancerous blood was varied Number of yearsAdjusted RR 41.00 (0.93-1.07) 31.00 (0.92-1.07) 20.93 (0.84-1.02) 10.93 (0.81-1.05)

19 19 Results Sensitivity analyses Little variation in adjusted rate ratios of cancer among recipients of precancerous blood from donors at different anatomical sites compared to recipients of non- cancerous blood Risk of cancer transmission did not vary by type of cancer in the donor Little variation in adjusted rate ratios of site-specific cancers among recipients of precancerous blood relative to recipients of non-cancerous blood There was no excess occurrences of cancers at any specific sites in the recipients

20 20 Table 3

21 21 Table 4

22 22 Results Sensitivity analyses: No excess risk when the sites deemed at highest risk of hematogenous spread (lung, liver, skeleton and CNS) were combined Adjusted RR 1.00, 95% CI 0.85-1.17

23 23 Results Subanalysis (Danish data only) Recipients of blood from donors who presented with metastatic cancer within 5 years of donation vs. unexposed recipients had no excess cancer risk Adjusted RR 0.99 with 95% CI 0.48-1.79 Analyses according to type of blood component, storage time, and time to cancer death of the donor showed no notable variation

24 24 Critical Appraisal Were there clearly defined groups of patients, similar in all important ways other than exposure to blood from precancerous donors? Yes (Table 1) Strict definitions of exposed/unexposed to avoid misclassification Analysis restricted to individuals with at least 5 years of follow-up Follow-up began 6 months after transfusion to exclude cancers already present at first transfusion Transfusion information restricted to the first 30 days of an individual’s recorded transfusion history

25 25 Critical Appraisal Was assessment of outcomes either objective or blinded to exposure? Exposure not blinded, however, assessment was unbiased by virtue of study design Since impending cancer of a blood donor was unknown at the time of transfusion, the possibilities for confounding were limited Subanalyses taking into account other potential confounders (ex. blood group, area of residence, calendar period) yielded the same results Outcome was objective (diagnosis of cancer)

26 26 Critical Appraisal Was the follow-up of study patients long enough? Follow-up probably sufficiently long Time between exposure and clinical cancer outcome was assumed to be less than 5 years unrealistically short induction period for early stage carcinogens circulating tumour cells can be detected at an early stage (ex. 16-45% of men with localized prostate cancer have detectable disease in peripheral circulation or bone marrow) Long-term excess risk is probably very low Point estimate of relative risk is slightly below 1 with an upper 95% CI 1.38 for the follow-up period 20-34 years after first transfusion

27 27 Critical Appraisal Was the follow-up of study patients complete? Yes SCANDAT database of high quality (internally and externally consistent) Cancer registers of Sweden and Denmark are known to have a high degree of completeness

28 28 Results Do the results satisfy “diagnostic tests for causation”? Did exposure precede the onset of outcome? Yes Is there a dose-response gradient? Not observed Is association consistent from study to study? No, some studies support and others refute the association Does association make biological sense? Yes (see introduction)

29 29 Critical Appraisal Are these valid results of this harm study important? Adverse Outcome PresentAbsent Exposed Yes97811034 No28 673313 409

30 30 Critical Appraisal Are these valid results of this harm study important? Relative risk (RR) RR = [ a / (a+b) ] / [ c / (c+d) ] = [978/12012]/[28673/342082] = 0.97 Number needed to harm (NNH) NNH = 1 / [( a / (a+b) ) - ( c / (c+d))] unable to calculate

31 31 Critical Appraisal Should these valid, potentially important results change the treatment of our donors/recipients? Practice of transfusion medicine (donor suitability criteria, universal leukoreduction) in Sweden and Denmark is similar to ours LR efficiently removes spiked cancer cells from blood (Evans 1997) Study addressed risk of transfusing blood from donors with subclinical cancer Suggests that blood from donors with cancer may be safe

32 32 In lieu of discussion Cancer is common American Cancer Society 2005 1.3 million new cancer diagnoses/year 9.8 million cancer survivors in US 10 000-100 000 donors each year have cancer cells in peripheral circulation at time of donation Post-donation information (PDI) 5% of PDIs in US >1000 donors per year report a history of cancer after donation

33 33 In lieu of discussion Is this a risk to a donor? Unlikely Is this a risk to a recipient? Unlikely No current federal regulations (FDA) or industry standards (AABB) In U.S., donors evaluated and deemed suitable by a blood centre medical director

34 34 In lieu of discussion How do other blood agencies treat donors with cancer? ABC survey 2005: 65% of blood centres had a 5 year deferral for breast cancer, adenocarcinoma, and sarcoma; donor had to be cancer and treatment free before eligible to donate again 50% of blood centres permanently deferred patients with melanoma Majority of centres deferred donors with history of hematological malignancy indefinitely Majority of centres accepted donors with basal cell or squamous cell carcinoma as long as the cancers were excised and healed

35 35 In lieu of discussion How do other blood agencies treat donors with cancer? ABC survey 2005: For donors deferred with a cancer diagnosis, most centres retrieved all active products but did not perform lookback; others retrieved in-date components and performed lookback or did none of the above American Red Cross Defer donors with solid cancers for 5 years after curative treatment Donors with hematological cancers are permanently deferred) CBER workshop 1999 Cured donors should be allowed to donate

36 36 In lieu of discussion How does CBS treat donors with a history of cancer? Donors with fully treated basal cell or squamous cell carcinoma as well as treated in situ cervical carcinoma are eligible to donate Permanent deferral for all other types of cancer Retrieval of in-date components, lookback and notification of recipients at the discretion of the medical director Some CBS stats (courtesy of Heather Hume) For 2004-2006, 1750 cancer-related PDIs were reported to CBS Transfused minimum 2625 labile blood components from donors who were subsequently diagnosed with cancer

37 37 Conclusion Blood transfusions from precancerous blood donors are not associated with increased risk of cancer among recipients Should we consider accepting blood from donors with a history of cancer? Yes What type of cancer? How long after cure? Increase donor base at a price of a small (real?) risk of transmitting a cancer


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