K. Pavenski , MD FRCPC Transfusion Medicine Resident, McMaster University TMR Journal Club

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

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

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. 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. 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. 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. Results

12. Table 1

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 (<40, 40-59, 60-69, or >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. 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. Table 2

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. 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. Results • Sensitivity analyses • No obvious pattern observed when definition of precancerous blood was varied

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. Table 3

21. Table 4

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. 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. 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. 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. 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. 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. 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. Critical Appraisal • Are these valid results of this harm study important?

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. 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. 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. 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. 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. 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. 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. 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