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K. Pavenski, MD FRCPCTransfusion Medicine Resident, McMaster University

TMR Journal ClubJune 20, 2007

Risk of Cancer After Blood Transfusion From Donors with Subclinical Cancer:

A Retrospective Cohort Study

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IntroductionCan 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 studiesBlomberg 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)

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IntroductionCan 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)

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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)

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IntroductionCan blood transfusion transmit cancer? NO

Proof of principleUnsuccessful 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)

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MethodsDesign:

Retrospective cohort studyGoal of the study:

To investigate the possible risk of cancer transmission through blood transfusion

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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

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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

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MethodsDefinitions:

Exposed – recipients of blood from precancerous donors

Unexposed (controls) – recipients of blood exclusively from donors NOT diagnosed with cancer within 5 years of donation

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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

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Results

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Table 1

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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

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ResultsAll recipients

Contributed 3 200 800 person-years of follow-up29 651 primary cancers were diagnosed

Exposed12 012 (3%) of recipientsContributed 90 928 person-years of follow-up978 cancers were recorded

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Table 2

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ResultsOverall, 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) 0.94-1.07The relative risk was not substantially affected by

sex, age, calendar period, or number of transfusions

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ResultsAnalyses 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 transfusionAdjusted RR 1.19, 1.03-1.38

This was not true for women or any other follow-up period

Spurious result?

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ResultsSensitivity analyses

No obvious pattern observed when definition of precancerous blood was varied

Number of years Adjusted RR

4 1.00 (0.93-1.07)

3 1.00 (0.92-1.07)

2 0.93 (0.84-1.02)

1 0.93 (0.81-1.05)

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ResultsSensitivity 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

donorLittle variation in adjusted rate ratios of site-specific

cancers among recipients of precancerous blood relative to recipients of non-cancerous bloodThere was no excess occurrences of cancers at any specific sites

in the recipients

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Table 3

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Table 4

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ResultsSensitivity analyses:

No excess risk when the sites deemed at highest risk of hematogenous spread (lung, liver, skeleton and CNS) were combinedAdjusted RR 1.00, 95% CI 0.85-1.17

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ResultsSubanalysis (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 riskAdjusted 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

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Critical AppraisalWere 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

misclassificationAnalysis restricted to individuals with at least 5 years of follow-

upFollow-up began 6 months after transfusion to exclude cancers

already present at first transfusionTransfusion information restricted to the first 30 days of an

individual’s recorded transfusion history

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Critical AppraisalWas assessment of outcomes either objective or blinded

to exposure?Exposure not blinded, however, assessment was

unbiased by virtue of study designSince impending cancer of a blood donor was unknown at the

time of transfusion, the possibilities for confounding were limitedSubanalyses taking into account other potential confounders (ex.

blood group, area of residence, calendar period) yielded the same results

Outcome was objective (diagnosis of cancer)

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Critical AppraisalWas the follow-up of study patients long enough?

Follow-up probably sufficiently longTime 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 lowPoint 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

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Critical AppraisalWas the follow-up of study patients complete?

YesSCANDAT database of high quality (internally and

externally consistent)Cancer registers of Sweden and Denmark are known to

have a high degree of completeness

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ResultsDo the results satisfy “diagnostic tests for

causation”?Did exposure precede the onset of outcome?

YesIs there a dose-response gradient?

Not observedIs association consistent from study to study?

No, some studies support and others refute the associationDoes association make biological sense?

Yes (see introduction)

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Critical AppraisalAre these valid results of this harm study important?

Adverse Outcome

Present Absent

Exposed

Yes 978 11034

No 28 673 313 409

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Critical AppraisalAre 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

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Critical AppraisalShould 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 oursLR efficiently removes spiked cancer cells from blood (Evans

1997) Study addressed risk of transfusing blood from donors

with subclinical cancerSuggests that blood from donors with cancer may be safe

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In lieu of discussionCancer is common

American Cancer Society 20051.3 million new cancer diagnoses/year9.8 million cancer survivors in US10 000-100 000 donors each year have cancer cells in peripheral

circulation at time of donationPost-donation information (PDI)

5% of PDIs in US>1000 donors per year report a history of cancer after donation

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In lieu of discussionIs this a risk to a donor?

UnlikelyIs this a risk to a recipient?

UnlikelyNo current federal regulations (FDA) or industry

standards (AABB)In U.S., donors evaluated and deemed suitable by a

blood centre medical director

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In lieu of discussionHow 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

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In lieu of discussionHow 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 CrossDefer donors with solid cancers for 5 years after curative

treatmentDonors with hematological cancers are permanently deferred)

CBER workshop 1999Cured donors should be allowed to donate

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In lieu of discussionHow 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 cancerRetrieval of in-date components, lookback and notification of

recipients at the discretion of the medical directorSome 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

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ConclusionBlood 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