- Email: [email protected]
Risk of cancer from blood donated by people with cancer
Correspondence
reduction (2% per annum) in mortality due to cardiovascular disease could save 250 000 Russian men’s lives every year. I am founder and director of ICHARM.
Harald M Lipman [email protected] ICHARM, The Dutch House, 77a Fitzjohn’s Avenue, London NW3 6NY, UK 1
2
Leon DA, Saburova L, Tomkins S, et al. Hazardous alcohol drinking and premature mortality in Russia: a population based casecontrol study. Lancet 2007; 369: 2001–09. WHO. The European health report 2005. Geneva, Switzerland: World Health Organization, 2005. http://www.euro.who.int/ document/ehr05/e87325_table4.pdf (accessed Aug 1, 2007).
for investigators from developing countries to pursue their own research goals. These investigators should concentrate their energies on doing genuine, good-quality, investigatorinitiated trials. Although the number of such centres and individuals who are committed to ensuring that clinical trials conform to the prescribed clinical and ethical standards might be small (but increasing), one hopes the efforts of such investigators3,4 are not clouded by the general negative perception in the medical literature. I declare that I have no conflict of interest.
Rakesh Jalali
Conduct of clinical trials in developing countries
Science Photo Library
It was refreshing to see Miran Epstein (June 2, p 1859)1 raise some pertinent points in response to your Editorial2 about clinical trials in developing countries. There is little doubt that the global pharmaceutical industry sees great potential for exploitation of the excellent infrastructure and less “difficult” patients and ethics committees in such countries. It is disturbing that many investigators from these countries readily agree to and, indeed, feel excited about participation in these trials. Besides the opportunity to provide a proportion of patients with “new” drugs, which would have been otherwise prohibitively expensive, investigators perceive a thrill in sharing space with well known global investigators and cooperative groups. The principal investigators are, however, almost always from the Western world. The onus of allowing such trials lies with the local investigators, who are ultimately responsible for the ethical conduct of trials. It could also be argued that such responsibility should be shared by the principal investigators, who ought to ensure ethical standards on a par with those of their own countries. Participation in “outsourced” trials provides little time and incentive 562
[email protected] Tata Memorial Hospital, Parel, Mumbai 400012, India 1 2 3
4
Epstein M. Clinical trials in the developing world. Lancet 2007; 369: 1859. The Lancet. Strengthening clinical research in India. Lancet 2007; 369: 1233. Laskar S, Gupta T, Vimal S, et al. Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubcin, bleomycin, vinblastin and dacarbazine chemotherapy: is there a need? J Clin Oncol 2004; 22: 62–68. Jalali R, Sarin R, More N, et al. Prospective neuropsychological and endocrine evaluation in children with benign/low-grade brain tumours treated with stereotactic conformal radiotherapy and conventional radiotherapy: early results of a randomised trial. NeuroOncology 2004; 6: 439.
Miran Epstein’s interesting and provocative letter1 on clinical trials in India ends with a call not for “more ethics” but for a “pharmaceutical industry with a different agenda”. Attractive as this call sounds, if it means expecting this industry to think in a fundamentally different way from other industries, it seems doomed to go unanswered. The pharmaceutical industry undoubtedly has an important role in the advance of health worldwide, but it must have effective scrutiny and appropriate limits if it is to fulfil this role. We cannot count on moral leadership to come from within the industry, but it must come from somewhere. The active participation of communities in appropriately regulating research that concerns
their people must be part of the answer, as the Lancet Editorial2 Epstein refers to suggests. Good Clinical Practice (GCP), which aims to protect study participants, must also be adhered to. The industry’s promotion of GCP and regulations such as the EU Clinical Trials Directive should be viewed positively but not uncritically. Industry’s acceptance that it needs to play by the rules to make a return on its investment suggests a measure of success for international leadership in this area. But this sword has two edges: the very regulations designed in part to keep the industry honest, by their complexity and compliance costs, might be the means by which the industry gains undue influence over trials worldwide.3 The standards we agree on must facilitate all needed trials, of whatever sponsorship, if we are to promote the integrity of research globally. I declare that I have no conflict of interest.
Stephen Howie [email protected] MRC Laboratories, Banjul, The Gambia 1 2 3
Epstein M. Clinical trials in the developing world. Lancet 2007; 369: 1859. The Lancet. Strengthening clinical research in India. Lancet 2007; 369: 1233. Hoey R. The EU clinical trials directive: 3 years on. Lancet 2007; 369: 1777–78.
Risk of cancer from blood donated by people with cancer Gustaf Edgren and colleagues (May 19, p 1724)1 report that blood transfusions from donors with precancer are not associated with increased risk of cancer among recipients. They also show that recipients of blood from donors with metastatic cancer did not have increased risk of cancer. However, some believe that malignant cells in haematological cancers are more likely to contaminate blood products than those in solid www.thelancet.com Vol 370 August 18, 2007
Correspondence
tumours. Although Edgren and colleagues showed the relative risk of cancer among recipients of blood from donors with cancers of different anatomical sites in their table 3, we would appreciate it if they could provide the relative risk for recipients of blood from donors with all the haematological cancers (including leukaemia, lymphoma, and myeloma) versus solid tumours. We declare that we have no conflict of interest.
information on potential confounding factors such as cigarette smoking, alcohol consumption, and coexisting medical disorders, suggests the possibility of residual confounding in the subgroup analysis. We declare that we have no conflict of interest.
*Young Kwang Chae, Jeong Hyun Yun [email protected] Johns Hopkins University, Baltimore, MD 21231, USA 1
Momoko Suzuki, *Hiroto Narimatsu [email protected] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya, Aichi 466-8550, Japan 1
Edgren G, Hjalgrim H, Reilly M, et al. Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study. Lancet 2007; 369: 1724–30.
Gustaf Edgren and colleagues1 concluded that their data did not support the hypothesis that recipients of blood from precancerous donors are more likely to develop cancer than recipients of blood from noncancerous donors. However, they reported that exposed male recipients had a significantly greater cancer risk than exposed recipients 5–9 years after the first transfusion. We suspect that the reported finding probably results from random error in their subgroup analysis. Lagakos2 mentioned this problem of increasing false-positive reports in subgroup analyses. Assuming the same effects across strata, the probability of finding at least one significant result by chance alone increases when undertaking eight independent subgroup analyses, as is the case in Edgren and colleagues’ analysis (“sex” by four categories of “time since first transfusion”). Moreover, subgroup analyses always risk being biased. Subgroups do not contain the balance between confounding factors seen in the whole cohort. The fact that screening for hepatitis C virus was not available before 1990,3 and that there is no www.thelancet.com Vol 370 August 18, 2007
2
3
Edgren G, Hjalgrim H, Reilly M, et al. Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study. Lancet 2007; 369: 1724–30. Lagakos SW. The challenge of subgroup analyses—reporting without distorting. N Engl J Med 2006; 354: 1706–17. Degos F. Epidemiology of hepatitis C virus in Europe. FEMS Microbiol Rev 1994; 14: 267–71.
Authors’ reply Momoko Suzuki and Hiroto Narimatsu wish us to add to the list of subgroup analyses in our paper. Young Kwang Chae and Jeong Hyun Yun, on the other hand, voice concern about chance findings as the number of subgroup analyses increases. We took an intermediate standpoint, inspired by Rothman.1 Although adjustment of the p value, as advocated by many, including Lagakos,2 might help researchers realise the true effect of repeated significance testing, reducing the false-positive rate for null associations also reduces the statistical power for detection of true associations. Rothman1 claims that not making adjustments for multiple comparisons will lead to fewer errors of interpretation when the data under evaluation are actual observations on nature and not random numbers. Our final interpretation of the moderate but significant excess risk among men 5–9 years after the transfusion of “cancerous” blood was therefore a hybrid of statistical reasoning and biology-based causal inference. Knowing that the risk of a false-positive result was substantial, and in light of the absence of any excess in the corresponding stratum of women—and without any plausible biological mechanism by which men
would be affected but not women— we interpreted it as a chance finding. We are glad to learn that Chae and Yun share our interpretation. In terms of Chae and Yun’s concerns about increased bias among subgroups, we wish to emphasise that balance between confounding factors was never expected in this observational study. The impending cancer of a blood donor was unknown at the time of transfusion, and of the allocation of “cancerous” or “non-cancerous” blood to the single patient contained an element of chance. However, any factor that was linked both to the probability of getting “cancerous” blood and to the risk of subsequent cancer (ie, number of transfusions, linked to subsequent cancer risk via the underlying disease, area of residence, calendar period, and possibly blood group) had to be adjusted for in all our models. Cigarette smoking and alcohol consumption, proposed by Chae and Yun, are unlikely to be confounders. Although they are associated with cancer in the recipient, they are not linked to the probability of getting blood from a “cancerous” donor. The comparison requested by Suzuki and Narimatsu would be expected to yield similar or smaller associations than comparisons of blood from donors who had leukaemias or lymphomas with “non-cancerous” blood (table 3 of our paper) but with the additional concern of multiple testing. We did such an analysis and found no indication that recipients exposed to blood from donors with haematological cancers were more likely to develop a cancer than were those exposed to blood from donors with solid cancers (adjusted incidence rate ratio 0·93, 95% CI 0·72–1·18). We declare that we have no conflict of interest.
*Olof Nyrén, Gustaf Edgren, Henrik Hjalgrim, Marie Reilly, Mads Melbye [email protected]
563
reduction (2% per annum) in mortality due to cardiovascular disease could save 250 000 Russian men’s lives every year. I am founder and director of ICHARM.
Harald M Lipman [email protected] ICHARM, The Dutch House, 77a Fitzjohn’s Avenue, London NW3 6NY, UK 1
2
Leon DA, Saburova L, Tomkins S, et al. Hazardous alcohol drinking and premature mortality in Russia: a population based casecontrol study. Lancet 2007; 369: 2001–09. WHO. The European health report 2005. Geneva, Switzerland: World Health Organization, 2005. http://www.euro.who.int/ document/ehr05/e87325_table4.pdf (accessed Aug 1, 2007).
for investigators from developing countries to pursue their own research goals. These investigators should concentrate their energies on doing genuine, good-quality, investigatorinitiated trials. Although the number of such centres and individuals who are committed to ensuring that clinical trials conform to the prescribed clinical and ethical standards might be small (but increasing), one hopes the efforts of such investigators3,4 are not clouded by the general negative perception in the medical literature. I declare that I have no conflict of interest.
Rakesh Jalali
Conduct of clinical trials in developing countries
Science Photo Library
It was refreshing to see Miran Epstein (June 2, p 1859)1 raise some pertinent points in response to your Editorial2 about clinical trials in developing countries. There is little doubt that the global pharmaceutical industry sees great potential for exploitation of the excellent infrastructure and less “difficult” patients and ethics committees in such countries. It is disturbing that many investigators from these countries readily agree to and, indeed, feel excited about participation in these trials. Besides the opportunity to provide a proportion of patients with “new” drugs, which would have been otherwise prohibitively expensive, investigators perceive a thrill in sharing space with well known global investigators and cooperative groups. The principal investigators are, however, almost always from the Western world. The onus of allowing such trials lies with the local investigators, who are ultimately responsible for the ethical conduct of trials. It could also be argued that such responsibility should be shared by the principal investigators, who ought to ensure ethical standards on a par with those of their own countries. Participation in “outsourced” trials provides little time and incentive 562
[email protected] Tata Memorial Hospital, Parel, Mumbai 400012, India 1 2 3
4
Epstein M. Clinical trials in the developing world. Lancet 2007; 369: 1859. The Lancet. Strengthening clinical research in India. Lancet 2007; 369: 1233. Laskar S, Gupta T, Vimal S, et al. Consolidation radiation after complete remission in Hodgkin’s disease following six cycles of doxorubcin, bleomycin, vinblastin and dacarbazine chemotherapy: is there a need? J Clin Oncol 2004; 22: 62–68. Jalali R, Sarin R, More N, et al. Prospective neuropsychological and endocrine evaluation in children with benign/low-grade brain tumours treated with stereotactic conformal radiotherapy and conventional radiotherapy: early results of a randomised trial. NeuroOncology 2004; 6: 439.
Miran Epstein’s interesting and provocative letter1 on clinical trials in India ends with a call not for “more ethics” but for a “pharmaceutical industry with a different agenda”. Attractive as this call sounds, if it means expecting this industry to think in a fundamentally different way from other industries, it seems doomed to go unanswered. The pharmaceutical industry undoubtedly has an important role in the advance of health worldwide, but it must have effective scrutiny and appropriate limits if it is to fulfil this role. We cannot count on moral leadership to come from within the industry, but it must come from somewhere. The active participation of communities in appropriately regulating research that concerns
their people must be part of the answer, as the Lancet Editorial2 Epstein refers to suggests. Good Clinical Practice (GCP), which aims to protect study participants, must also be adhered to. The industry’s promotion of GCP and regulations such as the EU Clinical Trials Directive should be viewed positively but not uncritically. Industry’s acceptance that it needs to play by the rules to make a return on its investment suggests a measure of success for international leadership in this area. But this sword has two edges: the very regulations designed in part to keep the industry honest, by their complexity and compliance costs, might be the means by which the industry gains undue influence over trials worldwide.3 The standards we agree on must facilitate all needed trials, of whatever sponsorship, if we are to promote the integrity of research globally. I declare that I have no conflict of interest.
Stephen Howie [email protected] MRC Laboratories, Banjul, The Gambia 1 2 3
Epstein M. Clinical trials in the developing world. Lancet 2007; 369: 1859. The Lancet. Strengthening clinical research in India. Lancet 2007; 369: 1233. Hoey R. The EU clinical trials directive: 3 years on. Lancet 2007; 369: 1777–78.
Risk of cancer from blood donated by people with cancer Gustaf Edgren and colleagues (May 19, p 1724)1 report that blood transfusions from donors with precancer are not associated with increased risk of cancer among recipients. They also show that recipients of blood from donors with metastatic cancer did not have increased risk of cancer. However, some believe that malignant cells in haematological cancers are more likely to contaminate blood products than those in solid www.thelancet.com Vol 370 August 18, 2007
Correspondence
tumours. Although Edgren and colleagues showed the relative risk of cancer among recipients of blood from donors with cancers of different anatomical sites in their table 3, we would appreciate it if they could provide the relative risk for recipients of blood from donors with all the haematological cancers (including leukaemia, lymphoma, and myeloma) versus solid tumours. We declare that we have no conflict of interest.
information on potential confounding factors such as cigarette smoking, alcohol consumption, and coexisting medical disorders, suggests the possibility of residual confounding in the subgroup analysis. We declare that we have no conflict of interest.
*Young Kwang Chae, Jeong Hyun Yun [email protected] Johns Hopkins University, Baltimore, MD 21231, USA 1
Momoko Suzuki, *Hiroto Narimatsu [email protected] Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumaicho, Showa-ku, Nagoya, Aichi 466-8550, Japan 1
Edgren G, Hjalgrim H, Reilly M, et al. Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study. Lancet 2007; 369: 1724–30.
Gustaf Edgren and colleagues1 concluded that their data did not support the hypothesis that recipients of blood from precancerous donors are more likely to develop cancer than recipients of blood from noncancerous donors. However, they reported that exposed male recipients had a significantly greater cancer risk than exposed recipients 5–9 years after the first transfusion. We suspect that the reported finding probably results from random error in their subgroup analysis. Lagakos2 mentioned this problem of increasing false-positive reports in subgroup analyses. Assuming the same effects across strata, the probability of finding at least one significant result by chance alone increases when undertaking eight independent subgroup analyses, as is the case in Edgren and colleagues’ analysis (“sex” by four categories of “time since first transfusion”). Moreover, subgroup analyses always risk being biased. Subgroups do not contain the balance between confounding factors seen in the whole cohort. The fact that screening for hepatitis C virus was not available before 1990,3 and that there is no www.thelancet.com Vol 370 August 18, 2007
2
3
Edgren G, Hjalgrim H, Reilly M, et al. Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study. Lancet 2007; 369: 1724–30. Lagakos SW. The challenge of subgroup analyses—reporting without distorting. N Engl J Med 2006; 354: 1706–17. Degos F. Epidemiology of hepatitis C virus in Europe. FEMS Microbiol Rev 1994; 14: 267–71.
Authors’ reply Momoko Suzuki and Hiroto Narimatsu wish us to add to the list of subgroup analyses in our paper. Young Kwang Chae and Jeong Hyun Yun, on the other hand, voice concern about chance findings as the number of subgroup analyses increases. We took an intermediate standpoint, inspired by Rothman.1 Although adjustment of the p value, as advocated by many, including Lagakos,2 might help researchers realise the true effect of repeated significance testing, reducing the false-positive rate for null associations also reduces the statistical power for detection of true associations. Rothman1 claims that not making adjustments for multiple comparisons will lead to fewer errors of interpretation when the data under evaluation are actual observations on nature and not random numbers. Our final interpretation of the moderate but significant excess risk among men 5–9 years after the transfusion of “cancerous” blood was therefore a hybrid of statistical reasoning and biology-based causal inference. Knowing that the risk of a false-positive result was substantial, and in light of the absence of any excess in the corresponding stratum of women—and without any plausible biological mechanism by which men
would be affected but not women— we interpreted it as a chance finding. We are glad to learn that Chae and Yun share our interpretation. In terms of Chae and Yun’s concerns about increased bias among subgroups, we wish to emphasise that balance between confounding factors was never expected in this observational study. The impending cancer of a blood donor was unknown at the time of transfusion, and of the allocation of “cancerous” or “non-cancerous” blood to the single patient contained an element of chance. However, any factor that was linked both to the probability of getting “cancerous” blood and to the risk of subsequent cancer (ie, number of transfusions, linked to subsequent cancer risk via the underlying disease, area of residence, calendar period, and possibly blood group) had to be adjusted for in all our models. Cigarette smoking and alcohol consumption, proposed by Chae and Yun, are unlikely to be confounders. Although they are associated with cancer in the recipient, they are not linked to the probability of getting blood from a “cancerous” donor. The comparison requested by Suzuki and Narimatsu would be expected to yield similar or smaller associations than comparisons of blood from donors who had leukaemias or lymphomas with “non-cancerous” blood (table 3 of our paper) but with the additional concern of multiple testing. We did such an analysis and found no indication that recipients exposed to blood from donors with haematological cancers were more likely to develop a cancer than were those exposed to blood from donors with solid cancers (adjusted incidence rate ratio 0·93, 95% CI 0·72–1·18). We declare that we have no conflict of interest.
*Olof Nyrén, Gustaf Edgren, Henrik Hjalgrim, Marie Reilly, Mads Melbye [email protected]
563