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Comment
www.thelancet.com/oncology Vol 18 August 2017 997
ATLG (Neovii) formulation might also profit from
these more in-depth analyses of pharmacokinetics
and pharmacodynamics, perhaps resulting in more
individualised rabbit ATLG (Neovii) dosing for different
HSCT settings. In-depth immune-reconstitution
monitoring should also be part of these studies to
better understand the effect of rabbit ATLG exposure
on functional immune reconstitution. Furthermore,
immune monitoring also helps to improve
understanding of the differences in survival between
matched and mismatched donor recipients for the
two ATLG doses tested in Locatelli and colleagues’
Article.
In conclusion, randomised trials studying different
ATLG doses, as presented by Locatelli and colleagues,
are timely and highly warranted in children. We have
learned that in children receiving a myeloablative HSCT
for a malignancy, less ATLG is more survival, particularly
for children receiving HSCT from a mismatched
unrelated donor. Future studies should focus on
analyses of pharmacokinetics and pharma codynamics to
further fine tune the dosing and in turn improve survival
chances in these vulnerable children.
Jaap Jan Boelens
Pediatric Blood and Marrow Transplantation Program, University
Medical Center Utrecht, Utrecht, 3512 EA, Netherlands
j.j.boelens@umcutrecht.nl
I declare no competing interests.
1 Storb R, Gluckman E, Thomas ED, et al. Treatment of established human
graft-versus-host disease by antithymocyte globulin. Blood 1974;
44: 56–75.
2 Storek J, Mohty M, Boelens JJ. Rabbit anti-T cell globulin in allogeneic
hematopoietic cell transplantation. Biol Blood Marrow Transplant 2014;
21: 959–70.
3 Kröger N, Solano C, Wolschke C, et al. Antilymphocyte globulin for
prevention of chronic graft-versus-host disease. New Eng J Med 2016;
374: 43–53.
4 Bacigalupo A, Lamparelli T, Barisione G, et al. Thymoglobulin prevents
chronic graft-versus-host disease, chronic lung dysfunction, and late
transplant-related mortality: long-term follow-up of a randomized trial in
patients undergoing unrelated donor transplantation.
Biol Blood Marrow Transplant 2006; 12: 560–65.
5 Walker I, Panzarella T, Couban S, et al. Pretreatment with anti-thymocyte
globulin versus no anti-thymocyte globulin in patients with
haematological malignancies undergoing haemopoietic cell
transplantation from unrelated donors: a randomised, controlled,
open-label, phase 3, multicentre trial. Lancet Oncol 2016; 17: 164–73.
6 Locatelli F, Bernardo ME, Bertaina A, et al. Efficacy of two different doses of
rabbit anti-T-lymphocyte globulin to prevent graft-versus-host disease in
children with haematological malignancies transplanted from an unrelated
donor: a multicentre, randomised, open-label, phase 3 trial.
Lancet Oncol 2017; published online July 10. http://dx.doi.org/10.1016/
S1470-2045(17)30417-5.
7 Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association
between anti-thymocyte globulin exposure and CD4+ immune
reconstitution in paediatric haemopoietic cell transplantation: a
multicentre, retrospective pharmacodynamic cohort analysis.
Lancet Haematol 2015; 2: e194–203.
8 Admiraal R, Nierkens S, de Witte MA, et al. Association between
anti-thymocyte globulin exposure and survival outcomes in adult
unrelated haemopoietic cell transplantation: a multicentre, retrospective,
pharmacodynamic cohort analysis. Lancet Haematol 2017; 4: e183–e191.
9 Admiraal R, Lindemans CA, van Kesteren C, et al. Excellent T-cell
reconstitution and survival depend on low ATG exposure after pediatric
cord blood transplantation. Blood 2016; 128: 2734–41.
See Series pages e445, e457,
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Precision medicine has been proposed as a new frontier
to tackle the emergence of non-communicable diseases.
According to one definition, “Precision medicine is a
revolutionary approach for disease prevention and
treatment that takes into account individual differences
in lifestyle, environment, and biology.”1 Prevention is
mentioned side-by-side with treatment. However, what
is precision prevention? How can it be conceptualised?
In this Comment, we raise some key considerations
relating to the development of a science of precision
prevention of cancer.
First, although some definitions clearly indicate that
the term precision refers to an application to individuals,
on occasion it is used more narrowly, with reference
to molecules—ie, a drug that is tailored to a particular
underlying molecular change in a tumour, which
happens to reside within a given individual patient.
However, although an effect might be established at the
molecular level, it is usually limited in scope and could
give the false impression of a curative or preventive
power that is absent when transferred into practice.
Availability of the tools should not be confused with
achievement of the goal. Consequently, the ‘precision’
in precision prevention should refer to the individuals
who are the target of the intervention.
Second, consideration of inter-individual variability
in prevention is hardly new—eg, a focus on more
susceptible subgroups has been discussed for decades in
relation to cancer screening. In addition, a focus on high-
risk individuals because of their genetic background
Comment
998 www.thelancet.com/oncology Vol 18 August 2017
has been repeatedly proposed—eg, screening for
phenylketonuria in newborns, which permits simple
dietary preventive actions. In this context, perhaps
the most promising example involves the genotypic
selection of individuals based on prostaglandin pathway
studies for aspirin chemoprevention in patients with
colorectal neoplasia.2 This example illustrates how
complex the application of precision to prevention
can be, because, at a molecular level, aspirin is unlikely
to exert its effects through a single pathway, but
rather through several, either independently or in
combination.2 Multiple pathways complicate the
identification of individuals who might benefit because
their status (genetic or phenotypic) would ideally need
to be assessed in relation to each molecular target.
Such additional assessments would dilute the promises
of precision prevention, especially in terms of cost-
effectiveness.
Third, as Geoffrey Rose pointed out a long time ago,
a large number of people at a small risk might give rise
to more cases of disease than the small number who are
at a high risk.3 This problem is not trivial and is related
to the frequent gap between individual and population
benefit. Rose called it the prevention paradox:
“A preventive measure which brings much benefit to the
population offers little to each participating individual.”3
The opposite is also true: a useful intervention for a
single individual might be irrelevant at the population
level. This idea is captured well by the concept of number
needed to treat (NNT)—ie, how many people need to be
treated to avoid a death or other outcomes. The NNT
depends on the efficacy of the intervention and on the
frequency of the outcome. For a frequent outcome,
the NNT will be lower—ie, fewer individuals need to
be treated to obtain a success—thus explaining the
quantitative advantage of restricting the intervention
to high-risk individuals because the frequency of the
outcome is higher among these individuals. However,
for relatively rare outcomes (as is the case for many
cancers), the NNT might be quite high, and might be
even higher if screening is needed to identify susceptible
people.
Fourth, prevention carries the risk of being
medicalised. The lure of mirroring precision therapy
with precision prevention should not be allowed to
distract from the many opportunities for prevention at
the population level.4 It would be ironic if the benefit of
a much needed shift to redress the imbalance between
cancer prevention and treatment were to be replaced
by a dominant search for a medical solution for all
impending ills, combined with a resulting imbalance
between the emphasis on the population and high-risk
groups.
The message is especially important in low-income
and middle-income countries, where even the
implementation of preventive interventions with a
strong evidence base are frustrated by major resource
constraints and other barriers.5,6 Indeed, examples
already exist, even in low-income countries, in which
affordable and applicable screening tests for high-risk
individuals might be combined with cheap and effective
drugs to reduce the cancer burden in a cost-effective
manner.7,8 However, without careful consideration being
given to equitable access, more sophisticated medical
interventions for treatment or prevention pose the risk
of exacerbating social inequalities in health, rather than
helping to resolve them.
To take the field forward, the development of a science
of precision prevention of cancer is needed to avoid
both an underestimate of the challenges and the risks of
falling into conceptual traps.
Paolo Vineis, *Christopher P Wild
MRC-PHE Center for Environment and Health, School of Public
Health, Imperial College, London, UK (PV); and International
Agency for Research on Cancer, 69008 Lyon, France (CPW)
director@iarc.fr
We declare no competing interests.
1 National Institutes of Health. The future of health begins with all of us.
2017. https://allofus.nih.gov/about/about-all-us-research-program
(accessed May 4, 2017).
2 Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of
precision chemoprevention. Nat Rev Cancer 2016; 16: 173–86.
3 Rose G. Sick individuals and sick populations. Int J Epidemiol 2001;
30: 427–32.
4 Stewart BW, Bray F, Forman D, et al. Cancer prevention as part of precision
medicine: ‘plenty to be done’. Carcinogenesis 2016; 37: 2–9.
5 Vineis P, Wild CP. Global cancer patterns: causes and prevention. Lancet
2014; 383: 549–57.
6 Bray F, Jemal A, Torre LA, Forman D, Vineis P. Long-term realism and
cost-effectiveness: primary prevention in combatting cancer and
associated inequalities worldwide. J Natl Cancer Inst 2015; 107: djv273.
7 Lemoine M, Shimakawa Y, Njie R, et al. Acceptability and feasibility of a
screen-and-treat programme for hepatitis B virus infection in The Gambia:
the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study.
Lancet Glob Health 2016; 4: e559–67.
8 Nayagam S, Conteh L, Sicuri E, et al. Cost-effectiveness of
community-based screening and treatment for chronic hepatitis B in
The Gambia: an economic modelling analysis. Lancet Glob Health 2016;
4: e568–78.
Reproduced with permission of copyright owner.
Further reproduction prohibited without permission.
- The science of precision prevention of cancer
References