Found in translation: Integrating laboratory and clinical oncology research
Division of Radiation Oncology, Penn State Hershey Cancer
Institute, Hershey, Pennsylvania, United States
Translational research in medicine aims to inform the
clinic and the laboratory with the results of each other�s work, and to bring
promising and validated new therapies into clinical application. While laudable
in intent, this is complicated in practice and the current state of
translational research in cancer shows both striking success stories and
examples of the numerous potential obstacles as well as opportunities for
delays and errors in translation. This paper reviews the premises, promises,
and problems of translational research with a focus on radiation oncology and
suggests opportunities for improvements in future research design. � 2008
Biomedical Imaging and Intervention Journal. All rights reserved.
Keywords: translational research, clinical trials, targeted
therapy, protons, radiation therapy
"A good many times I have been present at gatherings
of people who, by the standards of the traditional culture, are thought highly
educated and who have with considerable gusto been expressing their incredulity
of scientists. Once or twice I have been provoked and have asked the company
how many of them could describe the Second Law of Thermodynamics. The response
was cold: it was also negative. Yet I was asking something which is the
scientific equivalent of: Have you read a work of Shakespeare's?
I now believe that if I had asked an even simpler question
-- such as, What do you mean by mass, or acceleration, which is the scientific
equivalent of saying, Can you read? -- not more than one in ten of the highly
educated would have felt that I was speaking the same language. So the great
edifice of modern physics goes up, and the majority of the cleverest people in
the western world have about as much insight into it as their neolithic
ancestors would have had."
������� � CP Snow The
Two Cultures (1959)
� Italian Proverb,
loosely translated as �To translate is to betray.�
�Translation is the action of interpretation of the meaning
of a text, and subsequent production of an equivalent text, also called a
translation, that communicates the same message in another language.�
� Wikipedia accessed 1
Twenty-five years ago when I was completing my Fellowship
in Radiation Oncology there was little use of the term �translational
research�, in cancer or elsewhere in medicine. There were clinicians and there
were laboratory scientists. They kept different hours (6AM to 6PM for the
clinicians, noon to midnight for the basic scientists). They tended to differ
in age, dress, style of music, and a host of other superficialities. To some
degree they represented two tribes within the common culture of science. While
not yet speaking the different languages that Snow cites, they were clearly
using quite different dialects.
But even then some saw the need to bring these two groups
together in the service of a goal more exciting and more important what either
could do alone. One of my first mentors combined a full time cardiology
practice with running an immunology lab, which resulted in the development of
diagnostic and therapeutic antibodies against cardiac glycosides . During my
Residency in Radiation Oncology at Tufts-New England Medical Center Hospital, we had a tradition that Radiation Physicists and Radiation Biologists would
routinely attend our daily new patient presentation conference. Their
questions, often unencumbered by the then current clinical dogmas, sometimes
seemed to come out of left field, but perhaps that is where the best answers
are to be found.
Translational research has now become somewhat of a
buzzword in medicine, along with such concepts as �molecular medicine� and
�personalised medicine�. This is all to the good of medicine. The close
intermingling of theory and practice, in vitro and animal models with
the human reality of clinical practice, has brought significant advances both
in our basic understanding of the biology of human cancer and in its treatment.
Yet general acceptance of the concept does not mean that its implementation is
either widespread or easy. And contrary to the simplistic �Bench to Bedside�
slogan that we use to drum up support for translational research, in practice
it is a complex dance from bench to bedside and back again, repeatedly, with
not only the clinician and basic scientist as dancers but with the active (for
good or bad) involvement of academic, governmental, and commercial onlookers
and regulators. Recently the United States National Cancer Institute has
created a Translational Research Working Group (TRWG) specifically charged with
defining and improving the processes by which new compounds and/or devices are
brought from initial conception or discovery to the point of clinical
evaluation in patients . The general overview of this process, as well as
specific considerations apropos to the development of drugs for medical
oncology and devices for radiation oncology, have been recently published
[3-5]. In this article I will review some of the premises, explicit and
implicit, that underlie the concept of translational research, give some
examples of successful and unsuccessful attempts at their implementation, and address
structural impediments and possible solutions. The high cost and relative
inefficiency of the development of new treatments in oncology, with only a
small portion of promising new therapies proving superior to established ones,
mandates a review of our clinical research practices [6-8]. If the focus seems at
times negative, this is not because I think that translational research is a
failure, which I emphatically do not, but because I think that we often learn
more from an analysis of our failures than a celebration of our successes.
Principles of translational research
A core premise of translational research, whether in
oncology or other disciplines, is that clinical trials are more likely to
advance knowledge and lead to improved treatment when they are done in close
collaboration with basic science. Trials should not simply compare clinical
endpoints, such as survival, for patients given �Treatment A vs. Treatment B�
but also provide information which will allow testing of the proposed
underlying mechanisms behind the two treatments. This will typically entail
inclusion of some, if not all, of the following features:
- Design of clinical trials is based on laboratory observations regarding
tumour biology and agents which may be able to perturb it.
- Intermediate endpoints which may address the clinical hypothesis being
tested whether or not the primary endpoint is satisfied.
- Collection of data on additional endpoints (e.g. quality of life,
economic impact on patients and caregivers).
- Collection of biologic specimens (tumour, normal tissue, blood, urine)
for studies correlating DNA, RNA, protein, and drug metabolite information with
clinical outcomes in this trial and hypothesis generation for later studies.
- Feedback of outcome data (e.g. local control, survival, patterns of
failure) to basic scientists for evaluation of original study hypothesis and
generation of new hypotheses and agents with which to test them.
In practice these criteria are fully met in only a
minority of trials. Limitations in our understanding or the mechanisms of
actions of agents, particularly �off-target� effects, cost and difficulty of
obtaining tissue specimens from patients, especially those with solid tumours �
with which to make the desired correlations between administered agent,
molecular effects in target tissues, and clinical outcomes, as well as
commercial and academic pressures to succeed quickly � have all distorted the
idealised research process. As it is currently practised, translational
research is often too slow and ineffective in developing successful new
The development of agents which can interfere with
signaling pathways mediated through the epidermoid growth factor receptor (EGFR)
signal pathway provides a good example of the translational research approach,
including its successes, failures, and surprises. Over the past three decades,
the existence of this pathway has been recognised , leading to description of
its significance to tumour growth and frequent correlation of its activity with
resistance of tumours to treatment such as radiotherapy, the development of several
classes of agents including monoclonal antibodies directed against the receptor
(e.g. Cetuximab) and low molecular compounds (TKI) which target the ATP binding
site in the intramolecular kinase domain of the receptor , and the completion
of clinical trials evaluating several of these either as single agents or in
combination with radiation therapy or chemotherapy [11-15]. The result of this
effort has been both the approval of several agents for clinical use and marked
increase in our understanding of the biology of this signaling pathway and its
perturbation in a variety of tumours. The observation that some groups of
patients (such as nonsmoking Asian women with adenocarcinoma of the lung) had
very high response rates to TKI led to the discovery of activating mutations in
the kinase domain of the EGFR and a much better appreciation of the molecular
heterogeneity of the family of diseases we call lung cancer. While this has
been a translational success story in many respects, key elements have been
frustratingly incomplete or absent. Despite the early interest in EGFR
inhibition as a strategy for radiosensitisation, only one Phase III trial with
Cetuximab in head and neck cancer has been completed and published. Several
small Phase II trials with Cetuximab and chemoradiation have been reported in
non-small cell lung cancer (NSCLC) and have led to a currently active RTOG
Phase III trial. Correlation between either overexpression or mutation of the
EGFR in subjects on these trials has been largely lacking. Even in the much
larger trials looking at either Cetuximab or the TKI Gefitinib or Erlotinib in
NSCLC, the lack of assay standardisation has left us with a somewhat confusing
picture regarding the relative importance of mutations (which seek key for
single agent activity of the TKI in NSCLC) versus overexpression of EGFR which
may be sufficient for radiosensitisation. The relative lack of clinical success
of the TKI as radiosensitisers is surprising in view of their in vitro
activity, and it is only recently that we are beginning to recognise that while
both antibodies such as Cetuximab and TKI will block EGFR mediated cell
signaling, they do so via profoundly different ways with markedly different
downstream effects. Such facets of EGFR activity as its nuclear localisation
were unknown when these agents were developed, and the feedback from the clinic
to the laboratory that has occurred with the results of first generation trials
has greatly enhanced our understanding of EGFR biology.
Inhibition of farnesyltransferase and ras
At about the same time that the EGFR story was developing,
it was recognised that mutational activation of the ras protein was a major feature
of a variety of malignancies. It was also observed that increased ras signaling
was associated with radiation resistance in several cell lines . As is
often the case, this was first thought to be a simple phenomenon, and the
importance of the various members of the ras protein family underappreciated.
With the realisation that, for ras to play its role in cell signaling it
required post-translational modification including attachment of a prenyl group
to allow its incorporation into lipid membranes, the search was on for a
selective inhibitor of the enzyme thought to be most responsible for this, ras
farnesyltransferase (FTase). A number of compounds of varying structures were
developed which were active FTase inhibitors and which showed impressive
clinical activity against tumour lines harboring ras mutations.
In the clinic these compounds have been major
disappointments, either as single agents or in combination with chemotherapy or
radiation [17-18]. In hindsight, it seems that there were at least four key
areas in which our basic understanding of this set of signaling pathways and
its modification were inadequate to the task of developing active and specific
- Insufficient understanding of the complexity of the Ras isoform system
in human malignancies.
- Incomplete understanding of alternate prenylation pathways (e.g.
geranylgeranylation) when farnesyltransferase is inhibited.
- Other effects of the farnesyltransferase inhibitors. It is estimated
that at least 20 other proteins contain the CAAX sequence targeting them for
farnesylation. The effects of the agents developed as FTase inhibitors on these
largely unknown targets is not known.
- Lack of clear understanding as to which pathways downstream of ras were
critical for its effects on radiation sensitivity. Identification of such
pathways might lead to more selective agents for altering radiosensitivity.
While the search for agents targeting the EGFR pathway and
those targeting Ras began at about the same time, attracted considerable
commercial interest, and were touted as heralds of the new molecular oncology,
they have at present led to rather different endpoints. Detailed study of what
went right and wrong in these two approaches may be valuable in improving
future efforts at targeted drug development.
Altered Radiation Fractionation in Head and Neck, and Lung Cancer
Prior to the development of chemical agents capable of
altering the response of cells and tissues to radiation, it was recognised that
alterations in radiation fractionation could differentially affect tissues. In
classic experiments performed in the 1920s Regaud showed that small daily doses
of radiation could produce sterility in rams while preserving skin, whereas
unfractionated treatment caused desquamation without sterility . This and
similar observations led to the adoption of daily radiation fractionation for most
malignancies. In the 1960s and 1970s data in model animal systems suggested
that accelerating dose delivery, either by administering larger daily fractions
(Accelerated fractionation) or keeping the fraction size small but giving two
or more fractions on each treatment day (hyperfractionation), could increase
local tumour control . Among other possible benefits, such a technique
could be widely adopted in radiation oncology centres throughout the world,
required no new and potentially expensive technology, and did not require
infusion of any sensitising or protecting drugs. Clinical trials were soon
mounted in a variety of disease sites with particular interest being placed in
ones such as tumours of the head and neck where control of locoregional disease
is closely associated with both quality of life and survival. A recent
meta-analysis has demonstrated that both the hyperfractionated and accelerated
approaches have produced modest but significant improvements in local control,
albeit with an increase in acute toxicity .
At about the same time that these trials were being
implemented, other investigators were exploring the use of chemotherapeutic
agents such as cisplatin and carboplatin as radiation sensitisers. Thus, by the
time that results of the daily vs. accelerated or hyperfractionated radiation
trials became mature, the baseline had changed and daily radiation as a single
modality was no longer considered appropriate standard therapy for patients of
good performance status. A somewhat similar situation arose a few years later
in trials of daily radiation therapy with or without the anti-EGFR monoclonal
antibody Cetuximab. This lack of coordination of trials resulted in the current
situation in which we know that any of the three approaches, modified
fractionation and dose escalation, concurrent chemotherapy with cisplatin, or
concurrent biologic therapy with Cetuximab, is superior to conventional daily
fractionation as a single modality but we do not know whether one of these
approaches is �best� for head and neck cancer patients in general or for
It is unfortunate that we lack good correlative biologic
studies to help individualise the choice of sensitiser in specific patients (or
to identify those patients whose tumours would be controlled with conventional
therapy and who could be spared the additional toxicities associated with more
aggressive treatment). Several candidates have been suggested and appeared
promising in small studies, such as proliferative index or potential doubling
time for fractionation, ERCC1 expression for cisplatin, and EFRG expression for
Cetuximab. Unfortunately it has not been possible, to date, to do these assays
prospectively across different trials (some academic, some industry sponsored),
to obtain a better ability to select the appropriate fractionation and
sensitisation strategy on an individual patient basis.
Many factors make extrapolation from the laboratory to the
clinic difficult and inaccurate. We tend to use differing endpoints for
laboratory and clinical evaluation of agents . Most screening tests for
drug-drug or drug-radiation interactions are based on assessing relatively
early endpoints. These will assess the effects of therapy on the bulk of tumour
cells but may tell nothing about the effects of this therapy on the rare tumour
stem cells whose death or survival will determine whether the patient enjoys
long term local disease control or response followed by recurrence. In vitro
endpoints such as dye exclusion, metabolic activity, apoptosis, and short term
colony formation and in vivo ones of tumour regression and re-growth
delay are all assays of differentiated rather than stem cells. At present only in
vivo assays of local control truly address the issue of elimination of stem
cells. We have only slowly come to realise that tumors are not composed simply
of tumour cells in great numbers, but are organised tissues with stroma,
vasculature, and tumour cells, and that models addressing only a single one of
these components will rarely be accurate reflections of the clinical
situations. The recent development and modest success of anti-vascular agents
such as Bevacizumab in combination with radiation and chemotherapy attests to
the wisdom of the late Judah Folkman�s insight of many years ago that targeting
tumour vasculature might be worthwhile.
Quality assurance in radiation oncology trials
The increasing precision in determining macroscopic tumour
extent as well as radiation dose delivery which have come with the development
and introduction of 4D multimodality imaging and IGRT have increased the need
for robust quality assurance programs in clinical trials as well as routine
clinical care. The assessment of a potentially radio sensitising drug will be
confounded when there is substantial heterogeneity in the radiation dose
delivered to patients on a clinical trial designed to evaluate its efficacy.
During the past decades it has become routine for Clinical Cooperative Groups
and most commercially funded trials to implement rigorous radiation therapy
quality assurance (RTQA) procedures for credentialing radiation therapy
facilities prior to their participating in a trial and to monitor individual
cases. Even with these efforts, major variation rates of 5-10% are not uncommon,
even for relatively straightforward treatments (e.g. lateral opposed fields for
prophylactic cranial irradiation) and the potential for significant variation
increases with more complex treatments [23-28].
Pober et al. have reviewed the obstacles facing
academic medical centres conducting translational research . While their
examples came primarily from the areas of vascular biology and organ
transplantation, the general principles they identified apply equally well to
- Inadequate financial support
- Shortage of �translational investigators�
- Impediments in the academic culture to collaboration
- Academic Medical Centre structural organisation often hinders
- Regulatory impediments to translation
- Absence of mechanisms for facilitation of translational research
So long as collaboration is not actively encouraged and
incentivised, the cultural, administrative, and practical (where to meet, can
you get surgeons, medical and radiation oncologists, and biochemistry post-docs
to agree on what a �good� meeting time is) impediments to good translational
research will make it the exception rather than the rule.
Emerging Applications and Issues for Radiation Oncology
The following are a number of areas of current translational
research in radiation oncology which exemplify some of the foregoing issues.
Many others could be considered.
- The definition of target volumes for radiation therapy is coming to rely
increasingly on functional as well as the traditional anatomic information. Techniques
including PET with FDG or other tracers, MR spectroscopy, and functional MRI
give us the potential to image such biological parameters as proliferation
rate, hypoxia, specific gene expression, and correlation of anatomy with neurologic
function (e.g. language). With appropriate image fusion this will allow us to
sculpt radiation doses to volumes biologically deemed appropriate for dose
escalation . While this is an appealing approach there are few data to
indicate its practicality or correctness and clinical trials will need to
validate that the imaging indeed correlates with function, that complex
heterogeneously planned dose distributions are indeed delivered accurately, and
capture detailed patterns of failure data to correlate with delivered dose. The
implications for the RTQA process are formidable.
- The development of hypo-fractionated RT for NSCLC, pancreatic
adenocarcinoma, and other malignancies has major interplay with both physics
and biology. In physics, this has involved determination of, and adaptation to,
real-time tumour motion with respiration and cardiac activity, plus development
of better algorithms for calculating doses with small beams and air-tumour
tissue heterogeneities. In biology, the effect of large fraction size, long
overall treatment time, hypoxia, and the effects of radiation on vasculature as
well as tumour cells come into play. We are badly in need of better methods of
assessing tumour response and local control in view of the marked fibrotic
changes developing following such regimens in the chest and the frequent
intercurrent death of patients who have been treated with such regimens.
- Observations in patients with malignant mesothelioma as well as lung
cancer treated with complex conformal or IMRT plans in which large volumes of
lung are treated to low doses (e.g. 5Gy during the entire course of treatment)
have increasingly shown that the dose-volume relationships developed for
patients treated for lung cancer and Hodgkin�s disease do not adequately
predict pulmonary toxicity . The dose distributions outside the �high-dose
volume� with these newer planning approaches are very different from those from
which we had previously developed �safe� dose levels, which were based
primarily on relatively simple APPA and oblique field arrangements. The
possible role of low dose hypersensitivity in lung tissue and the interaction
between radiation and concurrent chemotherapy will also have to be considered
as we develop new guidelines for tolerance of thoracic irradiation .
- To what degree can we accept and widely implement (i.e. pay for) new
approaches based on intermediate endpoints? Or do we need to show a clear
survival or quality of life benefit before adopting �promising but unproven�
treatments? The use of proton beams to supplement or replace photon beams in
radiation oncology is an example of an emerging technology whose true clinical
value (local control and complication rates) in many common malignancies may
become known only after decades, but where intermediate endpoints (radiation
dose distributions in phantoms) are being used to justify the large cost of
construction of such facilities and where there may be substantial financial
rewards for early adopters. The physical properties of proton beams differ from
those of photon beams in several ways, particularly in the deposition of a
large amount of energy at the end of their range (the Bragg peak) and very
rapid dose falloff after this. As a result, the relative distributions of dose
to target and normal tissue volumes from proton beams should in theory be
superior to those from photon beams, leading to a better therapeutic ratio.
While this is undoubtedly true in theory, there is some question as to whether it
is actually being achieved with present implementation of proton beams in which
the beam modulation is not as advanced as with photon IMRT. Concerns have also
been raised about the late carcinogenic effects of neutron contamination using
the current implementations of scattered proton beams. But the greater question
is whether this in silico dosimetric superiority will translate to a
clinically meaningful difference in outcomes, and whether we can move to
implement this expensive technology as routine treatment for common
malignancies such as prostate, lung, and breast cancers without clinical
demonstration of benefit. (For paediatric malignancies there seems a stronger
consensus that the ability of proton therapy to reduce radiation dose to normal
tissues in young patients, for whom both growth impairment and the risk of
second malignancies are major concerns with IMRT, will make proton therapy the
treatment of choice.) For common adult malignancies, the Radiation Oncologic
community is rather sharply divided on this question and whether randomised
Phase III trials are necessary or ethical before this technology becomes widely
adopted and advertised [33-42]. Unfortunately, the issue is becoming one in
which the scientific concerns are being overwhelmed by both uncritical
enthusiasm that protons are the �magic bullet� of radiotherapy and can be
easily implemented in many facilities and by critics who assume that the high
costs of current proton facilities cannot come down substantially in the future
[43-45]. Some have argued that the benefits of protons are as obvious as those
of parachutes, another medical therapy adopted without randomised trials
[46-47]. I would argue that comparing proton and photon radiotherapy is more
like comparing two differing designs of parachutes, for which randomised trials
might not be out of the question. There is also the perception by some that
there is a lot of money to be made by early adopters, before either clinical or
regulatory reality sinks in. �The interest in protons has also been fueled by
the perception that, although (or, perhaps, because) proton facilities are
expensive, proton therapy can be highly profitable.� 
The Roles of Government and Industry
Neither laboratory nor clinical research is done in an
ivory tower or in a clinic isolated from the pressures of society. Despite
rigorous scientific design and the availability of suitable patients, these
forces can raise significant impediments to the execution of translational
The limitation of research on embryonic stem cells in the
United States during the past decade is one recent example of this. Despite
strong scientific arguments favouring the unrestricted establishment and
clinical investigation of embryonic derived stem cell lines in many areas of
medical research, Federal restrictions adopted in 2001 forbade the use of
Federal research funds for stem cell research except with a limited number of
lines which had already been established. Laboratories wishing to work with
�unauthorised� lines were required to set up redundant parallel mechanisms in
the laboratory so that equipment purchased with Federal funding for approved
research would not be used for work with these unauthorised lines. Faced with
this additional expense, a number of programs dropped their stem cell research
programs, or have had to expend additional time searching for alternative
private or state funding. Numerous scientific bodies and patient advocacy groups
have argued cogently but to date unsuccessfully against these limitations,
which appear based more on political expediency than any reasoned scientific
Commercial funding of clinical and translational research
can also introduce serious constraints on the design of clinical trials. This
is an understandable result of the differing goals of the pharmaceutical or
device manufacturer, which is to bring an effective product to market and
benefit its stockholders, and clinical researchers. Manufacturers will be
reluctant to fund trials which run a high risk of showing their product in a
less than favourable light, either ineffective or toxic, particularly before it
receives approval from the FDA for its primary indication. This has often
limited evaluation of new agents with potential clinical application as
radiosensitisers until after their initial approval. A second problem arises
when it is desired to study two or more agents which are being developed by
different manufacturers. While there may be a strong scientific reason to study
the combination, such as their inhibiting different components of a signaling
pathway, pharmaceutical companies have been highly reluctant to make their
developing agents available for such study, again largely for fear that
toxicities noted for the combination may delay approval of their agent. The
balance between patient protection and speedy development of promising new
agents is a delicate one under the best of circumstances but is complicated
further by commercial interests.
One might think that after the successful testing of a
basic hypothesis in a well-conducted clinical trial, the hard work would be
over and the newly validated therapy would see rapid clinical adoption.
Unfortunately, this has often not been the case in radiation oncology,
particularly in trials which have involved altered fractionation. Two recent examples
in lung cancer are good examples of this problem.
The North American Intergroup trial 0096 compared two
fractionation schemes, 45Gy/30fx/3wks (BID fractionation) and 45 Gy/25fx/5 wks
(QD fractionation). The BID regimen had been designed based on laboratory
observations of the minimal shoulder on the radiation dose-survival curve for
SCLC cell lines and the rapid clinical growth of this disease, and had been
tested in Phase II trials with encouraging results. Mature results of this
trial published in the New England Journal of Medicine showed a statistically
significant improvement in survival (17% vs. 27%) at five years favouring the
BID regimen . The BID regimen did cause more acute Grade 3 esophagitis but
other toxicities were similar for the QD and BID regimens. Yet few Radiation
Oncologists in the US have adopted this as a standard regimen, only about 10%.
The more popular (but not validated in Phase III trials) approach has been to
increase the total tumour dose to 60-65 Gy using daily fractionation. This
variation between evidence-based and common practice has been recognised by
leaders of the US clinical cooperative groups for more than five years during
which there have been several proposals for a randomised trial comparing a
higher dose QD regimen to the 45Gy BID regimen, which have been turned down by
the NCI on several occasions. We thus remain in a position where an evidence-based
standard has not been adopted by the practice community.
A similar situation exists in NSCLC. Again, based on
laboratory data on accelerated repopulation of tumour clonogens during a
protracted period of fractionated radiotherapy, investigators developed
accelerated fractionation schedules in which fraction size was modestly reduced
(e.g. to 1.5-1.8 Gy) but two or three fractions given per treatment day in
order to shorten the overall treatment time. The prototype of such regimens was
the British CHART (Continuous Hyperfractionatd Accelerated Radiation Therapy)
regimen which treated patients for three fractions per day, seven days a week,
delivering 54 Gy in 36 fractions over 12 treatment days. In prospective trials
this was shown to be equivalent to conventional fractionation for patients with
squamous cell head and neck cancer and superior to conventional fractionation
for both local control and overall survival for patients with NSCLC. A
subsequent trial conducted in the US compared a modification of CHART called
HART, which eliminated the weekend treatments and increased total dose to 57.6
Gy in 36 fractions over 2.5 weeks, to conventional fractionation in patients
with Stage III NSCLC following two cycles of induction carboplatin and
paclitaxel and found an improvement in median survival of 14.9 to 20.3 months
and three-year survival from 14% to 34% . These differences unfortunately
did not reach statistical significance because the trial was closed prematurely
with only half of its planned accrual.
Macbeth surveyed radiotherapy centres in the UK two years
after the publication of these results and found that only two of 22 were
offering CHART to patients with lung cancer . Several others were
considering such implementation but had not yet done so. He proposed that three
reasons were possible for this lack of adoption; the evidence was not believed,
the current financial climate limited more labour intensive fractionation
strategies, or that there were not enough patients who fit the entry
requirements of the CHART trials in routine clinical practice to make it
worthwhile. He further speculated that behind these �reasonable� concerns lay
three more important reasons not so likely to be articulated publically:
changing workflow patterns and practice culture is difficult, particularly
without strong financial or academic incentives, the potential value of curative
radiation therapy for patients with NSCLC is undervalued in the oncologic
community, and, since CHART required no new drugs or radiotherapy technology to
purchase it is without a champion in the marketplace. The general failure of
altered fractionation schemes to make major inroads into clinical practice,
while not confirming his suspicions, is certainly consistent with them. We seem
to prefer to radiosensitise with cisplatin than with fractionation even when
the results are similar.
The development of better targeted and possibly
individualised therapies raises new questions about the marketing of these
agents. An agent which can be marketed as being effective, albeit only
marginally so, for all patients with a common disease such as lung cancer has a
huge potential market. A more selective agent with a much greater likelihood of
activity but only in a select subgroup of patients with the correct pattern of
molecular targets has, from the standpoint of industry, a much smaller
potential market, yet similar development costs as a �me-too� drug for a common
indication. This leads to the realistic fear that the development and marketing
of these effective but niche agents may be left to languish, and some would
argue that the current status of radiolabelled antibody therapy for patients
with non-Hodgkin�s lymphomas is an early example of this phenomenon (53).
Translational research in its broader sense involves not
the single step of taking a clever idea from the laboratory into clinical
trial, but a coordinated series of steps back and forth between these two
partners, while a large number of not-disinterested parties including society
as a whole, its governmental representatives, public and private funding
sources, regulatory bodies look on from the side.
Academic conflicts of interest based on pride and desire
for advancement can be no less compelling and distorting of reality than the
obvious financial conflicts of interest which come with stock ownership or
commercial funding of research. The recent and ongoing controversy over the
indirect funding of a major trial evaluating CT-based screening for lung cancer
by a foundation established by the Liggett Group, a major tobacco company,
illustrates that even the perception of possible distortion of research
objectives and study design can undermine confidence in the results .
Although some have questioned whether patients are as concerned with such
conflicts of interest so long as active new treatments are developed, it seems
highly likely that governmental and academic regulatory agencies will be even
more stringent in keeping a clear separation between the commercial funding of
medical research and its design and publication. Unfortunately, with US
government funding of cancer research failing to match inflation and increasing
regulatory costs, clinical investigators increasingly find themselves in the
painful situation of having an exciting variety of agents and combinations to
test and little money to do so at a time when advances in cancer biology give
real promise of more effective treatments.
While it seems an intuitively good idea to bring together
various specialists involved in the treatment of a disease, it has not always
been easy to demonstrate objectively the benefits of such an approach. Several
studies of lung cancer treatment before and after the organisation of
multidisciplinary clinical teams have found relatively little change in either
intermediate endpoints such as time between diagnosis and treatment, percent of
patients receiving multimodality treatment, or more important clinical
endpoints such as disease-free or overall survival. It may be the case that
these were well-functioning programs before the institution of formal teams.
But it is also possible that the effective implementation of multidisciplinary
teams, whether among clinicians of varying specialties or the more complex
admixture of clinicians and basic scientists, requires active management to be
successful and cannot be left to random variation and selection (through grant
funding) of effective modes of organisation. This may indeed be one, probably
the only valid, application of intelligent design to biology. Yet the
application of formal management skills and operations research to multidisciplinary
cancer management is relatively recent.
Analysis of key milestones in the development of drugs
which have successfully negotiated the process from promising to established
has shown how tediously long this process has been . Agents were selected as
successful based on citation frequency. The average lag between publication of
the first article describing the preparation, isolation, or synthesis of a new
agent, and the publication of the first highly cited article on its clinical
application was 24 years (interquartile range 14-44 years). A secondary
analysis which considered other drugs in the same class found an even longer
lag (median 27 years, interquartile range 21-50 years). The authors observed
that �Successful translation is demanding and takes a lot of effort and time
even under the best circumstances; making unrealistic promises for quick
discoveries and cures may damage the credibility of science in the eyes of the
public.� They recommend several steps to improve the present system:
- Give proper credit and incentives to high quality clinical research
including that designed to evaluate earlier claims of effectiveness of agents.
- Encourage collaborations between basic and clinical scientists.
- Require large, robust randomised clinical trials as the criterion of
effectiveness of promising new therapies.
- �For common diseases, the research focus should be more on developing
novel agents and technologies rather than demonstrating a real but minor
benefit from an established therapy. It is unlikely that an established
treatment with a major benefit has gone unnoticed.
An additional constraint on entry of patients to clinical
trials has been the reluctance of some health insurers and other payers to
extend coverage for treatments deemed experimental, whether or not these are
part of a formal clinical trial. In some cases not only the experimental
portion of treatment but the entire treatment course has been turned down.
Attempts to better define the actual costs of participation in clinical trials
through such efforts as the Cost of Cancer Treatment Study may help convince
payers that trials which can properly identify effective treatments (and
conversely indicate which treatments are ineffective and should not be
re-imbursed) may be both scientifically valuable and cost effective . The
increasing willingness of carriers to support Oncotype� testing for women with breast cancer, with the understanding
that the identification of low risk women who do not need adjuvant chemotherapy
benefits not only the patient but saves the insurance carrier the costs of
chemotherapy, may be one example of the convergence of scientific, clinical,
and financial objectives.
The movement of senior investigators from university-based
to industrial laboratory-based research, and back again has increased in recent
years, as cultural barriers to such participation have faded, grant funding
become more scarce, and federal limitations on stem cell research constrained
some lines of investigation except with private funding . While such
increased flexibility may be all to the good it should not be forgotten that
the need to produce a marketable product has the potential to distort the goals
and means of commercial research just as much as the desire for publication and
promotion can sully the academic research enterprise. Hopefully the incremental
and ultimately self correcting methods of the scientist, whether basic or
clinical, will be able to withstand such pressures in the long run.
Fortunately, there is increasing interest in the more
efficient design and organisation of the basic, translational, and clinical
biomedical research enterprise. This is stimulated both by frustration with the
high cost and slow progress of the systems which have developed in the past as
well as recognition that the revolutions in molecular biology, synthetic
chemistry, medical imaging, and medical informatics both mandate and empower
new approaches to clinical trial design. Considerations range from modified
statistical design, use of alternative endpoints to the old 1 or 2 dimensional
response criteria, particularly for agents expected to be cytostatic rather
than cytotoxic, and better engineering of molecular specificity for
�multitargeted� agents with both activity and toxicity in model systems. This
creative ferment in trial design, along with an increasingly robust
understanding of tumour biology, provides the scientific underpinning for a
strong future for translational research in oncology.
Finally, it must be kept in mind that we have not completed
our task when we have developed an effective new therapy, but rather when we
have made it available to the patients in need of it. Such translation �from
bench to bedside to community� remains a challenge in much of medicine and will
require our personal and social commitment in the coming decades .
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|Received 10 January 2009; accepted 10 January 2009
Correspondence: Director, Division of Radiation Oncology, Clinical Director, Thoracic Oncology Program, Penn State Hershey Cancer Institute, Hershey, PA, United States. E-mail: firstname.lastname@example.org (Henry Wagner).
Please cite as: Wagner H,
Found in translation: Integrating laboratory and clinical oncology research, Biomed Imaging Interv J 2008; 4(3):e47