Download Reuben Sum - Cancer Council Australia

Research and the Changing Landscape
of Oncology:
Past, Present, and Future Trends
A review by Reuben Sum
University of Tasmania (MBBS 5)
Cancer Council Australia 2015 Essay Competition
1
Table of Contents
Contents
Introduction ............................................................................................................................... 3
The Past ...................................................................................................................................... 3
Understanding the genetics of cancer ................................................................................... 3
The influence of cancer biology ............................................................................................. 5
Expansions in epidemiological studies ................................................................................... 5
The Present ................................................................................................................................ 6
The Future .................................................................................................................................. 8
Conclusion .................................................................................................................................. 9
References................................................................................................................................ 10
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Introduction
The field of oncology has rapidly evolved since the advent of modern medicine. Although once
heralded as a death sentence, drastic improvements to all areas of cancer care have resulted
in promising outcomes worldwide.1 This is demonstrated by data highlighting a marked
decrease in mortality and improved survival rates – telling signs that cancer no longer bears
the bleak outlook it once possessed.2 At the crux of the changing face of oncology lies the
efforts of contemporary scientific inquiry and its impact in spawning a flurry of paradigm shifts
that have enabled a more intimate understanding of oncology. Cancer research has since
expanded into vast territories with the evolution of its methodology, and now encompasses a
myriad of approaches ranging from molecular to population-based studies. This has served as
an impetus for reshaping the scene of clinical practice - namely, the detection, prevention, and
treatment of many common cancer types. As a result, surgery, radiotherapy, and
chemotherapy now witness an influx of innovations at a staggering pace. Indeed, as the
complexity enveloping cancer now begins to unravel at an exponential rate, research
underpins an important frontier for ushering society into a golden age of cancer control.
This essay explores the advancements of knowledge at the molecular, biological, and
epidemiological levels and how the approaches to cancer research in these areas have
changed. Screening, prevention, and treatment are explored, and landmark achievements in
cancer research that have shaped these respective areas of oncology are examined.
Furthermore, the implications that these changes have had on clinical practice in the Australian
health system are also highlighted. Next, the trajectory of oncology is discussed. Finally, health
professionals and medical students are called upon to embrace this ever-shifting environment
as the growing tide of cancer continues to encroach on all aspects of healthcare in Australia.
The Past
Understanding the genetics of cancer
Knowledge of the molecular basis of tumour biology has been fundamental to the successes
seen in the current setting of oncology. Historical evidence suggests that past perceptions
surrounding cancer lacked a unifying theory capable of explaining its behaviour and, thus,
3
research at the time did not have a clear direction.3 A myriad of hypotheses were postulated
in an effort to explain the phenomena – imbalances in bodily fluids, trauma, parasites, and
lymphatic fluid by-products.3, 4 However, the conception of cancer research truly began after
the discovery of deoxyribonucleic acid (DNA), which served as a vital platform in underscoring
the link between genetic abnormalities of cancerous cells and the biological characteristics
conducive to further growth.4, 5
As the focus of research shifted towards the identification of important genetic associations, it
opened new opportunities for understanding the complexities of carcinogenesis, the
development of cancer cells. The ensuing discovery of vital genes critical to this process
followed suit, first beginning with the recognition of oncogenes and tumour suppressor genes,
key coding regions responsible for cellular proliferation and inhibition of growth respectively,
through experimentation on animal and human cell models.6 Subsequent discoveries of
cancer-critical genes that regulate cellular growth and differentiation, preserve genetic
integrity, and protect against damage have since been made.6, 7 Additionally, many of these
genes are now recognised as common denominators among different cancer types and
subtypes.6, 7, 8 The significance of discovering this homogeneity among cancers was two-fold –
it provided a guide for the classification of cancer subtypes and identified potential shared
treatment targets.3
Further genomic sequencing revolutionised cancer ideology by disproving previous notions
that cancer was a single, discrete anomaly, and instead began acknowledging its highly diverse
and dynamic behaviour.3 This represented a turning point in oncology; although cancers may
originate from a single cell, it is the reiterative process of clonal proliferation, genetic
diversification through mutations, and subsequent selection of favourable cells that is
ultimately responsible for the tremendous heterogeneity of malignant tissue.3, 9, 10
With the ‘multistep theory of carcinogenesis’ model now established as the archetypal
paradigm in cancer genetics, the very definition of cancer changed from a well-defined entity
to a complex spectrum of diseases.3, 7, 9 Moreover, this contemporary view of carcinogenesis
was key to explaining many facets of oncology including disease behaviour and progression,
optimising cancer medicine, and therapeutic resistance.3, 10
4
The influence of cancer biology
Advancements in understanding cancer genetics have had equally significant downstream
effects in developing principles quintessential to the future of oncology. One such progress is
seen in cancer biology, where it is now hypothesised that carcinogenesis is dictated by a
framework, unlike the chaotic phenomenon that was once purported.4, 11 In a seminal paper
describing the hallmarks of cancer, eight common traits are believed to be responsible for
altering normal cell physiology towards malignancy: self-sufficiency in growth signals,
insensitivity to anti-growth signals, evasion of programmed cell death, limitless replicative
potential, sustained growth of new blood vessels, tissue invasion and metastasis,
reprogramming of energy metabolism, and evading immune destruction.3, 11, 12
Without a doubt, the reconceptualization of cancer biology into these categories primes all
aspects of current oncological research towards greater advances. This is exemplified by the
current transition now seen in the detection of cancer at genetic and biochemical levels,
assessing the cancer susceptibility of individuals, and the development of unique therapies.11,
12
At the same time, carcinogenesis in specific cancer types are now becoming increasingly
delineated, as seen through the colorectal adenoma-carcinoma sequence which theorises the
stepwise mutations from benign cells to bowel cancer.13
Expansions in epidemiological studies
Many of the notable achievements in research and prevention have occurred in the context of
population-based studies in cancer epidemiology. With the cause of mortality shifting primarily
from infectious diseases to chronic disease during the latter part of the 20th century, study
methods began to adopt the notion that cancer had multiple causes.14 This ultimately resulted
in the recognition of extensive risk factors implicated in carcinogenesis including diet, cigarette
smoking, alcohol, occupational exposures, radiation and sunlight exposure, infections, and
hormonal factors.14, 15, 16, 17
The identification of these exogenous influences has been crucial to the scene of cancer
prevention in Australia, where changes to the exposure to risk factors have reduced incidence
rates in several cancers.18, 22 For example, establishing an association between UV radiation
and skin cancers has allowed for cost-effective solutions, such as the SunSmart awareness and
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prevention program, to be implemented widely across the nation.19, 20 Recent trends illustrate
the efficacy of these initiatives, with plateauing skin cancer incidence rates attributed to a
combination of attitude, behavioural, and structural changes.21
Similarly, the distinguishing of tobacco smoking as a major risk factor for developing many
cancers, including lung, bowel, kidney, stomach, and cervical, has been central to curbing both
incidence and mortality rates through various means.22, 23 The human papillomavirus (HPV)
vaccine against cervical cancer is one such innovative example of intervention.22, 24
One systematic review reiterates the need for large changes in infrastructure as the trends in
cancer outcomes begin to shift.14 This is demonstrated with the establishment of a number of
centralised bodies such as the Australasian Association of Cancer Registries and Cancer Council
Australia, as well as dedicated research units that encourage interdisciplinary collaboration –
for example, the Victorian Comprehensive Cancer Centre, Lowy Cancer Research Centre, and
the Ludwig Institute for Cancer Research.14, 16, 20, 25
The Present
As cancer research becomes steadfast in the Australian culture, its effects are becoming
increasingly tangible in many areas of clinical oncology. Current population data is alarming as
the number of new cases of cancer detected in 2014 was 2.6 times greater than in 1982.17
Although the ageing population and changes in risk factor exposure are thought to be
responsible, advancements in early detection through screening programs is central to this
rising trend.22 Early detection of disease is known to lead to a higher probability of survival in
many cancer types.22,
26
For this reason, Australia’s current national screening programs,
though currently limited to breast, cervical, and bowel cancers, have reflected this tenet with
greater rates detected shortly after their implementation.2, 22, 27
Techniques involved in these screening procedures are also undergoing major transitions with
the aid of clinical research, thereby adding further layers of complexity and accuracy to the
diagnosis of cancer. Emerging evidence suggests that previous screening, which relied solely
on the microscopic confirmation of disease, could be more specific with the aid of molecular
and immunochemical tests aimed at improving the yield of early precancerous changes.27, 28,
6
29
Such instances include HPV DNA testing for cervical cancer, and immunochemical faecal
occult blood tests for bowel cancer.28, 29
Furthermore, the detection of cancer biomarkers in blood tests are also in the midst of a similar
transition as longitudinal trials assess their accuracy in a multitude of cancers including breast,
ovarian, bowel, prostate, and leukaemia.27, 30, 31,
32, 33
Many of them are now considered
mainstay in determining treatment regimens - for instance, describing breast cancers based
on the composition of hormone receptors and the well-recognised biomarker, HER2.34, 35, 36
While this wide array of markers can aid in screening, classifying, and guiding treatment plans,
they can often be detrimental and cause more harm than good.37 A prime example of this is
the reliance on prostate specific antigen (PSA) for prostate cancer screening in asymptomatic
men which has led to the over-diagnosis and overtreatment of suspected cancers.37
Wide improvements in cancer treatment and the greater use of combination therapy have led
to positive outcomes among oncology patients – most notably, decreasing mortality.2, 17, 22
Over the last two decades, the survival rate of common cancers in Australia have risen by 30%;
reflecting overall changes to both the type of treatment and its increasingly multidisciplinary
input.2, 22 Surgical techniques have grown to become less invasive and, in turn, less destructive
to the patient.38 In breast cancer surgery, the evolution from mastectomy to breast
conservation surgery now allows for deformities to be avoided almost entirely while still
enabling the complete excision of tumours.38,
39
Likewise, utilising axillary dissection for
determining the spread of breast cancer, which often rendered women with intractable arm
pain and swelling, has been superseded by the minimally invasive technique of sentinel lymph
node biopsy in certain cases.40, 41
In oncology’s second arm of treatment modalities, radiotherapy, developments have been
most prevalent through technological improvements.42 This has permitted more precise
imaging of tumours, thus allowing exact doses to be delivered to tumours at all times during
radiotherapy.42 With newer devices introduced yearly, they are now encouraging meaningful
changes to the delivery of radiation.42
Even as the improvements in surgical and radiation oncology so far have been promising,
arguably the most evident manifestation of evolving oncological treatments has been in cancer
medicine. With evidence supporting the effectiveness of combination therapy, regimens
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consisting of multiple chemotherapeutic agents have since been devised, each specific for a
cancer type.43 Moreover, previous principles now act as roadmap for creating highly targeted
novel anti-tumour agents and also a revision of previous agents to inflict fewer adverse
effects.11, 12
One such medication is Herceptin, a drug used to target HER2-positive breast cancer, which
has shown to improve disease-free survival rates by 46%.44 In Australia, the 30% decrease in
mortality rate of breast cancer is credited to the introduction of Herceptin in clinical practice.45
More recent innovations are epitomised in melanoma treatments which have traditionally
proven to be a futile expense in displaying survival benefit over supportive care.46 The recent
introduction of world leading clinical trials in melanoma research now sets Australia in the map
of oncological research.46 Drawing inspiration from the hallmarks of cancer, the development
of current generation chemotherapeutic agents do not target tumour cells, but rather
potentiates the normal immune response to cancer.47, 48 With recent data underlining an
increase in 1-year survival from 30% to 80%, these treatments are indeed extraordinary in the
face of a disease once considered untreatable.47, 48
The Future
With the trajectory of oncology heading towards a positive direction, many additions to the
existing base of knowledge are expected. It is believed the trend will continue towards a highly
tailored style of medicine, with personalised molecular tests driving therapeutic planning.49
Further discovery of useful cancer biomarkers is expected, and they will guide the
classification, diagnosis, and treatment of cancers with a higher specificity.49 In addition, as the
effects of signalling and metabolic pathways affecting cancer at the microscopic level become
clearer, oncology will likely be pushed into an endless pool of new cellular interactions that
represent novel therapeutic targets.15, 16, 49
Cancer medicine is likely to once again change with the amalgamation of gene therapy and
vectors.54 These particles, which mimic viruses, have shown promising evidence of efficacy
against cancerous cells while preserving normal tissue – especially against cancers still
considered untreatable.50, 51 Certainly, they symbolise the next generation of truly non-invasive
cancer therapy.51
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Demographics are now expected to be reshaped through the combined effect of increasing
incidence, improved survival rates, and decreased mortality.22 As a result, cancer is expected
to be more prevalent in the Australian society as this survivorship population grows.22
The refocusing of cancer control towards the consequential effects after treatment is therefore
an imperative.22 Cancer survivors are prone to persistent psychological distress which can have
wide reaching and persistent effects on family, friends, and caregivers.22, 52 As such, further
research into psycho-oncology and how it can be best prevented will surely gain traction with
the maturity of cancer survivorship programs.53
Lastly, the importance of educating the future generations of health professional must be
underscored. As they will inevitably face cancer as a common comorbidity in the setting of
other health conditions, it is paramount that they possess a rigid foundation of knowledge to
be competent in managing these complex medical issues. The proposed medical education
curriculum by Cancer Council serves as a basis to introduce fundamental principles in all areas
of oncology to medical students and junior doctors.54 The complexities and nuances in
oncological practice can then be added through other Cancer Council Australia resources
directed at health professionals. To match the overwhelming and ever-evolving scope of
research, medical students can be presented with opportunities to learn the fundamentals in
scientific methodology and conduct their own studies, thereby enabling them to foster a
personal interest in cancer research.
Conclusion
The evidence presented here is a mere snapshot into this expansive field of medicine. The close
interactions between all areas of cancer research – from biology to epidemiology – proves that
they are equally important forces in improving cancer control. Although much has been
learned, the prevalence of cancer in the 21st century is a testament to how little is known. Yet,
as new accomplishments in research are appearing on a daily basis, oncology will only continue
to change and adapt until a cure is finally discovered. With juniors doctors now handed the
responsibility of a changing demographic, they must embrace this knowledge requirement and
become the bastions for improving the future landscape of oncology.
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