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Cancer treatment has come far over the ages; from the barbaric beginnings of radical mastectomies and infusions of mustard gas¹, to the robotic thyroidectomies of today, and cancer outcomes have followed suit^2,3. This is largely attributable to dramatic leaps forward in medical knowledge garnered from research⁴. In order for advancements in treatments to continue, it becomes apparent that continuing our investment into research is necessary. But in order to maximise our impact, we must consider the direction oncology and treatments are heading, invest in the most promising of prospects, and ensure our research system has maximal efficiency.

In this essay, I'll discuss the changing nature of cancer treatments and outline where and how we should direct our research to achieve maximum improvements for patients. I'll also delve into the challenges clinical and academic research face, and suggest systemic solutions that will ensure research of all kinds are done in the most time-and-cost efficient manner. And finally, I'll discuss the importance of preparing future physicians to deliver the fruits of research.

The Changing Landscape of Oncology:

Epidemiological: Increasing Incidence Due to Age

Before discussing solutions we need establish how the field is changing. Largely preventable cancers, like lung and colorectal cancer, are declining or stabilizing in most-all developed nations^5,6, following improved treatments, systems, screening programs and prevention measures^7,8. But overall, in the developed world, cancer incidence by type is changing slowly⁵. The major epidemiological change is an increase in overall cancer incidence due to an older population^9-11, who, through various intracellular and extracellular processes, are more likely to develop cancer^12,13. Hence research, especially clinical-trial research, should reflect lower tolerance of toxicities, higher rates of co-morbidities¹⁴, and other factors prevalent in older populations.

Biological: The Targeted, Personalised Future

Where oncology is changing most though is in the direction of new treatments, and advances in cancer genomics is driving much of this change. The human Genome sequence set the ground-layer of this field, allowing for cancer genome analysis to occur, and predictions of cancer genomics leading to cancer biology discoveries and guiding patient treatments are already proving true¹⁵. Large projects such as The Cancer Genome Project and The Cancer Genome Atlas, which identify and store tumour-mutation profile in databases and direct research from data collected, have already elucidated aspects of cancer biology and development^47,48, found potential targets for therapeutics^17,18and highlighted many tumour profiles that influence clinical management of individual patients today^16,19-21.

The latter benefit of genomics describes another growing trend of personalisation in cancer treatment, and this has led to new lines of treatment that differ from traditional small-molecule (small, biochemically active molecules that engage with pathways of cancer development and progression) applications. Biologicals, such as monoclonal-antibodies and growth factors are being recognised for their more targeted, less toxic applications²⁵as well as their increased likelihood to pass early drug development²³, and are already attracting more pharmaceutical patents than small-molecules²⁴. Biologicals also offer novel avenues of delivering drugs to cancer sites and cells^26,27, especially significant given our growing knowledge of the importance of the tumour-microenvironment in promoting tumour survival and protecting them from drugs^39-41,49,50, joining the ranks of other innovative delivery systems such as nanotechnology^28,29. Microenvironment importance has also driven new lines of therapy targeting angiogenesis⁵⁰, epidermal-growth-factor and downstream pathways^109,110, and the newfound understanding of the role of stem cells in tumour growth and recurrence are leading to new therapeutic lines too^42-44.

Biologicals have also opened up many exciting avenues in an already exciting field of therapy; immunotherapy²². In addition to the recent discovery and early trial successes of checkpoint inhibitors that work on CTLA4, PD1 and PDL1, which work by allowing patients' immune systems to recognise and kill cancers^30,31, the use of biologicals like monoclonal antibodies, which attack cancers by targeting or attaching to proteins on cancer cell or host tissue surfaces^32-34, cancer-antigen vaccines^35-37and T-Cell Modification therapies³⁸, which prime patients' immune cells to recognise and kill tumours, are promising potential treatments.

When these are combined with increasing discoveries into processes that aid cancer treatment and research, such as the discovery of new bio-markers and the development of adaptable trial-designs^45,46, future avenues of cancer research are promising, varied and diverse. But due to the more isolated nature of these targets, the heterozygous natures of tumour mutations, and the multitude of tumour-genesis and survival pathways^15,41,42-44, these treatments need be combined for maximal clinical benefit.

Translational: Less New Drugs, More Expensive Research

Yet though there are many avenues, and much research directed to new treatment pathways, less and less are being translated into treatments. Industry, which funds the vast majority of clinical trials⁵¹, is bringing significantly less new molecular entities(NMEs) to the market each year^52-55, despite exponential increases in the amount invested into trial research^53-55.

The tremendous, increasing cost of developing and funding drugs through clinical trials and approval is the reason behind this reluctance to invest in new therapies. Funding a drug from early trials to approval costs in excess of a billion dollars^70-73, with more recent analyses showing companies spend as much as 4-11billion per drug⁷⁸. This takes between 11 and 14years⁷⁴; all for a 6-11%^75-77chance of being approved for sale. Most of this is attributable to increased regulatory requirements⁷⁹, reduction in effective patent, marketable, length, by a third^80,81,a shift to more targeted treatments, causing drug peak-sales to halve⁸²,and higher attrition rates in early discovery⁸¹.

Big-Pharma has reacted. Since 2008, pipeline sizes have decreased by a fifth in top Companies like Pfizer, with the proportion of budget diverted to R&D following suit^56-60, and patent filings have also fallen by nearly a third industry-wide⁶¹, highlighting this reluctance to initiate new projects. Simultaneously, marketing and sales, which obscure and corrupt physician judgement^62,83and harm investor confidence through bloated sales forecasts⁶³, have increased to half the budget; double that of R&D spend^62,64. The nature of drugs developed are also impacted by the nature of pharmaceutical investments, with more “Me-Too”, copy-cat drugs; ones that mimic the actions of already developed drugs, hence producing only-slightly-better-than-previous outcomes, being funded in preference to novel ones^65,66. Also observable is a focus on blockbuster drugs, those targeting diseases with larger markets, which garner higher returns^67,68over rarer, underfunded diseases like neuroendocrine cancers^4,69. Other factors such as managerial pressure to deliver short-term profits exacerbate this⁶⁸, but the reluctance to initiate projects by industry is by far motivated mostly by this cost/time intensive, risky investment that is drug development. In order to stimulate industry, more streamlined, innovative trial structures must be enacted to reduce costs and foster innovation.

How to Increase Clinical Trial Outputs Which Create New Treatments

The changing nature of oncology established above highlights that systematic changes need be implemented to ensure continued improvement of cancer outcomes. The Australian government can play a crucial role in strengthening clinical trial infrastructure and funding to support industry in Australia, and electronic databases may present a unique opportunity to do this. Research, both industry-funded and academic, should be directed toward promising avenues of cancer research, and strategic direction and partnerships can improve output.

Improving Clinical Trial Infrastructure

Australian clinical-trial centres have great potential in attracting more industry activity that benefits not only oncology, but also overall care for Australians. Australia is already renowned as a quality nation to conduct trials in; we produce high quality, reliable data accepted by regulatory bodies around the world, have fast ethics-approval structures and an informed and willing population^84,85. But Lisa Askie, the manager of the Australia/New-Zealand Clinical Trial Registry, professed, in an interview I conducted with her that Australia needs “more investment in clinical trial infrastructure”, as sites are “underequipped” and “many trials are done on investigator initiative” with little in the way of compensation made for clinical staff conducting trials⁸⁵. The government’s role in this is clear. Though industry funds nearly 70% of trials in Australia⁵¹, it employs only a quarter of clinical-trial staff⁵¹. She pointed to the UK’s system in particular as one to emulate.

The UK implemented the National Cancer Research Network after noting their cancer survival and cancer-trial recruitment rates were remarkably low compared to other developed nations^86-88. The central features of this overhaul included increasing the number of clinical trial sites along geographic distributions, increasing clinical-trial staff, coordinating both research focuses and enrolment services nationally to increase synergy in the system, and increased funding to public research bodies^86,88,89. And it worked. Cancer clinical trial participation increased five-fold⁸⁸to world-leading rates, clinical-trial recruitment target fulfillment nearly doubled⁸⁸, and, most importantly, improvements in patient outcomes and access to trials and new drugs were noted^90-92. Hospitals that conducted trials provided better care with lower mortality rates, likely due to more trained, up-to-date physician teams⁹². Increased economic benefits from industry was also observed, with industry-funded trial staff and investigator numbers rising⁸⁸. Liverpool Hospital, Sydney, has self-funded the establishment of its own clinical-trial site to a point where it's self sustaining, and even bringing profits to the hospital, showing such increases to infrastructure is feasible in Australia too¹³⁷. With Australia’s already positive physician perception of clinical trials⁵¹and the fact that industry provides $650million in investments⁹³ and $100million in healthcare savings to the nation⁹⁴, it’s clear that any government investment that facilitates more clinical trials in Australia is a wise one.

Using Technology to Reduce Time and Costs Taken to Trial.

Though structural changes to clinical trial funding is invaluable as a means of reducing time/cost taken to trial, technology has even greater potential to streamline the clinical trial process. Factors that have escalated the time-and-cost of conducting clinical trials exponentially are systemic and greatly increase pre-trial attritions of potentially game-changing compounds too^68,100. 90% of clinical trials are finished later than scheduled, with patient recruitment accounting for a quarter, and data collection and discrepancy resolution taking up two-fifths, of time^96,97. The reasons for the former are varied; physicians don’t even consider clinical-trials 40% of the time⁹⁸, patients are hardly aware of their existence^98,136, and even physical encumbrances like distance from trial centre hamper patients’ trial enrolment rates^98,99.

In his best-seller, Bad Pharma, Ben Goldacre not only lambasts Big-Pharma for their unscientific, unethical practices, but also suggests a novel solution for these issues that is currently being trialled in the UK^83,95. He proposed that Electronic Medical Records (EMRS) be harnessed as tools to conduct live, randomised trials, arguing key issues prolonging time to trial like time spent recruiting patients, data-collection delays, and also that overall trial costs would fall significantly through such a scheme^83,101.They have added benefits of being able to conduct retrospective analyses; saving millions in PhaseIV study costs, provide more clinically relevant and representative results, and can even evaluate combinational therapies¹⁰¹. Research applications of EMRs has been recommended by the American College of Physicians¹⁰³, but in establishing such a system in Australia, measures like communicating benefits and privacy-securing measures to the public; why UK’s Care.Data failed to pass parliament¹⁰², ironing out ethics and efficiency issues^101,104, and forward thinking in database-design, which minimises complex, costly data-mining and ensures data quality^105,106, need to be considered to ensure our E-Health Record is widely used and effective for research purposes.

How to Promote Combinational Trialling of Therapeutics

The ability to study the effects of combinational therapies is a promising application of trial-friendly EMRs, but even if they were to exist now, industry and regulatory bodies need to modify policy to facilitate their trialling. Many upcoming drugs, due to the trend of more targeted therapeutics being developed, isolate single strands of the web of cancer-cell biology, and, when used alone, will allow cancers to survive down alternate pathways, resulting in reduced success and increased relapse rates^{15,41,42-44,107-110}. Hence combination therapies warrant further investigation. However, though there are many examples of combinational therapies improving care outcomes significantly, between both standard^114-116, and more targeted therapies^111-113, regulatory bodies’ policies currently restrict their investigation. The FDA heretofore have required such therapies to be given in fixed-dose combinations; in the same vial or tablet with set compound ratios¹¹⁷; understandably hard for biologics, which usually require intravenous administration²⁵, personalised immunotherapies, and personalised dose-analysis studies, to do. They've responded to the need though by drafting a policy that allows two therapies to be combined into one “co-development” study, and data to demonstrate the contributions of each drug to be attained from earlier trials or pharmacological studies rather than expensive, time-consuming, clinical-trials¹¹⁸. This should stimulate more investigation. But another factor which stops these combination studies from happening is the conflicting financial interests of pharmaceuticals.

How to Streamline Basic Discovery/Development Research

Teamwork Strategies That Unite Researchers From All Sectors

The latter factor is one that seems impossible to evade, but recently, teamwork has become prominent in cancer research; something much needed⁴⁵. Consortia, an association of multiple bodies with shared research goals, bring together all sectors; not-for-profits, government and industry, to create broadly-usable tools such as biomarkers (useful for diagnostics, clinical trial evaluation and acceleration of drug discovery/development¹²¹) that would otherwise be deemed too economically infeasible to fund by singular entities¹²⁰. Data-sharing is also a focus of many consortia, reducing wasteful duplication of research and producing invaluable knowledge-platforms, such as the cancer genomics consortia discussed above^47,48,120. The development of innovative Intellectual Property contracts in Industry Consortia, that allow short term exclusivity of discoveries made by members, also spells out future hope for industry working together on projects where both parties can benefit, such as combinational therapies¹¹⁷.

Strategically Directing Basic research

Foundation and government research is a lifeline for treatment development, and should also be optimised through teamwork and strategy. Basic research required to discover biochemical pathways and therapeutic targets and proof of concepts, seen as the investment “valley of death” by pharmaceuticals¹²², for their inability to deliver profits, are essential to therapy development. 85% of this research is funded by governments and foundations¹²³. In addition, rare or neglected diseases, and recent personalised immunotherapy developments, which are largely unprofitable, require this sectors’ funding^{4,120,122,124}.

Innovative, assertive, collaborative strategies, such as the one used by Australia’s own Cure Bain Cancer Foundation, reduce wastage and increase output in this vital research stage¹²⁵. The Foundation proactively outreaches to researchers when providing grants, saving over a month of work per-researcher-per-year¹³⁵, collaborates, and indeed, directs research strategies for the Global Brain Exchange consortia¹²⁶, and works actively with industry to ensure treatments reach patients¹²⁵. Similar strategies, if employed by others, would lead to leaps-forward in treatment prospects, and thence, patient outcomes.

Why Medical Students Need to be Prepared for Change

The complexities associated with the personalisation of clinical management and our ever-expanding discoveries in fields like genomics are already stumping doctors¹²⁷. Though innovative educational tools, such as medical calculators¹²⁹and the Regulome Explorer genome-map¹²⁸, and technological training are being provided to bring doctors up-to-date, the most effective way to ensure future physicians are aware of, and can apply these advances is to teach them in medical school. This knowledge isn’t just necessary for future oncologists. All specialists are becoming more involved in cancer care due to multidisciplinary, team-based care¹³⁰, and GPs, comprising nearly half the profession¹³¹, have the most important, currently underused role, in prevention and co-management of cancers^132-134. With cancer burden only rising^9-11, this becomes vital.

Conclusion

The changing landscape of oncology due to advances in research has made it essential we transform and optimise our clinical trial infrastructure, focus of research and research partnerships, so patient outcomes continue improving. The recommendations made in this essay provide benefits not only to science and patients, but also to industry, researchers and Australia’s health system, and many suggestions can be implemented around the world too. There are many other complex interactions and strategies that can further increase the output of new treatments that couldn’t be discussed in the length of this essay. I'm actually writing a book on the topic. But the fact that there are many pathways and much desire to improve treatments makes the future of cancer treatments bright. Hopefully, these suggestions, if implemented, will make them even brighter.

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Tuesday, April 28, 2015

How to Ensure Cancer Treatments Keep Getting Funded, and Treatments Keep Improving; 2015 Cancer Council Essay Competition Entry