Tagged: commentary

  • The MedTech industry is undergoing an era of unprecedented change
  • Pressure on revenues and margins have forced leaders to cling tightly to business as usual
  • In the next decade business as usual will come with significant commercial risks
  • For commercial success future MedTech leaders will need to be different to past leaders
Who should lead MedTech?
Questions about who should lead medical device (MedTech) companies in the future and what strategies and business models they should pursue are critical. Over the next decade MedTech faces an era of unprecedented change, when it will be necessary to develop new strategies, new business models, new markets, new capabilities and new technologies, while keeping the legacy business running. Future MedTech leaders will be tasked with bridging the gap between traditional manufacturing and sophisticated, digitally driven services while managing unprecedented change and significant competition. For the past 20 years MedTech leaders have been drawn from a relatively narrow set of people with a relatively narrow set of skills. Although this has served the industry well, it might not be the most appropriate policy to ensure commercial success over the next decade.
In this Commentary

In this Commentary we: (i) describe the traditional MedTech market, indicate the structure parameters of the industry and note that there is a rapidly evolving parallel digital healthcare technology market: one that is growing more than twice as fast and soon will be comparable in size to the traditional manufacturing-based market, (ii) suggest that MedTech leaders tend to be men in their 50s with limited understanding of this parallel digital healthcare universe, which is positioned to play a significant role in  shaping MedTech companies of the future, (iii) suggest that because MedTech leaders have performed relatively well over the past two decades, they have tended to become prisoners of their own traditions and felt little or no need to evolve their strategies and business models, (iv) contend that MedTech leaders’ principal response to market changes to-date has been increased M&A activity, which has made companies bigger but not better, (v) suggest that the industry is undergoing a significant market shift from manufacturing to solutions and services driven by the 4th industrial revolution, which is characterized by a fusion of technologies, and (vi) conclude that future MedTech leaders will require a deep knowledge and understanding of the 4th industrial revolution if they are to successfully transform traditional strategies and business models in order to deliver superior healthcare solutions at lower prices.
MedTech market and the structure of the industry

MedTech is a conservative manufacturing industry, which produces and markets a diverse group of product offerings predominantly in a few developed wealthy markets. Over the next decade the MedTech market is expected to change significantly. For the past two decades the industry has fallen into three broad segments: (i) diagnostic products, which include imaging devices, with a global market of some US$100bn, (ii) medical aids including consumer durables, such as hearing aids and bandages with a worldwide market of about US$150bn, and (iii) surgical products that include equipment and instruments used in the operating room, which has a global market of some US$140bn.
A 2017
EvaluateMedTech report suggests the global MedTech market is projected to eclipse US$500bn in sales by 2021, over 33% of which is expected to be derived from the US. The worldwide market is projected to continue growing at a compound annual growth rate (CAGR) of 5%. Ranked by 2017 revenues, seven of the world’s largest MedTech companies are American and a significant proportion of the world’s MedTech companies trade on Nasdaq. This includes 13 large companies with a market cap in excess of US$10bn, some of which are divisions of even larger corporations such as Johnson & Johnson Medical Devices and Diagnostics, with estimated global sales of US$38bn for 2018; this equates to approximately 7.6% of the worldwide MedTech market. Medtronic, which is the world's largest stand-alone MedTech company, has a market cap of US$117bn and in 2017 recorded revenues of US$29.7bn; 26% of which was generated in the US. Nasdaq has about 24 mid-cap MedTech companies ranging in value from US$2bn to US$10bn. The majority of these are American and tend to be regionally based with relatively small markets outside the US, Europe and Japan. There are some 27 small-cap companies with market caps between US$300m and US$2bn, 46 micro-cap companies ranging from US$50m to US$300m and finally some 28 nano-cap MedTech companies with market caps less than US$50m.
In recent years, a digital healthcare technology industry, where medical devices meet innovative software, has grown substantially, but mostly in parallel to the traditional manufacturing-based MedTech industry. According to
Transparency Market Research, in 2016 this industry, which is based on healthcare information systems and wearable devices, had annual sales of US$180bn, and is projected to grow at a CAGR of 13.4% between 2017 and 2025, reaching US$537bn in annual sales by the end of 2025.

MedTech executive leadership
There is a relative dearth of data specifically on MedTech leaders and the demographics of MedTech C-suites (senior executives which tend to start with the letter C). Notwithstanding, there are data on Fortune 500 and S&P 500 company leaders from regular surveys undertaken by executive search firms Korn Ferry, and Spencer Stuart. Some of the larger MedTech companies, such as Abbot Laboratories, Baxter International, Stryker and Boston Scientific, are listed in the Fortune 500 and S&P 500. If we assume a significant similarity between the demographics of Fortune 500, S&P 500 and MedTech company executives, then MedTech leaders will tend to be white males in their 50s, predominantly drawn from similar sector company C-suites and will have an average tenure of about eight years.
Middle-aged men
Over the past 20 years MedTech leaders have benefitted from the industry’s commercial success, albeit in recent years at a slower pace than before 2007. Most leaders are constrained by quarterly earnings targets, shareholder expectations, regulations and the high risk and cost associated with changing manufacturing systems. MedTech CEOs received their formative education before the widescale uptake of the Internet and email. Many had just started their careers in large corporations when giant technology companies such as Amazon (launched 1994) and Google (1998) in the US and their Chinese equivalents - Alibaba (1999) and Baidu (2000) - were start-ups, and the Chinese and Indian economies were still somewhat underdeveloped and inchoate. Consequently, most MedTech leaders were entering middle-age when US social media giants such as Facebook (2004), YouTube (2005), WhatsApp (2009) and Instagram (2010) and their Chinese counterparts such as WeChat (2011), RenRen (2005), Weibo (2009) and Youku (2005), were just taking off.
This might partly explain why some MedTech leaders appear to be challenged by the rapidly evolving new digital technologies and the industry’s shift from manufacturing to solutions and services. Such is the pace of change, it will require a shift of mindset among incumbent MedTech leaders if they are to fully grasp this new and significant opportunity set.
Similarly, with emerging markets. Most CEOs have knowledge of the wealthy MedTech markets, in particular the US and Europe. Few, however, have in-depth knowledge or first-hand experience of the large and fast-growing emerging economies such as Brazil, Russia, India and China (BRIC). The BRIC countries are at a similar stage of their economic development, and have a combined population of more than 3bn, which equates to about 40% of the global population. BRIC countries are differentiated from other promising emerging markets by their demographic and economic potential to rank among the world’s largest and most influential economies in the 21st century, and by having a reasonable chance of realizing this potential.
A future HealthPad Commentary will examine the opportunities for Western MedTech companies seeking or expanding their franchise in China and will suggest that they might not find it as easy as it would have been 5 years ago. Opportunities in China for global MedTech players are becoming tougher as the Chinese economy slows and restructures; Beijing’s healthcare reforms kick-in and local MedTech producers, buoyed by legislation, revenue growth and increased capacity, become commercially stronger, more technically sophisticated and take a bigger share of both the Chinese domestic and international emerging MedTech markets.
Underrepresentation of women
Not a single woman serves as CEO of a large MedTech company. Only 22% of their board members are women, which is about the same proportion as the Fortune 500 overall (20%), and about 22% of MedTech C-suites are women. In 2017, nearly 50% of the US labour force were women and 40% of these worked in management, professional and related occupations.  Although women are underrepresented in MedTech leadership positions they are key stakeholders in healthcare. About 35% of active US physicians are women. According to the Association of American Medical Colleges, (AAMC), 46% of all physicians in training and almost 50% of all medical students in the US are women.  60% of pharmacists in America are women.

It should not be forgotten that women have played significant roles in medicine and healthcare. For example, Marie Curie, the only person to win a Nobel Prize in two different sciences, pioneered research on radioactivity. Curie made a significant contribution to the fight against cancer and is credited with having created mobile radiography units to provide X-ray services to field-hospitals during World War I. Sussman Yalow, was awarded the Nobel prize in Physiology or Medicine in 1977 for the development of the radioimmunoassay technique, and Gertrude Elion won a Nobel Prize in Physiology or Medicine in 1988 for her work in helping to develop drugs to treat leukaemia and AIDS. More recently, Jennifer Doudna, and Emmanuelle Charpentier, were credited with the discovery of the ground-breaking CRISPR-Cas9 gene-editing technology, which effectively changes genes within organisms and is positioned to radically change healthcare and MedTech in the 21st century.

In addition to under-representation, which suggests that the pipeline of women candidates for top jobs in MedTech is weak, there is some evidence to suggest that the MedTech industry does not have a positive attitude towards women. Findings of a 2015 survey conducted by AvaMed, the industry’s principal trade association, suggest that women in the industry feel discriminated against. Some 42% of women respondents of the survey said they, “felt held back from senior leadership positions” and 37% felt “overtly discriminated against”. "The world cannot afford the loss of the talents of half its people if we are to solve the many problems which beset us,” said Yalow in her 1977 Nobel Prize acceptance speech.
MedTech’s business model
Over the past two decades MedTech leaders have drawn comfort from the fact that the global MedTech market is highly centralized. The US, Western Europe and Japan, which represent only about 13% of the world’s population, account for more than 86% of the global MedTech market share (US: 42%, Europe: 33%, Japan: 11%). Conversely, the BRIC countries, which represent about 40% of the world’s population, currently only account for about 5% of the global MedTech market. This has enabled MedTech leaders to market their product offerings to healthcare providers principally in a few wealthy developed regions of the world via well-compensated sales representatives with deep product knowledge and expertise. The industry’s predominant business model has been to raise prices on existing products and market new offerings at higher prices than the products they are meant to replace. This worked very well before 2007 during a period of sustained global economic growth, predominantly fees-for-service healthcare systems and relatively benign reimbursement policies; all of which contributed to high margins and significant sales growth.
Market changes not perceived as acute enough to trigger transformation
Since the 2008 recession the MedTech market has changed. The global economy has weakened, debt (sovereign, corporate and personal) has escalated, populations have continued to grow, and the prevalence of chronic lifetime diseases and multi-morbidities have increased. Over that period, healthcare systems have become fiscally squeezed, costs have become pivotal and impacted all stakeholders. This has led to: (i) a shift in healthcare systems from fees-for-service to fees-for-value (ii) increased consolidation, convergence, and connectivity of stakeholders and a consequent change in purchasing decisions from individual (fragmented) hospitals and clinicians to centralized procurement bodies, which can leverage economies of scale and negotiate for larger purchases at volume discounts, (iii) the decline of MedTech R&D productivity, and (iv) increased competition from new market entrants, often from different industries. MedTech’s gross margins have been squeezed and annual growth rates have slowed to a CAGR of between 4 and 5%. Notwithstanding, MedTech leaders, buoyed by continued but slower revenue growth, and doubtless comforted by a prolonged surge in US equity markets, have not perceived these market changes as being with sufficient acuity to transform their strategies or business models.  Their principal response has been to increase M&A. 
M&A main strategic response to market changes
Over the past decade M&A has provided MedTech leaders with a means to: (i) increase scale and leverage, (ii) drive stronger financial performance, (iii) obtain a broader portfolio of product offerings, (iv) enhance therapeutic solutions and (v) increase international expansion; without changing their companies’ fundamental manufacturing structures and strategies. According to a January 2018 McKinsey report, between 2011 and 2016, 60% of the growth of the 30 largest MedTech companies was due to M&A. The report also suggests that between 2006 and 2016, only 20% of 54 pure-play publicly traded MedTech companies, “mostly relied on organic growth”.  M&A activity has resulted in bigger MedTech companies but not necessarily better ones. This is because M&A and collaborative relationships have not encouraged healthcare providers to change their strategies and business models and develop powerful data-sharing networks, which help drive integration across the continuum of healthcare.
Need for portfolio transformation
Encouragingly, the 2018 McKinsey report also suggests that some MedTech companies are beginning to use M&A to acquire “non-traditional” assets, such as software and service companies, to assist them in transforming their portfolios. Notwithstanding, portfolio change in a rapidly evolving and increasingly competitive healthcare ecosystem requires a sound strategic understanding of the potential role that the 4th industrial revolution can provide for MedTech. Given our discussion so far, it seems reasonable to assume that many current MedTech leaders and C-suite executives might not have fully grasped the commercial implications of this revolution for their industry. Portfolio change in the MedTech industry is arguably more likely to be led by executives from, or with an intimate knowledge of, adjacent, service-based companies; those who have successfully employed sophisticated digital technologies and big data strategies to transform their business models and who are now looking to do something similar in MedTech and healthcare markets.
The relative slowness of the MedTech industry to transform its strategies and business models is perceived as an opportunity by giant technology corporations. They sense the disruptive potential, just as they do in financial markets due to Wall Street’s inertia to digital change.  For example, in early 2018, Amazon, Apple, Google, and Uber announced their intentions to enter and disrupt the healthcare market by leveraging digital technologies to provide quality healthcare solutions and services at lower costs.
Rather than marketing products, MedTech companies are now increasingly being tasked with marketing solutions that can deliver better care at lower prices. The 4th Industrial Revolution is a primary enabler for achieving this. However, given the demographics and the conservatism of the MedTech industry, it seems reasonable to suggest that companies in the sector, which do not adapt, run the risk of becoming simple commodity producers stuck in the middle of a new and rapidly evolving value chain.

The 4th Industrial Revolution

The 1st industrial revolution used water and steam to mechanize production, the 2nd used electric energy to create mass production, the 3rd used electronics and information technology to automate production. The 4th industrial revolution, also known as ‘industry 4.0’, is characterized by a fusion of technologies, which is blurring the boundaries between medical devices, drugs, software and patient data and redefining relationships between the physical, biological and digital worlds. These exogenous shifts are likely to demand different strategies, different business models and different leaders for the MedTech industry.
Industry 4.0 provides MedTech with an opportunity for portfolio transformation by developing sophisticated data and digitization strategies to enhance company operational and financial performance. Industry 4.0 is driven by greater connectivity via the Internet and computing devices embedded in physical objects and advanced digital technologies, which enable them to send and receive data to help integrate producers, suppliers, business partners and customers; at the same time providing opportunities for MedTech companies to become smarter, more efficient and fully-networked organizations.
Key for superior shareholder returns
To date, MedTech leaders have been relatively slow to integrate new and evolving digital technologies into their core business operations, although there are encouraging signs that some companies are beginning to do so. Findings of a 2017 report by the Boston Consulting Group, (BCG) suggest MedTech companies are, “masking unsustainably high costs and underdeveloped commercial skills” and relying, “on an outdated commercial model”.  The BCG findings are based on a survey of some 6,000 MedTech employees in commercial functions, more than 100 interviews with MedTech leaders and benchmarking financial and organizational data across 100 MedTech businesses (including nine of the 10 largest companies) worldwide. According to BCG, although the industry overall has made little progress to change its business model and upgrade its skill levels, the companies, which have done so, are winning in the market and generating superior shareholder returns.

MedTech leaders should not mistakenly think that because their companies hold plenty of enterprise data they are implementing industry 4.0 strategies. Often, enterprise data do not provide any competitive advantage whatsoever but are simply a legacy cost of doing business. New sources of data, and the ability to use data’s power, are essential to enhance a company’s competitive advantage. A next-generation enterprise resource planning (ERP) platform, launched by SAP in 2017, is already being used by service companies to provide them with a digital core, which helps to create real-time matrixed data produced by social media, third party information, genetics, the Internet of Things, points of sale, etc.

Shift from selling products to selling solutions

To remain competitive in the next decade MedTech leaders will need to employ artificial intelligence (Al), augmented reality, robotics, advanced sensors, the Internet of Things (IoT), blockchain, nanotechnology, 3D printing, petabytes of data, enhanced processing power and storage capacity to help them transform their strategies and business models and enable their companies to evolve from being product-centric to customer-centric, with an emphasis on digitization and the capture and communication of data. Industry 4.0 and the convergence of the physical, biological and digital worlds will fundamentally change MedTech strategies and business models, as decision-making powers continue to shift from manufacturers to other healthcare stakeholders. Critical to this transformation will be those MedTech leaders who are well positioned to ensure that companies remain competitive in their core markets while establishing new markets underpinned by 4.0 technologies.
"Out-of-touch leaders" the main cause of company failure

A book published in 2016 entitled Lead and Disrupt suggests that company transformations fail because of out-of-touch leaders rather than competition. According to Michael Tushman, co-author of Lead and Disrupt, “The things that help organizations execute their current strategy - the cultures they build, the structures they forge, the processes that work so well to get today’s strategy executed - actually collude to hold the organization hostage to that soon-to-be-obsolete strategy. The more firms engage in getting today’s work done, it actually reduces the probability of making shifts in innovation and strategy. That is what is so strikingly paradoxical to leaders: The very recipes that work so well for today often get in the way of the future. It’s a challenge to incrementally improve what you’re doing as you’re trying to complement it with something different. The dual strategies are inconsistent.”

Over the past two decades MedTech companies have helped to shape healthcare systems in wealthy advanced industrial societies and have been rewarded with commercial success. But just as the fund investment axiom tells us, past performance is no guarantee of future success.

Crucial to the future success of MedTech companies will be their leaders. We have suggested that employing recruiting criteria, which have worked in the past might not guarantee future success. The next 10 years will be an era of unprecedented technological change for MedTech companies when the boundaries between medical devices, drugs, software and patient data become blurred.

Business as usual, which has served the industry well in the past, is unlikely to bring continued commercial success in this new healthcare ecosystem. In recent years, investment in digital healthcare has soared and the momentum towards a digital future has gathered pace. Future successful MedTech leaders will be those who combine a deep understanding of the 4th industrial revolution to leverage sophisticated digital technologies and data to assist them in creating and delivering enhanced healthcare solutions at lower costs, with an ability to keep the legacy manufacturing business running.  

MedTech companies face a stark choice: either appoint leaders similar to those of the past and become challenged or appoint leaders able to integrate new and evolving technologies into the core of the business to create and market cost effective quality healthcare solutions and remain profitable. MedTech leaders might consider adopting the motto: tempora mutantur et nos mutamur in illis.
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  • A novel drug called niraparib which freezes tumours and can prevent ovarian cancer recurring is now available to NHS patients
  • Ovarian cancer is a silent killer: each year in the UK it affects 7,400 women and kills 4,100
  • Oncologists have called niraparib, which is taken as a daily pill, a “game changer
  • Approval of niraparib is predicated upon a clinical study that enrolled 553 patients with recurrent ovarian cancer
  • The endpoint of the study was progression free survival
  • The study reignited discussion about the relative merits of different metrices used to assess the efficacy of cancer therapies
  • Patient groups and some oncologists suggest health-related quality of life should be given more significance in the measurement of drugs
Niraparib made available on the NHS to halt the spread of ovarian cancer

There is some good news for women in Britain living with ovarian cancer. In June 2018 niraparib, a life extending drug, was recommended by the UK’s National Institute for Health and Care Excellence (NICE) for inclusion in the Cancer Drugs Fund, (CDF) which will make niraparib available on the NHS to women living with ovarian cancer, who already have had two or more courses of chemotherapy.  The drug, which was first marketed in the USA in April 2017, is the first PARP inhibitor (described below) taken as a daily pill to be approved in Europe that does not require BRCA mutation or another biomarker testing. (Women with harmful mutations in the BRCA1 or BRCA2 genes have a 10 to 30 times higher risk than normal of ovarian cancer). Niraparib is expected to benefit around 850 UK patients each year at an annual cost of about £58,661 for the 200mg daily dose or £86,786 for the 300mg dose; but is available to the NHS at an undisclosed discount. Some oncologists have heralded niraparib as a “game-changer” because it freezes tumours and can prevent ovarian cancer recurring for 12 to 16 months.
In this Commentary

This Commentary: (i) describes niraparib and how it halts the spread of ovarian cancer, (ii) summaries the findings of the clinical study, which is the basis on which niraparib has been approved, (iii) describes questions raised about the endpoints of clinical studies and the growing debate about a trade-off between progression free survival and health-related quality of life, (iv) briefly describes the epidemiology of ovarian cancer, (v) uses video of a leading oncologists to describe the standard of care for the disease, (vi) explains the reasons why ovarian cancer is frequently diagnosed late with more video contributions from leading clinicians, and (vii) emphasises and repeats the signs and symptoms of ovarian cancer in an attempt to help educate women and encourage them, whatever their age, to seek immediate attention from their primary care doctor if they have any tell-tale signs of the disease.
How niraparib works

Niraparib is one of a class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors and is indicated for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Because of the high recurrence rates associated with ovarian cancer maintenance therapy, measured by progression free survival (PFS) rather than overall survival (OS), has become the appropriate treatment for this disease.  Niraparib is a targeted therapy, which uses agents to identify and attack cancer cells while causing minimal damage to normal cells. Such therapies attack cancer cells' nuclei that contain the programs, which differentiates them from normal healthy cells. Each type of targeted therapy works differently, but they all change the way a cancer cell grows, divides, repairs itself, or interacts with other cells.
NOVA clinical study

The approval of niraparib is predicated upon findings of an international Phase 3 clinical study called NOVA, which were published in the December 2016 edition of the New England Journal of Medicine. The study sought to evaluate the efficacy of niraparib versus placebo as a maintenance therapy for patients with platinum-sensitive, recurrent ovarian cancer. The double-blind study enrolled 553 patients with recurrent ovarian cancer, who had achieved either a partial or complete response to their most recent platinum-based chemotherapy. The primary endpoint of the study was progression free survival.

Researchers were keen to discover whether having a BRCA mutation affected how well the therapy worked. Approximately 66% of participants did not have BRCA mutations. Findings demonstrated that women with an inherited BRCA gene mutation saw the time to relapse increase from 5.5 months to 21 months compared with chemotherapy alone. Niraparib was also shown to help women without a BRCA mutation, doubling the length of time before recurrence from 3.9 months to 9.3 months. So, niraparib significantly increased progression free survival in patients with or without BRCA mutations as compared to the control group. The results of the study position niraparib as the first PARP-inhibitor to reduce the risk of ovarian cancer progression or death by 73% in patients with BRCA mutations and by 55% in patients without BRCA mutations. Research is ongoing.

More data needed
While the NOVA study represents a significant step forward more data is needed before all asymptomatic patients with recurrent platinum-sensitive ovarian cancer can be treated effectively with niraparib and other maintenance PARP inhibitors. The challenge for clinicians is to select the right drug for the right patient at the right time. To decide which patient receives PARP inhibition and at what point in her therapy is challenging and stands to benefit from further research. Until further research is undertaken on niraparib and other PARP inhibitors, patients with advanced ovarian cancer will continue to incur treatment related toxicity without definitive benefits. 
Quality of life versus progression free survival

The side effects from approved cancer therapies raise questions about the metrices clinical studies use to measure their endpoints. All drugs have safety risks. The sole reason why a patient would want to take a drug is because it: (i) improves survival, (ii) results in a detectable benefit, (iii) decreases the chances of developing complications or undesirable side effects. Primary endpoints in clinical studies should be something that are important to a patient and can be objectively measured. When clinical studies use surrogate endpoints, similar tests apply. Thus, clinically meaningful endpoints directly measure how a patient feels, functions, or survives and include overall survival (OS), progression-free survival (PFS) and health-related quality of life (QOL).
The NOVA study used progression free survival (PFS) as its primary endpoint. This is an accepted metric for maintenance therapy for advanced ovarian cancer and other metastasized cancers.  Employing PFS instead of overall survival as the primary outcome has the advantage that study completion can be quicker with fewer patients required and it is cheaper. While the NOVA study successfully demonstrated that niraparib helps to stop ovarian cancer returning, it failed to show that the drug reduces health-related quality of life for patients.
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After 20 years of the cancer drug Herceptin is less more?
There is some evidence to suggest that women with ovarian cancer might be willing to accept lower progression free survival for enhanced health-related quality of life. A study published the December 2014 edition of Cancer suggested that women with recurrent ovarian cancer were prepared to trade several months of PFS for reduced debilitating side effects of chemotherapy, which include nausea and vomiting. The most common adverse reactions to niraparib, which affect about 10% of patients, include thrombocytopenia, anaemia, neutropenia, leukopenia, palpitations, nausea, constipation, vomiting, abdominal pain, mucositis/stomatitis, diarrhoea, dyspepsia, dry mouth, fatigue, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnoea, cough, rash, and hypertension.
Ovarian Cancer

Epithelial ovarian cancer accounts for 90% of all ovarian tumours. It typically presents in post-menopausal women and is a significant challenge for gynaecological oncologists since most patients are diagnosed when the disease is already advanced and therefore have a poor chance of survival. The natural history of the disease is characterized by a high response rate to primary treatment of debulking surgery followed by platinum-taxane chemotherapy, which is quickly followed by early recurrence and a second-line treatment with platinum; then most patients experience further platinum-resistance and die from the disease. Although ovarian cancer is relatively rare - based on 2013-2015 data 1.3% of women are expected to contract the disease sometime in their lifetime -  it is the 7th most common cancer in women worldwide. In 2012 there were 239,000 new cases of the disease diagnosed globally. In the UK ovarian cancer is the 5th most common cancer in females, the 2nd most common malignant gynaecological disease and the 1st cause of death from gynaecological malignancy. The UK has one of the highest incidence rates of the disease in Europe, affecting some 7,500 women every year, and its survival rates are among the lowest. Every year 4,100 women in Britain lose their lives to the disease, which equates to about 11 women every day. Over the past 2 decades there has been a slowing of the rate of diagnosis of ovarian cancer in the UK, which is partly due to the large number of women having taken the oral contraceptive pill after it was made available on the NHS in December 1961 and is known to have a protective effect. According to the World Ovarian Cancer Coalition, over the next 2 decades the incidence rates of ovarian cancer worldwide is expected to rise by 55% and by 15% in the UK. This is mainly because: (i) post-menopausal women are living longer, (ii) populations are increasing, and (iii) there is a significant increase in the rate of urbanization.
The standard of care for ovarian cancer
Although advances in research and technology have contributed additional and sometimes more effective therapy options for women with ovarian cancer such as niraparib and other PARP inhibitors, both the American and European guidelines recommend surgery as the initial approach to ovarian malignancies. After surgery, adjuvant chemotherapy is mandatory in cases of suboptimal debulking, advanced stages, or early stages with a high risk of recurrence. Mike Birrer, Professor of Medicine at Harvard University Medical School, Director of Medical Gynecologic Oncology and also Director of the Gynecologic Oncology Research Program at the Massachusetts General Hospital Cancer Center describes the standard treatment for ovarian cancer. “Ovarian cancer is diagnosed surgically. It’s important that the patient undergoes proper diagnostic and staging procedures. This would include an exploratory laparotomy (a surgical procedure, which involves an incision through the abdominal wall to gain access into the abdominal cavity), which would then evolve onto a staging laparotomy, (to determine the extent and stage of a cancer), which would include a TAH (total abdominal hysterectomy), BSO (bilateral salpingo-oophorectomy, which is when either the uterus plus one ovary and fallopian tube are removed, or the uterus plus both ovaries and fallopian tubes are removed), removal of the ovaries and the uterus. The removal of the omentum (a layer of fatty tissue that covers the abdominal contents like an apron; the procedure to remove it is called an omentectomy, which involves removing the uterus, cervix, fallopian tubes and ovaries), and lymph nodes in the regiterial cavity, scraping of the upper abdomen and then a peritoneal lavage (a procedure to determine if there is free floating fluid, most often blood, in the abdominal cavity). This would give accurate staging for the patient and anything less would be considered less than the standard of care. Once the stage is established and the patient has an advanced stage of the disease, which has spread throughout the abdomen or outside the abdomen, the patient would then undergo further therapy. This would inevitably involve a combination of chemotherapy. The specific regimen would depend, in part, upon the surgical results.”  See video below.
Current options for ovarian cancer maintenance therapy

In addition to niraparib, current options for ovarian cancer maintenance therapy include bevacizumab and olaparib. The former is a monoclonal antibody designed to block a protein called vascular endothelial growth factor (VEGF). Some cancer cells make this protein and blocking it may prevent the growth of blood vessels that feed tumours, which can stop the tumour from growing. Notwithstanding, bevacizumab can only be given once and improves progression-free survival by just a few months. Olaparib is a PARP inhibitor, which blocks how PARP proteins work in cancer cells that have a BRCA gene mutation. Without PARP proteins, these cancer cells become too damaged to survive and die. In the first instance, olaparib was only approved in patients with a germline BRCA mutation, which accounts for about 10–15% of ovarian cancer patients. In 2014, when olaparib was approved in Europe and the USA, it was the first cancer treatment targeted against an inherited genetic fault to be licensed. Subsequently, evidence suggested that the drug could also benefit patients whose tumours have defects that are not inherited.
Non-specific signs and symptoms

The unresolved challenge for ovarian cancer is that in its early stage it rarely presents with any symptoms. Compounding this is the further problem that later stages of the disease may present few and nonspecific symptoms, which are commonly associated with benign conditions. Were ovarian cancer detected in its early stage when the disease is confined to the ovary it is more likely to be treated successfully. Ovarian cancer suffers from another challenge because screening for the disease in not an option, as we explain below. Further, often women do not know what symptoms to look out for and primary care doctors misdiagnose the disease especially in younger women. This results in about 80% of ovarian cancer cases being diagnosed late when 60% have already metastasised, which reduces the 5-year survival rate from 90% in the earliest stage to 30%. Signs and symptoms of ovarian cancer include abdominal bloating or swelling, quickly feeling full when eating, weight loss, discomfort in the pelvis area, changes in bowel habits such as constipation, and a frequent need to urinate.

A patient’s view
The 3 primary symptoms of ovarian cancer are bloating, feeling full and pelvic pain. Secondary symptoms include fatigue, bowel and urinary issues. In reality women don’t have all the primary symptoms and they may not have any of the secondary symptoms but may have a combination of the 2. The most prevalent symptom is bloating, especially if it persists. If this occurs women should immediately go to their doctors and ask for a CA-125 blood test. And whatever the outcome of the test they should also insist on a TVUS scan. There is no one easy method of diagnosing ovarian cancer and doctors sometime mistake the symptoms for something less serious like irritable bowel syndrome,” says an ovarian cancer patient. In addition to a pelvic examination, the 2 most frequent diagnostic tests for ovarian cancer are transvaginal ultrasound (TVUS), which puts an ultrasound wand into the vagina to examine the uterus, fallopian tubes and ovaries and the CA-125 blood test, which measures the amount of the protein CA-125 (cancer antigen 125) in your blood.
Late diagnosis

According to Christina Fotopoulou, Professor of Surgery at Imperial College London and Consultant Gynaecological Oncologist at Queen Charlotte’s Hospital NHS Trust , “Ovarian cancer is a very silent disease. It has a tumour dissemination pattern of very small nodules spread throughout the whole skin of the abdomen. In the beginning these nodules are so small that they go undetected. The nodules are only detected when they get larger and produce water. So, women with ovarian cancer get abdominal distention and water in their tummies, which prompts them to seek advice from their doctors. But then it’s too late because it’s already at a late stage of the disease.” See video below.
The ‘bar’ is too high to screen for ovarian cancer
Hani Gabra, Professor of Medical Oncology at Imperial College London and Chief Physician Scientist and Head of the Oncology Discovery Unit at AstraZenecaUK supports Fotopoulou and says, “Ovarian cancer is often diagnosed late because in many cases the disease disseminates into the peritoneal cavity almost simultaneously with the primary declaring itself. Unlike other cancers the notion that ovarian cancer goes from stages 1 to 3 is possibly a myth. In reality these cancer cells often commence in the fallopian tube with a very small primary tumour and disseminate directly into the peritoneal cavity. In other words, they go from the earliest stage 1 directly to stage 3, which renders screening a significant challenge. This is compounded by the fact that ovarian cancer is relatively rare in the population. So, to be effective a screening test would have to be extremely sensitive and extremely specific, which it does not have to be for commoner cancers. The combination of these makes screening for ovarian cancer extremely difficult to achieve.”

Ovarian cancer is a devastating disease, which is diagnosed more infrequently and often at a later stage. Patients are typically older, symptoms are non-specific and easily confused with a number of benign conditions. In its earliest and most curable stage, there may not be any physical symptoms, pain or discomfort. Standard treatment is radical and a harrowing experience for women diagnosed with the disease. About 85% of patients experience a recurrence of the disease after their first treatment cycle, which means that they often face repeated bouts of chemotherapy to keep the disease under control. In a significant proportion of cases even after a second round of chemotherapy the cancer can recur. Previously, at this point patients have had limited pharmacological help, but as research advances, this is beginning to change, and some novel and efficacious drugs are entering the market. Niraparib is one of the latest PARP inhibitors, which has demonstrated efficacy in the treatment of advanced ovarian cancer.
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  • 15 to 20% of breast cancer patients suffer a type of the disease that could benefit from the drug Herceptin
  • Herceptin is very effective and normally administered for 12-months but it is expensive and can cause heart damage
  • New research has found that the treatment period for Herceptin could be reduced from 12-months to 6 without compromising outcomes
  • A 6-month course would reduce the cost of the drug, increase access and potentially reduce the number of patients suffering debilitating side effects
  • The research findings reignited broader concerns about the sustainability of cancer care and the competing interests of patients, producers and providers
  • Herceptin’s patents are expiring and biosimilars are entering the market which is expected to lower costs and increase access
After 20 years of the cancer drug Herceptin is less more?

Findings of a phase III clinical study funded by UK government grants and presented at the June 2018 meeting of the American Society of Clinical Oncology (ASCO) suggest that the time a patient needs to spend on Herceptin, (chemical name trastuzumab), a drug widely used to treat an aggressive form of breast cancer, could be halved from 12 to 6 months. This would save insurers, governments, healthcare providers and patients significant sums of money and possibly reduce the incidence of side effects, which can include heart problems.
In this Commentary
This Commentary: (i) summarizes the findings of the clinical study and some expert reactions to it and (ii) describes the different subtypes of breast cancer and the drug trastuzumab.  The Commentary also broaches a broader concern about the escalating costs of life-saving or life-extending cancer therapies, which show no sign of either slowing or reversing. According to ASCO, in the US, newly approved cancer drugs cost on average US$10,000 per month, with some costing as much as US$30,000 per month. This causes financial hardship for many American patients and their families. In the UK, which has a large devolved public healthcare system, cancer therapies are a postcode lottery because medicines that patients receive depend on whether their local healthcare provider can afford them. In emerging economies, where the prevalence of breast cancer is rising, only a privileged few breast cancer patients have access to trastuzumab. Notwithstanding, patients should gain some comfort from Herceptin’s patents expiring and biosimilar versions of trastuzumab entering the market, which is expected to make the drug cheaper and more accessible.  

Breast cancer and HER2

Breast cancer is a heterogenic disease and biomolecular changes in breast cancer involve the expression of genes. The disease is classified according to the 4 subtypes of genes expressed: (i) luminal A, which accounts for 51 to 61% of all breast cancer patients, (ii) luminal B, which accounts for 14 to 16%, (iii) basal-like, which accounts for 11-20% and (iv) the HER2 subtype, which accounts for 15 to 20% of all breast cancer patients and is the focus of this Commentary. Each subtype has different clinical features, different prognoses and different responses to therapies. HER2 protein overexpression is the result of amplification of the HER2 gene and is associated with aggressive tumour growth and consequent high rates of recurrence and mortality in patients. HER2-positive breast cancer is not inherited but is a somatic genetic mutation, which occurs after conception and therefore the new DNA does not enter the eggs or sperm.
Trastuzumab the first gene targeted drug
Trastuzumab was first approved by the US Food and Drug Administration (FDA) in 1998 and became the first FDA-approved therapeutic antibody targeted to a specific cancer-related molecular marker. The FDA recommended that the drug should be administered for 12 months. Robert Leonard, formerly Professor of Cancer Studies at Imperial College London, UK, and a consultant medical oncologist specialising in breast cancer at the BUPA Cromwell Hospital, the London Clinic and the London Oncology Clinic describes HER2 positive breast cancer and trastuzumab: see video below.  “We like to talk about targeted therapies since we’ve learnt more about the basic biology of cancer, which uses subtle techniques of investigation including biological and immunological profiling of cancers. We now have the ability for new molecules to target specific abnormalities in cancer cells and these can be effective in sublimating standard breast cancer treatments. A good example are Herceptin and Lapatinib, both of which target the HER2 pathway, which is a very important pathway in breast cancer,” says Leonard.
Trastuzumab and advanced breast cancer
Trastuzumab’s approval followed 4 randomized clinical studies involving more than 8,000 patients with stages II or III HER2-positive breast cancers. These showed that when trastuzumab was administered for a period of 12 months in combination with or after chemotherapy agents, it potentiated the efficacy of chemo- and immunotherapy; reduced the risk of breast cancer recurrence by approximately 50% and significantly improved survival. In 2000, trastuzumab's use for advanced breast cancer was approved in Europe and has since been approved in a number of countries outside Europe. In 2002 the UK government’s watchdog, the National Institute for Health and Clinical Excellence (NICE), endorsed the use of trastuzumab for advanced HER2 breast cancer.

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Cancer drugs that neither improve nor extend lives

Trastuzumab and early stage breast cancer
Shortly afterwards, trastuzumab expanded its use to early stage HER2 breast cancer. Findings of 2 papers in the October 2005 edition of the New England Journal of Medicine (NEJM), suggested that following initial interventions, a 12-month course of trastuzumab in combination with other agents, could also be a lifesaver for those still in the early stages of breast cancer because it reduced the risk of recurrence and death of patients by 46% compared with chemotherapy alone. In this respect trastuzumab has been viewed as a possible “cure” for early stage breast cancer. Based on these findings, trastuzumab’s approval was extended for the treatment of early stage HER2 cancers. Commenting on the 2 studies in the same edition of the NEJM Gabriel Hortoboagyi, a breast cancer specialist from MD Anderson Cancer Center in Huston, USA, said, “the results reported in this issue of the Journal are not evolutionary but revolutionary. . . . . . trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.” In September 2013, a time-saving subcutaneous formulation of trastuzumab was approved in Europe, which can be administered in just 2 to 5 minutes, rather than the standard 30 to 90 minutes intravenously.
Was the 12 months treatment time a “guess”?
After regulatory approval in 1998 and following some subsequent clinical studies, a 12-month regimen for trastuzumab became the standard of care. Notwithstanding, some oncologists view the 12-month treatment period as a “guess”, and some smaller trials have questioned the duration of treatment.
Clinical study and the 2018 ASCO Meeting
The study presented at the 2018 ASCO meeting is the largest and most significant study to-date, which suggests that the treatment time for trastuzumab could be halved. The randomized clinical study followed 4,088 women with early-stage breast cancer across 152 sites in the UK for a median of more than 5 years: 2043 received trastuzumab for 6 months and 2045 received the drug for 12 months. The disease-free survival rate at 4 years was 89.4% with 6 months of therapy and 89.8% with 12 months of therapy. In addition, 4% of patients on the shorter treatment dropped out due to cardiac toxicity versus 8% of those treated for a year. Across both groups, cardiac function recovered within a few months following treatment with trastuzumab but patients in the 6-month group recovered more rapidly.

Helena Earl, Professor of Clinical Cancer Medicine at the University of Cambridge, UK and the study’s lead investigator is confident that the study will, “mark the first steps towards reduction of treatment duration for many women with HER2-positive breast cancer." According to Richard Schilsky, ASCO’s Chief Medical Officer, “There’s no reason to not immediately change practice. The findings are persuasive”.

Expert reaction to the study

Although oncologists view the study’s findings as “persuasive”, changing the length of treatment time for trastuzumab might not occur quickly. Generally, clinicians appear hesitant to immediately support a shorter duration of trastuzumab as a new standard of care. Some believe that since so few women have died or relapsed after being treated with trastuzumab, longer follow-up may be required to make sure the findings hold up before guidelines are changed. 

My guess is that people will continue to aim for a year of treatment' because of lingering concerns that longer use is better, as a smaller previous study suggested,” says Harold Burstein, a breast cancer expert at the Dana-Farber Cancer Institute in Boston, USA. However, Burstein is mindful that a shorter treatment regimen might increase access to trastuzumab for patients in emerging economies where the prevalence of breast cancer is increasing but where many women cannot afford a 12-month treatment course of the drug.  Other experts suggest that the study’s findings are significant for women who suffer the toxic effects of trastuzumab.

Jennifer Litton, a breast cancer specialist at MD Anderson Cancer Center points to another issue the ASCO study raises. She suggests the study’s findings show just how important it can be to study drugs that are already on the market. “It's really important that we continue to have public funding for clinical trials, so we can continue to ask all of these questions for our patients. Scaling back treatment whenever possible is important to patients,” says Litton.

Industry response
A spokesperson for Roche Genentech, Herceptin's developers, suggested that the ASCO study should be viewed along with several smaller studies, which conclude that the optimum duration for trastuzumab is 12 months. The goal of the treatment, “is to provide people with the best chance for a cure.” Courtney Aberbach, a spokesperson for Genentech, which was acquired by Roche, in March 2009 for US$$46.8bn, suggested that previous studies had not found that a shorter duration worked as well as the longer one. She said the 12-month course was still the only regimen approved for early-stage disease by the FDA and recommended by several international organizations that issue treatment guidelines.

The HERA Trial
Industry views are influenced by a clinical study sponsored by Roche in the expectation that the 12-month trastuzumab treatment period could be doubled. Referred to as the HERA trial, the study was conducted by France's Institut National du Cancer and reported at the 2012 meeting of the European Society for Medical Oncology (ESMO). HERA was an international multi-centre, phase III randomized study involving 5,102 women with early HER2-positive breast cancer. After finishing primary therapy with surgery, chemotherapy and radiotherapy, they were randomly assigned to trastuzumab therapy every 3 weeks for 1 year, 2 years or observation.
In April 2012, when the study’s findings were presented at the ESMO meeting, the overall survival rate of the 24-month treatment cohort versus the 12-month cohort was comparable. The principal conclusion of the study was that 12-month treatment remains the standard of care for HER2 positive early breast cancer patients. Results also suggested that shortening treatment of trastuzumab to 6 months may offer a worse result than a 12-month course of treatment. While the study’s findings meant that Roche missed an opportunity to expand sales of trastuzumab on the back of a longer recommended treatment period, they were also a relief to the company, which had faced the risk of losing significant sales revenues from trastuzumab had a shorter treatment period turned out to be as effective as the current standard of 12-months.
Unsustainable of cancer care

Cancer treatment has always been expensive, but the costs of newer molecular targeted therapies, such as trastuzumab, have escalated, which significantly reduces access for a lot of breast cancer patients to efficacious drugs. According to a 2015 study by the US National Bureau of Economic Research, each year between 1995 and 2013 the prices of cancer drugs increased 10%. This finding led some health professionals to suggest that cancer therapies are becoming “unsustainable”. In England, NICE has come under intense criticism from patient groups for rejecting numerous cancer drugs for use on the NHS because they were not judged to be cost effective. The UK’s Cancer Drugs Fund, which was set up in 2011 to plug gaps in NHS funding for cancer drugs, overspent its allocated budget by 35% between 2013 and 2015. The debate of the rising cost of cancer therapies is exacerbated by the revenues generated by cancer drugs for big pharmaceutical companies. For example, in 2017 Roche-Genentech recorded annual sales of US$6.8bn for Herceptin alone, which some analysts suggested was driven partly by the duration of the treatment and partly by strong sales growth of the drug in Brazil and China.

When vast revenues from the sale of drugs are mentioned there is negative reaction directed at giant pharmaceutical companies. In their defence drug producers stress the vast costs of developing new drugs and the tenure of patents, which limit the time drug companies have to recoup R&D costs before copycats are introduced into the market. According to the most recent report from the Tufts Center for the Study of Drug Development, and published in the May 2016 edition of the Journal of Health Economics; the cost of developing a medicine from invention to pharmacy shelves is estimated to be some US$2.7bn. Patents protect drugs for 20 years after the initial invention. This exclusivity is designed to promote a balance between new drug innovation and greater public access to drugs, which result from copycat versions.  Notwithstanding, big pharmaceutical companies stress that it can take 8 to 12 years after invention to accumulate enough data to get a drug past the FDA.

For 20 years now Roche-Genentech has benefited from its 90% market share of the HER2-positive global breast cancer market. Notwithstanding, the main EU patent for Herceptin expired in 2014 and is due to expire in the US in 2019. Already, the market has experienced the entry of biosimilar versions of trastuzumab, which are expected to be cheaper and therefore extend patient access to the drug. Biosimilars are not to be confused with generic drugs. Regulators require biosimilars to be “highly similar” to the “reference product” but not exact copies of the biologic medicine. Biologic medicines are comprised of large complex molecules, which may be composed of living material. Here we provide some examples of the biosimilar versions of trastuzumab, which are coming onto the market.
Trastuzumab biosimilars
In December 2017, a biosimilar version of trastuzumab was approved by the FDA and is marketed in the US as Ogivri. Approval of Ogivri was based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data, which demonstrated that Ogivri is biosimilar to trastuzumab. In 2018, Merck Sharp and Dohme (MSD) launched Ontruzan, in the UK, which is Europe’s first biosimilar to Herceptin. Clinical studies have shown Ontruzan to be similar to trastuzumab in terms of its structure, biological activity and efficacy, safety and immunogenicity profile. Studies also showed that in early breast cancer, breast pathologic complete response rates were 51.7% with Ontruzant and 42% with Herceptin, while overall response rates were 96.3% and 91.2% respectively. Mylan and Biocon have launched a biosimilar version of trastuzumab called Canmab in India, and Celltrion, has launched Herzuma, another biosimilar version of trastuzumab in South Korea. According to Mark Verrill, head of the Department of Medical Oncology at the Newcastle upon Tyne Hospitals NHS Foundation TrustUK, “The launch of biosimilar trastuzumab provides a high-quality treatment alternative for patients, while offering significant potential savings for health providers and patients.”
The clinical study presented at the June 2018 meeting of ASCO suggested that the treatment time for trastuzumab could be reduced from 12 months to 6 without compromising outcomes. This would significantly reduce the cost of trastuzumab and thereby make the drug available to more breast cancer patients. Although the study’s findings are “persuasive” there is a reticence among clinicians to reduce the treatment time of trastuzumab. The ASCO study throws light on the challenges to reconcile the competing interests of patients, healthcare providers and drug companies. While pharmaceutical companies spend billions on R&D they are challenged to reconcile the demands of shareholders and society. Public funds for medical research, while important, are limited especially at a time of relatively slow economic growth and fiscal constraint. Given that there does not appear to be any credible suggestion to curtail the vast and escalating cost of cancer care more generally, the current situation, which incentivises giant pharmaceutical companies to invest in R&D with 20-year patents, appears to be a formula that will prevail for some time to come, and patients will have to wait significant lengths of time before they get access to biosimilars.  
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  • A Lancet study suggests moderate alcohol use over time can “significantly shorten your life
  • Experts call for the study’s findings to be widely disseminated and discussed
  • A 2010 Lancet study suggested alcohol is more harmful than heroin or crack cocaine
  • Alcohol related harm is a global epidemic caused by a commercial product
  • There are 3.3m deaths each year caused by alcohol use
  • Policies to reduce the harmful effects of alcohol are palliative rather than preventative
  • A few giant alcohol beverages corporations dominate the global market
  • But 50% of the market is in the hands of informal small-scale producers
  • There is a dearth of reliable information on the alcohol beverages industry
  • Public health research has not kept up with the industry’s ability for innovative marketing
  • British drinkers contribute more in alcohol-related taxes than the direct costs of alcohol-related health and crime issues
Moderate alcohol use can kill
Just when you thought you knew everything there is to know about the harmful effects of alcohol, a study published in the April 2018 edition of The Lancet, brings new evidence to suggest that even modest alcohol use over time is as dangerous as smoking and can “significantly shorten your life”.  The study reinforces the fact that alcohol-related harm is a ‘global epidemic’ caused by a commercial product, which is aggressively marketed throughout the world. Policies aimed at reducing the harmful effects of alcohol have a limited effect and alcohol use continues to be a significant challenge to medicine and society.  
In this Commentary

This Commentary discusses some of the reasons why public policies to limit alcohol use fail to dent the vast and escalating burden caused by alcohol use. We begin by describing the findings of The Lancet 2018 study, which highlights the association between regular modest drinking and early death. The study’s findings motivated healthcare professionals to renew calls for lower limits on alcohol use. A study published in The Lancet in 2010 suggested alcohol is more harmful than heroin or crack cocaine. Public policies to reduce the harmful effects of alcohol use are compromised by the competing interests of the principal industry stakeholders. Such policies tend to be orientated towards the demand side of the market and focus on individual consumers and are less engaged with the supply side and large producers. This results in: (i) public policies that are more palliative than preventative, (ii) alcohol use continuing to be a major healthcare and social challenge, (iii) giant alcohol beverages producers receiving a “free pass”, and (iv) governments enhancing their “political capital” by pointing to the millions spent to correct the drinking habits of vulnerable individuals. This ecosystem is further influenced by: (i) the duty and tax revenues governments collect from alcohol use, (ii) public research failing to keep pace with the sophisticated marketing strategies of large drinks companies, and (iii) well resourced, and smart producers’ marketing strategies out-maneuverering government bureaucracies in endeavours to influence the tastes and preferences of individuals.
The Lancet study

The contribution of alcohol use to premature death is less well recognised than the connection between smoking, lung cancer and early death. The Lancet 2018 study helps to redress this by improving on previous meta-analyses to define low-risk drinking thresholds, and to suggest that people who consume more than 7 drinks a week can expect to die sooner than those who drink less. According to a February 2018 World Health Organization (WHO) report, an estimated 3.3m people a year worldwide die as a result of alcohol misuse. The harmful effects of alcohol ranks among the top 5 risk factors for disease, disability and death globally, and alcohol misuse is the 5th leading risk factor for premature death and disability worldwide. Most people who die because of their drinking patterns are not alcoholics, but are people who drink regularly over a number of years.
The Lancet 2018 study is significant because of its size and methodological robustness.  There is a high degree of comparability in the datasets used by the authors, which combined data from 83 previous studies undertaken in 19 countries, which yielded a cohort of 600,000 current drinkers for analysis. The previous studies used by the researchers to attain their cohort employed similar methods to quantify alcohol use, cardiovascular risk factors, and cardiovascular disease outcomes and cause-specific deaths. All participants in the cohort were from developed industrial economies, displayed similar patterns of alcohol use and none had a known history of cardiovascular disease.
The study’s findings imply that drinking alcohol is as harmful as smoking and suggest that there is a significant increase in all causes of death when more than 100g of alcohol (equivalent to about 4 large glasses of wine) is consumed weekly over a period of time. Every glass of wine or pint of beer over the daily recommended limit - the upper “safe” limit in the UK is 5 standard 175ml glasses of wine or 5 pints of beer a week - will cut 30 minutes from the expected lifespan of a 40-year-old and increase the risk of stroke, fatal aneurysm (a ruptured artery in the chest), heart failure and death. A 40-year-old who drinks up to twice that amount (200g or 8 large glasses of wine per week) will shorten their life expectancy by 6 months. Drinking between 200g and 350g (8 to 20 large glasses of wine) a week will reduce their life expectancy by 1 to 2 years, and 40-year-olds who drink more than 350g (>20 large glasses of wine) a week over a period, shorten their lives by 4 to 5 years.
Lowering the recommended limits of alcohol consumption
According to Angela Wood, from the University of Cambridge in the UK and lead author of the 2018 study, “The key message of this research for public health is that, if you already drink alcohol, drinking less may help you live longer and lower your risk of several cardiovascular conditions.” Although moderate drinking is commonly associated with reducing your chance of a non-fatal heart attack, “This must be balanced against the higher risk associated with other serious, and potentially fatal cardiovascular diseases,” says Wood. According to the researchers the study’s findings support, “limits for alcohol consumption that are lower than those recommended in most current guidelines [and add] long-term reduction of alcohol consumption from 196g per week (the upper limit recommended in US guidelines) to 100g per week or below was associated with about 1–2 years of longer life expectancy at age 40 years”. Co-author Naveed Sattar, Professor of Metabolic Medicine at the University of Glasgow’s Institute of Cardiovascular and Medical Science in Scotland said: "This study provides clear evidence to support lowering the recommended limits of alcohol consumption in many countries around the world."

Experts call for lower limits on alcohol use

Commenting on the study’s findings, Tim Chico, Professor of Cardiovascular Medicine at the University of Sheffield,UK, said, smokers lose on average 10 years of their life. “However, we think from previous evidence that it is likely that people drinking a lot more than 43 units (about 14 large glasses of wine a week) are likely to lose even more life expectancy, and I would not be surprised if the heaviest drinkers lost as many years of life as a smoker. . . The study makes clear that on balance there are no health benefits from drinking alcohol, which is usually the case when things sound too good to be true.”

In a commentary in the same edition of The LancetJason Connor and Wayne Hall both professors from the University of Queensland Centre for Youth Substance Abuse Research in Australia, anticipated that the suggestion to lower recommended drinking limits would be opposed by giant alcohol beverages corporations. “The drinking levels recommended in this study will no doubt be described as implausible and impracticable by the alcohol industry and other opponents of public health warnings on alcohol. Nonetheless, the findings ought to be widely disseminated and they should provoke informed public and professional debate,” say Connor and Hall.

A 2010 study published in The Lancet claims alcohol is more harmful that heroin

In the November 2010 edition of The Lancet David Nutt, Professor of Neuropharmacology at Imperial College London and co-author of the study suggested that alcohol is more harmful than heroin or crack cocaine when the overall dangers to the individual and society are considered. Nutt was the clinical scientific lead on the 2004-5 UK Government Foresight initiative “Brain science, addiction and drugs”. The Lancet 2010 study suggested that if drugs were classified on the basis of the harm they do, alcohol would be a class ‘A’ drug, alongside heroin and crack cocaine. In 2006 Nutt was dismissed for challenging the UK Government’s refusal to take the advice of the official Advisory Council on the Misuse of Drugs,  which he then chaired.

In answer to The Lancet 2010 study a UK government Department of Health spokesperson said: "In England, most people drink once a week or less. If you're a woman and stick to 2 to 3 units a day, or a man and drink up to 3 or 4 units, you are unlikely to damage your health".
No agreed international limits for alcohol use
The reality is that there are no internationally agreed limits on alcohol use and current recommended limits vary significantly between nations. In a study published in the June 2012 edition of the Drug and Alcohol Review  researchers from the University of SussexUK, examined government issued guidelines on alcohol limits in 57 countries and found, “a remarkable lack of agreement about what constitutes harmful or excessive alcohol consumption on a daily basis, a weekly basis and when driving”.

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Alcohol use and dementia

In 2016 the UK Government updated its 1995 guidelines  for limits on alcohol use and recommended that neither men nor women should drink more that 14 units of alcohol per week. A unit in the UK is equivalent to 8g of pure alcohol. This means British men are now being told they should drink less than those in Ireland (21.2 British units), Denmark (21), New Zealand (19) and considerably less than the recommended upper limit for men in Spain (35).
The supply side of the alcohol industry

Current public policies and industry pledges
Although public policies to reduce the harmful effects of alcohol use are aimed at both the individual and population levels, they tend to orientate towards individual problem drinkers. Among the most effective policy options are alcohol taxes, restrictions on alcohol availability and drink-driving countermeasures. The giant alcohol beverages corporations advocate responsible drinking and pledge their commitment to, “supporting balanced initiatives that are linked to their core business functions and those that address wider social and public health issues, relying on initiatives that are evidence based, culturally sensitive, and collaborative.” The drinks producers support the WHO’s Global Strategy to reduce the harmful Effects of Alcohol, and are committed to: (i) reducing under-age drinking, (ii) strengthening and expanding marketing codes of practice, (iii) providing consumer information and responsible product innovation, (iv) reducing drinking and driving, and (v) enlisting the support of retailers to reduce harmful drinking.  

Growth of service economies and the importance of individual preferences
Despite public policies and industry pledges to limit alcohol use, the large and escalating burden of alcohol problems continue to present significant challenges to medicine and public health. In part, this is because population-based public health policies tend to be overlooked in favour of policies oriented towards individual drinkers. This orientation can be explained by globalization.
Over the past 40 years globalization has shifted the economic base of developed nations from manufacturing to services, which places greater emphasis on consumer markets and individual preferences. In such a context, efforts to reduce the harmful effects of alcohol use are mainly focused on the demand side of the market, emphasising individual behaviours and preferences; and less focused on the supply side, which is dominated by producers. As a consequence, public policies to limit alcohol use tend to focus on the choices of vulnerable individual drinkers and call for responsible drinking. In effect this provides producers with a “free pass” to pursue and develop their strategies to sustain consumption.
50% of alcohol production is in the hands of “informal” small producers
Shifting the policy emphasis to focus equally on the demand and supply side of the alcohol beverages market is not straightforward. Although nearly half of the of the world's alcohol supply is dominated by giant producers, more than 50% is in the hands of ‘informal’ home and local producers. At the national level the industry comprises large and small beer, wine or spirit producers or importers, as well as bars, restaurants and a variety of retail outlets, which markets alcohol to the public. These players have diverging interests as well as interests in common in regard to policy frameworks. There is a dearth of reliable information on the industry and the principal sources of information come from market research firms and business journalism.  
Large global fast-growing market
The alcohol beverages market is large, global and fast growing. According to an April 2018 report by Transparency Market Research, in 2017 the market was worth US$1,205bn and is expected to expand at a CAGR of 6.4% and reach US$2,000bn by the end of 2025. Recent consolidation in the industry puts a significant and increasing proportion of alcohol production, distribution and marketing in the hands of a few giant corporations, which dominate national, regional and global markets and wield considerable political influence. Mergers and acquisitions are expected to continue, so the consolidation of the industry is expected to continue.

The market is driven by increasing urbanization, the global young-adult demographic, high and growing disposable incomes and increasing consumer demand for premium and super premium beverages. The latest figures suggest that the average alcohol use in the UK is about 9.7 litres per adult, which compares with 8.8 litres for adults in 34-member countries of the Organisation for Economic Co-operation and Development  (OEDC), and ranks the UK 16th out of the OEDC countries. Since 1970, alcohol consumption has decreased by an average of 15% across OEDC countries, while in the UK it has risen 14% over the same period. Alcohol use has declined 69% in Italy, 48% in France, 36% in Spain and 30% in Germany, but has increased 51% in Ireland. Consumption of alcohol per head in the UK has fallen by about 17% since its recent peak in 2004. But that followed a steep rise.

A study reported in 2015 in the International Journal of Advertising suggests that advertising has little impact on how much we drink, but it is effective at influencing what we drink. ‘Premiumization’ is a term used in the industry to describe how spirit brands have had success convincing consumers that they should drink “higher quality” and more expensive beverages. An example of this is the recent boom in the sale of gin, which corresponded with the industries premiumization strategies that linked gin with “fashionable” early 20th century style.
UK alcohol taxes far exceed the costs to public services
The “free-pass” enjoyed by alcohol beverages corporations is strengthened by the relative lack of public scrutiny they receive. This might be partly explained by the fact that governments benefit significantly from alcohol related taxes and duty. Consider Britain. In 2016 the UK government made nearly £3.4bn in tax revenue from spirits; beer sales made the UK government £3.3bn in 2017. Some 60% of the price of a pint of beer is taken in VAT and alcohol duty, while VAT on the price of a bottle of gin is 76%. Wine is the biggest earner for the UK exchequer yielding over £4bn in taxes from sales in 2016. These sums accord with a September 2015 Institute of Economic Affairs (IEA) study on alcohol taxes, which suggests that the annual revenue generated from alcohol taxes in the UK is  “illogical and excessive.”  Rather than tax alcohol the UK government taxes drinks. For instance, a unit of alcohol is taxed at 28p if it happens to be in a glass of whisky but only 8p if it is in a pint of cider. Further, if the cider is strong, the tax is 7p but if it is fizzy the tax is 34p. The tax on a unit of alcohol in a glass of wine is 20p, but if wine is sparkling, the tax is 25p. Confused? The structure of alcohol excise taxes is partly restricted by an EU Directive, which sets out different tax rates for different alcoholic beverages.

Revenues from UK alcohol taxes and duty far exceed the actual direct costs of alcohol-related health and crime issues. According to the IEA study, the UK exchequer collects about £10bn a year in alcohol taxes while the direct costs of alcohol related problems to the health, police, prison services, welfare system and judiciary, amount to some £4.6bn per year. Although studies that report cost-of-alcohol data are notoriously unreliable, the IEA suggests that British drinkers contribute about £6.5bn each year to the UK exchequer and believes that, even within the current constraints, the UK tax system could more effectively target problem drinking. In a February 2017 paper the IEA describes a suggested reform of the UK’s alcohol tax policy.

Findings of the 2018 study published in The Lancet suggest that risks from alcohol start from any level of regular drinking and rise with the amount being consumed and any amount of regular alcohol use can significantly shorten your life. This echoes a 2010 study also published in The Lancet, which suggested that because alcohol is so widely available it is more harmful than heroin and crack cocaine.

This commentary reaffirms the global epidemic of disease, injury, social problems and death caused by alcohol and suggests an explanation why for decades governments have failed to effectively limit alcohol use.
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  • Dementia has emerged as one of the biggest killer diseases of the 21st century
  • Studies suggest that moderate alcohol use significantly increases the risk of dementia
  • There are no treatments that slow or stop the progression of dementia
  • There are 50m people worldwide living with dementia, by 2050 there will be 132m
  • 0.85m people in the UK are living with dementia and this is expected to rise to 1m by 2025
  • Public policies alone are not sufficient to limit and control alcohol use
  • This increases the importance of a medical solution for dementia
  • Recent innovative research on neurodegenerative disorders provide some hope for future dementia sufferers
Alcohol use and dementia

Two significant recent studies described in this Commentary link alcohol use and the onset of dementia. One study published in the June 2017 edition of the British Medical Journal (BMJ) suggests that moderate alcohol use increases the risk of adverse brain outcomes and a steeper decline in cognitive abilities. The other, published in the February 2018 edition of the Lancet Public Health, suggests that excessive alcohol consumption is a significant risk of early onset dementia.

Dementia is a chronic progressive disorder, which has emerged as one of the biggest killers and the only leading cause of death without a treatment that can slow or stop its progression. Of the 529,655 deaths recorded in the UK in 2015, dementia accounted for 61,686 (11.6%): the majority are women, 41,283, compared to 20,403 men.

In this Commentary
In this Commentary we outline how alcohol affects you, explain its misuse and describe some of the UK’s drinking patterns and their consequent costs. We then suggest that public policies alone, which are aimed at both the individual and population levels to reduce and control alcohol use in order to save lives and reduce healthcare costs, are insufficient. This shifts the burden of a solution for alcohol related dementia onto potential medical treatments. We describe dementia and provide a few epidemiological facts before describing the findings of the 2 studies. We suggest that the studies are significant because there are no effective treatments or cures for dementia despite the vast amounts of money spent on neurodegenerative diseases over the past 2 decades. We end by mentioning a couple of significant UK-based innovative dementia research initiatives, which signal hope for future dementia sufferers.


How alcohol affects you and its misuse

Alcohol is a dependence-producing psychoactive beverage, which has been widely used throughout the world for centuries. Problems associated with the consumption of alcohol have been around since the beginning of recorded history. There are 3 mechanisms by which alcohol can affect you: (i) alcohol has toxic effects on your brain and other organs and tissue, (ii) alcohol has intoxicating effects, which manifest themselves in physical and mental impairment and (iii) you may become dependent of alcohol, which means control over your drinking habit is impaired. Alcohol’s harmful impact is influenced by, (i) the volume you consume, (ii) your pattern of drinking and (iii) the quality of the alcohol. When your body takes in more alcohol than it can metabolize, the excess builds up in your bloodstream. Your heart circulates the blood alcohol throughout your body leading to changes in your body’s chemistry and normal functions. 

Studies have consistently suggested that heavy alcohol consumption is detrimental to health and a leading preventable cause of death. There is an increasing awareness of the harmful impact of alcohol misuse on individuals and societies. According to the 2011 World Health Organization’s (WHO) Global status report on alcohol and health, only about 50% of the world's population consumes alcohol, and most users are in the wealthier northern hemisphere countries, although alcohol use is increasingly becoming a problem in emerging economies. Eastern European countries have the highest consumption, riskiest patterns of drinking and the highest levels of alcohol-related deaths and disabilities. According to a February 2018 WHO report, an estimated 3.3m people a year worldwide die as a result of alcohol misuse, which accounts for about as much death and disability worldwide as tobacco and hypertension. 
Drinking in the UK and its costs
The latest available data suggest that the total alcohol consumption in the UK is 9.5 litres per person aged 15 years and older and 7.8 litres per person on average throughout the entire population in 2015. This forms part of a recent downward trend from a peak of 11.6 and 9.5 litres per head respectively in 2004 and positions the UK 16th out of the 34 OEDC countries. 21m people in the UK do not drink alcohol. According to NHS Digital, in 2014 there were 1.1m hospital admissions in England wholly or partially attributable to alcohol use: more than double the number recorded a decade earlier. In 2014 about 6,600 people in England died from causes related to alcohol and about 115,000 adults received specialist alcohol treatment. Treating alcohol related conditions is estimated to cost NHS England about £3.5bn per year: around 3.6% of its annual budget. About 6% of adults in England are dependent on alcohol. 195,000 prescriptions were written in 2014 by the NHS to treat alcohol dependence at a cost of £3.4m. Over the past decade these prescription costs, measured in 2014 prices, have increased by nearly 80% from £1.9m in 2004.
Public policies to curb alcohol use are insufficient

In May 2018, Scotland became the first country in the world to introduce legislation for minimum pricing on cheap, high-strength alcohol. The government said it was an endeavour to cut the consumption of alcohol and save lives. For several decades, similar alcohol reduction and prevention measures have been available at both the individual and population levels in the UK and elsewhere. The most effective include alcohol taxes, restrictions on alcohol availability, and drink-driving countermeasures. Despite the success of these policies, alcohol problems continue to present a major challenge to medicine and public health. In part, this is because population-based public health alcohol control policies tend to be overlooked in favour of approaches aimed at the individual and these have tended to be more palliative than preventative. It is reasonable to assume therefore that, in the near- to medium-term, alcohol related dementia will neither be significantly slowed nor reduced by public policies alone. This shifts the emphasis to a medical solution for alcohol related dementia.


Dementia is an umbrella term, which describes a group of symptoms that impair your cognitive functions and behavioural abilities severely enough to interfere with your daily life and activities. It is a chronic, progressive and incurable disorder, which ranges in severity from ‘mild’, when it is just beginning to affect your functioning, to ‘severe’, when you depend completely on others for basic activities of living. Dementia involves damage of nerve cells in your brain, which can occur in several areas and affect people differently, depending on the area of the brain affected. Alzheimer's, a neurodegenerative disease, is the most common irreversible cause of dementia, accounting for 60% to 80% of all dementia cases.
The biggest risk factor for dementia is age. We are living in the age of the aged, which represents the successes of improved healthcare over the past century. There are some 50m people worldwide living with dementia. The total number of people with dementia worldwide is projected to increase to 75m by 2030 and 132m by 2050, with the largest proportion of these in low- and middle-income countries. There are 0.85m people diagnosed with dementia in the UK, with numbers set to rise to over 1m by 2025 and to 2m by 2050. 225,000 people in Britain will develop dementia this year. There is a similar story to be told in most wealthy developed countries. For example, in the US an estimated 6m people have Alzheimer's, which equates to 10% of people aged 65 and older. The current annual cost of dementia globally is estimated to be about US$1tr: 1% of global GDP. The annual cost of the condition in the US is US$259bn, which is expected to rise to US$1tr by 2025. Dementia costs the UK exchequer about £26bn each year.
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Dementia is not an inevitable part of ageing. The notion that dementia is a disease rather than a side-effect of aging has been around for 100 years. Early onset of the disease can begin when people are in their 30s, 40s, or 50s. For example, over 42,000 people under 65 have dementia in the UK. Age, family histories and heredity are factors of dementia that we cannot change. But lifestyle factors such as alcohol use are modifiable risks. There is no cure for the condition and no therapy that slows or stops its progression although some drug treatments may temporarily improve its symptoms.

The BMJ study

For some time, scientists have suggested that moderate alcohol consumption could delay the onset of cognitive impairments in ageing, but few studies have examined the effects of modest consumption of alcohol on the brain. This increases the significance on the BMJ study, which includes an analysis of the relationship between moderate alcohol consumption and dementia. Researchers from Oxford University  and University College London studied a cohort of 550 healthy adult civil servants over a 30 year period between 1985 and 2015. At the beginning of the study the average age of the cohort was 43 and none were dependent on alcohol. At regular intervals during the study tests were administered to assess participants’ levels of alcohol consumption and cognition. At the end of the study participants underwent an MRI brain scan, which enabled researchers to analyse correlations between average alcohol consumption, cognition and brain structure. Findings suggest that alcohol use is associated with reduced right hippocampal volume. The hippocampus is a small region of your brain associated with memory and spatial navigation. Poor memory is linked with small hippocampal volume as measured by an MRI scan. The more you drink, the more you are likely to have hippocampal atrophy, which is regarded as an early marker for dementia. Significantly, the study found that even moderate drinkers were 3 times more likely to have hippocampal atrophy than abstainers.

The principal strength of the study is that it is a longitudinal observational analysis of a specific cohort, which yielded detailed information on long term alcohol consumption and cognition and confounding variables. These are “extra” variables, which are important to know in order to avoid bias. Because this was an observational study the researchers were unable to draw any conclusions on cause and effect. Notwithstanding, they were able to conclude that moderate alcohol use is associated with adverse brain outcomes and, “Alcohol might represent a modifiable risk factor for cognitive impairment, and primary prevention interventions targeted to later life could be too late.” In an editorial note in the same BMJ, Killian Welch, a consultant neuropsychiatrist at the Royal Edinburgh Hospital suggests the findings of the study, “strengthen the argument that drinking habits many people regard as normal, have adverse consequences for health.”

The Lancet Public Health study
The second study from The Lancet Public Health presents findings of a large retrospective study predicated upon data of more than 1m adults diagnosed with dementia between 2008-2013 from the French National Hospital Discharge database. These data provide details on all hospital admissions, including patient demographics, reasons and durations for hospital stays and treatments received. Findings suggest that being hospitalised with alcohol dependence or a health issue caused by continuous heavy drinking is a significant risk factor for dementia. Although the condition is more common in people over the age of 65, the study identified and examined 57,000 cases, which presented with the onset of dementia before 65. Of these, 57% were heavy drinkers, 39% regularly consumed alcohol and 18% had an alcohol use disorder as an additional diagnosis. “Heavy drinkers” were found to be more than 3 times likelier to develop dementia. Excluding alcohol-related brain damage, alcohol use disorders were still found to be associated with a 2 times greater risk of dementia.

According to Michael Schwarzinger, the lead author of the study, who is the director of the French Translational Health Economics Network and a researcher at the Universite Paris Diderot, France, “Chronic heavy drinking was the most important modifiable risk factor for dementia onset in both genders and remained so after controlling for all known risk factors for dementia onset.” While other studies have reached similar conclusions, some research suggest that drinking one or two units of alcohol a day - a small glass of red wine particularly - could be of benefit to brain health and slow the onset cognitive deterioration. Indeed, the Lancet Commission on dementia, associates light to moderate alcohol use with a healthier brain. Schwarzinger and his colleagues however are clear, “Our findings suggest the burden of dementia attributable to alcohol use disorders is much larger than previously thought . . .. Chronic heavy drinking leads to irreversible brain damage [and even] heavy drinkers who got sober didn’t have a lower dementia risk than their peers who remained problem drinkers. . . Additionally, clinicians should be better aware of the role of alcohol use disorders in dementia onset over the lifetime, which seems to be a risk factor often omitted.”
Why there is no cure for dementia

Over the past 2 decades pharmaceutical companies, biotech’s, governments, universities and charities have devoted vast amounts of money, time and effort to the dementia challenge, but without being able to develop any credible treatment let alone cure. This partly reflects the complexity of neurodegenerative disorders. The brain is a complex organ, which scientists are still endeavouring to understand. This lack of understanding is one of the main obstacles preventing the development of effective treatments for dementia. The disorder seems to present as a result of an intricate interaction of genes, lifestyle factors and other environmental influences. But, without knowing the exact mechanisms that cause damage, especially in Alzheimer's, it is impossible to target the disease process effectively.

In addition to our rudimentary understanding of the brain there are some specific challenges faced by researchers into neurodegenerative disorders. One is the blood-brain barrier, which is formed by brain endothelial cells, which protect the brain by preventing toxins from reaching it. This presents dementia researchers with a significant challenge because the blood-brain barrier also prevents treatments getting through to the brain and working effectively. Newer immunotherapy drugs, also known as biologics, are large complex molecules or mixtures of molecules, which because of their size and shape may only partly cross the blood-brain barrier. This suggests that dangerous doses would be needed for them to work effectively. And even if the biologics could penetrate the blood-brain barrier and target the proteins causing damage to brain cells, dementia is irreversible and may have started to develop decades before the presentation of symptoms and before the administration of drugs. Further, there is no test for dementia, which means the disorder is difficult to diagnose. This leads some health professionals to suggest that with no effective treatments, early diagnosis has no benefits. A significant proportion of those living with dementia have not received a formal diagnosis, which presents further challenges not least for clinical studies.

The amyloid hypothesis

For the past 2 decades dementia drug development has been dominated by the ‘amyloid hypothesis’, which suggests that Alzheimer’s can be treated by attacking the sticky plaques of beta amyloid protein that builds up in patients’ brains. The pharmaceutical industry has lost billions in failed development of drugs designed to target amyloid, and there is still no treatment that affects the underlying progression of the disease. In January 2018 Pfizer, the world’s largest pharmaceutical company, which has spent billions on dementia R&D, announced that it was pulling out of research into drugs to treat complex neurological disorders. Notwithstanding, many pharmaceutical companies, driven by the potential financial gains from finding a medicine that can arrest the disease of 50m people, continue to work on treatments for neurodegenerative diseases.
Innovative research endeavours that target dementia

The UK’s 2013 presidency of the G8, (an inter-governmental political forum comprised of the major industrialized democracies) focused on dementia. This resulted in the condition rising up global political agendas and the UK Government unlocking more money for research into neurodegenerative disorders. In 2015 the UK government with the help of JP Morgan, an American multinational investment bank, set-up the Dementia Discovery Fund, with an initial investment of £15m and the commitment from several big pharmaceutical companies to invest. The fund’s strategy was to raise £100m for dementia R&D and move beyond the amyloid hypothesis. It has invested in some 12 start-ups and projects investigating novel ways to stop or reverse the complex biological processes that lead to dementia. In November 2017 the Bill and Melinda Gates Foundation invested US$50m into the fund, which took its total to £130m. Other well-funded novel research projects include the UK Dementia Research Institute, which brings together the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK in a £250m initiative involving more than 400 scientists, who are leading efforts to transform the treatment and care for people with dementia.

Dementia is a 21st century Damocles Sword positioned to bankrupt healthcare systems in the developed world. Dementia is a vast, fast growing global killer disease effecting about 7% of people living in wealthy nations and costing billions. Despite billions spent on dementia R&D over the past 2 decades there are no viable treatments to either slow or stop the progression of the disorder. Alcohol use has been suggested as a significant contributory factor for the onset dementia. Public policies to curb the use of alcohol are insufficient to significantly dent the vast and escalating burden of dementia. This shifts the emphasis for a solution to medicine. Despite the dearth of medical solutions, things are beginning to change with some recent novel research initiatives specifically targeting neurodegenerative disorders, which might help to lift the Damocles Sword
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  • More than 50% of cancer drugs available in the UK do nothing to extend or improve the lives of patients
  • The efficacy of drugs was not considered by authorities as a factor in the UK’s higher cancer mortality rates compared with other European nations
  • Recent scientific and technological advances have significantly changed our understanding of cancer biology and impacted cancer diagnoses and treatments
  • Increasingly traditional randomized controlled trials (RCT) are viewed as too long, too expensive and too inefficient

Cancer drugs that neither improve nor extend lives 
A retrospective cohort study of drug approvals published in the October 2017 edition of the British Medical Journal, (BMJ) found that 57% of cancer drugs approved by the European Medicines Agency (EMA) between 2009 and 2013 and prescribed to UK patients do nothing to extend or improve their lives.
Recurring explanations for Britain’s cancer mortality rates lagging those of other European nations make no mention of the quality of cancer medicines. Although cancer drugs approved by the EMA might be expected to affect all European nations equally, drug efficacy is a significant factor in cancer care, and merits consideration. Not least because the ‘revolution’ in molecular science is responsible for the shift from the medicine for crowds to the medicine of molecules; from treating diseases to treating individuals. Traditional regulatory protocols support crowd-science medicine and struggle to find ways to adjust to molecular science.
In this Commentary

Before describing the findings of the BMJ study, we briefly provide descriptions of 4 of the 48 drugs scrutinized in the BMJ paper and approved by the EMA. Within this context we describe the role of the UK’s Cancer Drugs Fund (CDF) and its relation to the EMA. We then describe the findings of the BMJ study and mention a cautionary note about the research suggested by BMJ editors. It is not altogether clear that criticism of cancer drugs coming to market without showing any sign that they extend life will put pressure on regulatory bodies to change their protocols before recommending drugs for use in clinics. There is evidence to suggest an opposite position: that randomized controlled trials, the “gold standard” for drug delivery over the past 70 years, are increasingly challenged by molecular science and are changing as a result.
4 cancer drugs scrutinized

Four of the 48 drugs scrutinized by the study reported in the October 2017 edition of the BMJ were: 1. Everolimus, which is a type of targeted therapy for breast cancer, (also indicated for kidney cancer and brain tumours). It is taken as a tablet once a day for an average of 5.5 months at a cost of about £18,000 per patient per course. Each year, some 1,500 breast cancer patients are eligible for the drug. Evertlomus is manufactured by Novartis, and sold under the trade name Afinitor. The drug stops some of the growth of cancer cells and slows their spread. Side effects include diarrhoea, constipation, mild nausea or vomiting and weight loss. Evertlomus was approved by the EMA in 2012 without either survival rate or quality of life data. In 2016 it was moved on to routine provision through the National Institute for Health and Care Excellence (NICE), the UK government’s watchdog. 2. Bosutinib, which is a drug taken either as a tablet or a capsule and used by adult patients to treat chronic myeloid leukaemia (CML), which has an abnormal chromosome called the ‘Philadelphia chromosome’. 95% of people with CML have the Philadelphia chromosome. Bosutinib is manufactured by Pfizer, marketed under the trade name Bosulif and is used when other CML treatments no longer work or cause severe side effects. In 2013 bosutinib was approved by the EMA with no evidence that it extended life. Each year about 80 NHS England patients receive the drug at an annual cost per patient of about £45,000. Patients have blood tests before starting and during treatment to monitor the effect of the drug. Up to 85% of patients see white blood cells return to normal levels. The most common adverse reactions, which affect more than 20% of patients, include diarrhoea, nausea, abdominal pain, rash, anaemia, and fatigue. Serious adverse reactions reported include anaphylactic shock. 3.Panitumumab, which is a targeted biological therapy belonging to a group of drugs called monoclonal antibodies. These are drugs that stimulate the body's immune system to act against cancer cells. Panitumumab is used for the treatment of advanced bowel cancer, which has progressed after treatment with other drugs. It is administered via a small cannula into a vein and works by attaching itself to growth factor specific proteins found on the surface of cells and stopping them from attaching themselves to the cancer and triggering the cancer to divide and grow. Panitumumab is manufactured by Amgen and sold under the trade name Vectibix. The drug was approved by the EMA in 2011 without evidence that it extended life.  However, more recent data suggest panitumumab boosts survival by 10 months more than other treatments. Common side effects include skin reactions, diarrhoea, nausea, tiredness and constipation. Each year about 84 NHS England patients are given the drug. In 2017 NICE made panitumumab routinely available at a cost of about £54,000 per year per patient. 4. Bevacizumab, which is a drug that blocks a cancer cell protein that helps cancers to grow by providing them with blood. It  belongs to a class of cancer treatments, which interfere with the development of blood supply to cancers called ‘anti-angiogenesis therapies’. Bevacizumab is manufactured by Rochemarketed as Avastin and costs £42,000 per patient per year. It is administered intravenously, and side effects include mild headache, back pain, diarrhoea, loss of appetite, cold symptoms and dry or watery eyes. Bevacizumab was approved by the EMA in 2009 with no evidence that it extended life and is not available on the NHS. Initially the drug was available in the UK on the Cancer Drugs Fund but was stopped in 2015. Clinical studies show that bevacizumab stops the progression of the disease for an average of 3 months.
The UK’s Cancer Drugs Fund

These and the other drugs examined in the BMJ paper were all approved by the European Medicines Agency. This approval permits pharmaceutical companies to market their medicines across Europe. NHS England, however, will not use medicines unless NICE assesses them as showing value for money. The UK’s Cancer Drugs Fund (CDF) was specifically introduced in England in 2011 to provide a means by which NHS England patients could obtain cancer drugs rejected by NICE because they were too expensive. Some of the drugs deemed by the researchers to have shown no benefit are now available to UK patients, but only after pharmaceutical companies reduced their prices.  
The BMJ study is significant because it is one of the only recent studies that has systematically examined evidence associated with the extent of the benefits of cancer drugs approved by the European Medicines Agency. Researchers, from Kings College London and the London School of Economics, who conducted the study assessed 48 cancer drugs for 68 indications approved during the 5 year study period and concluded that, at the time of market approval, there was an improvement in the quality of life  for only 7 of 68 indications and no evidence of a survival gain for 44 indications. However, subsequent evidence showed that life was extended in 3 indications and quality of life was enhanced in 5.
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When drugs did show survival gains over existing treatments the benefits were marginal, the report says. Treatments that improved life expectancy gave patients a median of an extra 2.7 months of life often at significant cost. Notwithstanding, researchers stressed that when someone is dying of cancer even a few extra months of life with loved ones are priceless, and they also understood that it takes time to prove a drug will improve life expectancy. Notwithstanding, researchers suggested that drug firms could be needlessly raising the hopes of cancer patients and exposing them to unnecessary side effects. “At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications,” researchers said. Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up, 35 had shown a significant improvement in survival or quality of life, while 33 remained uncertain.
It is remarkable that cancer drugs enter the European market without any clear data on outcomes that matter to patients and their doctors: longer survival and better quality of life,” said Huseyin Naci, a co-author. “There is a clear need to raise the bar for approving new cancer drugsWhen expensive drugs that lack robust evidence of clinical benefit are approved and reimbursed within publicly funded healthcare systems, individual patients may be harmed, and public funds wasted,” say the researchers. “There is growing concern that the benefits offered by many new treatments for cancer, which are often discussed and promoted as ‘breakthroughs’, are marginal and might not be clinically meaningful to patients, despite rapidly escalating costs,” says Courtney Davis of Kings College London  (KCL) and the lead author of the study.
Editors’ note of caution

Editors of the BMJ noted that the study was limited by the EMA’s“incomplete and variable” reporting of clinical studies, which contributed to the “possible overestimation of the proportion of drugs that offer survival or quality of life benefits”. They further suggested that the researchers did not consider the “appropriateness of clinical trial design”, which affects patient outcomes, and they also failed to take into account the “negative studies” for the indications they were studying.
Randomized controlled trials

Paradigm shifts in science, rapidly changing technologies, the increasing influence of patient advocacy groups and economic pressures on pharmaceutical companies are conspiring to drive change in randomized controlled trials (RCT), which were introduced 70 years ago to reduce bias when testing for a new treatment. RCTs have reshaped medical knowledge and practice and have become the “gold standard means to assess the clinical efficacy of new or improved cancer therapies. In such procedures participants are randomly assigned to receive either the treatment under investigation or, as a control, a placebo or the current standard treatment. The randomization process helps ensure that the various groups in the study are identical across a number of relevant variables such as age, gender and socioeconomic status. This minimizes the potential for bias. Despite their strengths, only a modest percentage of therapies successfully navigate the regulatory minefield of RCTs from early stage to final approval. It takes between 10 to 15 years for a drug to pass through all the development stages and become approved for prescription. Only 5 in 5,000 drugs that enter preclinical testing progress to human testing, and only 1 in 5 of these is approved for prescription in clinics. The cost of developing a drug that gains market approval is estimated to be about US$2.6bn.  
Enhanced understanding of cancer biology

One of the main limitations of cancer care has been our understanding of the biology of the disease, but this is beginning to change. Over the past 2 decades, oncologists have witnessed significant advances in our understanding of cancer biology and major breakthroughs in a number of therapeutic areas, which impact on drug targets and drug development. For example, next generation genome sequencing has increased the application of more robust models for different types of cancers. Cancer immunotherapy has captured the attention of scientists and has become a significant focus for drug delivery, and the development of genome editing technologies such as CRISPR Cas-9 have significantly impacted the direction and progress of nonclinical anticancer drug development.

Personalized medicine approaches have led to significant changes in the way oncology is practiced. Clinical and translational research is adapting to a rapidly changing environment with the intention to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients, but not without significant challenges. Some of which are described by Axel Walther a medical oncologist and Director for Research in Oncology at University Hospitals Bristol, see video below. “If we combine patients in clinical trials with the concept of personalized medicine we start to add a lot of variables. This is because we want to target a novel treatment to the individual cancer of a specific patient. The challenge is to find that patient for whom the specific treatment is appropriate. If you have a treatment that addresses a specific abnormality you need to find all the patients with that abnormality. This is relatively easy if it’s a common abnormality but significantly more difficult if the abnormality isn’t common,” says Walther.
Pressures to change RCTs

Such scientific advances have shifted the emphasis of cancer treatment from histopathologically based methods (the microscopic examination of tissue in order to study the manifestations of disease) to molecular and genetically based treatments, which has significantly improved our understanding of disease processes and advanced drug development. Technologies, which use high-throughput screening of a number of potential target molecules are significant additions to our investigational medicinal product portfolio. Further, enhanced big data assets benefit from enhanced high volume, high velocity, high variety processing and interpretation and increasingly provide new and significant opportunities to conduct large-scale studies with many of the benefits of RCTs but without the expense. Big data techniques also allow for the study of rare cancers effecting small populations, which are often excluded from RCTs because of cost and other constraints. Such scientific and technological advances, together with the rapid expansion of the portfolio of therapeutic modalities, which can be used in various combinations to improve clinical outcomes, challenge traditional RCTs. Further, the costs and increasing complexity of RCTs means that promising drug candidates are sometimes abandoned for economic or logistical reasons rather than for their efficacy. For these reasons regulatory bodies, including the EMA, support changes in RCTs and are encouraging ‘adaptive clinical trials”.
 Adaptive clinical trials

Adaptive clinical trials can be used in every phase of drug development. Rather than wait until the end of the trial to analyse data, adaptive trials accumulate and analyse data during the trial period and use results to change the actual direction of the trial. Adapting trials in this way is expected to reduce risks for both patients and pharmaceutical companies, particularly at challenging decision-points, such as dose selection. Significantly, adaptive trials can reduce the total number of patients required to obtain results. This, cuts cost and alleviates time constraints on sponsors, researchers, monitors, and trial sites and increases the capacity of the entire clinical development system. Notwithstanding, a concern is that data from such studies tend to be challenging to provide definitive answers.

Researchers drew attention to the fact that a significant number of cancer drugs become available in the UK without evidence that they significantly extend life. The slow pace and the eye-watering costs of traditional RCTs are increasingly being challenged by pharmaceutical companies, governments, scientists, patient advocacy groups and regulators. Fuelling such challenges is the unprecedented pace of change in our understanding of cancer biology, which has significantly influenced drug development and the modalities of treatments. New science is positioned to transform medicine beyond our recognition. But the science itself and the process by which it is transformed into useful medicine collide with RCTs.
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  • International study shows that while British cancer survival has improved over the past 20 years the UK’s cancer survival rates lag behind the European average in 9 out of 10 cancers
  • 10,000 cancer deaths could be prevented each year if the UK hit the European average
  • Analysis shows that some British cancer survival rates trail that of developing nations such as Jordan, Puerto Rico, Algeria and Ecuador
  • Since the inception of the NHS in 1948 policy makers and clinicians have viewed the problem as the NHS being under staffed and underfunded
  • But the answers to the cancer care challenge in the UK are not that straight forward
  • The world has changed and is changing while policy responses to challenges have remained static
UK cancer care lags that of other European nations: reasons and solutions
Part 1


This Commentary is in 2 parts
Part 1 focusses on cancer care in the UK, but much of its substance is relevant to other advanced nations with aging populations and large and escalating incidence rates and costs of cancer. Before drilling down into cancer care in Britain we briefly describe the etiology of cancer, the epidemiology of the condition as it relates to the UK and other wealthy nations, mention immunotherapy as indicative of evolving and significant new therapies, which give hope to cancer sufferers. We then describe the CONCORD-3 study reported in The Lancet in 2018. This is a highly regarded and significant international study, whose findings are widely recognised as the “gold standard” of comparative cancer care. It reports that although 5-year cancer survival rates (the internationally accepted indicator of cancer care) have improved in Britain over the past 2 decades, the UK is still trailing that of most large European countries. We conclude Part 1 with a brief description of UK initiatives to close its cancer-gap with other European countries.
Part 2, which will be published in 2 weeks, is an analysis of the cancer-gap between Britain and other European countries. We suggest that for decades, healthcare providers, policy makers and leading clinicians have suggested that the UK cancer-care gap is because of the lack of funding and the lack of healthcare professionals. Since the inception of the NHS in 1948 a policy mantra of “more” has taken root among policy makers, providers and clinicians: predominantly, “more money”, “more staff”, and “the government should do more”. We suggest that, over the lifetime of NHS England, a combination of Britain’s economic growth, its historical ties with Commonwealth countries and, since 1973, the reduction of barriers to the flow of labour between European countries, has given UK policy makers a convenient “get-out-of-jail-card” because they could always provide more money and more staff. Over the past 2 decades, this option has become less and less effective because of a combination of the slowdown of world economic growth, the rise of emerging economies such as India, and more recently Brexit.
We conclude with some thoughts about why a significant cancer care gap has opened between the UK and other European nations, and briefly describe some UK initiatives to close the gap. We suggest that the world has changed quicker than the thinking of policy makers and quicker than structural changes in the UK’s healthcare system. Improving cancer care in the Britain will require more than inertia projects. It will require more innovation, more long-term planning, more courage from policy makers, more focus on actual patients’ needs rather than what we are simply able to provide. Since 1948, the healthcare baton in the UK has been with an establishment comprised of policy makers, providers and leading clinicians. Over the past 70 years this establishment has become increasingly entrenched in past and narrow policy solutions. It has failed because the world has changed while It has remained static. It is time that the healthcare baton is passed to people with less self-interest at stake, who are less wedded to the past, and understand the new and rapidly evolving global healthcare ecosystem.

The UK’s cancer challenge

While British policy makers and health providers appear keen to stress that trends in the 5-year cancer survival rates (the internationally accepted measure for progress against cancer) have improved over the past 20 years, there is an element of “economy with the truth” in what they say. The UK is being left behind by significant advances in cancer survival rates in other nations. Treatment for 3.7m UK cancer patients diagnosed since 2000 is struggling to progress, especially for people diagnosed with brain, stomach and blood cancers. Further, your chances of dying after being diagnosed with prostate, pancreatic and lung cancer in Britain is significantly higher than in any other large European nation. This is according to CONCORD-3, the largest ever international cancer study reported in the January 2018 edition of the The Lancet.

The emperor of all maladies
Cancer is the uncontrolled proliferation of cells. In his 2010 Pulitzer Prize winning book, ‘The Emperor of All MaladiesSiddhartha Mukherjee, professor of oncology at Columbia University Medical School in New York describes cancer cells as, "bloated and grotesque, with a dilated nucleus and a thin rim of cytoplasm, the sign of a cell whose very soul has been co-opted to divide and to keep dividing with pathological, monomaniacal purpose." Cancer occurs when a cell starts to divide repeatedly, producing abnormal copies of itself, rather than dividing occasionally just to replace worn out cells. If the immune system fails to destroy these cells, they continue to reproduce and invade and destroy surrounding healthy tissue. A number of forces can trigger these cell divisions, such as certain chemicals (carcinogens), chronic inflammation, hormones, lack of exercise, obesity, radiation, smoking, and viruses. ‘The emperor of all maladies’ is not just one disease. There are over 200 different types of cancer, each with its own methods of diagnosis and treatment. Most cancers are named after the organ or type of cell in which they start: for example, cancer that begins in the breast is called breast cancer. Cancer sometimes begins in one part of the body and can spread to other parts of the body through the blood and lymph systems This process is known as metastasis.
A practitioners’ views

According to Whitfield Growdon, an oncological surgeon at the Massachusetts General Hospital and Professor of Obstetrics, Gynaecology and Reproductive Biology at the Harvard University Medical School, Cancer is a complicated set of events, which can happen in any cell in your body. Your body is comprised of tiny cells, which have the ability to grow, stop growing and to re-model, which is necessary to do all the functions that are required for living. But every cell in nature has the potential to lose control of its growth. It is this uncontrolled growth of an individual cell, which we call cancer. Cells can grow, they can spread, and if the cell growth is uncontrolled it can invade other tissues, which can lead to you losing the ability to perform vital functions that are required for your life,” see video below:

There is scarcely a family in the developed world unaffected by cancer. But, this has not always been the case. Cancer only became a leading cause of death when we began to live long enough to get it. In 1911, the prevalence of cancer was low compared to what it is today. Then life expectancy in the UK was 51.5 and 52.2 years for males and females respectively. Similarly, in the US, at the beginning of the 20th century, life expectancy at birth was 47.3 years. Today, the median life expectancy in the UK is 81.6 and in the US 78.7.  Significantly, the age at diagnosis for prostate cancer today is 67 and 61 for breast cancer. Approximately 12% of the UK population are aged 70 and above and account for 50.2% of the total cancers registered in 2014. 87% of all cancers in the US are diagnosed in people over 50.
Late diagnoses
Every 2 minutes in Britain someone is diagnosed with cancer, and almost 50% of these are diagnosed at a late stage. Every year in the UK there are more than 360,000 new cancer cases, which equates to nearly 990 newly diagnosed cancers every day. Taking a closer look at the UK data, we notice that since the early 1990s, incidence rates for all cancers combined have increased by 12%. The increase is larger in females than males. Over the past decade, incidence rates for all cancers combined have increased by 7%, with a larger increase in females: 8% as opposed to 3% in males. Over the next 2 decades, incidence rates for all cancers combined in Britain are projected to rise by 2%. Incidence rates in the UK are lower than in most European nations in males, but higher in females.

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Incidence rates of specific cancers in the UK

In 2015, breast, prostate, lung and bowel cancers together account for some 53% of all new cancer cases in the UK. Over the past decade, thyroid and liver cancers have shown the fastest increases in incidence in both males and females.  Incidence rates of melanoma, small intestine, and kidney cancers have also increased markedly in males over the past 10 years. Over the same period, Incidence rates of kidney, melanoma, and head and neck cancers have also increased markedly in females. Despite the rise in incidence rates, in recent years mortality rates from cancer in England and Wales have fallen. Between 1994 and 2013, mortality rates from cancer for males and females fell by 30% and 22% respectively.
New therapies: immunotherapy/biologics
What gives hope to people living with cancer is partly new and innovative therapies. Over the past few decades immunotherapy, also called biological therapy, is an evolving treatment, which has become a significant part of the management of certain cancers. Immunotherapy is any form of treatment that uses the body's natural abilities that constitute the immune system to fight infection and disease or to protect the body from some of the side effects of treatment. This may be achieved either by stimulating your own immune system to attack cancer cells specifically, or by giving your immune system components to boost your body’s immune system in a general way. Immunotherapy works better for some types of cancer than for others. It is used by itself for some cancers, but for others it seems to work better when used with other types of therapy.

According to Hani Gabra, Professor of Medical Oncology at Imperial College, London, and Chief Physician Scientist and Head of the Oncology Discovery Unit at AstraZeneca, UK, “Biological therapies are treatments gaining importance globally as we progress with the management of cancer. Understanding the biology of cancer has enabled us to understand the targets that go wrong in those cancers. We have successfully used many treatments that hit directly those cancer targets in order to inhibit or “switch-off” the cancers. These biological therapies either can be useful on their own or more commonly, combined with standard treatments such as chemotherapy, surgery and radiotherapy.” See video below:

Why is the CONCORD-3 study significant?

CONCORD-3 reported in a 2018 edition of The Lancet is an international scientific collaboration designed to monitor trends in the survival of cancer patients throughout the world, and involves 600 investigators in over 300 institutions in 71 countries. The study compares the overall effectiveness of health systems to provide care for 18 cancer types, which collectively represent 75% of all cancers diagnosed worldwide. The study is specifically designed to: (i) monitor trends in the survival rates of cancer patients world-wide to 2014, (ii) inform national and global policy on cancer control, and (iii) enable a comparative evaluation of the effectiveness of health systems in providing cancer care. The study is the third of its kind and supports the over-arching goal of the 2013 World Cancer Declaration, to achieve “major reductions in premature deaths from cancer, and improvements in quality of life and cancer survival”.
CONCORD’s evidence base
The evidence base of the CONCORD-3 study is significant and is predicated upon the clinical records of 37.5m patients diagnosed with cancer between 2000 and 2014. Data are provided in over 4,700 data sets by 322 population-based cancer registries from 71 countries and territories; 47 of which provided data with 100% population coverage. The analysis is centralised, based upon tight protocols and standardised quality controls, and employs cutting-edge methods. The 71 participating countries and territories are home to a combined population of 4.9bn (UN figures for 2014). This represents 67% of the world's population (7.3bn). The 322 participating cancer registries contributed data on all cancer patients diagnosed among their combined resident populations of almost 1bn people (989m), which is 20% of the combined population of those countries. CONCORD-3 contributes to the evidence base for global policy on cancer management and control.
CONCORD-3 data base drives national and global policies on cancer control

Despite the care taken of the data management processes, no study is perfect, and It is reasonable to assume that a study the size of CONCORD-3 will have weaknesses. Notwithstanding, the study is “best in class” and its results are comparable within the limits of data quality. The international trends in cancer patient survival reported in the study reflect the comparative effectiveness of health systems in managing cancer patients. The findings of CONCORD-3 form part of the evidence that drives national and international policies on cancer control. For example, the International Atomic Energy Agency use the findings in its campaign to highlight global inequalities in cancer survival. The Organisation for Economic Co-operation and Development (OEDC) use the results of CONCORD as indicators of the quality of healthcare in 48 countries in its Health at a Glance publications, and the European Union use the findings in its Country Health Profiles for EU Member States.
Overall cancer survival is improving

Overall findings of the CONCORD-3 study suggest that the prospects for cancer patients are improving throughout the world and survival rates are increasing for some lethal cancers. Several cancers show significant increases in 5-year survival, including breast (80% to 86%), prostate (82% to 89%), rectum (55% to 63%) and colon (52% to 60%); reflecting better cancer management. Notwithstanding, there are significant differences in cancer outcomes between nations.
UK has worse cancer survival rates compared with other European nations

Despite the fact that increasingly more people are surviving cancer, British adult cancer patients continue to have worse survival rates after 5 years compared to the European average in 9 out of 10 cancers. Research comparing 29 countries shows survival rates in Sweden are almost 33% higher than in the UK. For ovarian cancer, which affects 7,400 British women each year, the UK comes 45th out of 59, with only 36.2% sufferers surviving 5 years. Some countries achieve nearly double this survival rate. When the largest 5 European countries - Germany, France, Britain, Italy and Spain - were compared for the 3 most common cancers, Britain came bottom for 2 of them. Britain’s survival rates were worse than the other 4 European nations for lung and prostate cancer, and second worst for breast cancer. With regard to pancreatic cancer British patients had just a 6.8% chance of survival, compared to 7.7% in Spain, 8.6% in France, 9.2% in Italy and 10.7% in Germany. This puts the UK 47th out of the 56 countries that had full data for this cancer. Studies suggest 10,000 deaths could be prevented each year if the UK were to keep up with the European average. The UK only exceeds the European average in melanoma. See table below.

Here we have introduced and described the findings of CONCORD-3, which suggests the UK lags significantly other European nations with regard to cancer survival rates.  This sets the scene for part 2 of this Commentary, which will briefly describe some of the UK’s cancer initiatives to reduce premature death from cancer and enhance the care of people living with the disorder. Much has been achieved and over the past 2 decades, cancer mortality rates in the UK have been significantly reduced. Notwithstanding, more innovative and effective policies, which address the actual needs of patients rather than provide “more money and more staff” will be required if the UK is to reduce the cancer-care gap.
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  • International study shows that while British cancer survival has improved over the past 20 years the UK’s cancer survival rates lag behind the European average in 9 out of 10 cancers
  • 10,000 cancer deaths could be prevented each year if the UK hit the European average
  • Analysis shows that some British cancer survival rates trail that of developing nations such as Jordan, Puerto Rico, Algeria and Ecuador
  • Since the inception of the NHS in 1948 policy makers and clinicians have viewed the problem as the NHS being under staffed and underfunded
  • But the answers to the cancer care challenge in the UK is not straightforward
  • The global healthcare ecosystem has changed and is continuing to change faster than national policy responses
  • The UK’s cancer care challenges require more innovation not just more reports, more money and more staff
UK cancer care lags that of other European nations: reasons and solutions
Part 2

Part 1 of this Commentary  described the CONCORD-3 study reported in the January 2018 edition of The Lancet, which suggested that although 5-year cancer survival rates (the internationally accepted indicator of cancer care) have improved in Britain over the past 2 decades, the UK lags behind most large European countries in cancer care.
This is part 2 of the Commentary, which begins by describing some of the UK’s initiatives over the past 20 years to improve cancer mortality rates, speed up diagnoses and enhance the quality of cancer care for people living with the disease. All arrive at similar conclusions: that UK cancer care strategies have reduced cancer mortality rates over time, but there is still more that can be done. They do not compare Britain’s cancer mortality rates with other European nations. Notwithstanding, there appears to be some consensus among leading clinicians and policy makers that the UK’s failure to close the cancer care gap with other European nations is because NHS England is underfunded and understaffed. While this explanation might provide part of the answer it does not tell the whole story. The answer might be less to do with extra funds and extra staff, and more to do with the fact that the global healthcare ecosystem has changed quicker than the thinking of UK policy makers and quicker than structural changes to NHS England. To the extent that this is the case, improving cancer care in Britain may not require more money and more staff, but more innovation and more focus on actual patients’ needs rather than on what policy makers can provide politically.
National cancer initiatives: resolving patients’ needs or perpetuating the status quo?
Over the past 20 years the UK government has commissioned a number of strategies, taskforces and reports all aimed at improving cancer diagnoses, treatments, and management, and enhancing the quality of life of people living with the disease and reducing premature deaths. In 2000, NHS England launched a National Cancer Plan, which was, “committed to addressing health inequalities through setting new national and local targets for the reduction of smoking rates, the setting of new targets for the reduction of waiting times, the establishment of national standards for cancer services, and investment in specialist palliative care, the expansion and development of the cancer workforce, cancer facilities, and cancer research.” This was followed in 2007 by the Cancer Reform Strategy, which was designed to build, “on the progress made since the publication of the NHS Cancer Plan in 2000, and sets a clear direction for cancer services for the next five years. It shows how by 2012 our cancer services can and should become among the best in the world.”

Independent cancer taskforce
In January 2015, an Independent Cancer Taskforce was launched by NHS England, “to develop a five-year action plan for cancer services that will improve survival rates and save thousands of lives.” The NHS established the taskforce on behalf of the Care Quality Commission, Health Education England, Monitor,  Public Health England and theTrust Development Authority. The taskforce was chaired by Harpal Kumar, then, CEO of Cancer Research UK, and was comprised of representatives from a cross section of the cancer and healthcare communities.

In July 2015, the Independent Cancer Taskforce published a report entitled: Achieving world-class cancer outcomes: a strategy for England 2015-2020. The report identified key elements of a world class cancer care system and suggested that this is what British cancer patients should expect and what NHS England should aim to provide by 2020. The strategy included, “effective prevention (so that people do not get cancer at all if possible); prompt and accurate diagnosis; informed choice and convenient care; access to the best effective treatments with minimal side effects; always knowing what is going on and why; holistic support; and the best possible quality of life, including at the end of life.” According to the report such a strategy would achieve world-class cancer outcomes and save 30,000 lives a year by 2020.

2nd National Cancer Strategy

Two months before the publication of the Taskforce’s report, in May 2015, the UK government launched a National Cancer Strategy. This was its second 5-year program to implement a world-class cancer strategy designed to increase the prevention of cancer, speed up its diagnosis, and improve the experience of people with the condition. It suggested that rapid progress had been made in a number of key and high-impact areas, and stated that, “if someone is diagnosed with cancer, they should be able to live for as long and as well as is possible, regardless of their background or where they live. They should be diagnosed early, so that the most effective treatments are available to them, and they should get the highest quality care and support from the moment cancer is suspected.”

Report of the National Cancer Transformational Board
In December 2016, a National Cancer Transformation Board, led by Cally Palmer, the Cancer Director for England, published a number of specific steps to improve cancer care, and reported that over the past decade, 5-year cancer survival rates in the UK have improved across all main cancers, and at the end of 2016, cancer survival rates in Britain were at a record high with 7,000 more people surviving cancer compared to 2013.
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Interim report of the 2nd National Cancer Strategy

In October 2017, NHS England published an interim report of its 2015 National Cancer Strategy, which suggested that, “Survival rates for cancer have never been higher, and overall patients report a very good experience of care. However, we know there is more we can do to ensure patients are diagnosed early and quickly and that early diagnosis has a major impact on survival. We also know that patients continue to experience variation in their access to care, and this needs to be addressed. Early diagnosis, fast diagnosis and equity of access to treatment and care are central to the ‘National Cancer Programme’ and the transformation of services we want to achieve by 2020-21.” According to an NHS spokesperson, “Figures show that cancer survival is now at an all-time high in England, as a result of better access to screening, funding for effective new treatments and diagnostics and continued action to reduce smoking.”
Why cancer mortality rates in Britain lag other European countries
If you look at similar European countries the proportion of GDP (Gross Domestic Product) the UK has spent on health in the last 10 to 15 years is low and has increased less than the others,” says Michael Coleman, Professor of Epidemiology and Vital Statistics at the London School of Hygiene & Tropical Medicine and co-author of the international cancer study reported in the March 2018 edition of The Lancet. UK healthcare spending fell from 8.8% of GDP in 2009 - when it averaged 10.1% in leading European countries - to 7.3% in 2014-15. “This difference between the likes of Germany and France is likely to explain some of what we are seeing,” says Coleman and he also suggests that, “The number of medical specialists who deal with these diseases [cancer] tends to be low compared to other similar countries,” [Our emphasis]. Let us examine the relative European healthcare spends and levels of staffing in NHS England.
Comparative GDP spends on healthcare

The OECD’s November 2016 Health at a Glance report suggests that in 2013 (the latest year for which data have been published) the UK spent 8.5% of its GDP on public and private healthcare. And, a 2016 report from the King’s Fund, a charity, suggests that projected spending on NHS England as a proportion of the UK’s GDP in 2020-21 is 6.6%, just 0.3% above what it was in 2000.
Challenges comparing healthcare spends

Notwithstanding, linking cancer mortality rates to the proportion of GDP nations spend on healthcare is not straightforward. This is partly because of, (i) different nations have different sources of healthcare funding, and (ii) a person’s purchasing power is different in different countries. Fluctuations in relative national economic growth make such comparisons over time and between nations challenging. According to The Health Foundation, a higher percentage of UKhealthcare spending is publicly funded compared to other European countries. For example, “In 2012, publicly funded spending accounted for 84.0% of UK healthcare spending. This is the third highest level in the EU-15 (average: 76.5%).  In 2012, UK public spending on healthcare was slightly higher than the EU-15 average of 7.6% of GDP”. Between 2008 and 2012 the average annual change in healthcare spending per person was lower for the UK than most EU-15 countries, which was largely the result of Greece, Ireland and Portugal making significant cuts to their healthcare spending. The rising prevalence of cancer and other chronic long-term diseases, is a significant driver of increased healthcare costs. According to OEDC data, UK spend on chronic lifetime conditions is similar to the European average. However, the UK spends less than other European countries on pharmaceuticals and out-of-pocket payments. Further, on average, UK patients spend less time in hospital and generally use fewer resources (measured in terms of staff and beds).
A 2017 paper published by the Nuffield Trust suggests that, when taking into consideration different sources of healthcare funding and purchasing power parity, the UK’s healthcare spend actually might be keeping up with that of other European nations.
NHS “dangerously” understaffed

Let us now consider staffing. In 2017, The Royal College of Emergency Medicine reported that primary and emergency care doctors, which are crucial for the early diagnosis of cancer, were experiencing significant recruitment and retention challenges. According to 2018 figures, NHS England has nearly 100,000 jobs unfilled, which include 35,000 nursing posts and 10,000 doctor vacancies.  The total vacancies represent 1 in 12 of all NHS posts, which is enough to staff about 10 large hospitals. Further, the high number of unfilled NHS posts coincides with 0.25m more people visiting A&E in the first quarter of 2018 than in the equivalent period in 2016. According to Saffron Cordery, the director of policy and strategy for NHS ProvidersThese figures show how the NHS has been pushed to the limit. Despite working at full stretch with around 100,000 vacancies and a real risk of staff burnout, and despite treating 6% more emergency patients, year on year in December (2017), trusts cannot close the gap between what they are being asked to deliver and the funding available”. A February 2018 finance report suggests that NHS England is heading for a £931m deficit in 2018 and is "dangerously" understaffed. This year-on-year deficit was revised to a projected £1.3bn shortfall, which is 88% worse than planned.
Reasons for shortages of health professionals

The NHS staffing challenges are aggravated by the fact that British trainee primary care doctors are dwindling, newly qualified doctors are moving abroad, and experienced doctors are retiring early. Over the lifetime of NHS England, the UK has trained significantly fewer healthcare professionals than it needed, and the supply of qualified young British people has consistently outstripped the number of places in medical schools and nurse training. According to data from the General Medical Council (GMC), between 2008 and 2014 an average of 2,852 certificates were issued annually to enable British doctors to work abroad. A 2015 British Medical Association (BMA) poll of 15,560 primary care doctors, found that 34% of respondents plan to retire early because of high stress levels, increasing workloads, and too little time with patients.  Further, it is estimated that 10% of doctors and 7% of nurses employed by NHS England are nationals of other European countries. The uncertainties of Brexit (a term for the potential departure of the UK from the EU) add to NHS’s recruitment and retention challenges of healthcare professionals. According to a 2017 Health Foundation Report, in 2016, more than 2,700 nurses left the NHS; an increase of 68% since 2014.
UK policy approach to healthcare shortages has not changed

Notwithstanding, NHS staff shortages are not new. In the 1960s, NHS hospitals in Britain introduced mass recruitment from Commonwealth countries, and this has influenced staffing policies ever since. Being able to recruit doctors and nurses from foreign countries provided NHS England with an “easy” solution to staff shortages. However, over the past 2 decades the global healthcare ecosystem has changed significantly, while UK healthcare staffing policies have not kept pace with the changes. Today, there is a substantial gap globally in the supply and demand of healthcare professionals. Countries such as India, which traditionally could be relied upon to provide healthcare professionals for NHS England, have changed and the pool of potential Indian recruits have shrunk. Over the past 2 decades, the Indian economy has improved and the nation has developed a number of world-class hospital groups such as Apollo, Fortis and Narayana Health, which offer internationally competitive terms and conditions to Indian doctors and nurses. Increasingly Indian hospitals retain more of the nation’s healthcare professionals, and indeed attract doctors working in the UK and the US to return. Further, NHS England has tended to be staffed on the basis of what successive governments can afford rather than what NHS patients’ actually need.
Challenges of planning healthcare needs

Although there is a significant shortage of healthcare professionals in NHS England, it is not altogether clear that, (i) significantly increasing the number of NHS health professionals in the short to medium term will be possible, and (ii) simply increasing staff numbers will improve cancer care. Over the past 2 decades, as technologies and demographics have changed, so the demands on cancer professionals have changed. It is not necessarily the case that the NHS has the right mix of staff with the right mix of skills to deal effectively with changing conditions.  Changing traditional roles rather than simply boosting numbers might contribute more to reducing cancer mortality rates and improving the quality of cancer care. Further, it seems reasonable to suggest that, with the aforementioned challenges, a greater proportion of the UK’s annual healthcare spend might be more effective were it directed at cancer prevention rather than “diagnosis and treatment”.
Preventing cancer
A substantial proportion of cancers can be prevented including cancers caused by tobacco use, heavy consumption of alcohol, and obesity. According to the World Cancer Research Fund about 20% of all cancers diagnosed in the developed world are caused by a combination of excess body weight, physical inactivity, excess alcohol consumption, poor nutrition, and tobacco use, and thus could be prevented. Certain cancers caused by infectious agents such as the human papilloma virus (HPV), hepatitis C, (HCV), and human immunodeficiency virus (HIV) can be prevented by human behavioural changes, vaccination or treatment of the infection. Further, many of the 5m skin cancer cases worldwide (16,000 in the UK), which are diagnosed annually could be prevented by protecting skin from excessive sun exposure and not using indoor tanning machines.
Cancer screening
Screening is known to reduce the mortality of cancers of the breast, colon, rectum, cervix, and lung. Screening can help colorectal and cervical cancers by allowing for the detection and removal of pre-cancerous lesions. Screening also provides an opportunity for detecting some cancers early when treatment is less expensive and more likely to be successful. Early diagnosis is an important factor in improving cancer outcomes. Currently, the UK offers 3 national screening programs for bowel, breast and cervical cancer. Notwithstanding, recent reports suggest that these programs are not being fully utilised. For example, in 2017 the percentage of women taking up invitations for breast cancer screening was at the lowest level in a decade, dropping to 71%. Over 1.2m women in the UK (25% of the eligible population) did not take up their invitation for cervical screening. Further, a heightened awareness of changes in certain parts of the body, such as the breast, skin, eyes and genitalia may also result in the early detection of cancer.
Reconciling bureaucracy with innovation
We have described how UK cancer strategies are determined from the top. Cancer care professionals conform to internationally accepted standard processes, which facilitate and reinforce control. ‘Control’ and ‘conformism’ are in the DNA of cancer healthcare professionals and provide the cultural norms of NHS cancer care programs. NHS managers ensure conformance to clinical procedures, medications, targets, budgets, and quality care standards. This describes a classic “bureaucracy”, which is the technology of control and conformism, and the 70-year old command and control structure of NHS England. While control, alignment, discipline and accountability are very important to cancer care programs, innovation is equally important. If NHS England’s cancer mortality rates are to be compatible with those of other European healthcare systems we will have to find a way to reconcile the benefits of bureaucracy - precision, consistency, and predictability - while making the architecture and culture of our cancer care programs more innovative and more compatible with the demands of rapidly evolving 21st century science and technology.

Cancer is a vexed and profoundly challenging disorder. As soon as you read about a breakthrough you have news that the cancer has outwitted the scientists, hence the name, “the emperor of all maladies”. Cancer care in the UK has improved, but still the majority of British cancer patients would faire significantly better in other European countries. When reflecting on the myriad of cancer strategies, reports, and taskforces over the past 2 decade you cannot help but think that NHS England suffers from an element of bureaucratic inertia: the inevitable tendency of the NHS to perpetuate its established procedures and modus operandi, even if they do not reduce cancer mortality rates to those experienced by other European nations. The UK policy debate to resolve this problem tends to be dominated by “more”: more money, more doctors, more nurses. Historically this has provided successive governments with a “get-out-of-jail-card” because circumstances meant that the NHS could always provide more. This is not the case today. The global healthcare ecosystem has changed quicker than UK cancer strategies and quicker than structural changes in the nation’s healthcare system. Improving cancer care in the UK will require more than inertia projects. It will require more innovation, more long-term planning, more courage from policy makers, more attention to actual patients’ needs rather than providing what is politically available. The UK healthcare establishment should be minded of Darwin who suggested that, “It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
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  • 16% of cancers in the UK are linked to excess weight and type-2 diabetes (T2DM)
  • 62% of adults are overweight or obese in England
  • 4m people are living with T2DM in the UK and another 12m are at increased risk of T2DM
  • Prevalence rates of both obesity and T2DM are rising
  • Ineffective prevention initiatives should be replaced with effective ones if we are to dent the vast and escalating burden of obesity, T2DM and related cancers
  • Public health officials, clinicians and charities need to abandon ineffective inertia projects embrace innovation and look to international best practice 

Excess weight and type-2 diabetes linked to 16% of cancers in the UK
Being overweight and living with type-2 diabetes (T2DM) is a potentially deadly combination because it significantly increases your risk of cancer and contributes to the projected increase in cancer cases and deaths in the UK. Findings of a study published in the February 2018 edition of The Lancet Diabetes and Endocrinology suggest that a substantial number of UK cancer cases are linked to a combination of excess body mass index (BMI) and T2DM, which here we refer to as diabesity. To lower the growing burden of cancer associated with diabesity, more effective prevention strategies will be required. To achieve this, clinicians, public health officials and charities will need to reappraise their current projects, innovate, and learn from international best practice. 

BMI, obesity and T2DM defined
Body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify overweight and obesity in adults. It is a person's weight in kilograms divided by the square of his height in meters (kg/m2). Overweight is a BMI greater than or equal to 25; and obesity is a BMI greater than or equal to 30. T2DM is a long-term metabolic disorder characterized by high blood glucose (sugar), insulin resistance, and relative lack of insulin. Insulin is a hormone produced in the pancreas, which is used by the body to manage glucose levels in the blood and helps the body to use glucose for energy.

 In this Commentary
This Commentary describes the findings of a study reported in a 2018 edition of The Lancet Diabetes and Endocrinology, which suggests that current initiatives to prevent and reduce the burden of diabesity are ineffective. Previous Commentaries have described the Mexican Casalud and the Oklahoma City projects, which have successfully reduced obesity and type-2 diabetes (T2DM). These represent innovative international best practice, which have been largely gone unnoticed by the UK’S diabetes establishment. Also, we describe findings of a study published in the May 2017 edition of Scientific Reports, which suggests that although Google trend data can detect early signs of diabetes, they are underutilized by traditional diabetes surveillance models. The prevalence of diabesity in the UK is significant and growing so fast that public health officials, clinicians and charities will have to replace failing inertia projects with more effective ones if they are to dent the growing burden of cancer linked to a combination of obesity and T2DM.
The Lancet Diabetes and Endocrinology study
A comparative risk assessment study published in The Lancet Diabetes and Endocrinology was carried out by researchers from Imperial College London, Kent University and the World Health Organization. It suggests that in 2012, 5.6% of all cancers worldwide were linked to the combined effect of obesity and diabetes, which corresponded to about 0.8m new cancer cases. 25% of these account for liver cancer in men, and 38% account for endometrial cancer, which affects the lining of the womb in women.

Obesity T2DM and cancer
There is a close association between obesity and T2DM. The likelihood and severity of T2DM are closely linked with BMI. If you are obese your risk of T2DM is 7-times greater than someone with a healthy weight. If you are overweight your risk of T2DM is 3-times greater. Whilst it is known that the distribution of body fat is a significant determinant of increased risk of T2DM, the precise mechanism of association remains unclear. It is also uncertain why not all people who are obese develop T2DM and why not all people with T2DM are either overweight or obese. Also, the link between obesity and some cancers is well established. More recently, researchers have linked diabetes to several cancers, including liver, pancreatic and breast cancer. The 2018 Lancet Diabetes and Endocrinology study described in this Commentary is the first time anyone has calculated the combined effect of excess BMI and T2DM on cancer worldwide.

According to the Lancet study’s findings, cancers diagnosed in 2012, which are linked to diabesity are almost twice as common in women (496,700 cases) as men (295,900 cases). The combination of excess BMI and T2DM risk factors in women accounts for the highest proportion of breast and endometrial cancer: about 30% and 38% respectively. In men, the combination accounts for the highest proportion of liver and colorectal cancers. Overall, the biggest proportion of cancers linked to diabesity is found in high income western nations, such as the UK (38.2% of 792,600 cancer cases diagnosed in 2012), followed by east and southeast Asia (24.1%). 16.4% of cases of cancer in men and 15% in women in high income western nations are linked to being overweight, compared to 2.7% and 3% respectively in south Asia. Researchers suggest that on current trends, the number of cancers linked to a combination of excess BMI and T2DM could increase by 30% by 2035, which would take the worldwide total of these cancers from 5.6% to 7.35%. 
Uneven prevalence of cancers resulting from diabesity

While cancers associated with diabesity are a relatively small percentage of the total - the global 5.6% masks wide national variations of cancer prevalence resulting from diabesity. For example, in high income western nations, such as the UK, 16% of cancers are linked to excess BMI and T2DM, which suggests a potentially significant trend. As known cancer risk factors such as smoking tobacco have declined in the UK and other wealthy nations, so diabesity has increased as a significant risk factor.
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According to Jonathan Pearson-Stuttard,of Imperial College London and lead author of the 2018 Lancet study, the prevalence of cancer linked to excess BMI and diabetes is, “particularly alarming when considering the high and increasing cost of cancer and metabolic diseases. As the prevalence of these cancer risk factors increases, clinical and public health efforts should focus on identifying optimal preventive and screening measures for whole populations and individual patients”.
Risks of cancer and their vast and escalating costs

Clinicians, public health officials and charities are mindful of the vast and escalating risks of excess BMI and T2DM on cancer. According to Diabetes UK, 4.5m people are living with diabetes in the UK, 90% of these have T2DM, and another 11.9m are at increased risk of T2DM. Research published in the May 2016 edition of the British Medical Journal reports that prevalent cases of T2DM in the UK more than doubled between 2000 and 2013: from 2.39% to 5.32%, while the number of incident cases increased more steadily.
According to a 2014 report by Public Health England entitled “Adult obesity and type-2 diabetes”, the direct annual economic cost of patient care for people living with T2DM in 2011 was £8.8bn; the indirect costs, such as lost production, were about £13bn, and prescribing for diabetes accounted for 9.3% of the total cost of prescribing in 2012-13. The Report concludes, “the rising prevalence of obesity in adults has led, and will continue to lead, to a rise in the prevalence of type 2 diabetes. This is likely to result in increased associated health complications and premature mortality . . . Modelled projections indicate that NHS and wider costs to society associated with overweight, obesity and type 2 diabetes will rise dramatically in the next few decades”.
Preventing excess BMI and T2DM as a way to reduce the burden of cancer

Because of the increasing prevalence of diabesity clinicians, healthcare providers and charities have invested substantially in programs to prevent obesity and T2DM. Notwithstanding, the UK’s record of reducing the burden of these disorders is poor. According to the authors of The Lancet study, “Population-based strategies to prevent diabetes and high BMI have great potential impact … but have so far often failed.” Despite an annual NHS spend of £14bn on diabetes care, and over £20m spent annually by Diabetes UK  on “managing diabetes, transforming care, prevention, understanding and support”, over the past 10 years people with diabetes have increased by 60%.
Healthier You a national diabetes prevention program

Healthier You, a joint venture between NHS England, Public Health England and Diabetes UK was launched in 2016 and aims to deliver evidence-based behaviour change interventions at scale to people at high risk of T2DM to support them in reducing their risk. In December 2017, an interim analysis of the program’s performance was published in the journal Diabetic Medicine. Findings suggest that Healthier You has achieved higher than anticipated numbers of referrals: 49% as opposed to 40% projected, and the, “characteristics of attendees suggest that the programme is reaching those who are both at greater risk of developing Type 2 diabetes and who typically access healthcare less effectively.”
Cautionary note
Notwithstanding, the study’s authors conclude with a cautionary note and say that when data become available from the 2019 National Diabetes Audit (NDA) they will be better positioned to assess the program’s performance. Specifically, whether Healthier You participants changed their weight and HbAc1 levels over time. (HbA1c is a blood test that indicates blood glucose levels and is the main way T2DM is diagnosed). We are mindful that earlier National UK Diabetes Audits suggest there are significant challenges associated with incomplete and inconsistent patient data at the primary care level, and also significant variation in diabetes care across the country. It seems reasonable to assume that incomplete and inconsistent data will present analytical challenges.
Outcomes as key performance indicators
Notwithstanding, the authors of the interim appraisal of Healthier You are right to attempt to link key performance indicators (KPI) with patient outcomes rather than provider activities, which tend to be the preferred performance indicators used by public officials, clinicians and charities engaged in preventing obesity and T2DM. At the population level, there is a dearth of data that associate specific prevention programs with the reduction of the prevalence of obesity and T2DM. Until actual patient outcomes become the key performance indicators, it seems reasonable to suggest that inertia rather than innovation in prevention and care of T2DM and obesity will prevail, and year-on-year the burden of diabesity and associated cancers will continue to increase.

Two significant and effective innovations to reduce excess BMI and T2DM, which have been largely ignored by the UK’s diabetes establishment are the Casalud and Oklahoma City projects. Casalud is a nation-wide online continuing medical education program launched in Mexico in 2008, which has demonstrated influence on the quality of healthcare, and subsequent influence on patient knowledge, disease self-management, and disease biomarkers. Casalud provides mHealth tools and technical support systems to re-engineer how primary care is delivered in Seguro Popular (Mexico’s equivalent to NHS England) primary health clinics.  By focusing on prevention and using technology, Casalud has increased the number of diabetes screenings and improved clinical infrastructure. An appraisal of the program published in the October 2017 edition of Diabetes, Metabolic Syndrome and Obesity suggests that the Casalud program successfully impacts changes in obesity and T2DM self-management at the primary care level throughout the country.
Oklahoma city’s transformation

Oklahoma is a city of about 550,000 people. In 2007, it was dubbed America’s “fast food capital" and “fattest city". A decade later, the city was in the middle of a transformation. While the state still has among the highest adult obesity rates in the nation – climbing from 32.2% to 33.9% between 2012 and 2015 – obesity rates in Oklahoma City dropped from 31.8% to 29.5% during that time frame, according to the US Centers for Disease Control and Prevention data. The city’s transformation started with city’s Mayor Mick Cornett. Cornett, who has been in office since 2004, brought notoriety to the city’s public health efforts beginning at the end of 2007 with the goal to collectively lose 1m pounds. The people of Oklahoma City met that goal in 2012, but have not slowed down their efforts. What began as a campaign to promote healthy eating and exercise became a citywide initiative to, "rebuild the built environment and to build the city around people instead of cars," Cornett says.
Underutilized data that detect early people at risk of T2DM
Findings of a study published in the May 2017 edition of Scientific Reports suggest an innovative way to improve early diagnosis of excess BMI and T2DM when the diseases are easier and less costly to treat, but so far these data are underutilised. The study reports that increasingly people are searching the Internet to assess their health and records of these activities represent an important source of data about population health and early detection of T2DM. The study based on data from the 2015 Digital Health Record produced by Push Doctor, a UK based online company, which has over 7,000 primary care clinicians available for online video consultations. According to the study, which is based on 61m Google searches and a survey of 1,013 adults, 1 in 5 people chose self-diagnosis online rather than a consultation with their primary care doctor. The study makes use of commercially available geodemographic datasets, which combine marketing records with a number of databases in order to extract T2DM candidate risk variables. It then compares temporal relationships with the search keywords used to describe early symptoms of the T2DM on Google. Researchers suggest that Google Trends can detect early signs of T2DM by monitoring combinations of keywords, associated with searches. Notwithstanding, the value of these data they are underutilized by clinicians, public health officials and charities engaged in reducing the risks of excess BMI and T2DM, which can lead to cancer.

Over the past decade, NHS England has spent more than £100bn on diabetes treatment alone, and Diabetes UK has spent some £200m on education and awareness programmes, yet diabetes in the UK has increased by 60%. 90% of diabetes cases are T2DM, which is closely linked to obesity. The combination of excess BMI and T2DM causes some 16% of all cancers in the UK. The burden of these diseases destroys the lives of millions and cost billions. It is imperative that this vast and escalating burden is dented. This will not be achieved if clinicians, public health officials and charities continue with ineffective inertia projects. They will need innovate and embrace best practice if they are to prevent and reduce the vast and escalating burden of excess BMI, T2DM and cancer.
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  • A 2018 clinical study in China is the first to use CRISPR to edit cells inside the human body in an attempt to eliminate the human papilloma virus (HPV) and is hugely significant for millions of women
  • Nearly all sexually active people get an HPV virus at some point in their lives and persistent high-risk HPV infections are the main cause of cervical cancer
  • Respectively 34,800 and 256,000 women in the UK and US live with cervical cancer and each year about 3,200 and 12,200 new cases of cervical cancer are diagnosed in the UK and US respectively nearly all related to HPV
  • Cervical cancer is increasing in older women not eligible for the HPV vaccine and not availing themselves of Pap test screening programs
  • A new study suggests that cervical cancer mortality among older women could increase by 150% in the next 20 years

CRISPR positioned to eliminate human papilloma viruses that cause cervical cancer

January 2018 marked the beginning of the first CRISPR clinical study to attempt to edit cells while they are in the body of women in the hope to eliminate the human papilloma virus (HPV), which is the main cause of cervical cancer. The study, led by Zheng Hu of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China, is the first to edit human cells while inside the body. Zheng Hu will apply a gel that carries the necessary DNA coding for the CRISPR machinery to the cervixes of 60 women between the ages of 18 and 50. The study’s aim is to prevent cervical cancers by targeting and destroying the HPV genes that cause tumor growth while leaving the DNA of normal cells untouched. Current estimates suggest that every year 527,624 women are diagnosed with cervical cancer and 265,672 die from the disease. Zheng Hu’s study is expected to be completed by November 2018 and findings reported in January 2019.
In this Commentary

This Commentary describes the Chinese CRISPR study and the etiology and epidemiology of cervical cancer. It also describes the current cervical cancer vaccination possibilities and the challenges they face. Further, the significance of the Chinese study is demonstrated by an English study, published in December 2017 in the Lancet Public Health, which warns that although HPV vaccination programs have significantly reduced the incidence of cervical cancer among young women, the incidence of the disease is increasing significantly among older women who do not qualify for the cervical cancer vaccine, and fail to avail themselves of regular Pap tests (A Pap test is a simple, quick and essentially painless screening procedure for cancer or precancer of the uterine cervix). The latter part of the Commentary describes advances that CRISPR technology has made over the past decade as well as describing its main ethical and technical challenges.
Human papilloma virus (HPV)

There are over 200 different types of HPV related viruses. Viruses are the etiological agents of approximately 15% of human cancers worldwide, and high-risk HPVs are responsible for nearly 5% of cancers worldwide. It is estimated that about 75% of the reproductive-age population has been infected with 1 or 2 types of genital HPV. About 79m Americans are currently infected with HPV, and about 14m people become newly infected each year. The American Centers for Disease Control and Prevention estimates that more than 90 and 80% of sexually active American men and women respectively will be infected with at least one type of HPV at some point in their lives. Most HPV infections are harmless, they last no more than 1 to 2 years, and usually the body clears the infections on its own. More than 40 HPV types can be easily spread by anal, oral and vaginal sex. About 12 HPV types are high risk, and it is estimated these persist in only about 1% of women. However, a central component of the association between HPV and cervical carcinogenesis is the ability of HPV to persist in the lower genital tract for long periods without being cleared. These persistent high-risk types of HPV can lead to cell changes, which if untreated, may progress to cancer. Other HPV types are responsible for genital warts, which are not sexually transmitted.
Etiology of cervical cancer
 “The way that the HPV causes cancer informs us about how cancer occurs in other settings. Virus particles insert foreign DNA into a person’s normal cells. This virus then turns off the “off-switch” and allows the oncogenes [Genes that can transform a cell into a tumor cell] to progress unchecked and create an oncogenic virus. So, in this case the 'insult' is known: it’s an HPV virus. However, in many circumstances we’re not sure what that initial switch is that upsets the balance between a tumor suppressor and an oncogene,” says Whitfield Growdon, of the Massachusetts General Hospital and Professor of Obstetrics, Gynecology and Reproductive Biology at the Harvard University Medical School: see video below:

HPV and cervical cancer

The association of risk with sexual behavior has been suggested since the mid-19th century, but the central causal role of HPV infection was identified just 40 years ago. HPV infection is the main etiologic agent of cervical cancer. 99% of cervical cancer cases are linked to genital infection with HPV and it is the most common viral infection of the reproductive tract. HPV types 16 and 18 are responsible for about 70% of all cervical cancer cases worldwide. Further, there is growing evidence to suggest that HPV also is a relevant factor in other anogenital cancers (anus, penis, vagina and vulva) as well as head and neck cancers. The importance of prevention and cervical cytological screening was established in the second half of the 20th century, which preceded and even advanced etiologic understanding.
Epidemiology of cervical cancer
Cervical cancer is one of the most common types of gynecological malignancies worldwide. It ranks as the 4th most frequent cancer among women in the World, and the 2nd most common female cancer in women between 15 and 44. According to the World Health Organization there were some 630m cases of HPV infections in 2012, and 190m of these led to over 0.5m new diagnoses of cervical cancer. The World has a population of some 2,784m women aged 15 and older who are at risk of developing cervical cancer. Each year about 3,200 and 12,200 new cases of cervical cancer are diagnosed in the UK and US respectively; nearly all related to HPV. There is estimated to be 34,800 and 256,000 women in the UK and US respectively living with cervical cancer. Each year some 890 and 4,200 women die from cervical in the UK and US respectively.
HPV vaccines
HPV vaccines, which prevent certain types of HPV infections, are now available to females up to the age of 26, and have the potential to reduce the incidence of cervical and other anogenital cancers. “Vaccinations work by using your own immune system against foreign pathogens such as viruses and bacteria. Vaccination against some high risk sub-types of cancer-causing HPV viruses is one of the most meaningful interventions we’ve had since the development of the Pap test,” says Growdon: see video below.

Gardasil and Cervarix

Gardasil, an HPV vaccine developed by Merck & Co., and licenced by the US Food and Drug Administration (FDA) in 2006, was the first HPV vaccine recommended for girls before their 15th birthday, and can also be used for boys. In 2008 Cervarix, an HPV vaccine manufactured by GlaxoSmithKline,  was introduced into the UK’s national immunization program for girls between 12 and 13. Both vaccines have very high efficacy and are equally effective to immunise against HPV types 16 and 18, which are estimated to cause 70% of cervical cancer cases. Both vaccines significantly improve the outlook for cervical cancer among women living in countries where it is routinely administered to girls before they become sexually active. “Both Gardasil and Cervarix vaccines have been shown to be incredibly effective at preventing the development of high-grade dysplasia, which we know, if left unchecked, would turn into cervical cancer,” says Growdon: see video above.

Gardasil also protects against HPV types 6 and 11, which can cause genital warts in both men and women. Second-generation vaccines are under development to broaden protection against HPV. In 2014 the FDA approved Gardasil 9, an enhanced vaccine, which adds protection against an additional 5 HPV types that cause approximately 20% of cervical cancers.
Global challenge

Despite the availability of prophylactic vaccines, HPVs remain a major global health challenge due to inadequate vaccine availability and vaccination coverage. Despite the promise, vaccine uptake has been variable in developed nations, and limited in developing nations, which are most in need. The available vaccines are expensive, require a cold chain to protect their quality, and are administered in 2 to 3 doses spanning several months. Thus, for a variety of practical and societal reasons (e.g., opposition to vaccination of young girls against a sexually transmitted agent, fear of vaccination), coverage, particularly in the US has been lower than would be optimal from a public health perspective.
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Gene editing battles

Success among young women

Notwithstanding, a study referred to above and published in the Lancet Public Health suggests cervical cancer cases are expected to fall by 75% among young women for whom vaccination is now the norm. Death from cervical cancer among the generation who were 17 or younger in 2008 when the UK vaccination program was introduced is expected to virtually disappear.
Challenges for older women

Notwithstanding the success of HPV vaccines for young women, there are continuing challenges for older women who, because of their age, do not qualify for HPV vaccines, and do not attend their Pap screening test when invited. “Pap tests involve scraping the cervix on the outside for cells, which then udergo microscopic examination. Today this is carried out by a computer. Further examination is carried out by a cytopathologist who determines status . . . . . . . . . . Pap tests do not diagnose cancer, but tell you whether you are at high risk of either having pre-cancerous or cancerous cells. Actual diagnosis of cervical cancer involves a colposcopy. This is a simple procedure, which uses a specific type of microscope called a colposcope to look directly into the cervix, magnify its appearance, and helps to take biopsies of abnormal areas,” says Growdon: see videos below.

What is a Pap smear test?

Diagnostic tests for cervical cancer
Older women and Pap tests

Pap tests, which are offered by NHS England to women between 25 and 64, is the most effective way of preventing cervical cancer; yet data show that in 2016 there was a significant drop in Pap test screening as women’s age increased. If such screening covered 85% of women, it is estimated that it would reduce deaths from cervical cancer by 27% in 5 years, and the diagnosis of new cases of cervical cancer by 14% in 1 year. According to the authors of the 2017 Lancet study, “The risk of acquiring an HPV infection that will progress to cancer has increased in unvaccinated individuals born since 1960, suggesting that current screening coverage is not sufficient to maintain – much less reduce – cervical cancer incidence in the next 20 years.”
Cervical cancer projected to increase in older women

Over the next 2 decades, diagnoses of cervical cancer in women between 50 and 64 are projected to increase by 62%, which could increase mortality from the disease by nearly 150%. “The main reason for this is that the population is ageing and women currently 25-40 will not benefit from vaccination – and they are in the age range where the likelihood of getting an HPV infection is quite high,” saidAlejandra Castanon one of the authors of the Lancet study.
Chinese study extends CRISPR technology

The Chinese study mentioned above to eliminate the HPV virus employs an innovative extension of CRISPR, which is a ‘game-changing’ technology. Over the past decade CRISPR has become a significant tool for genetic manipulation in biomedical research and biotechnology.  
CRISPR and genome editing

CRISPR is a complex system that can recognize and cut DNA sequences in order to provide organisms a strong defence against attacks and make them immune from further assaults. CRISPR has been adapted for both in vitro and in vivo use in eukaryotic cells to perform highly selective gene silencing or editing. Eukaryotic cells are those that contain a nucleus surrounded by a membrane and whose DNA is bound together by proteins into chromosomes.  CRISPRs are specialized stretches of DNA, and "CRISPR-Cas9" provides a powerful tool for precision editing due to its highly efficient targeting of specific DNA sequences in a genome, and has become the standard for genetic editing. Cas9 protein is an enzyme that acts like a pair of molecular scissors capable of cutting strands of DNA. The genomes of organisms encode messages and instructions within their DNA sequences. Genome editing involves changing those sequences, thereby changing the messages. This is achieved by making a break in the DNA, and tricking a cell's natural DNA repair mechanisms to make desired changes; CRISPR-Cas9 provides a means to do this. The technology’s ease of use and low cost have made it popular among the scientific community, and the possibility of its use as a clinical treatment in several genetically derived pathologies has rapidly spread its significance worldwide.
Changing ethical concerns

Despite CRISPRS promise there have been significant ethical concerns to genome editing, which center around human germline editing. This is because germline editing entails deliberately changing the genes passed on to children and future generations; in other words, creating genetically modified people. The debate about genome editing is not a new one, but has regained attention following the discovery that CRISPR has the potential to make such editing more accurate and even "easy" in comparison to older technologies. As of 2014, there were about 40 countries that discouraged or banned research on germline editing, including 15 nations in Western Europe. There is also an international effort, launched in December 2015 at the International Summit on Human Gene Editing and led by the US, UK, and China, to harmonize regulation of the application of genome editing technologies. 
After initially being opposed to using CRISPR in humans, in June 2016, the US National Institutes of Health advisory panel approved the technology for a study designed to target three types of cancer and funded by the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. In 2017 the UK approved the use of CRISPR for research in healthy human embryos. 

Off-target effects

Soon after scientists reported that CRISPR can edit DNA in 2012, experts raised concerns about “off-target effects,” meaning either CRISPR changes a gene scientist did not want changed or it fails to change a gene that they do. Although CRISPR-Cas9 is known for its precision a study, published in 2017 in the journal Nature Methods, raised concerns that because of the potential for “off-target effects” testing CRISPR in humans may be premature. Non-intended consequenes can happen because one molecule in the CRISPR system acts like a “molecular bloodhound”, searching the genome until it finds a match to its own sequence of  genetic letters; but there are 6bn genetic letters of the human genome, which suggests that there may be more than one match. Scientists anticipate and plan for this by using a computer algorithm to predict where such flaws might occur, then they search those areas to see if such off-target effects did occur. Notwithstanding such procedures and despite CRISPR’s precision, substantial efforts still are required to make the technology a common device safe for human clinical treatments.
Advances using CRISPR
The first clinical study using CRISPR began in October 2016 at the West China Hospital in Chengdu. Researchers, led by oncologist Lu You from Sichuan University, removed immune cells from the blood of a person with lung cancer, used CRISPR to disable a gene called PD-1, and then returned the cells to the body. This study is part of a much larger CRISPR genome editing revolution. Today, there are about 20 human clinical studies taking place using CRISPR technology most of which are in China. Different studies focus on different cancers including, breast, bladder, oesophageal, kidney, and prostate cancers. Further, a 2017 paper published in the journal Cell describes a number of innovative ways CRISPR being used; including editing cells while inside the body.
Despite the efficacy of HPV vaccines, immunization against cervical cancer still has significant challenges. Vaccines only target young people before they become sexually active, and are not recommended for slightly older and sexually active women. There is an urgent and growing concern about older women therefore who were not eligible for HPV vaccination, and are not availing themselves of regular Pap tests, and in whom the incidence of cervical cancer is increasing significantly. This makes Zheng Hu’s clinical study extremely important because it holds out the potential to substantially dent this large and rapidly increasing burden of cervical cancer.
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