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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.”
 
 
Takeaways

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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  • 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.  
Findings
 
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.
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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.
 
Takeaways

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:
 
 
Epidemiology

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.
 
 
Takeaways

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.
 
Takeaways

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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  • A number of new studies on ovarian cancer show “promising” results for patients who develop chemo-resistance
  • A Dutch study uses conventional chemotherapeutics more intensively
  • Another study uses a new class of drug discovered by the UK’s Institute of Cancer Research
  • Genetic testing is playing an increasing role in the reduction of chemo-resistance
  • Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients
  • The UK’s Chief Medical Officer suggests that whole genome sequencing should become standard practice on the NHS across cancer care
  • A new class of chemotherapeutic agent is directed at targeting cancers with defective DNA-damage repair
  • Improvements in cancer care have been both scientific and organizational
  • Utilizing and sequencing the treatment options for ovarian cancer may have a significant impact on the overall survival rates of patients
  • Multidisciplinary teams are transforming ovarian cancer care 
 
Improving ovarian cancer treatment 

Part II

Part-1 described ovarian cancer, the difficulties of diagnosing the disease early, and the challenges of developing effective screening mechanisms for it in pre-symptomatic women. Here, in part-2, we report new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.
 
1

Established chemotherapy agents combined and used intensively

The first study we describe is Dutch, published in 2017 in the British Journal of Cancer. It reports findings of a pioneering type of intensive chemotherapy, which was effective in 80% of patients with advanced ovarian cancer and whose first line of chemotherapy had failed. Currently, such patients have few options because more than 50% do not respond to follow-up chemotherapy.
 
Intensive combinations
The study, led by Dr. Ronald de Wit, of the Rotterdam Cancer Institute, involved 98 patients who first responded to chemotherapy only later to relapse. Patients in the study were divided into three groups according to the severity of their condition, and treated with a combination of two well established chemotherapy agents:  cisplatin and etopside, but the new treatment used the drugs much more intensively than usual.
 
Usually, chemotherapy is delivered as a course of a number of 21-day sessions (cycles) over several months. Between cycles patients are given time to recover from the toxic side effects, including neurotoxicity, nephrotoxicity, ototoxicity, and chemotherapy-induced nausea and vomiting (CINV). In de Wit’s study the combined chemotherapy drugs were given intensively, on a weekly basis, along with drugs to prevent adverse side effects.
 
Findings
Among the group of women in de Wit’s study who were most seriously ill, 46% responded to the new treatment, compared with less than 15% for current therapies. The response rates of the two groups of women who were least ill to the new treatment were 92% and 91%. This compares to responses of 50% and 20 to 30% with standard therapies. Overall, 80% of the women's tumours shrank, and 43% showed a complete response, with all signs of their cancers disappearing.
 
Immediate benefit
"We were delighted by the success of the study. The new drug combination was highly effective at keeping women alive for longer, giving real hope to those who would otherwise have had very little . . . . We were worried the women would be too ill to cope with the treatment, but in fact, they suffered relatively few side effects. And since these drugs are readily available, there's no reason why women shouldn't start to benefit from them right away," says de Wit.
 
2
 
ONX-0801 study

The second study we report was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting in Chicago. It describes findings of an experimental new treatment that was found to dramatically shrink advanced ovarian cancer tumors, which researchers suggest is, “much more than anything that has been achieved in the last 10 years”.
 
“Very promising” findings
Dr. Udai Banerji, the leader of the study, is the Deputy Director of Drug Development at the UK’s Institute of Cancer Research (ICR). Banerji and his team were testing a drug, known as ONX-0801, for safety, but found that tumors, in half of the 15 women studied, shrank during the trial. A response Banerji called, “highly unusual”, and “very promising”. The drug, which is, “a completely new mechanism of action,” could add, “upward of six months to the lives of patients with minimal side effects”. If further clinical studies prove the drug’s effectiveness, it could potentially be used in early-stage ovarian cancer where, “the impact on survival may be better,” says Banerji.
 
New class of drug
ONX-0801 is the first in a new class of drug discovered by the ICR, and tested with the Royal Marsden NHS Foundation Trust. It attacks ovarian cancer by mimicking folic acid in order to enter the cancer cells. The drug then kills these cells by blocking a molecule called thymidylate synthase. ONX-0801 could be effective in treating the large group of chemo-resistant sufferers for whom there are currently limited options. Additionally, because the new therapy targets cancer cells and does not affect surrounding healthy cells, there are fewer side effects. Further, experts have developed tests to detect the cells that respond positively to this new treatment, which means oncologists can identify those women who are likely to benefit from the therapy the most.
 
Cautious note
Although the study is said to be “very promising”, Michel Coleman, Professor of Epidemiology at the London School of Hygiene & Tropical Medicine, suggests caution in interpreting its findings as it is such a small study and while, “shrinkage of tumors is important . . . it is not the same as producing the hoped-for extension of survival for women with ovarian cancer.”
 
3
 
Genetic testing

Resistance to chemotherapy can be reduced by DNA testing to obtain an increased knowledge of the molecular mechanisms of ovarian cancer pathogenesis, which facilitate personalized therapies that target certain subtypes of the disease. “Some people choose to have DNA testing because either they have developed cancer or family members have,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia. “In the context of cancer, personalized medicine is the concept that we look into the cancer cell and understand for that person what specific genetic changes have occurred in their cancer. Based on those specific changes, for that person we then decide on a type of therapy, which is most appropriate for the genetic changes that have occurred in that cancer . . . . . Typically this involves taking a sample of the cancer, running it through DNA sequencing machines, and using bioinformatics to interpret the information. Then, the results, which include gene mutations need to be interpreted by a multidisciplinary team, in order to decide the best possible treatment options for that particular patient,” says Bowtell: see videos below.
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How do genetic mutations translate into personalised medicine?


How is personalised medicine implemented?
 
Mainstreaming cancer genetics
Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients, and have used laboratories with enhanced genetic testing capabilities to streamline and speed up processing time, lower costs, and help meet the large and growing demand for rapid, accurate and affordable genetic testing. The program called, Mainstreaming Cancer Genetics, helps women cancer patients make critical decisions about their treatment options. Currently, fewer than 33% of patients are tested, but this study spearheaded the beginning of a significant change. In her 2017 Annual Report, Professor Dame Sally Davies, England’s Chief Medical Office suggested that within the next 5 years all cancer patients should be routinely offered DNA tests on the NHS to help them select the best personalized treatments.
 

Bringing genetic testing to patients
According to Nazneen Rahman, Professor and Head of the Division of Genetics and Epidemiology at the ICR, and Head of the Cancer Genetics Unit at the Royal Marsden Hospital, London, “There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex . . . . We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital.” 
 

More people benefiting from affordable rapid advanced genetic testing
Treatment strategies that improve the selectivity of current chemotherapy have the potential to make a dramatic impact on ovarian cancer patient outcomes. The Marsden is now offering genetic tests to three times more cancer patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.” If the UK government acts on the recommendations of Davies, there could be a national center for genetic testing within the next 5 years.
 
4

PARP Inhibitors and personalized therapy
 
Since 2 seminal 2005 publications in Nature,  (Bryant et al, 2005; and Farmer et al, 2005) which reported the extremely high sensitivity of BRCA mutant cell lines to the enzyme poly (ADP-ribose) polymerase (PARP) inhibition, there has been a scientific race to exploit a new class of cancer drug called PARP inhibitors. The family of PARP inhibitors represents a widely researched and promising alternative for the targeted therapy of ovarian malignancies. Over the past few years, PARP inhibitors have successfully moved into clinical practice, and are now used to help improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer.

 
Recent (PARP) approvals
In 2014, olaparib was the first PARP inhibitor to obtain EU approval as a treatment for ovarian cancer patients who had become resistant to platinum-based chemotherapy. In 2017, the FDA granted the drug ‘priority review’ as a maintenance therapy in relapsed patients with platinum-sensitive ovarian cancer while confirmatory studies are completed. In December 2016, the FDA granted ‘accelerated approval’ for rucaparib, another (PARP) inhibitor for the treatment of women with advanced ovarian cancers who have been treated with two or more chemotherapies, and whose tumors have specific BRCA gene mutations. 
 
Early in 2017, the drug niraparib was the first PARP inhibitor to be approved by the FDA for the maintenance treatment of adult patients with recurrent gynaecological cancers who are resistant to platinum-based chemotherapy.  The approval was based upon data from an international randomized, prospectively designed phase III clinical study, which enrolled 553 patients, and showed a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status. In conjunction with the accelerated 2017 FDA approval for rucaparib, the FDA also approved a BRCA diagnostic test, which identifies patients with advanced ovarian cancer eligible for treatment with rucaparib.
 

New class of chemotherapies
PARP inhibitors may represent a potentially significant new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. Currently, these drugs have a palliative indication for a relatively small cohort of patients. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clearer understanding of the mechanism of action, and a better understanding of their toxicity profile will be required. Once this is achieved PARP inhibitors could to be employed in the curative, rather than the palliative setting.
 
5
 
The future of cancer care and multidisciplinary teams
 
According to Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit, we now have “many options” for treating ovarian cancer. However, “how we utilize and sequence these options may have a significant impact on the overall survival of a patient. Better understanding of the disease through science is constantly turning up new options. For the first time in the last 5 years we are developing options in real time for patients. Patients almost are able to benefit from these options as they are relapsing from their disease. Keeping patients alive for longer allows them to access new treatments . . . It’s truly remarkable to see this in real time as a doctor,” says Gabra: see video.
 

A significant number of mostly private patients diagnosed with ovarian cancer draw comfort from the belief that they, “have the best oncologist”.  This view fails to grasp the challenges facing individual clinicians acting on their own to treat a devilishly complex disease such as ovarian cancer. “The main improvements in cancer care have been organizational and scientific.” says Gabra. “It is not enough to create new science and new treatments. It is also important to rigorously implement these. The most effective way to do this is via a ‘tumor board’ or a ‘multidisciplinary clinic or team’, where various specialists such as surgeons, radiotherapists, medical oncologists, pathologists, clinical nurse specialists, etc come together and discuss each individual patient. Such multidisciplinary discussion results in the best utilizations of currently available treatment options in the right sequence. It’s difficult to do this for a doctor acting on his or her own and making isolated decisions . . . Multidisciplinary decision-making has transformed cancer care,” says Gabra: see video.
 
 
Takeaways

This Commentary provides a flavor of some of the recent advances in ovarian cancer research and care, and suggests that treatment options have improved in the 4 years since Maurice Saatchi described ovarian cancer care as, “degrading, medieval and ineffective” leading “only to death”. However, it is worth stressing that care is both organizational and scientific, and multidisciplinary teams can transform care and prolong life.
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  • Ovarian cancer is a deadly disease that is challenging to diagnose and manage
  • Although it only accounts for 3% of cancers in women, it is the 5th leading cause of cancer death among women
  • If diagnosed and treated early before it spreads the 5-year survival rate is 92%
  • But only 15% of women with ovarian cancer are diagnosed early
  • The disease is hard to diagnose because it is rare, the symptoms are relatively benign, and there is no effective screening
  • Ovarian cancer is not one disease, but a collection of subtypes each demanding specific treatment pathways
  • Gold standard treatment is surgery followed by chemotherapy
  • A large proportion of patients develop resistance to chemotherapy
 
Improving ovarian cancer treatment

Part I
 
Are things beginning to improve for people living with ovarian cancer? When the British advertising magnate Lord Maurice Saatchi’s wife died of ovarian cancer in 2012 he described her treatment as, “degrading, medieval and ineffective” leading “only to death”. Ovarian cancer patients have long had limited treatment options, which have not changed much in the past two decades, but recently things have begun to change.

 
In this Commentary
 
This is the first of a 2-part Commentary on ovarian cancer, which briefly describes the condition, explains the difficulties of diagnosing it early, and discusses some of the challenges of developing effective screening mechanisms for the cancer in pre-symptomatic women. Part 2, which will follow separately next week, reports new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. It also suggests that improvements in ovarian cancer care are both organizational and scientific. Experts believe that they now have a number of treatment options available to them. Utilising and sequencing these appropriately can have a significant impact on the overall survival rates of patients. Multidisciplinary teams, which are not universally available to all ovarian cancer patients, bring together all specialisms involved in the therapeutic pathway to consider and suggest optimal treatment steps for individual patients, and make a significant contribution to improved ovarian cancer care. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.
 
Ovarian cancer: a complex and deadly disease
 
The ovaries are a pair of small organs located low in the stomach that are connected to the womb and store a woman’s supply of eggs. Ovarian cancer is driven by multicellular pathways, and is better understood as a collection of subtypes with changing origins and clinical behaviors, rather than as a single disease. The tumors often have heterogeneous cell populations, which form unique microcellular environments. The prevalence of ovarian cancer among gynecological malignancies is rising, and is one the most deadly and hard to treat malignancies. While the disease only accounts for about 3% of cancers in women, it is one of the most common types of cancer in women, the 5th leading cause of cancer-related death among women, and the deadliest of gynecologic cancers. The risk of ovarian cancer increases with age. It is rare in women younger than 40, most ovarian cancers develop after menopause. 50% of all ovarian cancers are found in women 63 or older. According to the American Cancer Society the five-year survival rate for all ovarian cancers is 45%. Most women are diagnosed with late-stage ovarian disease and, the 5-year survival rates for these patients are roughly 30%. Age adjusted survival rates of ovarian cancer are improving in most developed countries. For instance, between 1970 and 2010, the 10-year survival rates for ovarian cancer in England increased by 16%, and the 5-year survival rates have almost doubled. This is because of the favorable trends in the use of oral contraceptives, which were introduced early in developed countries. Declines in menopausal hormone use may also have had a favorable effect in older women as well as improved diagnosis, management and therapies. According to Public Health England, over the past 20 years the incidence of ovarian cancer in England has remained fairly stable, although it has decreased slightly in the last few years. Between 2008 and 2010 in England, 36% of some 14,000 women diagnosed with ovarian cancer died in the first year, and more than 1,600 died in the first month. There were 7,378 new cases of ovarian cancer in the UK in 2014 and more than 4,000 women died from the disease.
 
Benign symptoms difficult to diagnose

If ovarian cancer is diagnosed and treated early before it spreads from the ovaries to the abdomen, the 5-year relative survival rate is 92%. However, only 15% of all ovarian cancers are found at this early stage.  This is because it is hard to diagnose since the disease is so rare, the symptoms are relatively benign, and there is no effective screening. As a result, the illness tends not to be detected until the latter stages in around 60% of women, when the prognosis is poor. In about 20% of cases the disease is not diagnosed until it is incurable. Feeling bloated most days for three weeks or more is a significant sign of ovarian cancer. Other symptoms include: feeling full quickly, loss of appetite, pelvic or stomach pain, needing to urinate more frequently than normal, changes in bowel habit, feeling very tired, and unexplained weight loss.
 
“Tumors go from the earliest stage 1 directly to stage 3”
In the video below Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit 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 progresses from stage 1 to stage 2, to stage 3 is possibly mythological. The reality is, these cancer cells often commence in the fallopian tube with a very small primary tumor, which disseminates directly into the peritoneal cavity. In other words, the tumors go from the earliest of stage 1 directly to stage 3."
 
 
Ovarian cancer screening and CA-125

For years scientists have been searching for an effective screening test for ovarian cancer in pre-symptomtic women. The 2 most common are transvaginal ultrasound (TVUS) and the CA-125 blood test. The former uses sound waves to examine the uterus, fallopian tubes, and ovaries by putting an ultrasound wand into the vagina. It can help find a tumor in the ovary, but cannot tell if the tumor is cancerous or benign. Most tumors identified by TVUS are not cancerous. So far, the most promising screening method is CA-125, which measures a protein antigen produced by the tumor.
 
CA-125 studies
To-date, 2 large ovarian cancer screening studies have been completed: one in the US, and another in the UK. Both looked at using the CA-125 blood test along with TVUS to detect ovarian cancer. In these studies, more cancers were found in the women who were screened, and some were at an early stage. But the outcomes of the women who were screened were no better than the women who were not screened: the screened women did not live longer and were not less likely to die from ovarian cancer.

Another study published in 2017 in the Journal of Clinical Oncology screened 4,346 women over 3 years at 42 centers across the UK, undertook follow-up studies 5 years later, and came to similar conclusions as the 2 previous studies. Further, “there are a number of non-ovarian diseases, which can cause elevated CA-125’s. Breast cancer, endometriosis, and irritation of the peritoneal cavity can all cause elevated CA-125,” says Michael Birrer, Director of Medical Gynecologic Oncology at the Massachusetts General Hospital and Professor of Medicine at Harvard University.


Controversial findings
Findings from screening tests using CA-125 can give false positives for ovarian cancer, and this puts pressure on patients to have further, often unnecessary interventions, which sometimes include surgery. Also, the limitations of the CA-125 test mean that many women with early stage ovarian cancer will receive a false negative from testing, and not get further treatment for their condition. Thus, the potential role of CA-125 for the early detection of ovarian cancer is controversial, and therefore it has not been adopted for widespread screening in asymptomatic women.
 
In the video below Birrer explains that, “pre-operatively and during therapy physicians will usually check CA-125 as a measure of the effectiveness of the therapy. At the completion of therapy one would anticipate that the CA-125 would be normal. After that, it is somewhat controversial as to whether follow-up with CA-125 to test for recurring disease is clinically relevant,” says Birrer. Since the discovery of CA-125 in 1981, there has been intense research focus on novel biomarkers for cancer, and significant scientific advances in genomics, proteomic, and epigenomics etc., which have been extensively used in scientific discovery, but as yet no new major cancer biomarkers have been introduced to practicing oncologists. 

 
Limited treatment options

As most ovarian cancer patients are diagnosed late when the disease has already spread, treatment options are limited. The first line treatment is surgery called debulking, (also known as cytoreduction or cytoreductive surgery), which is the reduction of as much of the volume (bulk) of a tumor as possible. 
 
Be prepared for extensive surgery
Whether a patient is a candidate for surgery depends on a number of factors including the type, size, location, grade and stage of the tumor, pre-existing medical conditions, and in the case of a recurrence, when the last cancer treatment was performed, as well as general health factors such as age, physical fitness and other medical comorbidities. People diagnosed with ovarian cancer, “need to be prepared to have extensive surgery because the real extent of the tumor dissemination cannot be detected by conventional imagining pre-operatively,” says Professor Christina Fotopoulou, consultant gynaecological oncologist at Queen Charlotte's & Chelsea Hospital, London: see video below. 
 
 
Platinum resistance

Surgery is usually followed by chemotherapy. There are more than 100 chemotherapy agents used to treat cancer either alone or in combination. Chemotherapy drugs target cells at different phases of the process of forming new cells, called the cell cycle. Understanding how these drugs work helps oncologists predict, which drugs are likely to work well together. Clinicians can also plan how often doses of each drug should be given based on the timing of the cell phases. Chemotherapy drugs can be grouped by their chemical composition, their relationship with other drugs, their utility in treating specific forms of cancer, and their side effects.  
 
You can reduce chemotherapy resistance by using a combination of drugs that target different processes in the cancer so that the probability that the cancer will simultaneously become resistant to both drugs is much lower than if you use one drug at a time, ” says David Bowtell,  Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia: see video:
 
 
Improving the chemotherapy agent cisplatin
The standard chemotherapy treatment for ovarian cancer is a combination of a platinum compound, such as cisplatin or carboplatin, and a taxane, which represents a class of drug originally identified from plants. Since cisplatin’s discovery in 1965 and its FDA approval in 1978, it has been used continuously in treatments for several types of cancer, and is best known as a cure for testicular cancer. Scientists have searched for ways to improve the anti-tumor efficacy of platinum based drugs, reducing their toxicity, strengthening them against resistance by expanding the class to include several new analogues of cisplatin, and putting these through clinical studies to broaden the different types of cancers against which they can be safely used.
 
Slow progress transitioning research into clinical practice
Despite these endeavors, platinum resistance remains a significant clinical challenge. Between 55 and 75% of women with ovarian cancer develop resistance to platinum based chemotherapy treatments. Significant research efforts have been dedicated to understanding this, but there has been relatively slow progress transitioning the research into effective clinical applications. According to Birrer, “the mechanism of platinum resistance from a molecular standpoint has not been well defined. It is likely to be heterogeneous, which means that each patient’s tumor may be slightly different. The hope is for targeted therapies and personalised medicine to have a chance of overcoming this, in that we could characterize the mechanism of the platinum resistance and apply and target therapy.”
 
2 theories of platinum resistance
In the video below, Birrer posits 2 theories to explain platinum resistance. “One suggests that under the influence of platinum the tumor changes and becomes resistant. Another suggests that there are 2 groups of cells to begin with. The vast majority of the tumor is sensitive, but there are small clusters of resistant cells. Once you kill the sensitive cells you have only the resistant cells left. Although these 2 theories have been around for about 25 years, there are no definitive data to suggest which theory is right. I have a personal scientific bias to think that the resistant cells are present at the time that we start the therapy. Being able to identify and characterize these cells upfront would be a radical breakthrough because then we would be able to target them at a time when they are only a small portion of the tumor,” says Birrer.
 
 
Takeaways

Saatchi is right; for decades ovarian cancer treatment has been wanting, but studies we describe in part-2 of this Commentary suggest that the tide might be turning for people living with ovarian cancer. So don't miss part-2 next week!
 
 
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  • Each year cancer kills 8m people worldwide and cost billions
  • 40% of cancer deaths could be prevented by early detection
  • Nearly half of all cancer sufferers are diagnosed late when the tumors have already spread
  • Victims and doctors often miss early warning signs of cancer
  • Traditional tissue biopsies used to diagnose cancer are invasive, slow, costly, and often yield insufficient tissue
  • New blood tests are being devised that simultaneously detect cancer early and inform where the cancer is in the body
  • Such tests - liquid biopsies - are positioned to end the late diagnosis of cancer
  • But before liquid biopsies become common practice they need to overcome a number of significant challenges
  
World’s first blood tests that detect and locate cancer
 
Just as there is a global race among immunotherapists to enhance cancer treatment, so there is a parallel race among bioengineers to speed up and improve the detection of cancer. Such races are important because nearly half of all cancer sufferers are diagnosed late, when their tumors have already metastasized: 30% to 40% of cancer deaths could be prevented by early detection and treatment.
 
Here we describe advances in blood tests - “liquid biopsies” - which can simultaneously detect cancer early, and identify its tissue of origin. We also, describe the growing commercialization of the technology, and some significant hurdles it still has to be overcome.
 
A costly killer disease

Each year cancer kills more than 8m people worldwide, 0.6m in the US and nearly 0.17m in the UK. Survival rates for pancreatic, liver, lung, ovarian, stomach, uterine and oesophageal cancers are particularly low. A large proportion of people do not know they have cancer, and many primary care doctors fail to detect its early warning signs. According to The Journal of Clinical Oncology, a staggering 44% of some types of cancers are misdiagnosed. A significant proportion of people discover that they have cancer only after presenting a different condition at A&E. Each year, the total cost of cancer to the UK’s exchequer is nearly £20bn. In the US, national spending on cancer is expected to reach US$156bn by 2020. And as populations age so some cancer prevalence rates increase, despite substantial endeavours to reduce the burden of the disease.
  
The UK: a stereotypical case

The UK is indicative of what is happening elsewhere in the developed world with regard to cancer diagnosis and treatment. Epidemiological trends suggest that although progress is being made to fight the disease, much work is still required. Death rates for a number of individual cancer types have declined, but rates for a few cancers have increased.

Recently, the UK’s Department of Health invested £450m to improve diagnosis, including giving primary care doctors better access to tests such as CT and MRI scans. But each year there are still some 0.17m cancer deaths in the UK, and 1 in 4 British cancer patients are unlikely to live longer than 6 months after diagnosis because they and their doctors have missed early signs of the disease. For example, in the UK only 23% of lung cancer cases are diagnosed early, as are 32% of cases of non-Hodgkin lymphoma, and 44% of ovarian cancer.

Not only does late detection increase morbidity and mortality, it significantly increases treatment costs. According to the UK’s NHS National Intelligence Network, a case of ovarian cancer detected early costs an average of £5,000 to treat, whereas one detected late at stage three or four costs £15,000. Similarly, a colon cancer patient detected early typically costs £3,000, while one not identified until a later stage would cost some £13,000.

 
Traditional tissue biopsies

Currently, oncologists look to pathologists for assistance in tumor diagnosis. Indeed, oncologists cannot proceed with therapy without a tissue diagnosis, nor are they able to discuss prognosis with the patient. After detecting a tumor through a physical examination or imaging, doctors use traditional tissue biopsies to gather information on the attributes of a patient’s cancer.
 
These pinpoint a cancer’s mutations and malignancy, but solid tissue biopsies are not always straightforward. While some cancers are easily accessed, others are hidden deep inside the body or buried in critical organs. Beyond the physical challenge, sampling from such tumors can be dangerous to patients, and once achieved, they do not always inform on current tumor dynamics. Further, traditional solid tissue biopsies are costly and time consuming to perform; they can yield insufficient tissue to obtain a good understanding of the tumor, and they can be hampered by a patient’s comorbidities, and lack of compliance.

 
Two significant studies
 
Although solid tumor tissue is still the gold standard source for clinical molecular analyses, cancer-derived material circulating in the bloodstream has become an appealing alternative showing potential to overcome some of the challenges of solid tissue biopsies.

Findings of two significant studies of liquid biopsies published in 2017 promise a more effective and patient-friendly method for diagnosing cancer: one in the journal Genome Biology, and the other in the journal Nature Genetics. Both studies are on the cusp of developing the world’s first simple blood test, which can both detect early stage cancer, and identify where in the body the cancer is located.

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The Genome Biology study
 
​The study, reported in Genome Biology, describes findings of a blood test, referred to as the CancerLocator, which has been developed by Jasmine Zhou, Professor of Biological and Computer Sciences and her team at the University of California, Los Angeles (UCLA). The  Locator detected early stage cancer in 80% of breast, lung and liver cases.
 
Zhou and her colleagues devised a computer program that uses genetic data to detect circulating tumor DNA (ctDNA) in blood samples. Once identified, the ctDNA is compared to a database of genetic information from hundreds of people to identify where the tumor is located.  Zhou’s team discovered that tumors, which arise in different parts of the body, have different signatures, which a computer can spot. “The technology is in its infancy and requires further validation, but the potential benefits to patients are huge  . . . . . Non-invasive diagnosis of cancer is important, as it allows the early detection of cancer, and the earlier the cancer is caught, the higher chance a patient has of beating the disease,” says Zhou.
 
The Nature Genetics study

Researchers led by Kun Zhang, Professor of Bioengineering at the University of California, San Diego (UCSD), are responsible for the study published in the journal Nature Genetics. Zhang developed a test that examined ctDNA in blood from cancer patients and, like Zhou, discovered that not only could it detect cancer early, but could also locate where the tumor is growing in the body. When a tumor starts to take over a part of the body, it competes with normal cells for nutrients and space, killing them off in the process. As normal cells die, they release their DNA into the bloodstream; and that DNA can identify the affected tissue.
 
There are many technical differences on how each approach works . . . The work by the UCLA group is a computer program that uses data published previously by other groups, and has reduced the cancer detection error from roughly 60% to 26.5%. In contrast, we developed a new theoretical framework, generated our own data from over 100 patients and healthy people, and our accuracy of locating cancer in an organ is around 90%,” says Zhang, but he adds, “Major medical challenges don’t get solved by one team working alone”.
 
Confluence and advances in computing and biology

The research endeavors of Professors Zhou and Zhang have been made possible by the confluence and advances in computing and molecular biology. Over the past 20 years, there has been a paradigm shift in biology, a substantial increase in computing power, huge advances in artificial intelligence (AI), and the costs of data storage have plummeted. It took 13 years, US$3bn, and help from 7 governments to produce the first map of the human genome, which was completed in 2003. Soon it will be possible to sequence an entire genome in less than an hour for US$100.
 
The end of traditional in vitro diagnostics

Liquid biopsies are a sequencing-based technology used to detect microscopic fragments of DNA in just a few drops of blood, and hold out the potential to diagnose cancers before the onset of symptoms. Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry for his work in understanding how DNA is converted into RNA, “which gives a voice to genetic information that, on its own, is silent,” describes how advances in molecular science are fueling the replacement of traditional in vitro diagnostics with virtually instantaneous, point-of-care diagnostics without resort to complex processes or elaborate and expensive infrastructure. Liquid biopsies, such as those developed by Zhou and Zhang, have the potential to provide clinicians with a rapid and cheap means to detect cancer early, thereby enabling immediate treatment closely tailored to each patient’s disease state.

 
 
FDA approval of liquid biopsy
 
In 2016, the US Food and Drug Administration (FDA) granted Swiss pharmaceutical and biotech firm Roche approval for a liquid biopsy, which can detect gene mutations in the most common type of lung cancer, and thereby predict whether certain types of drugs can help treat it. 

The clinical implementations of such a test are not widespread, and there has been no regulatory approval of liquid biopsies for diagnosing cancer generally. Notwithstanding, ctDNA is now being extensively studied, as it is a non-invasive “real-time” biomarker that can provide diagnostic and prognostic information before and during treatment; and at progression.
 

cfDNA and ctDNA

Cell-free DNA (cfDNA) is a broad term that describes DNA, which is freely circulating in the bloodstream, but does not necessarily originate from a tumor. Circulating tumor DNA (ctDNA) is fragmented DNA, which is derived directly from a tumor or from circulating tumor cells (CTCs).
 
Commercialization of the liquid biopsy race
 
Bill Gates, Jeff Bezos and leading venture capitalists have poured hundreds of millions into the goal of developing liquid biopsies. The US market alone is projected at US$29bn, according to a 2015 report from investment bank Piper Jaffray. Currently, there are about 40 companies in the US analyzing blood for fragments of DNA shed by dying cancer cells. Notwithstanding, only a few companies have successfully marketed liquid biopsies, and these are limited to identifying the best treatments for certain cancers, and to update treatments as the cancer mutates. So far, no one has been successful in diagnosing incipient cancer from a vial of blood drawn from a patient who looks and feels perfectly healthy.
 
Some US companies in the liquid biopsy race

At the 2016 meeting of the American Society of Clinical Oncology (ASCO), a Silicon Valley start-up, Guardant Health, which has raised some US$200m, presented findings from a large study involving over 15,000 participants, which demonstrated the accuracy of its liquid biopsy test, Guardant360, for patients with advanced solid tumors. The study found the same patterns of genomic changes in cfDNA reported by the Guardant360 test as those found in 398 patients with matching tissue samples between 94% and 100% of the time.

The 70-gene test is the first comprehensive, non-invasive genomic cancer-sequencing test to market, and according to the company, about 2,000 physicians worldwide have used it. Guardant expects to continue to develop its technology, and maintain a commercial lead in the cfDNA liquid biopsy space. The next step for Guardant is to go beyond sequencing, which matches patients to targeted oncology drugs to the early detection of cancer itself. 
 
Also in 2016 Gates and Bezos teamed up with San Diego's Illumina, which makes most of the DNA sequencing machines that pick appropriate treatments for cancer patients, to launch another liquid biopsy start-up called Grail. In 2017, Grail raised US$900m to help it develop blood-based diagnostics to enable routine, early detection of cancer. The company aims to refine and validate its liquid biopsy technology by running a number of large-scale clinical studies where it expects to sequence hundreds of thousands of patients. Another Californian-based biotech start-up, Freemome,  raised US$65m to validate its liquid biopsy technology for the early detection of cancer.
 
Takeaways

Despite findings of the two 2017 studies reported in the journals Genome Biology and Nature genetics, FDA approval of Roche’s liquid biopsy, massive increase in investment, and significant commercial biotech activity, there is a gap between reality and aspirations for liquid biopsies. To provide doctors with a reliable, point-of-care means to detect cancer early, liquid biopsies will have to overcome several significant challenges. The major one is assay sensitivity and specificity for analysis of ctDNA and cfDNA. To compete with the gold standard solid tissue biopsy, and to ensure that patients receive early diagnosis and appropriate treatment, a successful liquid biopsy assay will have to demonstrate a high positive predictive value. Concomitantly, good sensitivity and excellent specificity will be required to yield acceptable rates of false positives and false negatives. Notwithstanding, the race among bioengineers to develop a non-invasive “real-time” liquid biopsy to detect cancer early is gaining momentum.
 
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  • Stem cell study aims to improve prospects for lung cancer sufferers
  • Professor Sikora suggests that lung cancer is associated with poverty
  • Current therapies for lung cancer extend life by only a few months
  • Lung cancer kills more people than any other cancer

Lung cancer and cutting edge stem cell therapy

In 2015 a combined stem cell and gene therapy for lung cancer started its first clinical study in the UK. Professor Sam Janes of University College London, the study’s leader, said: “This will be the first UK cell therapy for lung cancer, and the biggest manufacturing of cells of its kind.” 

Dr Chris Watkins, director of translational research at the Medical Research Council, which is funding the study, said: “Lung cancer kills more men and women than any other cancer, and improving the outcome for patients with this terrible disease is one of the biggest challenges we face. This new therapy, which uses modified stem cells to target the tumour directly is truly at the cutting edge.”

 
Few studies
 
The use of stem cells for treating lung diseases has increasing appeal, but as yet, little is known about the effects of administering stem cell therapy to patients with lung diseases. Currently, there are only a small number of approved clinical studies in the US and Canada investigating cell therapy approaches for lung diseases. Patrick O’Brien a consultant obstetrician and gynaecologist at University College Hospital, London describes an initiative to create a national stem cell bank in the UK: 
 
       
 
Lung cancer
 
Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. This year, an estimated 224,210 adults in the US, 40,000 in the UK, and 169,000 in India will be diagnosed with lung cancer, 90% of which are and caused by smoking. Of those diagnosed, 95% will die within ten years, although early stage lung cancer has a much better survival rate. Professor Karol Sikora, a world respected oncologist, and campaigner for better universal cancer treatment, suggests that lung cancer is associated with poverty:
 
    

Traditional therapies
 
Cell-gene therapy holds out new hope. “Lung cancer is very difficult to treat because the vast majority of patients are not diagnosed until the cancer has spread to other parts of the body. One therapy option for these patients is chemotherapy, but even if successful this treatment can normally only extend lives by a handful of months,” says JanesCurrent therapeutic strategies of chemotherapy, radiation therapy, and clinical studies with new-targeted therapies have only demonstrated, at best, extension in survival by a few months.
 
Innovative approach
 
“We aim to improve prospects for lung cancer patients by using a highly targeted therapy using stem cells, which have an innate tendency to home in on tumours when they’re injected into the body. Once there, they switch on a ‘kill’ pathway in the cancer cells, leaving healthy surrounding cells untouched,” says Janes. His study will test the treatment in human volunteers, firstly to check that the treatment is safe, and then in 56 lung cancer patients to see how effective the gene-cell therapy compares with standard care. Each patient in the study will receive three infusions comprised of billions of cells in parallel with chemotherapy.
 
Takeaways

A key advantage of Janes’ proposed treatment is that the cells do not have to be closely matched to a person’s tissue type or genetic profile. They are simply taken “off the shelf” from existing bone marrow supplies. This is because the cells have relatively few proteins on their surface, and do not induce an immune response in the recipient.
 
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Clinical study challenges off-label use of targeted cancer therapies

  • Oncologists increasingly use targeted agents directed at molecular features of cancer cells
  • There is increased off label use of these new targeted agents without evidence to support the practice
  • A landmark study concludes that off label use of targeted agents show no benefit and should be discouraged
  • Professor Gabra, head of cancer at Imperial College, says more research is needed
 

Despite significant progress in cancer care over the past decade, there remain substantial challenges in the treatment of advanced cancers. This has increased off-label use of newer drugs based on molecular studies of tumours, largely without much evidence to support the practice.

A landmark clinical study, known as SHIVA, led by Christophe le Tourneau, a senior medical oncologist at the Institut Curie in Paris, raised expectations among both doctors and patients, because it is one of the first randomized studies to explore molecularly targeted agents applied outside their indicated use (off-label) among those with advanced cancers for whom standard therapies had failed.
 
Findings, published in Lancet Oncology, September 2015, concluded that, “off-label use of molecularly targeted agents should be discouraged,” since the study detected no improvement in survival rates when compared to treatments selected by clinicians that were not based on such sophisticated DNA profiling. 

What are the implications of the study’s negative findings for personalised medicine?

Christophe le Tourneau

In the videos below Le Tourneau describes the SHIVA trail and some of the challenges it faced.

   

   
     (click to play the video) 

 

The context

Cancer is a heterogeneous, complex, and challenging disease to treat. Tumours formerly categorized as a single entity on the basis of microscopic appearance are now known to be diverse in their molecular characteristics. Cancer chemotherapy is on an evolutionary path from non-specific cytotoxic drugs that damage both tumour and normal cells to targeted agents that are directed at unique molecular features of cancer cells, and aims to produce greater effectiveness with less toxicity.
 
Over the past decade our understanding of cancer and the basis of its treatment has been significantly changed by the advent of rapid and cheap DNA sequencing technology. The application of these sophisticated analytic techniques to arrive at a therapy for a particular cancer has been called “personalized oncology.” The idea of personalized cancer care based on molecular characteristics of the tumour promises to expand the boundaries of precision medicine. Numerous case reports and other observations have suggested that therapy targeted at molecular characteristics of a tumour can have significant beneficial effects.
 
These personalized therapeutic strategies have rendered traditional classifications of many cancers redundant, because they have advanced our understanding of the underlying biology and molecular mechanisms of specific cancers. Cancer is no longer considered a single disease entity, and is now being subdivided into molecular subtypes with dedicated targeted and chemotherapeutic strategies. The concept of using information from a patient's tumour to make therapeutic and treatment decisions has changed the landscapes of both cancer care and cancer research.

 

The SHIVA study

The SHIVA study, carried out at eight academic centres in France and conducted in 195 patients with metastatic cancer resistant to standard care, was a proof-of-concept, open-label, randomized controlled study. The patients were randomly assigned to receive either molecularly targeted agents (used off-label) chosen on the basis of the molecular profile of the tumour; or therapy based on the clinician's choice. The median follow-up period was 11.3 months. Findings showed a median progression free survival (PFS) of 2.3 months for patients receiving targeted therapy, versus 2.0 months for patients receiving therapy based on the clinician's choice.

"So far, no evidence from our randomised clinical trial supports the use of molecularly targeted agents outside their indications on the basis of tumour molecular profiling . . . . . Our findings suggest that off-label use of molecularly targeted agents outside their indications should be discouraged, and enrolment into clinical trials encouraged," says Le Tourneau and his colleagues.
 

More research required

Hani Gabra, Professor of Medical Oncology and Head of Cancer, Imperial College London says, "SHIVA is important because it is the first randomized study carried out in this complex area of matching drugs to genomic profiles of tumours. Despite the fact that the results are negative we should continue research in this area because personalised medicine is a relatively new area. One thing to note is that the molecularly targeted agents used in SHIVA were single agents, which could increase resistance and reduce the agent’s efficacy. In clinical practice we tend to use several targeted agents in combination in order to counteract drug resistance. SHIVA tested specific agents and specific targets, which resulted in disappointing findings. This doesn’t necessarily negate the overall strategy, but it does suggest that more research is necessary to test the overall strategy, and this might be more challenging.”
 

Takeaways

SHIVA is one of several on going and proposed studies aimed at defining the role of targeting sequencing of tumours in an endeavour to enhance therapy. The SHIVA study did not uncover any new positive evidence to help in the management of advanced cancers. Le Tourneau and his colleagues suggest further studies in a subset of patients that have tumours with molecular alterations in the chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. Oncologists, while disappointed by SHIVA’S results, still hold out hope for their patients and advocate further studies.

 
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3 years, 10 months ago

A new test, called ADNEX, reported in the British Medical Journal in October 2014 helps to identify different types and stages of ovarian cancer more accurately, which scientists claim will reduce the incidences of unnecessary surgeries.

Accurate, simple and ready
The test, developed by an international team led by Imperial College London and KU Leuven, Belgium, is based on patient data, a simple blood test, and features that can be identified on an ultrasound scan. Doctors can use it simply by entering patient data into a smartphone app. It’s highly accurate, and discriminates between benign and malignant tumours, and also identifies different types of malignant tumours.

Successful treatment depends on accurate diagnosis, and diagnosis of ovarian cancer can be challenging. According to Professor Tom Bourne, Department of Surgery and Cancer at Imperial College London, "The way we assess women with ovarian cysts for the presence of cancer and select treatment lacks accuracy. This new approach to classifying ovarian tumours can help doctors make the right management decisions, which will improve the outcome for women with cancer. It will also reduce the likelihood of women with all types of cysts having excessive or unnecessary treatment that may impact on their fertility."

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