Oncology Care in the Future
Professor Angus Dalgleish, Professor Nicholas James, Professor Jonathan Waxman & Professor Will Steward
Session chair: Professor Karol Sikora
Reporter: Shethah Morgan MICR CSci
Keywords
Cancer vaccine, Oncology, Prevention, Prostate cancer
Professor Karol Sikora opened this half-day session by remarking that oncology drug development is a growth area, constituting 50% of new drugs in the pharmaceutical pipeline, which highlights the great medical need for treating cancer patients. Despite regulatory authorities approving new drugs, study findings published in the journal Lancet Oncology in March suggest that survival rates for common cancers in England have not improved significantly since the UK’s national cancer plan was introduced in 2000. Karol suggested that access to new cancer drugs remains poor in the NHS, noting that only six cancer treatments were approved in the UK over the past three years, which he estimated was five times less than the EU average.
To support oncology drug development, there are many specialist CROs and investigator sites that have access to patients and scientific know-how. The prevalence of cancer is set to rise, and this will put further pressure on process and outcomes. Real improvement requires a serious commitment from government and healthcare systems to reform. The future, however, is bright for oncology care with targeted therapies increasingly being administered chronically to stabilise disease, therefore increasing patient survival. Alongside new therapies, it is also important to provide prompt diagnosis with effective interventions, so that cancer patients do not live in poor health unnecessarily for long periods of time due to a lack of co-ordinated healthcare. The ultimate goal would be cancer prevention rather than cure.
History of immunotherapy & cancer vaccines
Professor
Angus Dalgleish presented on developments within the field of cancer
vaccines. Immunomodulation (ie, boosting a patient’s immune response to
fight disease) is not a recent phenomenon; even as early as the 19th
century, Coley made cell products as vaccines to treat patients.
Therapeutic vaccines aim to provide clinical benefit by inducing strong
immune responses to cancer cells. A large variety of cancer vaccines
have undergone extensive testing in early-phase clinical trials.
Several cancer vaccines have disappointingly shown negative results;
however, a key success has been the launch of human papilloma virus
vaccines, eg, Gardasil and Cerivax, for the prevention of cervical
cancer. It is important to note that vaccines for prevention of cancer
cannot be used to halt cancer progression because the molecular targets
can be different. Effective vaccines have been difficult to develop for
some indications like melanoma and have often failed in Phase III
clinical trials. Reasons for this attrition can be due to the
heterogeneity, unpredictable nature of the cancer and the target
antigens on the cell surface being down-regulated, thereby rendering
the vaccine unable to recognise and attack the tumour.
Vaccines for the treatment of slower growing and
more predictable cancers, eg, prostate, lung and colorectal cancers,
may be more successful. Encouraging trends toward increased survival in
cancer vaccine clinical trials have been recently observed. Cancer
vaccine clinical trials need to be performed at specialist investigator
sites with careful patient selection. Dr Philip Livingston at Memorial
Sloan Kettering Cancer Centre in the USA, is a medical oncologist with
interests focused on developing cancer vaccines. He has found that
autologous (ie, re-implanted in the individual that they came from)
cell-based vaccines are generally successful for prevention of cancer
recurrence after surgery or chemotherapy.
Biomarkers are required to try to predict patients
that will not respond to a vaccine from those patients that are
responders. Although research conducted at Professor Dalgleish’s
laboratory was unable to identify a genomic marker to predict
responders, scientists have discovered certain analytes linked to
chronic inflammation that can discriminate those patients who are
unlikely to respond to a cancer vaccine. Biomarkers linked to these
analytes can be used to exclude patients from future clinical trials.
Baseline measurement of immunosuppression may aid patient eligibility
into a vaccine clinical trial and may also be useful to monitor disease
progression. It seems likely that clinical trial success with vaccines,
and hence patient benefit, could be improved through better patient
identification, possibly by the discovery and use of novel immune
response biomarkers. Generally, in oncology early clinical development,
treatments are evaluated in the metastatic setting; intervention in
early disease may be more appropriate for vaccine studies.
Studies investigating vaccines across a range of cancers include:
- MUC1 vaccine in lung cancer
studies where a strong survival trend was observed. MUC1 is a mucinous
glycoprotein which is over-expressed and under or aberrantly
glycosylated in many human malignancies.
- In prostate cancer there have been several vaccine studies:
- Dendreon
recently reported results from the IMPACT trial for Provenge
(sipuleucel-T) in men with advanced prostate cancer, which showed that
the immunotherapy met the study's primary endpoint by extending median
survival by 4.1 months, compared with placebo. The product is under
review by the FDA.
- Onyvax's lead product
is in clinical trials for the treatment of prostate cancer. Onyvax-P
(currently in Phase II) is selecting patients based on inflammatory
status. Results have shown a reduction in PSA and increased progression
free survival.
- Prostavac is an
immune-therapeutic vaccine for the treatment of benigh prostatic
hyperplasia and prostatitis, showing improvements with marginal side
effects.
Current approaches to vaccinations in cancer, eg,
combining vaccines with radiotherapy, chemotherapy and endocrine
therapies hold out a great deal of promise, but at the same time, pose
important challenges in optimising doses and schedules to maximise
efficacy. Drugs that interfere with blood vessel growth, eg,
anti-angiogenic drugs like bevacuzimab and thalidomide analogues, when
combined with vaccines also appear to synergise and increase cancer
cell death.
Angus’s summarised his presentation with three key messages for therapeutic cancer vaccine development:
- Trials need to be conducted in early disease
- Stringent patient selection is required based on immune status
- Combination
strategies must be investigated, to first administer the vaccine before
other treatments to hopefully improve benefit
Future of cancer care
Professor
Nicolas James discussed the likely future trends in cancer care, and
highlighted that with 10 million cancer cases per year world-wide, the
financial implications of cancer treatment is becoming a major problem,
particularly for patients in less affluent countries or those with low
income. The cancer drug market is estimated by the WHO to be $346
billion, with current research costs of approximately $8 billion by the
pharmaceutical industry, and in the non-commercial sector about $3
billion in the USA and $1 billion in Europe. There is a rapid growth in
multiple therapies for potential chronic use (to stabilise disease);
however, these new drugs are increasing costs to healthcare systems as
the market price for these drugs is rising to enable the recouping of
R&D costs.
Multi-factorial reasons can make it difficult to
compare incidence rates, trends and economics of cancer care between
countries. For example:
- Different lifestyles (ie, demographics) shows that healthy, fit males have a reduced risk of developing prostate cancer.
- National
strategies, eg, screening for prostate cancer in the USA versus ‘watch
and wait’ approach in the UK. In the USA, for early prostate cancer
treatment it is common practice for surgical intervention using robotic
technology.
- Diet has been linked to
incidences of cancers. The SELECT trial evaluated the possible
anti-cancer properties of the dietary supplements, selenium and vitamin
E, in preventing prostate cancer. This trial was stopped because the
Independent Data Monitoring Committee (IDMC) found that selenium and
vitamin E, taken alone or together for an average of five and a half
years, did not prevent prostate cancer.
- Moderate
exposure to sunlight can have a beneficial effect through the action of
vitamin D, which reduces incidence of cancer. However, in melanoma (a
form of skin cancer) it is well recognised that high sun exposure can
be a major causal factor.
New drugs are usually initially licensed for
end-stage disease. About 30% of cancers are treatable by excision, a
further 30% are cured by radiotherapy and surgery, the remaining 40%
present as advanced cancer, of which only 5% is curable with drugs.
Nicholas focused on his experience in using renal
cancer drugs. Four drug treatments have been recently approved for
people with advanced and/or metastatic renal cell carcinoma: Pfizer’s
Sutent, Roche’s Avastin, Bayer’s Nexavar and Wyeth’s Torisel. An
interim analysis in 2005 of Nexavar versus placebo study in end-stage
metastatic renal cancer had a Hazard Ratio of 0.44. With such striking
benefit of Nexavar, the IDMC stopped the study and consequently the
long-term survival was unclear. A local audit was conducted at
Nicholas’ oncology clinic in Birmingham, as a pseudo-randomised
clinical trial assessing the use of Nexavar and Sutent based on
postcode. The audit findings showed that patients with a ‘B’ postcode
(ie, Birmingham area) who received the drugs had a median survival of
greater than 2 years, whereas patients with a ‘non B’ postcode (eg,
Herefordshire, Staffordshire, Warwickshire) who did not have access to
the drugs had a median survival of only 7 months. This alludes to the
‘postcode lottery’ highlighted by patients and healthcare professionals
in the UK.
Although Herceptin was first licensed in advanced
breast cancer (due to public pressure), the drug is now available for
early breast cancer treatment. This has increased its usage and
ultimately hospital waiting lists for the drug. The availability of
even more new approved drugs, and changes in prescribing patterns from
late to adjuvant treatment (ie, given in addition to initial cancer
treatment such as surgery) ultimately increases the overall cost burden
from millions to billions of dollars. A recent report from the
Karolinska Institute in Sweden showed that the UK’s average expenditure
on cancer treatment is lower than many European partners’ and that the
rate of change is also slower. Although there is both clinical and
regulatory drive to expedite development of safe, efficacious cancer
therapies, national payers have their own criteria to enable drugs to
get to patients through the healthcare systems. The UK National
Institute for Clinical Excellence (NICE) evaluates new drugs on
cost-effectiveness based on set criteria rather than budget. Primary
Care Trusts (PCTs) are now legally accountable for their budgets and do
not receive additional budget to fund NICE-approved drugs. Therefore,
this can lead to a situation where NICE approve a certain drug, which
cannot be prescribed due to insufficient PCT budgets.
Personalised medicine approaches can help to tailor
cancer care to patients where there is good data to support a response
with a particular treatment. For example, bladder cancer patients that
have a down-regulation in the biomarker Bcl2 should receive radio- and
chemo-therapies; and colorectal cancer patients with expression of
wildtype k-ras are likely to receive benefit with vectibix or cetuximab
when compared to patients that express a mutated form of the k-ras gene.
The future aim of cancer care should be to have
prompt access to correct treatment. Possible solutions to the financial
constraints in cancer care could be funding through general taxation,
insurance schemes or a mixed system that meets consumer requirements.
Additional ways to help save money include improved guidelines and
profiling of disease, so that patients receive the right treatment.
The challenge of prostate cancer
Professor Jonathan Waxman from Hammersmith Hospital, London noted that prostate cancer is the commonest malignancy in men in industrialised countries, and also the second leading cause of male cancer-related mortality. Prostate cancer accounts for 12% of deaths in men due to cancer, which makes the disease a common cause of death. The median age for onset of prostate cancer is 72 years; however, in genetically predisposed males it can manifest at a much younger age.
Several papers have been published linking prostate cancer to risk factors like diet, eg, meat and milk products. The current and traditionally accepted tools for screening of prostate cancer (such as prostate specific antigen, PSA) have their limitations. Nuclear magnetic resonance (NMR) analysis of blood from prostate patients and healthy subjects did not show profile differences. Following a recent metabolomic profiling study, sarcosine was identified as being increased in the urine of patients with metastatic prostate disease. Additionally, when added to benign cells, sarcosine can convert them to a malignant phenotype. A genome-wide analysis of markers that changed in prostate cancer, found that approximately 320 genes were up-regulated and about 270 genes were down-regulated. Some of these genes are involved in the androgen receptor pathway (which is implicated in prostate cancer aetiology). Glycine N-methyltransferase (GNMT) is thought to be an important regulatory protein that is highly influenced by androgen and can silence genes through the methylation process. GNMT when administered to prostate cancer cell lines can reduce sarcosine levels, therefore, theoretically may inhibit benign cells from becoming malignant. With further research, sarcosine levels may be a better screening tool than measuring PSA.
Early treatment of prostate cancer does not necessarily translate into an increase in survival. As evidence accumulates on the efficacy of new targeted agents combined with the further study of conventional forms of therapy, the hope is that the challenge of optimising the management of ‘early’ prostate cancer will be delivered. There seems to be a financial incentive to treat the disease rather than watch and wait for tumour-related changes. Currently there are no active treatments that can cure prostate cancer; however, some treatments can considerably reduce the progression of the cancer. In Jonathan Waxman’s opinion, the future points to ways of preventing prostate cancer rather than curing the disease.
Cancer prevention
Professor Will Steward explained that the incidence of people developing cancer in the West has been rising; currently it is 40% and in the next 10 to 20 years the forecast is 50%. The main reason underlying this trend is an aging population, but lifestyle choices are another major factor. An epidemiology study reported that 35% of cancers could be attributed to dietary factors, with two different cancers (colorectal and prostate) having been at least partly attributed to diet. The incidence of colorectal cancer in the West and Japan are 10-fold higher than in the rest of the world. This may be partly explained by genetics and a diet in the West that is meat-rich versus a more vegetarian diet in less affluent, developing countries. Prostate cancer is predominately a disease in affluent Western countries; however, when migrants move from East to West within 1 or 2 generations they also have equivalent incidence. Management of cancer (eg, by surgery) in Western countries leads to the cure of about 50% of patients, and those cancers that cannot be cured have a high impact on society, cost to healthcare systems, families, etc.
Prevention of cancer (through an increased understanding of the risk factors and modifications of lifestyle), in concert with an understanding of the biological mechanisms to develop targeted therapies, is the ‘Holy Grail’ for the future. Social patterns are now changing, eg, decrease in smoking with proactive educational campaigns. The 2007 report by the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) was an important publication that evaluated food, nutrition, physical activity, and the prevention of cancer from a global perspective. In terms of diet and nutrition, high fat content (eg, in many convenience and fast foods) seems to be the greatest offender, which may lead to disease; others include high alcohol intake, red meat, salted foods and sugary drinks. ‘Good’ foods containing fibre and non-starch vegetables can reduce the likelihood of developing colorectal, mouth, pharynx and larynx cancers. An article in The Lancet showed that fibre could reduce the risk of colorectal cancer by as much as 40% when fibre intake is doubled. Most dietary data, however, are from retrospective studies and need to be interpreted with caution. Getting the general population to change their dietary habits is difficult, but there have been some schemes (eg, in the UK) to encourage healthy eating for a period of 3 to 6 months. However, most people ultimately revert back to old ‘bad’ eating habits.
There is some evidence that non-steroidal anti-inflammatory drugs (NSAIDs), like aspirin, may reduce the risk of cancers (such as colorectal cancer). There have been several studies, eg, in Australia, which recruited 1440 subjects and found that NSAIDs taken on a regular basis reduced the risk of cancer by half. Will reported that a team of experts are looking at complex aspirin data to recommend a dose that is beneficial for cancer prevention; the dose is probably about 80mg per day.
Dietary components (such as polyphenols from fruit and vegetables) can exhibit chemopreventative properties. A UK study at Leicester University is investigating curcumin (from the spice turmeric) for its chemopreventative activities such as increasing apoptosis (cell death) and reducing angiogenesis (blood-vessel growth). Clinical trials with curcumin have shown it to be well tolerated and can be produced at low cost in tablet form. Cancer Research UK are funding a study to evaluate curcumin, as with any new chemoprevention agent, a robust study design is needed so that the data generated is accurate and unbiased.
Angus Dalgleish is Foundation Chair of Oncology at St George’s University of London.
Nicholas James is Professor of Clinical Oncology at the University of Birmingham.
Jonathan Waxman is Professor of Oncology at the Hammersmith Hospital, London.
Will Steward is Chair of Oncology at the University of Leicester.
Karol Sikora is Professor of Cancer Medicine at Imperial College School of Medicine.
Shethah Morgan MICR CSci is a Senior Research Clinical Scientist with AstraZeneca.
