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Unexpected benefits reported in biliary cancers
A number of patients with biliary cancer are deriving a longer than expected benefit from palliative chemotherapy, according to Dr Mark Doherty, a Young Investigator award-winner who addressed the Gathering around Cancer 2016.
Dr Doherty and his colleagues at the Princess Margaret Cancer Centre in Toronto, Canada, have been looking at data arising from a study of 398 patients undergoing palliative chemotherapy for biliary cancer at the Centre.
Biliary cancer is an umbrella term for cholangiocarcinoma and gall bladder cancer, explained Dr Doherty. These are rare tumours, which can have considerable differences in geographical incidence due to a concentration of risk factors.
For example, said Dr Doherty, there is a high incidence of gall bladder cancer in Chile. These are diseases that have generally poor survival outcomes and even in patients with early-stage gall bladder cancer, the median survival is 2.5 years following surgery.
The overall progress on treatment for the disease has been slow due to its rarity and the morbidity associated with it.
A key objective of research in the past 10-to-15 years has been to understand the underlying molecular biology of the cancer, he said.
Patients at the Princess Margaret Cancer Centre who underwent nine or more cycles of chemotherapy were deemed long-term responders, Dr Doherty told the meeting. There were 121 long-term responders against 277 patients who were treated with eight or fewer cycles of chemotherapy.
The Centre has a long database of all patients treated for biliary cancer, where the standard front-line chemotherapy is gemcitabine/cisplatin.
The practice at the Centre is to continue with cycles of chemotherapy until the patient no longer derives further benefit or until toxicity becomes too high.
The median number of cycles of chemotherapy in the 121 patients deemed long-term responders was found to be 12, with one patient undergoing 47 cycles.
The toxicity levels were found, not surprisingly, said Dr Doherty, to increase in patients as they underwent more cycles of chemotherapy.
It was found that the overall survival in the long-term responders was 19.4 months, which was “quite impressive”, said Dr Doherty, as in general the survival duration is much shorter in patients with biliary cancer.
“This is a clearly defined group of patients who are deriving a longer than expected benefit from palliative chemotherapy in this disease,” said Dr Doherty. “Additional studies to figure out who the patients are can help to provide more insight and to guide our treatment decisions.”
Pembrolizumab offers promise for non-small cell lung cancer — study
A study showing improved survival rates in patients with non-small cell lung cancer receiving the antibody pembrolizumab versus chemotherapy alone was a big news story this year, Dr Emer Hanrahan, Consultant Medical Oncologist, St Vincent’s University Hospital, Dublin, told the Gathering Around Cancer 2016 meeting.
The research highlighting the benefits of pembrolizumab featured prominently at the recent 2016 European Society for Medical Oncology (ESMO) meeting, said Dr Hanrahan.
The drug, which is a human monoclonal antibody against the cell surface receptor PD-1, was approved for use in the EU in August 2016. Its use is approved, she said, in patients with PD-L1 positive advanced non-small cell lung cancer who have undergone one or more previous chemotherapy regimens.
The approval came on the strength of data from the KEYNOTE-010 study, said Dr Hanrahan. This was a randomised trial in which patients with PD-L1-positive non-small cell lung cancer received either pembrolizumab or paclitaxel (standard chemotherapy).
The study found improved survival in patients who received pembrolizumab. This led to further testing of the drug in a front-line setting through the KEYNOTE -024 study. The results of this study were also presented at ESMO this year, said Dr Hanrahan, and published simultaneously in the New England Journal of Medicine.
The contribution of Dr Sinead Cuffe from St James’s Hospital to this important paper was cited by Dr Hanrahan as “a good achievement for a small country”.
Dr Cuffe, it was noted, was a principal investigator on the paper.
The research was conducted as a randomised phase 3 trial, with high expression of PD-L1 being a requirement for patients to get access to the study.
The patients in the study received either a platinum-based chemotherapy treatment regimen or pembrolizumab. The study found a significant survival advantage accrued to those who used pembrolizumab over standard chemotherapy.
The difference in median survival was 10.3 months for the group taking pembrolizumab versus six months for the group on chemotherapy alone.
The difference in survival rate was more pronounced after one year than it was after six months, with a 70 per cent versus 54 per cent survival rate after 12 months.
The response rate was also better for the group receiving pembrolizumab against chemotherapy alone, with a 45 per cent to 28 per cent response rate recorded.
Dr Hanrahan did note, however, that only one-third of patients had access to this pembrolizumab study, as they did not have sufficiently expressed PD-L1.
“So, this was not a trial for all comers,” said Dr Hanrahan.
HPV status must be recognised as risk factor for head and neck cancers
The incidence of Human Papilloma Virus (HPV) has increased hugely in recent decades, and along with it, oropharyngeal head and neck cancers it is linked with. It is therefore now time to integrate HPV status as part of the risk assessment status, according to Dr Cliona Grant, Consultant Medical Oncologist, St James’s Hospital, Dublin.
She told the Gathering Around Cancer 2016 meeting that HPV is now regarded as the most common sexually-transmitted disease in the world, with the US Centres for Disease Control (CDC) reporting that about 80 per cent of sexually active adults there have been infected by at least one HPV type by the age of 50 years.
The key risk factors for head and neck cancer are tobacco, alcohol, chemicals such as asbestos and some other factors such as ionising radiation, according to Dr Grant, but up until recently, HPV was not regarded as a ‘player’ in terms of risk.
She said that the type of patient that she now sees in her clinic includes patients such as a 33-year-old who presented with none of the ‘common’ risk factors, yet had locally-advanced disease.
The SEER (Surveillance, Epidemiology and End Results Programme) database at the National Cancer Institute looked at neck and head cancer incidence and survival over a three-decade period between 1973 and 2004, outlined Dr Grant.
They particularly looked at approximately 44,000 cases of both oral cavity and oropharyngeal squamous cell cancers.
They classified these as being potentially related or unrelated to HPV, depending on the primary site of the disease.
Those that were oropharyngeal were likely to be related to HPV, while oral cavity cases were likely to be unrelated, she reported. What researchers found looking at nine SEER registries is that in that period 1973 to 2004, HPV-related cancers were increasing in incidence, with a decrease in that of HPV-unrelated cancers.
Further studies by the same group looking at tumour registries within the SEER database found that HPV prevalence had actually increased from a level of 16 per cent in the 1980s to 70 per cent in the early 2000s.
This population-level increase in prevalence of HPV virus also resulted in an increase in HPV-positive oropharyngeal cancer by 225 per cent over the same period — with a decrease of 50 per cent in HPV negative tumours.
“We think that sexual behaviour, in the same way that it is very important in cervical cancer, will increase or decrease your odds of HPV infection and thereby increase your odds of oropharyngeal cancer,” said Dr Grant. “It is the same sexual behaviours that we see in cervical cancer.”
She added: “We know that the evidence for HPV in oropharyngeal cancer is every bit as strong as for cervical cancer.”
Research published in 2011 reported that if the incidence of oropharyngeal cancer were to increase at this rate, that the annual number of cases is going to be the exact same as that of cervical cancer by 2020, said Dr Grant.
She concluded: “It is really important that this virus is integrated into our classic risk factor groups for head and neck oropharyngeal cancer.”
‘Ireland should adopt French sarcoma care model’
The successful use of specialist reference centres for sarcoma across France has led to better outcomes for patients and should be adopted in Ireland.
That’s the view of sarcoma specialist Dr Deirdre O’Mahony, Consultant Medical Oncologist, Cork University Hospital, who discussed the implications from data emerging from 26 sarcoma reference centres in France.
NetSarc, said Dr O’Mahony, is the French clinical network for soft tissue and visceral sarcomas, which began operating in 2010. Meanwhile, ResOs is the French network for bone sarcoma and rare bone tumours (started in 2013).
Clinical data from thousands of patients referred to sarcoma multidisciplinary teams at NetSarc-ResOs centres is gathered, stored and analysed.
The evidence, which was presented at the recent 2016 European Society for Medical Oncology (ESMO) meeting, was that patient outcomes improve in these centres.
The big question that was addressed in the study, said Dr O’Mahony, was whether presentation of patients to a referring centre improved outcomes.
A comparison was made of sarcoma patients’ reference to non-NetSarc centres, and NetSarc centres. It found that there was better adherence to appropriate medical procedures among the sarcoma patients first referred to NetSarc centres, more successful surgeries were performed, a greater number of medical images were taken, and more biopsies were performed.
“The management of sarcoma patients in defined centres improved patient outcomes,” said Dr O’Mahony. “If a country with 66 million patients with 28 reference centres can do it, surely we can do with 4.5 million,” she concluded.
New thinking is needed to fund cancer care
Ireland’s massive €230 billion debt, and Government plans to balance the budget by 2018, mean new ideas are needed to fund cancer care, according to Dr Jerome Coffey, Director of the National Cancer Control Programme.
Dr Coffey posed the question, ‘How do we get around this massive number when we are trying to further invest in cancer care in this country?’ during a presentation at the recent Gathering Around Cancer 2016 meeting in Dublin.
The answer is that savings will have to be made and new sources of funding found, he said, if recent success is to be built upon.
Dr Coffey cited the example of the recent announcement by Trinity College Dublin and St James’s Hospital, Dublin, of their intention to develop a new cancer institute as an example of the new thinking that is required.
The rationale for the establishment of the centre is that the incidence of cancer, according to the National Cancer Registry Ireland, will increase by 50 per cent by 2025 and by 100 per cent in 2040.
Meanwhile, Dr Coffey confirmed that the new National Cancer Strategy will be published by the end of the year and it will be taking into account the enormous changes in molecular diagnostics and genetics of cancer care.
One major goal is to move to a situation where patients know what is going on with their care in terms of what the follow-up requirements are.
The draft document states that there will be regular reporting to the Department of Health on how the new Strategy is progressing.
The document removes geographical representation from the deliberations and discusses how a patient forum will be introduced.
There is an acknowledgement, said Dr Coffey, that public hospital IT systems are not well developed in all cases, and neither are they optimally linked.
One recommendation in the draft Strategy, he said, is that all cancer patient data will move to electronic format inside the next five years and there has already been progress towards this goal.
For example, the management of oncology information system is to be rolled out next year and that will capture the majority of data, he said.
In terms of research, Dr Coffee said that the Health Research Board is seeking the establishment of a new national cancer research group to focus on areas of research that do not tend to attract industry funding.
There will be an ethics committee set up for Ireland, as it is no longer efficient to have local ethics committees, he said.
There will also be a patient advisory committee on cancer care set up, and while this may be a difficult thing to do, it is unavoidable, he maintained.
Dr Coffey finished his address on the topic of change and cited the example of how alcohol and cigarettes were seen as beneficial in the past.
The big change in cancer is the movement towards greater monitoring and surveillance, a strategy that can be costly but is now the ‘standard of care’.
He acknowledged that there are areas that still need to be looked at, such as lung cancer, where survival rates in Ireland are still poor compared to those internationally.
Some 19 per cent of people in Ireland are smoking and the idea of screening people for lung cancer should be looked at again, he stated.
On prostate cancer, meanwhile, Dr Coffey noted the debate on whether it is worth investing in PSA screening or not is still ongoing. This debate is likely to continue, he said, but it may be the case that once-off screening of men in their 40s with low PSA is the way forward.
‘Genetic tests reasonable for all pancreatic patients’
It may soon be reasonable to offer genetic testing to all pancreatic cancer patients, the recent Gathering Around Cancer 2016 meeting heard.
A co-ordinated national effort could see the “mainstreaming” of genetic testing in pancreas cancer in the future, with surgeons and physicians ordering tests as they are needed, said Prof David Gallagher, Consultant Medical Oncologist and Consultant Medical Geneticist, St James’s Hospital, Dublin.
Adequate funding, as well as genetic testing and screening infrastructure, will be required to make this happen, he said, adding that the use of commercial panel testing, which offers a faster, cheaper method for screening for a range of genes, should also be considered.
During his presentation at the meeting, Prof Gallagher discussed the case of a healthy 37-year-old woman who had three children. The woman wanted to determine her own pancreatic cancer risk, as both of her parents had died from the disease — her father in his 80s and her mother in her 60s.
There was also a wider family history of breast and testicular cancer and leukaemia, said Prof Gallagher. “The question was, should she have genetic testing and what should we do about her pancreas cancer risk?”
Pancreatic cancer can be categorised into four genetic subgroups, he explained, and the one he chose to focus on for his talk was the form where there are defects in DNA damage repair mechanisms.
The outcomes from pancreatic cancer, he said, remain disappointingly low, while the National Cancer Registry Ireland states there are 1/122 women in Ireland at risk, with 1/170 men at risk.
Some are at very high risk. For example, male carriers of the STK-11 liver kinase gene are almost guaranteed to get pancreatic cancer by the age of 74 years.
It can be difficult to determine what genes are linked with the disease, as some people with a particular gene will have the disease, but others will not.
There can also be epigenetic factors at play, while not every genetic variation in a gene will be linked with a disease.
Clinicians can be faced with families that have a history of pancreas cancer, but no gene can be identified to determine who is at risk.
The question is, if genetic screening is to be done, who should be screened? At the moment, it might mean everyone in a large family. There are 200 families that Prof Gallagher sees at St James’s that had a pancreatic cancer diagnosis.
Of these 200 families, 95 underwent genetic testing and in those, 29 had a pathogenic or genetic variant of significance identified.
This is of interest currently for pancreas cancer prevention, said Prof Gallagher, but it is getting broader medical attention because of the therapeutic implications of knowing the underlying genetic mutation.
All of the genes that are involved in DNA repair in pancreatic cancer can be tested with commercial tests. This is cheap, with a quick turnaround.
It is still difficult to determine whether a particular DNA variant is truly significant or not and finding all the disease variants takes a lot of time.
At the moment there is no public funding in place to genetically test healthy individuals for pancreatic cancer risk, said Prof Gallagher.
Until then, people like the 37-year-old woman with a family history of pancreatic cancer must pay for their own tests, he said.
Chemotherapy ‘not enough for triple-negative breast cancer’
While the current standard of care for triple-negative breast cancer (TNBC) is chemotherapy, most women need something else but this does not yet exist, Dr Cathy Kelly, Consultant Medical Oncologist, Mater Hospital, Dublin, told the recent Gathering Around Cancer 2016 meeting in Dublin.
TNBC is a broad, heterogeneous cancer group that presents in young women and is more common among those of African and Spanish ethnicity.
The advance of genomics is proving that TNBC is made up of many different subtypes, with big differences between some of these.
Dr Kelly posed the question: “Is there a better way to think of triple-negative breast cancer? We have to be pragmatic. Genomics can see the differences, but how do we bring that into the clinic?”
The fact that TNBC is made up of many subtypes of breast cancer was first recognised about 10 years ago, she noted, but the standard of care — chemotherapy — has remained the same.
There can be response rates of over 50 per cent for some TNBC subtypes, while the response is 0 per cent for other types. The sub-types can be as different to each other as TNBC is to lung cancer.
The strategy must be to differentiate TNBC into subtypes and this can be done in a variety of ways, including looking at tissues of origin, she explained.
Differences can also be found by looking at mutational load, which can inform immunotherapies, and whether lymphocytes have been infiltrated.
In some cases, the best strategy is not to give chemotherapy, said Dr Kelly, as this may drive the progression of the tumour.
There are particular mutations associated with TNBC, she outlined, most commonly P53, but many of the mutations are at a low level. It can be difficult to set up a clinical trial to see if a low-frequency mutation is relevant.
“Are these passenger or driver mutations?” asked Dr Kelly.
TNBC must be examined on a genomic level, but the immune environment must also be considered. It is not just about what is happening in the tumour, but also around the tumour and the host response to the tumour, she said.
Then there is the so-called TNBC paradox, where some women have a dramatic response but not enough is known about why this happens.
“Sixty or 70 per cent of women are going to need something else apart from chemotherapy and at the moment, we don’t have that something else. That’s why clinical trials are so important,” concluded Dr Kelly.