Pancreatic Cancer Progress - An End to Nihilism

We are now in the era of active treatment for patients which can start to improve survival rates

However this needs everyone to take a more proactive, optimistic approach to patient care

The bad news

• 6th most common cause of cancer death in UK, 4th in US
• almost 7000 cases a year in the UK
• Most patients present too late for curative surgery
• Limited impact from current chemotherapies

The good news

• Increasing definition of molecular genetics of early disease
• Prospect of detecting disease at surgical curable stage
• Clinical trials showing promise for new agents

Until recently the survival rates for patients with pancreatic cancer have been dismal.

The 5 year survival rates have been the lowest of all the cancers.

For patients diagnosed in the UK between 1996 and 1999 the 5 year survival rate was only 2% for men and 3% for women.

For the most common type of pancreatic cancer, adenocarcinoma, this is as low as about 1%. Other rarer types such as neuroendocrine tumours have a much better 5 year survival rate.

This compares with 5 year survival rates in men of 95% for cancer of the testis (cf Lance Armstrong) and 65% for prostate and in women of 77% for breast, 73% for uterus and 61% for cervix.

People are aware of the high, preventable (through stopping smoking) death rate of lung cancer but even this has a higher 5 year survival rate of 6% for both men and women.

There have been great advances in survival rates for many cancers over the past 40 years. In the period 1986 to 1999 most cancers showed an improvement in the 5 year survival rate peaking at 12% improvement every 5 years for prostate cancer and 6% improvement every 5 years for breast cancer.

Again pancreatic cancer fell at the bottom of the list with hardly any change in 5 year survival and actually a slight reduction for men.

The outcomes in the UK until recently have been worse than in Europe and the USA. However this is now being addressed and guidance on how to improve diagnosis, treatment and care were produced in 2001. This is being implemented throughout the UK and we need to press for all areas to reach these new standards and for the funding to allow this to be achieved.

There have been many advances in the past 5 to 10 years which could help to improve survival if they are adopted more widely and which show that progress can be made in this disease which has been historically considered incurable.

Therefore it is worth investing in diagnosis, treatment and further research to start to make headway in the survival figures.

• availability of gemcitabine for palliative chemotherapy in patients with advanced cancer
• combination chemotherapy showing some increased survival benefit overall and more benefit for certain groups of patients
• concentration of surgery in regional expert centres
• trials showing benefit of adjuvant chemotherapy
• improved imaging techniques to improve diagnosis
• awareness of risk factors
• identification of some of the genes and proteins associated with development of pancreatic cancer

In the 30 years to 2001 1 year survival has doubled from 6% to 12%.

It will be interesting to see the figures for the years since 2001 to see if the progress shown in trials is coming through in the overall survival figures. This will only happen if all patients who could benefit from these advances are given the opportunity to do so.

In 2001 NICE produced the guidance that people with advanced or metastatic (when the cancer has spread to other parts of the body) pancreatic cancer may be treated with gemcitabine as a first line treatment if they have a Karnofsky performance score of 50 or more.

Karnofsky is a measure given by a health professional to a person's ability to perform certain ordinary tasks: 100 = normal, no complaints, 70 = unable to carry on normal activity, 50 = requires considerable assistance, 40 = disabled, 30 =hospitalisation recommended.

A trial of gemcitabine compared with an older form of chemotherapy 5-FU showed 24% versus 5% clinical response rate through reduction of symptoms such as pain. The 1 year survival was 18% compared with 2% and the median survival was 5.65 months compared to 4.41months.

A later trial using continuous infusion 5-FU showed a 1 year survival rate of 23%.

The current percentage of pancreatic cancer patients in the UK undergoing surgical removal of tumour is just 4%. These patients have much better 5 year survival rates than inoperable patients - up to 30% with adjuvant (following operation) chemotherapy.

In the USA more patients undergo surgery, about 10%, and there is no reason why the UK should have a lower percentage of patients undergoing surgery than elsewhere in the world.

It has been shown in studies that patients have better outcomes in hospitals where surgeons undertake a large number of operations each year.

These hospitals also build up the skills to provide faster diagnosis of pancreatic cancer. They can establish good multidisciplinary teams (MDTs) to look after the total care of the patient. They can establish teams of expert radiologists to detect the tumours on scans and to tell whether they are operable, expert gastroenterologists who are also involved in the initial diagnosis through ERCP and EUS, expert histopathologists to determine the type of pancreatic cancer, surgeons who are expert in the field and able to operate on more complex cases, expert clinical and medical oncologists who are involved in trials for pancreatic cancer as well as teams of dieticians, specialist nurses and palliative care teams, skilled in looking after the special needs of pancreatic cancer patients such as fighting weight loss ( including use of pancreatic enzyme supplements), treating jaundice and controlling pain.

The UK is reorganising its care of pancreatic cancer patients around regional MDTs so that even district general hospitals can call upon the team of experts to discuss the treatment of their patients who should be referred to the regional centre for assessment for surgery or inclusion in clinical trials. This should lead to more patients undergoing surgery and hence an improved overall 5 year survival rate.

Many regional centres have already been established but some parts of the country have not yet centralised their services.

Recent trials have shown the benefit of chemotherapy after surgery on survival of patients. In the ESPAC-1 trial the 2 year and 5 year survival rates for patients receiving post-operative 5-FU chemotherapy were 39.7% and 21.1% respectively compared to 30% and 8.4% without adjuvant chemotherapy.

Another recent trial has shown the benefit of post-operative gemcitabine chemotherapy and the ESPAC-3 trial is comparing the impact of gemcitabine against that of 5-FU.

• Patients usually have no symptoms until the cancer has spread
• Pancreas is located deep inside the body, so early tumours cannot be seen or felt
• Most imaging techniques are unable to detect tumours before they invade - but new methods are now much more sensitive
  • traditional abdominal ultrasound: accuracy: 70-80%
  • new multi-detector CT: accuracy: 85-90%
  • endoluminal ultrasonography (EUS): sensitivity: 98%
• New molecular tests may be able to pick up disease early

• The sensitivity and specificity of current diagnostic tools is not sufficient for effective screening of the general population
• Secondary screening may be feasible for high risk groups
• What are the high risk groups?

A number of risk factors have been identified for pancreatic cancer. Some allow people to take action to reduce their risk of developing the disease. Others patients have no control over but their identification can help in screening for early detection of the disease.

Controllable

• Tobacco smoking: Smokers have 2-3 times increased risk and probably account for 30% of cases of pancreatic cancer

Others

• Age: risk increases with age - almost all sporadic cases are older than 50 years, familial cases may be younger
• Chronic pancreatitis: approximately 10-20 fold risk: 1% of cases
• Genetic Component - family history: an inherited tendency to develop this cancer may be a factor in as many as 10% of cases: variable risk
• Hereditary pancreatitis (40% due PRSS1) approx 70 fold risk
• Familial pancreatic cancer: rare (aprrox 20% BRCA2 mutations)
• Familial Cancer syndromes
• Race: African Americans are 40% to 50% more likely than white Americans
• Late onset diabetes: 8 fold risk: 1 in 120 people newly diagnosed with diabetes age 50 and older have risk of developing pancreatic cancer

A study called EUROPAC (European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer) aims to find out more about the genes that can raise the risk of pancreatic cancer

People who have a family link to pancreatic cancer can enroll on the trial, and are given the option of screening if they are found to be at high risk of developing the disease themselves.

Doctors test them at regular intervals for pre-cancerous changes to their pancreas using a variety of techniques, including ultrasound, CT scans and testing their pancreatic juice for defective genes.

They are monitored every three years, or annually if they are found to carry a mutated K-ras gene. The faulty gene is known to raise the risk considerably.

Screening people at high risk of developing pancreatic cancer will help not only those families with clusters of pancreatic cancer - it will also help scientists pinpoint the genetic faults that cause all cases of the disease.

Research using this group of families has helped to identify faulty genes that raise risk of which the most important so far are p53, K-Ras and P16 . It has also shown that in those families with the highest incidence of pancreatic cancer, members developed the disease at a younger age in each generation. As well as giving important clues about the nature of the disease, this allows a more accurate estimate of the risk an individual faces of developing cancer in the short term so the cancer can be treated as soon as possible.

Hopefully clearer guidelines can improve diagnosis in the general population.

NICE (the National Institute for health and Clinical Excellence) produced new guidelines for referral for suspected cancer in June 2005. These included pancreatic cancer amongst the section on Upper Gastrointestinal(GI) Cancers.

Hopefully in future separate guidelines can be produced for pancreatic cancer as some features are different from the other GI cancers.

Patients do better with supportive care. The introduction of specialist nurses who can manage the patient journey, support carers and understand the special needs of pancreatic cancer patients (such pancreatic enzyme replacement, pain control, dietary requirements, impact of surgery and chemotherapy) should also help to improve outcomes for patients.

Progress is being made and hopefully this will be reflected in the survival rates if the improved diagnosis and treatment is made generally available throughout the UK.

However although progress is being made the improvements in survival from the new treatments are still only small and we need to build on this by actions to:

• Increase the UK national resection rate to at least 10%
• Finalise implementation of network of Regional Pancreas Centres in the UK
• Put in the resources (both staff and money) to enable them to do their work
• Ensure that Pancreas Cancer Networks focus on clinical objectives to improve diagnosis by engaging GPs and referring hospitals
• Ensure availability of new imaging techniques such as multi-detector CT scans and EUS
• Ensure patients are receiving optimum treatment eg chemotherapy and are offered the opportunity to take part in trials
• Invest in clinical audit of the patient's journey

• Build on the current work in identifying genes and proteins that are markers for pancreatic cancer such as those associated with change from pre-cancerous to cancerous cells
• Develop molecular diagnosis of body fluids for diagnosis of pancreatic cancer
• Investigate differing response to treatment in sub-sets of patients to develop targetted treatments
• Fund a national pancreas tissue resource to facilitate the research into new diagnostic methods (for detection and response to treatment) and treatment options
• Investigate novel treatment options such as gene-therapy, photodynamic therapy and immunotherapy
• Develop new diagnostic techniques based on imaging such as Pet
• Improve options for palliative care

and finally we believe that progress with diagnosis can be made by further research into the symptoms of pancreatic cancer to try to separate them from other causes of similar symptoms and to provide clearer information for the public and GPs on incidence, groupings or time history of symptoms. Earlier diagnosis is important to ensure that more patients are fit enough to undergo treatment or take part in trials.

Based on discussions with many of the pancreatic cancer specialists and research scientists in the UK (most who are listed on our Who are we? page) and some in the USA as well as their presentations at professional meetings on pancreatic cancer

Bipat et al 2005, J Computer Assisted Tomography, 29, 438-45

Burris et al 1997, JCO 15 2403-2413

G. Gaudernack, T. Buanes, M. Meo, S. Aamdal, P. Brunsvig, L. R. Braathen, K. Kernland, M. K. Gjertsen, J. A. Eriksen, M. Moller Clinical trials of a peptide based vaccine targeting telomerase. Proc Am Soc Clin Oncol 22: page 166, 2003 (abstr 666)

Hahn/Neoptolemos et al, 2003, JNCI, 95, 214-21

Howes et al 2004 Clin Gastroenterol Hepatol 2, 252-61

Karlson et al 1999, Radiology, 213, 107-11

Kindler et al ASCO 2004

Greenhalf et al, 2005, Gut;PMID: 15972300

Maisey et al, Journal of Clinical Oncology, Vol 20, Issue 14 (July), 2002: 3130-3136

Moore et al, ASCO 2005

Neoptolemos et al 2004, NEJM 350, 1200-10

Neuhaus et al, ASCO 2005

S. Rao and D. Cunningham, Annals of Oncology 13:1165-1168, 2002

Wong/Neoptolemos et al 2001, Pancreatology, 1, 486-509

Xiong et al. J Clin Oncol 2004

Yan et al 2005 Gastroenterology 128 2124-30

SWOG gemcitabine and cetuximab trial